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Do treatment outcomes after pars plana vitrectomy for endogenous endophthalmitis?

To evaluate the causative organisms of and predisposing medical conditions in endogenous endophthalmitis and review visual acuity after pars plana vitrectomy. Records of 23 patients (32 eyes) who were diagnosed with endogenous endophthalmitis and treated at Shanghai Eye, Ear, Nose & Throat Hospital from January 2000 to December 2003 were retrospectively reviewed. Final visual acuity was followed up. Of these 23 patients, 19 (86%) had endogenous endophthalmitis confirmed with a positive smear or culture; 12 cases (63%) were due to fungi, 6 (32%) were due to bacteria, and 1 (5%) was a mixed infection (fungus and bacteria). Culture specimens from four patients, which were obtained by vitrectomy, were all positive, while their initial vitreous needle biopsy specimens were negative. Of the 20 eyes that underwent pars plana vitrectomy, 17 (85%) had anatomical success, and 16 (80%) gained visual acuity of counting fingers or better; of these eyes, 8 (40%) had visual acuity of 20/200 or better.

Fungi, especially Candida albicans, were the most common causative organisms. The most common predisposing medical conditions were recent tumor surgery and intravenous administration in rural settings. Most patients with endogenous endophthalmitis who undergo pars plana vitrectomy will have useful vision (counting fingers). Vitreous specimens for culture that were obtained by vitrectomy were more sensitive in detecting the causative organism.

Is severe Acute Mastoiditis Admission Related to Delayed Antibiotic Treatment for Antecedent Acute Otitis Media?

Delayed antibiotic treatment for acute otitis media (AOM) is recommended for children >6 months with nonsevere illness, no risk factors for complications or history of recurrent AOM. This study evaluates relationship between delayed antibiotic treatment for antecedent AOM and severity of subsequent acute mastoiditis admission. A prospective observational study of children aged 0-14 years admitted with acute mastoiditis to 8 hospitals between 2007 and 2012 calculates rates of severe acute mastoiditis admission [defined by ≥1 of the following: complication (mastoid subperiosteal abscess, brain abscess and sagittal vein thrombosis), need for surgical procedure and duration of admission >6 days].Severe acute mastoiditis admissions in children with antecedent AOM treated with immediate antibiotics were compared with those with delayed antibiotic treatment. Antecedent AOM was diagnosed in 216 of 512 acute mastoiditis admissions (42.1%), of whom 159 (73%) immediately received antibiotics, and 57 (27%) had delayed antibiotic treatment. Higher rate of recurrent AOM was noted in the immediate compared with delayed antibiotic treatment group (29% vs. 8.7%, P = 0.0021). Complication rates were 19.5% versus 10.5% (P = 0.12), rates of surgical procedures required, 30% versus 10% (P = 0.0033); admission rates >6 days, 37% versus 29% (P = 0.28) for immediate antibiotic therapy and delayed antibiotic treatment. On logistic regression analysis, immediately treated AOM patients had increased need for surgery for acute mastoiditis with adjustment for history of recurrent AOM (relative risk: 3.2, 95% confidence interval: 1.4-7.0).

Delayed antibiotic treatment for antecedent AOM is not associated with an increase in severity parameters in subsequent acute mastoiditis admission.

Does mechanical ventilation aggravate transfusion-related acute lung injury induced by MHC-I class antibodies?

Transfusion-related acute lung injury (TRALI) occurs more often in critically ill patients than in a general hospital population, possibly due to the presence of underlying inflammatory conditions that may prime pulmonary neutrophils. Mechanical ventilation may be a risk factor for developing TRALI. We examined the influence of mechanical ventilation (MV) on the development of TRALI, combining a murine MV model causing ventilator-induced lung injury with a model of antibody-induced TRALl. BALB/c mice (n = 84) were ventilated for 5 h with low (7.5 ml/kg) or high (15 ml/kg) tidal volume, a positive end-expiratory pressure of 2 cm H(2)O and a fraction of inspired oxygen of 50%. After 3 h of MV, TRALI was induced by infusion of MHC-I antibodies (4.5 mg/kg); controls received vehicle. Non-ventilated animals receiving vehicle, isotype or MHC-I antibodies served as additional controls. All animals receiving MHC-I antibodies developed TRALI within 2 h. In mice in which TRALI was induced, MV with low tidal volumes aggravated pulmonary injury, as evidenced by an increase in neutrophil influx, pulmonary and systemic levels of cytokines and lung histopathological changes compared to unventilated controls. The use of high tidal volume ventilation resulted in a further increase in protein leakage and pulmonary edema.

Mechanical ventilation (MV) synergistically augmented lung injury during TRALI, which was even further enhanced by the use of injurious ventilator settings. Results suggest that MV may be a risk factor for the onset of TRALI and may aggravate the course of disease.

Can shielded brackets reduce mucosa alteration and increase comfort perception in orthodontic patients in the first 3 days of treatment?

Orthodontic patients can experience pain and discomfort on the oral mucosa from trauma caused by friction with the brackets and the wires. In this split-mouth design, single-blind randomized controlled trial, we aimed to investigate whether brackets with a self-snapping customized plastic shield would induce less mucosa alteration and discomfort than those without the shield. The overall sample comprised 42 patients (22 female, 20 male) from a government-funded orthodontic practice, with a mean age of 16.7 years. Eligibility criteria included, among others, no history of mouth ulcers or systemic diseases. Customized shields for the maxillary and mandibular brackets were fabricated and inserted on one side of the mouth. The null hypothesis was that bracket shielding would have no advantage. The primary outcomes were mucosal and discomfort assessments. As the secondary outcome, the numbers of spontaneous detachments of the shields were reported. Treatment allocation was mainly implemented using a random number table for selection of the intervention side. Only the raters in charge of assessing the oral mucosa were blinded to the side of the mouth where the shields had been placed. The mucosa was assessed by 3 calibrated raters at the following time points: immediately before bracket placement (baseline assessment, T0), 3 days after delivering the shields (direct assessment of intervention, T1), and 4 days after removal of the shields (indirect assessment of intervention, T2). The raters used a newly devised yardstick in which the higher the score, the more severe the alteration. Discomfort was assessed at T1 and T2 using a visual analog scale. The Mann-Whitney U test was performed at the 5% level of significance. Of 60 patients, 42 were eligible, and 35 were randomly selected to have one side of the mouth receive the intervention. Two patients discontinued the intervention at T1, and 5 stopped at T2. Seven additional patients were recruited and completed all time points. Thus, 42 patients participated at T0, 40 at T1, and 35 at T2. Thirty-five patients participated at all time points. At T1, no statistically significant difference in terms of mucosa alteration was observed between the 2 sides (median of all differences [MD], 0.0; 95% CI, 0.0-1.0; P = 0.11). The same occurred at T2 (MD, 0.0; 95% CI, 0.0-0.0; P = 1.00). The comfort level was statistically higher at T1 on the shielded side (MD, 14.0; 95% CI, 1.0-36.0; P = 0.04), whereas no difference was observed at T2 (MD, 0.0; 95% CI, 0.0-1.0, P = 0.81). No serious harm was observed.

The customized bracket shields were effective in reducing discomfort during the first 3 days of orthodontic treatment despite no significant difference in terms of visible mucosa alteration.

Variable phenotypic presentation of iron overload in H63D homozygotes: are genetic modifiers the cause?

First considered as a polymorphism of the HFE gene, the H63D mutation is now widely recognised as a haemochromatosis associated allele. But few H63D homozygotes with clinical manifestations of hereditary haemochromatosis (HH) have been reported. Concurrently, an increasing number of genes have been shown to interact with HFE in iron metabolism. To describe the clinical expression of iron overload (IO) associated with H63D homozygosity, and search for potential genetic modifiers (within the HFE or other genes) that could explain the variability of the phenotypes. We retrospectively analysed the clinical phenotype of 56 H63D homozygotes referred for a personal or family history of IO. For each subject we examined intragenic HFE haplotypes and transferrin receptor (TfR) gene polymorphisms and searched for the Y250X mutation on the TFR2 gene. Additionally, we sequenced the HFE gene of H63D homozygotes with HH. Fifty of 56 subjects had biological and/or clinical abnormalities of iron metabolism. Up to two thirds of patients (n=34) had no acquired cause of IO. Among these, 12 had a phenotypic diagnosis of HH. In the iron loaded group there was a strong prevalence of male patients. No correlation was found between the potential genetic modifiers and phenotypes. No additional mutation of HFE was identified.

The variable phenotypes associated with H63D homozygosity do not appear to be linked to other HFE mutations, to the TFR2 Y250X mutation, or to HFE or TfR gene intragenic polymorphisms. The exact role of H63D homozygosity in IO and HH needs to be further investigated in unselected populations.

Does bLT1 antagonist LSN2792613 reduce infarct size in a mouse model of myocardial ischaemia-reperfusion injury?

Restoration of coronary blood flow is crucial in the treatment of acute myocardial infarction. Reperfusion, however, induces ischaemia-reperfusion (IR) injury, which further deteriorates myocardial function. The innate immune system plays an important role in this process, mediating rapid influx of immune cells into the reperfused myocardium. Leukotriene B4 is an important leucocyte chemoattractant, performing its actions through binding to its specific receptor BLT1. We hypothesized that treatment with LSN2792613, a selective BLT1 antagonist, reduces infarct size (IS) in a mouse model of myocardial IR injury. Male C57Bl/6J mice were subjected to myocardial ischaemia for 30 min by surgical coronary artery ligation, followed by reperfusion. Mice received either LSN2792613 or vehicle, three times daily (orally) for up to 72 h after reperfusion. BLT1 inhibition with LSN2792613 reduced IS compared with vehicle treatment (26.9 ± 2.7 vs. 34.9 ± 2.2%, P = 0.030) at 24 h after reperfusion. The levels of IL-6 and keratinocyte chemoattractant were reduced in the infarcted tissue of LSN2792613-treated mice. Reduced apoptosis in LSN2792613-treated mice was suggested by increased levels of phosphorylated JNK and GSK3α/β, and confirmed by flow cytometric analysis showing less apoptotic and necrotic cardiomyocytes in the infarcted myocardium. Echocardiography at 4 weeks after myocardial IR showed a slightly higher ejection fraction and stroke volume in mice treated with LSN2792613 compared with vehicle-treated mice, whereas left ventricular volumes were comparable.

Selective BLT1 inhibition with LSN2792613 reduces inflammation and apoptosis following IR, resulting in reduced IS, and therefore might be a promising strategy to prevent myocardial IR injury.

Does sleep deprivation lead to a loss of functional connectivity in frontal brain regions?

The restorative effect of sleep on waking brain activity remains poorly understood. Previous studies have compared overall neural network characteristics after normal sleep and sleep deprivation. To study whether sleep and sleep deprivation might differentially affect subsequent connectivity characteristics in different brain regions, we performed a within-subject study of resting state brain activity using the graph theory framework adapted for the individual electrode level.In balanced order, we obtained high-density resting state electroencephalography (EEG) in 8 healthy participants, during a day following normal sleep and during a day following total sleep deprivation. We computed topographical maps of graph theoretical parameters describing local clustering and path length characteristics from functional connectivity matrices, based on synchronization likelihood, in five different frequency bands. A non-parametric permutation analysis with cluster correction for multiple comparisons was applied to assess significance of topographical changes in clustering coefficient and path length. Significant changes in graph theoretical parameters were only found on the scalp overlying the prefrontal cortex, where the clustering coefficient (local integration) decreased in the alpha frequency band and the path length (global integration) increased in the theta frequency band. These changes occurred regardless, and independent of, changes in power due to the sleep deprivation procedure.

The findings indicate that sleep deprivation most strongly affects the functional connectivity of prefrontal cortical areas. The findings extend those of previous studies, which showed sleep deprivation to predominantly affect functions mediated by the prefrontal cortex, such as working memory. Together, these findings suggest that the restorative effect of sleep is especially relevant for the maintenance of functional connectivity of prefrontal brain regions.

Are investigations anxiolytic or anxiogenic?

Aims were to investigate (a) whether neuroimaging in patients with chronic daily headache reassures patients or fails to reassure them and/or worsens outcome, impacting on service use, costs, health anxieties, and symptoms, and (b) whether this reassurance process occurs differentially in patients with different levels of psychological morbidity. randomised controlled trial; setting: headache clinic in secondary care, South London; participants: 150 patients fulfilling criteria for chronic daily headache, stratified using the Hospital Anxiety and Depression Scale (HADS); intervention: treatment as usual or the offer of an MRI brain scan; main outcome measures: use of services, costs, and health anxiety. Seventy six patients were randomised to the offer of a brain scan and 74 patients to treatment as usual. One hundred and thirty seven (91%) primary care case notes were examined at 1 year, 103 (69%) patients completed questionnaires at 3 months and 96 (64%) at 1 year. Sixty six (44%) patients were HADS positive (scored>11 on either subscale). Patients offered a scan were less worried about a serious cause of the headaches at 3 months (p = 0.004), but this was not maintained at 1 year; other health anxiety measures did not differ by scan status. However, at 1 year HADS positive patients offered a scan cost significantly less, by 465 pounds Sterling (95% confidence interval (CI): -1028 pounds Sterling to -104 pounds Sterling), than such patients not offered a scan, due to lower utilisation of medical resources.

Neuroimaging significantly reduces costs for patients with high levels of psychiatric morbidity, possibly by changing subsequent referral patterns of the general practitioner.

Are methadone doses of 100 mg or greater more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteers?

Methadone maintenance has been an effective pharmacotherapy for the treatment of heroin dependence for nearly four decades. Recent clinical research suggests that methadone doses larger than those used in most clinics are more effective at suppressing illicit heroin use. This greater efficacy may result from greater cross-tolerance to the reinforcing effects of heroin. The purpose of this double-blind, within-subject study was to examine the relationship between methadone maintenance dose and the reinforcing effects of heroin. Participants were stabilized on 50, 100 and 150 mg methadone (ascending order) during separate outpatient periods before being admitted to an inpatient research unit for testing at each maintenance dose. Five opiate-dependent volunteers completed the study. During each 4-week inpatient testing period, participants sampled three doses of heroin (0, 10, or 20 mg; random order; one dose per week) and were subsequently allowed seven opportunities to choose between another injection of that week's heroin dose and varying amounts of money (dollars 2-38). The number of heroin injections chosen decreased as methadone dose was increased. Larger alternative monetary reinforcers were required to suppress heroin self-administration during maintenance on 50 compared to 100 or 150 mg methadone. Larger methadone doses also completely blocked the subjective effects of heroin and produced greater withdrawal suppression during the outpatient periods.

These results support other clinical and laboratory-based research indicating that persistent heroin use may be reduced by providing larger methadone maintenance doses that produce more effective cross-tolerance to heroin.

Are levels of adiponectin , C-reactive protein and interleukin-1 receptor antagonist associated with insulin sensitivity : a population-based study?

We evaluated the relationship of insulin sensitivity (assessed with the quantitative insulin sensitivity check index, QUICKI) to adiponectin and pro-inflammatory markers, levels of high-sensitivity C-reactive protein (hs-CRP) and interleukin-1 receptor antagonist (IL-1 Ra). Cross-sectional study. Study population (N=923, i.e 411 men and 512 women) included five different population-based age groups (born in 1942, 1947, 1952, 1957 and 1962), [mean age 46 years and mean body mass index (BMI) 26 kg/m(2)]. Study protocol included an interview and measurements of anthropometric parameters and glucose, insulin, adiponectin, hs-CRP and IL-1 Ra. Correlation (r) between QUICKI and adiponectin level was 0.334 [95% confidence intervals (CI), 0.275-0.392] and partial correlation adjusted for gender, BMI, smoking status, physical activity and age was 0.247 (95% CI, 0.185-0.308). There was negative correlation between QUICKI and IL-1 Ra (r= -0.385; 95% CI, -0.440 to -0.328) which remained statistically significant after the adjustment for confounding factors (r= -0.178; 95% CI, -0.240 to -0.113). Similarly, QUICKI was negatively correlated with hs-CRP (r= -0.241; 95% CI, -0.302 to -0.178), but after the adjustment it lost its statistical significance. There was a statistically significant gender difference (p=0.018) in correlation between QUICKI and IL-1 Ra levels (men: r= -0.348; 95% CI, -0.436 to - 0.261; women r= -0.500; 95% CI, -0.537 to -0.398).

Our results show that adiponectin level and markers of low-grade inflammation are related to insulin sensitivity. Adiponectin and IL-1 Ra levels might be better markers of the risk of obesity and type 2 diabetes than hs-CRP.

Does apamin-sensitive potassium current modulate action potential duration restitution and arrhythmogenesis of failing rabbit ventricles?

Apamin-sensitive K currents (I(KAS)) are upregulated in heart failure. We hypothesize that apamin can flatten action potential duration restitution (APDR) curve and can reduce ventricular fibrillation duration in failing ventricles. We simultaneously mapped membrane potential and intracellular Ca (Ca(i)) in 7 rabbit hearts with pacing-induced heart failure and in 7 normal hearts. A dynamic pacing protocol was used to determine APDR at baseline and after apamin (100 nmol/L) infusion. Apamin did not change APD(80) in normal ventricles, but prolonged APD(80) in failing ventricles at either long (≥300 ms) or short (≤170 ms) pacing cycle length, but not at intermediate pacing cycle length. The maximal slope of APDR curve was 2.03 (95% confidence interval, 1.73-2.32) in failing ventricles and 1.26 (95% confidence interval, 1.13-1.40) in normal ventricles at baseline (P=0.002). After apamin administration, the maximal slope of APDR in failing ventricles decreased to 1.43 (95% confidence interval, 1.01-1.84; P=0.018), whereas no significant changes were observed in normal ventricles. During ventricular fibrillation in failing ventricles, the number of phase singularities (baseline versus apamin, 4.0 versus 2.5), dominant frequency (13.0 versus 10.0 Hz), and ventricular fibrillation duration (160 versus 80 s) were all significantly (P<0.05) decreased by apamin.

Apamin prolongs APD at long and short, but not at intermediate pacing cycle length in failing ventricles. I(KAS) upregulation may be antiarrhythmic by preserving the repolarization reserve at slow heart rate, but is proarrhythmic by steepening the slope of APDR curve, which promotes the generation and maintenance of ventricular fibrillation.

Does flow cytometry have a role in preliminary differentiation between urinary tract infections sustained by gram positive and gram negative bacteria?

Urine culture is the most frequently requested test for a Microbiology Lab. A reliable screening tool would be of paramount importance both to clinicians and laboratorians, provided that it could get fast and accurate negative results in order to rule-out urinary tract infection (UTI). We evaluated 1907 consecutive urine samples from outpatients. Culture was performed on chromogenic agar with 1μL loop, using 10(5)CFU/mL as a limit of positive growth. Using Sysmex Uf-1000i analyzer we evaluated bacteria forward scatter (B_FSC) and fluorescent light scatter (B_FLH) in a preliminary discrimination step for UTI caused by Gram+ or Gram- bacteria. We got 512 positive samples. A mono-microbial infection was observed in 490 samples; two bacterial strains were isolated in 22 samples, so 534 bacterial strains were found: 392 Gram-, 133 Gram+ and 9 yeasts. Comparing Gram+ and Gram- bacteria we observed a statistically significant difference for B_FSC but not for B_FLH. In this application experimental cut-off value for B_FSC was 25ch. Using this cut-off to perform a presumptive identification of UTI sustained by Gram-+ bacteria, we observed a SE 0.68, SP 0.84.

Our data although preliminary suggest that B_FSC could be useful in presumptive exclusion of UTI caused by Gram-positive bacteria.

Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia: Time to Move Toward a Minimal Residual Disease-Based Definition of Complete Remission?

Patients with acute myeloid leukemia (AML) who are in morphologic complete remission are typically considered separately from patients with active disease (ie, ≥ 5% marrow blasts by morphology) in treatment algorithms for allogeneic hematopoietic cell transplantation (HCT), which implies distinct outcomes for these two groups. It is well recognized that the presence of minimal residual disease (MRD) at the time of transplantation is associated with adverse post-HCT outcome for those patients in morphologic remission. This effect of pre-HCT MRD prompted us to compare outcomes in consecutive patients in MRD-positive remission with patients with active AML who underwent myeloablative allogeneic HCT at our institution. We retrospectively studied 359 consecutive adults with AML who underwent myeloablative allogeneic HCT from a peripheral blood or bone marrow donor between 2006 and 2014. Pre-HCT disease staging included 10-color multiparametric flow cytometry on bone marrow aspirates in all patients. Any level of residual disease was considered to be MRD positive. Three-year relapse estimates were 67% in 76 patients in MRD-positive morphologic remission and 65% in 48 patients with active AML compared with 22% in 235 patients in MRD-negative remission. Three-year overall survival estimates were 26%, 23%, and 73% in these three groups, respectively. After multivariable adjustment, MRD-negative remission status remained statistically significantly associated with longer overall and progression-free survival as well as lower risk of relapse compared with MRD-positive morphologic remission status or having active disease, with similar outcomes between the latter two groups.

The similarities in outcomes between patients in MRD-positive morphologic remission and those with active disease at the time of HCT support the use of treatment algorithms that use MRD- rather than morphology-based disease assessments.

Are transferrin receptor-1 gene polymorphisms associated with type 2 diabetes?

Iron is involved in oxidative stress and type 2 diabetes (T2D). Transferrin receptor (TFRC) constitutes the major receptor by which most cells take up iron. The aim of this study was to evaluate whether TFRC gene polymorphisms are associated with T2D. We evaluated TFRC gene polymorphism (rs3817672, 210AG, S142G) in a sample of T2D patients and nondiabetic controls (n = 722), and 39 SNPs within the TFRC genomic region analysed by the Welcome Trust Case Control Consortium (WTCCC) (1921 T2D subjects and 3000 controls). In a subset of subjects, glucose tolerance and insulin sensitivity were also studied. The frequency of the G allele at the position 210 of the TFRC gene was significantly higher in T2D patients. Both GG and GA genotypes had a 69% (P < 0.01) greater risk of developing T2D estimated under a dominant model. The increased prevalence of the G allele run in parallel to increased sex-adjusted log-serum ferritin and slightly increased soluble transferrin receptor among patients with T2D. Furthermore, post-load glucose and insulin sensitivity were significantly associated with circulating soluble transferrin receptor, and insulin sensitivity was significantly associated with serum ferritin among G allele carriers, (r = -0.33, P = 0.001) but not in AA homozygotes. Sixteen other TFRC SNPs were also associated to T2D according to the Welcome Trust Case Control Consortium data.

TFRC gene variants are associated with T2D.

Does voxel-based analysis of whole brain FLAIR at 3T detect focal cortical dysplasia?

Focal Cortical Dysplasia (FCD) is an important cause for pharmacoresistant epilepsy that can be treated surgically. The identification of the abnormal cortex on standard MRI can be difficult and computational techniques have been developed to increase sensitivity. In this study we evaluate the potential of a novel whole-brain voxel-based technique using normalized FLAIR signal intensity (nFSI) at 3 Tesla. Twenty-five patients with neuroradiologically reported FCD were included and compared to 25 healthy control subjects using Statistical Parametric Mapping (SPM5). T2 FLAIR scans were intensity normalized and each individual patient was compared against the control group. Each control subject was compared against the remaining control group. SPM correctly identified the FCD in 88% of cases (22/25) with only one false positive finding in the control group. In all but one of these cases the FCD was the most significant finding in the whole brain. All three missing cases could be detected at lower threshold levels but this would give rise to more false positive findings and thus reduce specificity.

We present a novel technique that uses standard clinical T2 FLAIR scans to automatically detect FCDs. It can give supplementary information to the established T1-based automated techniques and could be useful for additional screening test, to complement the visual reading and clinical interpretation of MRI scans.

Is there a correlation between androgens and sexual desire in women?

For women, the correlation between circulating androgens and sexual desire is inconclusive. Substitution with androgens at physiological levels improves sexual function in women who experience decreased sexual desire and androgen deficiency from surgical menopause, pituitary disease, and age-related decline in androgen production in the ovaries. Measuring bioactive testosterone is difficult and new methods have been proposed, including measuring the primary androgen metabolite androsterone glucuronide (ADT-G).AIM: The aim of this study was to investigate a possible correlation between serum levels of androgens and sexual desire in women and whether the level of ADT-G is better correlated than the level of circulating androgens with sexual desire. This was a cross-sectional study including 560 healthy women aged 19-65 years divided into three age groups. Correlations were considered to be statistically significant at P<0.05. Sexual desire was determined as the total score of the sexual desire domain of the Female Sexual Function Index. Total testosterone (TT), calculated free testosterone (FT), androstenedione, dehydroepiandrosterone sulfate (DHEAS), and ADT-G were analyzed using mass spectrometry. Sexual desire correlated overall with FT and androstenedione in the total cohort of women. In a subgroup of women aged 25-44 years with no use of systemic hormonal contraception, sexual desire correlated with TT, FT, androstenedione, and DHEAS. In women aged 45-65 years, androstenedione correlated with sexual desire. No correlations between ADT-G and sexual desire were identified.

In the present study, FT and androstenedione were statistically significantly correlated with sexual desire in the total cohort of women. ADT-G did not correlate more strongly than circulating androgens with sexual desire and is therefore not superior to measuring circulating androgens by mass spectrometry.

Does elevated red cell distribution width predict poor outcome in young patients with community acquired pneumonia?

Community acquired pneumonia (CAP) is a major cause of morbidity and mortality. While there is much data about risk factors for severe outcome in the general population, there is less focus on younger group of patients. Therefore, we aimed to detect simple prognostic factors for severe morbidity and mortality in young patients with CAP. Patients of 60 years old or younger, who were diagnosed with CAP (defined as pneumonia identified 48 hours or less from hospitalization) between March 1, 2005 and December 31, 2008 were retrospectively analyzed for risk factors for complicated hospitalization and 90-day mortality. The cohort included 637 patients. 90-day mortality rate was 6.6% and the median length of stay was 5 days. In univariate analysis, male patients and those with co-morbid conditions tended to have complicated disease. In multivariate analysis, variables associated with complicated hospitalization included post chest radiation state, prior neurologic damage, blood urea nitrogen (BUN) > 10.7 mmol/L and red cell distribution width (RDW) > 14.5%; whereas, variables associated with an increased risk of 90-day mortality included age ≥ 51 years, prior neurologic damage, immunosuppression, and the combination of abnormal white blood cells (WBC) and elevated RDW. Complicated hospitalization and mortality rate were significantly higher among patients with increased RDW regardless of the white blood cell count. Elevated RDW was associated with a significant increase in complicated hospitalization and 90-day mortality rates irrespective to hemoglobin levels.

In young patients with CAP, elevated RDW levels are associated with significantly higher rates of mortality and severe morbidity. RDW as a prognostic marker was unrelated with hemoglobin levels.

Is brahma required for proper expression of the floral repressor FLC in Arabidopsis?

BRAHMA (BRM) is a member of a family of ATPases of the SWI/SNF chromatin remodeling complexes from Arabidopsis. BRM has been previously shown to be crucial for vegetative and reproductive development. Here we carry out a detailed analysis of the flowering phenotype of brm mutant plants which reveals that, in addition to repressing the flowering promoting genes CONSTANS (CO), FLOWERING LOCUS T (FT) and SUPPRESSOR OF OVEREXPRESSION OF CO1 (SOC1), BRM also represses expression of the general flowering repressor FLOWERING LOCUS C (FLC). Thus, in brm mutant plants FLC expression is elevated, and FLC chromatin exhibits increased levels of histone H3 lysine 4 tri-methylation and decreased levels of H3 lysine 27 tri-methylation, indicating that BRM imposes a repressive chromatin configuration at the FLC locus. However, brm mutants display a normal vernalization response, indicating that BRM is not involved in vernalization-mediated FLC repression. Analysis of double mutants suggests that BRM is partially redundant with the autonomous pathway. Analysis of genetic interactions between BRM and the histone H2A.Z deposition machinery demonstrates that brm mutations overcome a requirement of H2A.Z for FLC activation suggesting that in the absence of BRM, a constitutively open chromatin conformation renders H2A.Z dispensable.

BRM is critical for phase transition in Arabidopsis. Thus, BRM represses expression of the flowering promoting genes CO, FT and SOC1 and of the flowering repressor FLC. Our results indicate that BRM controls expression of FLC by creating a repressive chromatin configuration of the locus.

Does tLR4 but not TLR2 regulate inflammation and tissue damage in acute pancreatitis induced by retrograde infusion of taurocholate?

Neutrophil infiltration is a key regulator in the pathophysiology of acute pancreatitis (AP), although the impact of Toll-like receptors (TLRs) in AP remains elusive. The aim of this study was to define the role of TLR2 and TLR4 in leukocyte recruitment and tissue damage in severe AP. AP was induced by retrograde infusion of sodium taurocholate into the pancreatic duct in wild-type, TLR2- and TLR4-deficient mice. Samples were collected 24 h after induction of AP. Taurocholate challenge caused a clear-cut pancreatic damage characterized by increased acinar cell necrosis, neutrophil infiltration, focal hemorrhage and edema formation, as well as increased levels of blood amylase and CXCL2 (macrophage inflammatory protein-2) in the pancreas and serum. Moreover, challenge with taurocholate increased activation of trypsinogen in the pancreas. Notably, TLR2 gene-deficient mice exhibited a similar phenotype to wild-type mice after challenge with taurocholate. In contrast, tissue damage, pancreatic and lung myeloperoxidase (MPO) activity, serum and pancreatic levels of CXCL2 as well as blood amylase were significantly reduced in TLR4-deficient mice exposed to taurocholate. However, taurocholate-induced activation of trypsinogen was intact in TLR4-deficient mice.

Our data suggest a role for TLR4 but not TLR2 in the pathogenesis of severe AP in mice.

Does whole exome sequencing identify a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome?

Dubowitz syndrome (DS) is an autosomal recessive disorder characterized by the constellation of mild microcephaly, growth and mental retardation, eczema and peculiar facies. Over 140 cases have been reported, but the genetic basis is not understood. We enrolled a multiplex consanguineous family from the United Arab Emirates with many of the key clinical features of DS as reported in previous series. The family was analyzed by whole exome sequencing. RNA splicing was evaluated with reverse-transcriptase PCR, immunostaining and western blotting was performed with specific antibodies, and site-specific cytosine-5-methylation was studied with bisulfite sequencing. We identified a homozygous splice mutation in the NSUN2 gene, encoding a conserved RNA methyltransferase. The mutation abolished the canonical splice acceptor site of exon 6, leading to use of a cryptic splice donor within an AluY and subsequent mRNA instability. Patient cells lacked NSUN2 protein and there was resultant loss of site-specific 5-cytosine methylation of the tRNA(Asp GTC) at C47 and C48, known NSUN2 targets.

Our findings establish NSUN2 as the first causal gene with relationship to the DS spectrum phenotype. NSUN2 has been implicated in Myc-induced cell proliferation and mitotic spindle stability, which might help explain the varied clinical presentation in DS that can include chromosomal instability and immunological defects.

Is beta-cell dysfunction in classic transient neonatal diabetes characterized by impaired insulin response to glucose but normal response to glucagon?

To investigate beta-cell function and the long-term health of four case subjects presenting with chromosome 6-associated transient neonatal diabetes (TND). Two unrelated case subjects presenting with paternal uniparental isodisomy of chromosome 6 (UPD6) and two siblings with a paternally inherited duplication of 6q24 were studied. Three case subjects presented with neonatal diabetes that recurred at 4-17 years, while diabetes was incidentally discovered in the other case subject at 14 years of age. beta-Cell function was investigated after diabetes relapse by means of an oral glucose tolerance test (OGTT), an intravenous glucose tolerance test (IVGTT), and glucagon tests. The quantitative insulin sensitivity check index (QUICKI) was calculated from fasting blood samples as an estimate of insulin sensitivity. beta-Cell function was investigated at diabetes relapse in two case subjects: the insulin response to both an OGTT and IVGTT was low, whereas the basal levels of C-peptide were normal. No evidence of insulin resistance was found. Residual beta-cell function was further explored by a glucagon test in all subjects at the age of 16-28 years and was found to be normal. Final height was within the normal percentiles, whereas one case, who had been poorly controlled since puberty, presented with diabetes-related microvascular complications.

In patients with chromosome 6-associated TND, the beta-cell is preserved and able to secrete insulin through the stimulatory G protein pathway while exhibiting a specific defect of insulin secretion after glucose stimulation. This form of diabetes can be managed with insulin or diet, although new therapeutic agents (glucagon-like synthetic analogs) may prove useful in the future. Lack of treatment leads to long-lasting hyperglycemia without the risk of ketoacidosis but associated with microangiopathy in adult life.

Does boarding inpatients in the emergency department increase discharged patient length of stay?

Boarding of inpatients in the Emergency Department (ED) has been widely recognized as a major contributor to ED crowding and a cause of adverse outcomes. We hypothesize that these deleterious effects extend to those patients who are discharged from the ED by increasing their length of stay (LOS). This study investigates the impact of boarding inpatients on the ED LOS of discharged patients. This retrospective, observational, cohort study investigated the association between ED boarder burden and discharged patient LOS over a 3-year period in an urban, academic tertiary care ED. Median ED LOS of 179,840 discharged patients was calculated for each quartile of the boarder burden at time of arrival, and Spearman correlation coefficients were used to summarize the relationship. Subgroup analyses were conducted, stratified by patient acuity defined by triage designation, and hour of arrival. Overall median discharged patient ED LOS increased by boarder burden quartile (205 [95% confidence interval (CI) 203-207], 215 [95% CI 214-217], 221 [95% CI 219-223], and 221 [95% CI 219-223] min, respectively), with a Spearman correlation of 0.25 between daily total boarder burden hours and median LOS. When stratified by patient acuity and hour of arrival (11:00 a.m.-11:00 p.m.), LOS of medium-acuity patients increased significantly by boarder burden quartile (252 [95% CI 247-255], 271 [95% CI 267-275], 285 [95% CI 95% CI 278-289], and 309 [95% CI 305-315] min, respectively) with a Spearman correlation of 0.18.

In this retrospective study, increasing boarder burden was associated with increasing LOS of patients discharged from the ED, with the greatest effect between 11:00 a.m. and 11:00 p.m. on medium-acuity patients. This relationship between LOS and ED capacity limitation by inpatient boarders has important implications, as ED and hospital leadership increasingly focus on ED LOS as a measure of efficiency and throughput.

Necrotizing fasciitis: is the bacterial spectrum changing?

Necrotizing fasciitis (NF) is a rare, but potentially fatal pathology. The aim of the present study was to identify the population characteristics of the NF patients, the responsible bacteria, and the differences between survivors and nonsurvivors. In this retrospective case-control study, all patients with NF from January 1, 2005, to December 31, 2010, treated in an academic level 1 trauma center, were identified, and their medical records were reviewed. The mortality rate of the 24 identified patients was 20.8 %. The majority of the infections (54.2 %) (13/24) were monomicrobial. Hemolytic Streptococcus of group A (25 %) and methicillin-resistant Staphylococcus aureus (20.8 %) were the commonest germs. The mean number of comorbidities was 3.62 (standard deviation (SD) 3.58). Diabetes mellitus, cardiovascular disease, and immunosuppression were the commonest. Mean number of operations was 8.1 (SD 4.7). Five patients (20.8 %) developed a disseminated intravascular coagulation (DIC); all of them died. Nonsurvivors, who presented with deteriorated coagulation factors, developed a DIC (p < 0.001) and received more often antibiotic monotherapy (ampicillin/sulbactam) as initial empirical therapy (p < 0.001).

The present study suggests a shift of the bacterial spectrum towards monomicrobial infections with multiresistant bacteria. The early recognition of high-risk patients and the aggressive surgical treatment with at least double-schema antibiotic therapy are of outmost importance.

Is recurrence rate of incidental hepatocellular carcinoma after liver transplantation similar to previously known HCC?

Incidental hepatocellular carcinoma (iHCC) generates uncertainty over risk of recurrence after liver transplantation (LT).AIM: To compare recurrence between iHCC and confirmed HCC diagnosed prior to transplant based on imaging criteria (cHCC). Fifty-four HCC patients were analyzed from a series of 309 consecutive adult transplanted patients. We developed a recurrence predicting score (RPS) applying ORs based on pathologic risk variables. Incidence of iHCC was 4.8% (n = 15) and overall recurrence 12.9% (cHCC 15.4% and iHCC 7%; P = 0.39). Variables included in the RPS were: microvascular invasion OR 17.8 (1.78-178.97; P = 0.014: 2 points), neural invasion OR 15.5 (1.13-212.17; P = 0.04: 1.5 points), nuclear grade>II OR 9.3 (1.17-74.84; P = 0.035: 1 point), and beyond Up-to 7 criteria OR 13.1 (1.66-103.67; P = 0.015: 1.5 points). Two risk groups were identified: low risk for recurrence (0-1 point) and intermediate-high risk groups (2-6 points). Low risk category remained an independent predictor of recurrence: OR 0.11 (0.01-0.67; P = 0.017); AUROC of 0.75 (0.54-0.96). A tendency towards more patients categorized as low risk group among iHCC patients was observed (69.2%; P = 0.13).

In this series iHCC was not associated to lower risk of recurrence when compared to cHCC. We propose application of an RPS as a clinical tool for recurrence risk estimation.

Does vitamin D affect survival independently of vascular calcification in chronic kidney disease?

Cardiovascular disease is the main cause of mortality in chronic kidney disease (CKD) patients. Vitamin D might have beneficial effects on vascular health. The aim of this study was to determine the prevalence of vitamin D deficiency (25-hydroxyvitamin D [25D] <or= 15 ng/ml) and insufficiency (25D levels between 16 and 30 ng/ml) in a cohort of patients at different CKD stages and the relationships between vitamin D serum levels, vascular calcification and stiffness, and the mortality risk. One hundred forty CKD patients (85 men, mean age 67 +/- 12 yr; CKD stages 2 [8%], 3 [26%], 4 [26%], 5 [7%], and 5D [(33%]) were allocated for a prospective study. Serum levels of 25D and 1,25-dihydroxyvitamin D, aortic calcification score, and pulse wave velocity (PWV) were evaluated. There was a high prevalence of vitamin D deficiency (42%) and insufficiency (34%). Patients with 25D <or= 16.7 ng/ml (median) had a significantly lower survival rate than patients with 25D >16.7 ng/ml (mean follow-up, 605 +/- 217 d; range, 10 to 889; P = 0.05). Multivariate adjustments (included age, gender, diabetes, arterial pressure, CKD stage, phosphate, albumin, hemoglobin, aortic calcification score and PWV) confirmed 25D level as an independent predictor of all-cause mortality.

Vitamin D deficiency and insufficiency were highly prevalent in this CKD cohort. Low 25D levels affected mortality independently of vascular calcification and stiffness, suggesting that 25D may influence survival in CKD patients via additional pathways that need to be further explored.

Does survival after kidney transplantation differ with 50-59- or over 60-year-old expanded-criteria donors?

Use of expanded-criteria donors (ECDs) for kidney transplantation has progressively increased in the past years with the intent to improve the number of available grafts. However, it is still uncertain if ECD kidneys have worse survivals than standard-criteria ones. The aim of this study was to retrospectively analyze a cohort of ECD patients comparing the 2 subgroups of 50-59- and >60-year-old donors in terms of donor, recipient, and transplant features and survival rates. Ninety-one cases were analyzed. The cohort was stratified into 2 subgroups according to donor age: group 1, age 50-59 years (n=26); and group 2, age ≥60 years (n=67). Group 2 represented older donors and a higher percentage of donors with a previous history of hypertension. In Group 1, preharvest creatinine values showed higher results. No difference was detected regarding patient and graft survivals, with 5-year survival rates of 92.3% versus 86.7%, and 70.8% versus 69.8%, respectively. The best way to select the donors is still under debate. In our experience, a biopsy-driven selection was performed exclusively for group 2 ECDs. Considering the similar survivals obtained, we speculated that an accurate biopsy-based selection of older grafts allows one to avoid "bad" donors from the allocation system, thereby obtaining improved survival results.

Biopsy-driven pretransplantation selection appears to be the main system to optimize results, to achieve outcomes similar to nonbiopsied younger donors. Routine biopsies also in the younger subgroup of ECD may achieve a further improvement in survival.

Regional versus general anesthesia in surgical patients with chronic obstructive pulmonary disease: does avoiding general anesthesia reduce the risk of postoperative complications?

Surgical patients with chronic obstructive pulmonary disease (COPD) are at increased risk of perioperative complications. In this study, we sought to quantify the benefit of avoiding general anesthesia in this patient population. Data from the National Surgical Quality Improvement Program database (2005-2010) were used for this review. Patients who met the National Surgical Quality Improvement Program definition for COPD and underwent surgery under general, spinal, epidural, or peripheral nerve block anesthesia were included in this study. For each primary current procedural terminology code with ≥ 1 general and ≥ 1 regional (spinal, epidural, or peripheral nerve block) anesthetic, regional patients were propensity score--matched to general anesthetic patients. Propensity scoring was calculated using all available demographic and comorbidity data. This match yielded 2644 patients who received regional anesthesia and 2644 matched general anesthetic patients. These groups were compared for morbidity and mortality. Groups were well matched on demographics, comorbidities, and type of surgery. Compared with matched patients who received regional anesthesia, patients who received general anesthesia had a higher incidence of postoperative pneumonia (3.3% vs 2.3%, P = 0.0384, absolute difference with 95% confidence interval = 1.0% [0.09, 1.88]), prolonged ventilator dependence (2.1% vs 0.9%, P = 0.0008, difference = 1.2% [0.51, 1.84]), and unplanned postoperative intubation (2.6% vs 1.8%, P = 0.0487, difference = 0.8% [0.04, 1.62]). Composite morbidity was 15.4% in the general group versus 12.6% (P = 0.0038, difference = 2.8% [0.93, 4.67]). Composite morbidity not including pulmonary complications was 13.0% in the general group versus 11.1% (P = 0.0312, difference = 1.9% [0.21, 3.72]). Thirty-day mortality was similar (2.7% vs 3.0%, P = 0.6788, difference = 0.3% [-1.12, 0.67]). As a test for validity, we found a positive association between pulmonary end points because patients with 1 pulmonary complication were significantly more likely to have additional pulmonary complications.

The use of regional anesthesia in patients with COPD is associated with lower incidences of composite morbidity, pneumonia, prolonged ventilator dependence, and unplanned postoperative intubation.

Does excessive erythrocytosis elevate capillary oxygen delivery in subcutaneous mouse tissue?

Acclimatization to reduced environmental oxygen includes erythropoietin-regulated increase in erythrocytes enhancing the blood's oxygen content. However, increased hematocrit levels result in elevated blood viscosity that might impair microcirculation and tissue oxygenation. To assess this oxygen supply to the skin, the authors used erythropoietin overexpressing transgenic mice (tg6) that develop excessive erythrocytosis in an oxygen-independent manner. These animals have been previously reported to elevate their blood viscosity 4-fold. The partial oxygen pressure (pO2) distribution was evaluated in microvessels as well as in subcutaneous interstitial tissue within a dorsal skinfold chamber of resting conscious mice using automated phosphorescence quenching. Compared to wildtype (wt) animals, transgenic blood viscosity increased 4-fold but microvessel diameter was not altered. Despite sharing similar blood pO2 as the wt siblings, tg6 animals nearly doubled their oxygen content. Moreover, tg6 erythrocytes reduced hemoglobin's oxygen affinity by decreased 2,3-DPG levels and an increased Hill number. Transgenic arterioles and venules showed increased pO2 compared to wt controls whereas capillary and tissue pO2 were not altered.

Excessive erythrocytosis does not elevate capillary oxygen delivery.

Is a juvenile polyposis tumor suppressor locus at 10q22 deleted from nonepithelial cells in the lamina propria?

Juvenile polyps are characterized by an abundant lamina propria that lacks smooth muscle and may contain cystically dilated glands, with epithelium that seems normal and is nondysplastic. Rarely, an autosomal dominant inheritance pattern occurs. The aim of this study was to test the hypothesis that the genetic defect in both sporadic juvenile polyps and hereditary juvenile polyposis involves loss of function for a tumor suppressor gene. Allelic losses were detected by comparing normal DNA with tumor DNA from a series of 47 juvenile polyps from 16 patients using polymerase chain reaction amplification of microsatellite markers and fluorescent in situ hybridization (FISH). Somatic deletions at 10q22 were detected in 39 of 47 juvenile polyps (83%) from 16 unrelated patients with either hereditary or sporadic juvenile polyps, and the minimum overlap localized juvenile polyposis coli to the 3-cM interval D10S219-D10S1696. Fluorescent in situ hybridization shows that the cells affected by deletion mutation reside exclusively in the lamina propria, not in the epithelium.

The location of a novel tumor suppressor gene on chromosome 10 that is affected by deletion mutation in the majority of juvenile polyps was mapped. Unlike adenomas and carcinomas of the colonic epithelium, juvenile polyps originate in the lamina propria.

Is the Sleep/Wake Cycle Directly Modulated by Changes in Energy Balance?

The rise in obesity has been paralleled by a decline in sleep duration in epidemiological studies. However, the potential mechanisms linking energy balance and the sleep/wake cycle are not well understood. We aimed to examine the effects of manipulating energy balance on the sleep/wake cycle. Twelve healthy normal weight men were housed in a clinical research facility and studied at three time points: baseline, after energy balance was disrupted by 2 days of caloric restriction to 10% of energy requirements, and after energy balance was restored by 2 days of ad libitum/free feeding. Sleep architecture, duration of sleep stages, and sleep-associated respiratory parameters were measured by polysomnography. Two days of caloric restriction significantly increased the duration of deep (stage 4) sleep (16.8% to 21.7% of total sleep time; P = 0.03); an effect which was entirely reversed upon free feeding (P = 0.01). Although the apnea-hypopnea index stayed within the reference range (< 5 events per hour), it decreased significantly from caloric restriction to free feeding (P = 0.03). Caloric restriction was associated with a marked fall in leptin (P < 0.001) and insulin levels (P = 0.002). The fall in orexin levels from baseline to caloric restriction correlated positively with duration of stage 4 sleep (Spearman rho = 0.83, P = 0.01) and negatively with the number of awakenings in caloric restriction (Spearman rho = -0.79, P = 0.01).

We demonstrate that changes in energy homeostasis directly and reversibly impact on the sleep/wake cycle. These findings provide a mechanistic framework for investigating the association between sleep duration and obesity risk.

Does [ Research of Herba Artemisiae Scoporiae inhibit the hepatic lipotoxicity ]?

To study the efficiency and effect mechanism of Herba Artemisiae Scoporiae inhibits the hepatic lipotoxicity model in vitro. Preparation rat regular serum and medicine serum. Under the safty of medicine thickness by toxicity testing, normal and model groups were added 10% normal rat serum, Herba Artemisiae Scoporiae group was added 10% medicine serum incubation for 24 h, FFA was added to all the groups but the normal incubation for 24 h. The indices were tested below: the content of serum tumor necrosis factor alpha (TNF-alpha) by ELISA, cellular triglyceride content (TG), Oil Red Staining; protein expression of cellular Bcl-2 Assaciated X protein (Bax), phospho-IKB (P-IkappaB) and Cathepsin B (ctsb) by Western Blotting; gene expression of cellular TNF-alpha, Bax and ctsb by real-time PCR; the expression and distribution of ctsb observed by immunofluorescence. After being incubated with FFA for 24 hours, TG deposition of HepG2 in the model group increased markedly. Compared with normal group, not only the content of serum TNF-alpha, but also the protein expression of cellular ctsb, P-IkappaB and mRNA expression of ctsb, TNF-a increased significantly. Contrast to model group, TG deposition decreased markedly in the Herba Artemisiae Scoporiae group. The Herba Artemisiae Scoporiae inhibited TNF-alpha content, the protein expression of cellular ctsb, P-IkappaB and mRNA expression of TNF-alpha significantly.

Herba Artemisiae Scoporiae has a direct inhibition on HepG2 steatosis and TNF-alpha secretion induced by long-chain FFA. The effect mechanism of Herba Artemisiae Scoporiae inhibits the hepatic lipotoxicity has close relationship with inhibition on the protein expression and mRNA expression of ctsb.

Does evaluation of simple blood count as inflammation markers for brain tumor patients?

Hemogram parameters in routine blood panels have been proposed as inflammation markers. These parameters, especially the red cell distribution width (RDW) and mean platelet volume (MPV), were evaluated as surrogate inflammatory markers in brain tumor patients. We aimed to observe RDW and MPV values of tumor patients and compare to those in healthy population. We recorded white blood cell count, neutrophil count, lymphocyte count, hemoglobin, hematocrit, RDW, platelet count, and MPV of the study group at the time of diagnosis and compared to those of the control subjects. The RDW was significantly elevated in study group compared to that of the control subjects (p=0.001). The MPV was significantly lower in study group than that of the control group (p=0.01).

Decreased MPV and increased RDW were both associated with brain tumor. However, prospective studies with larger sample sizes are needed to support the results and expose MPV and RDW variations between metastatic and primary brain tumors.

Can modeling of HIV treatment processes improve outcomes?

Mathematical modeling has been applied to a range of policy-level decisions on resource allocation for HIV care and treatment. We describe the application of classic operations research (OR) techniques to address logistical and resource management challenges in HIV treatment scale-up activities in resource-limited countries. We review and categorize several of the major logistical and operational problems encountered over the last decade in the global scale-up of HIV care and antiretroviral treatment for people with AIDS. While there are unique features of HIV care and treatment that pose significant challenges to effective modeling and service improvement, we identify several analogous OR-based solutions that have been developed in the service, industrial, and health sectors. HIV treatment scale-up includes many processes that are amenable to mathematical and simulation modeling, including forecasting future demand for services; locating and sizing facilities for maximal efficiency; and determining optimal staffing levels at clinical centers. Optimization of clinical and logistical processes through modeling may improve outcomes, but successful OR-based interventions will require contextualization of response strategies, including appreciation of both existing health care systems and limitations in local health workforces.

The modeling techniques developed in the engineering field of operations research have wide potential application to the variety of logistical problems encountered in HIV treatment scale-up in resource-limited settings. Increasing the number of cross-disciplinary collaborations between engineering and public health will help speed the appropriate development and application of these tools.

Do single T factors predict survival of patients with resected stage-IIB non-small-cell lung cancers?

In the seventh edition of TNM Classification of Malignant Tumours (TNM) staging, the stage-IIB category for lung cancer is comprised of four factors: lymph-node metastasis, chest-wall invasion, large tumor size (> 7 cm), and same-lobe nodules. Tumors are further classified into eight sub-categories based on each TN factor or factor combinations. This study evaluated the prognostic value of each TN factor or combinations for resected stage-IIB non-small-cell lung cancer (NSCLC). We retrospectively studied 186 consecutive patients who had resections for NSCLC at Chiba University Hospital and were diagnosed as stage IIB according to the seventh edition of TNM staging. Five-year survivals for each stage IIB were: T2bN1M0 = 47 ± 12% (± standard error); T3 (chest-wall invasion; N0M0) = 59 ± 7%; T3 (large tumor> 7 cm)=72 ± 11%; T3 (same-lobe nodules) = 78 ± 5%; T3 (invasion + > 7 cm)=44 ± 16%; T3 (invasion+same-lobe nodules) = 25 ± 22%; T3 (>7cm+same-lobe nodules) = 0%; and T3 (invasion + > 7 cm +same-lobe nodules)=0%. Among the four single factors, same-lobe nodules had the best prognoses, whereas T2bN1M0 had the worst prognoses. Comparing cases with single factors and multiple factors that decided stage IIB, cases with multiple factors had poorer prognoses (P=0.02).

The stage-IIB category is comprised of eight sub-categories, with either single factors or factor combinations; these sub-categories have different prognoses. The worst survivals were for cases with T2bN1M0 as a single factor or for cases with multiple factors, although these represented a small proportion of resected stage-IIB NSCLC cases.

Does respiratory health of workers exposed to metal dusts and foundry fume in a copper refinery?

To assess airflow limitation in workers exposed long term to metal dust, the prevalence of pleural plaques in those workers exposed in the past to asbestos, the influence of pleural plaques on lung function, and the possible association with airway disease caused by asbestos. A cross sectional and longitudinal (seven year) survey of 494 long term (mean (SEM) 21(1) years) workers in a copper refinery was carried out from medical questionnaires, chest radiographs, and forced spirometry. The prevalence of lifetime non-smokers was 19%, current smokers 39%, and ex-smokers 42%. The prevalence of chronic obstructive pulmonary diseases (COPD) (forced expiratory volume in one second (FEV1) < 80% predicted) was 5%, small airway dysfunction (SAD) (maximal mid-expiratory flow (MMEF) < 60% predicted) was 7%, and this did not differ from the control population. The COPD and SAD were associated with cumulative smoking index but not with the cumulative work years at the plant or with any type of work at the plant. The mean (SEM) reduction of FEV1 was 20(7) ml in non-smokers, 26(4) ml in smokers, and 26(5) ml in ex-smokers (P > 0.05). In the smokers and ex-smokers with COPD, the loss of FEV1 was 53(10) (P < 0.02). The prevalence of pleural plaques was 11% (P < 0.0001); pleural plaques were found in older workers with known exposure to asbestos. The pleural plaques were circumscribed and associated with a non-significant 196 ml reduction in forced vital capacity (FVC) and non-significant reduction of FVC over time. The pleural plaques were not associated with COPD or SAD. The cumulative smoking index obtained by a technician did not differ from that by a chest physician.

Despite exposures to asbestos that produced pleural plaques and exposures to metal dusts and foundry fumes the long term workers of this plant did not have excessive prevalence of COPD or SAD. The data suggest that low level long term exposure to metal dusts, gases, and foundry fumes do not necessarily cause respiratory dysfunction, circumscribed pleural plaques with low grades of width and extent do not reduce FVC significantly, and exposure to asbestos dust that produced pleural plaques does not necessarily produce airway dysfunction.

Do lactobacillus rhamnosus L34 and Lactobacillus casei L39 suppress Clostridium difficile-induced IL-8 production by colonic epithelial cells?

Clostridium difficile is the main cause of hospital-acquired diarrhea and colitis known as C. difficile-associated disease (CDAD).With increased severity and failure of treatment in CDAD, new approaches for prevention and treatment, such as the use of probiotics, are needed. Since the pathogenesis of CDAD involves an inflammatory response with a massive influx of neutrophils recruited by interleukin (IL)-8, this study aimed to investigate the probiotic effects of Lactobacillus spp. on the suppression of IL-8 production in response to C. difficile infection. We screened Lactobacillus conditioned media from 34 infant fecal isolates for the ability to suppress C. difficile-induced IL-8 production from HT-29 cells. Factors produced by two vancomycin-resistant lactobacilli, L. rhamnosus L34 (LR-L34) and L.casei L39 (LC-L39), suppressed the secretion and transcription of IL-8 without inhibiting C. difficile viability or toxin production. Conditioned media from LR-L34 suppressed the activation of phospho-NF-κB with no effect on phospho-c-Jun. However, LC-L39 conditioned media suppressed the activation of both phospho-NF-κB and phospho-c-Jun. Conditioned media from LR-L34 and LC-L39 also decreased the production of C. difficile-induced GM-CSF in HT-29 cells. Immunomodulatory factors present in the conditioned media of both LR-L34 and LC-L39 are heat-stable up to 100°C and > 100 kDa in size.

Our results suggest that L. rhamnosus L34 and L. casei L39 each produce factors capable of modulating inflammation stimulated by C. difficile. These vancomycin-resistant Lactobacillus strains are potential probiotics for treating or preventing CDAD.

Sickness certificates in Sweden: did the new guidelines improve their quality?

Long-term sickness absence is high in many Western countries. In Sweden and many other countries, decisions on entitlement to sickness benefits and return to work measures are based on information provided by physicians in sickness certificates. The quality demands, as stressed by the Swedish sick leave guidelines from 2008, included accurate sickness certificates with assessment of functioning clearly documented. This study aims to compare quality of sickness certificates between 2007 and 2009 in Östergötland County, Sweden. Quality is defined in terms of descriptions of functioning with the use of activity and participation according to WHO's International Classification of Functioning, Disability and Health (ICF), and in prescriptions of early rehabilitation. During two weeks in 2007 and four weeks in 2009, all certificates had been collected upon arrival to the social insurance office in Östergötland County, Sweden. Four hundred seventy-five new certificates were included in 2007 and 501 in 2009. Prolongations of sick leave were included until the last date of sick listing. Free text on functioning was analysed deductively using the ICF framework, and placed into categories (body functions/structures, activity, participation, no description) for statistical analysis. The majority of the certificates were issued for musculoskeletal diseases or mental disorders. Text on functioning could be classified into the components of ICF in 65% and 78% of sickness certificates issued in 2007 and 2009, respectively. Descriptions according to body components such as "sensations of pain" or "emotional functions" were given in 58% of the certificates from 2007 and in 65% from 2009. The activity component, for example "walking" or "handling stress", was more frequent in certificates issued in 2009 compared with 2007 (33% versus 26%). Prescriptions of early rehabilitation increased from 27% in 2007 to 35% in 2009, primarily due to more counseling.

An improvement of the quality between certificates collected in 2007 and 2009 was demonstrated in Östergötland County, Sweden. The certificates from 2009 provided more information linkable to ICF and incorporated an increased use of activity limitations when describing patients' functioning. Still, activity limitations and prescriptions of early rehabilitation were only present in one-third of the sickness certificates.

Does increased free flap size in the head and neck region impact clinical outcome?

There are few studies analyzing the long-term clinical effects related to increasing the size of head and neck free tissue reconstructions. The purpose of this study was to compare long-term clinical outcomes of patients undergoing very large area (≥200 cm(2)) and large area (100 to 199 cm(2)) free tissue reconstructions of head and neck defects. Institutional review board approval was obtained before conducting this retrospective cohort study at the authors' university-based tertiary care hospitals. The authors analyzed the charts of consecutive patients with free flaps of at least 100 cm(2) treated from July 2000 to December 2011. Very large area flaps were arbitrarily defined as larger than 200 cm(2). Intraoperative variables, flap success rates, overall survival, and total hospital and intensive care unit (ICU) stays for the 2 groups were analyzed. Fisher exact tests or χ(2) tests were used for categorical variables and Student t tests were used for continuous variables. Log-rank tests were conducted to investigate whether overall survival was significantly different between the 2 groups. Statistical significance was defined as a P value less than .05. The charts of 121 consecutive patients were analyzed. Thirty-eight patients (31%) had very large area flaps (277.1 ± 79.4 cm(2); range, 200 to 576 cm(2)) and 83 patients (69%) had large area flaps (140.1 ± 25.5 cm(2)). There was no difference between flap groups in presenting T4 stage disease (P = .448). Ninety-eight percent of the very large area flaps and 93% of the large area flaps survived. Total hospital stays for the very large area and large area flap groups were 12.8 ± 8.2 and 12.3 ± 8.3 days, respectively (P = not significant). In contrast, ICU stays were increased for the very large area flap group at 7.1 ± 7.5 versus 4.0 ± 4.0 days for the large area flap group (P = .022). The overall median patient survival for the very large area flap group was 7.6 months (95% confidence interval, 5.7-10.0) and that for the large area flap group was 8.4 months (95% confidence interval, 5.4-12.9; P = .376).

Performing very large area flaps for head and neck reconstruction did not negatively affect clinical outcome. Comparable success rates, total hospital stays, and overall survival can be safely achieved in this difficult patient population. More studies need to be conducted on resource usage.

Is defective expression of transforming growth factor beta receptor type II associated with CpG methylated promoter in primary non-small cell lung cancer?

Reduced expression of the transforming growth factor beta receptor type II (TGF beta RII), a key inhibitor of epithelial cell growth and tumor suppressor gene, was reported frequently in many types of tumors including non-small cell lung cancer (NSCLC). This study explored the significance of the TGF beta RII gene in NSCLC carcinogenesis. With 43 independent pairs of tumor and paracarcinoma tissue samples from patients with primary NSCLC, we carried out PCR-denaturing gradient gel electrophoresis screening for DNA variants over the coding sequence of the TGF beta RII gene, immunohistochemical assay of TGF beta RII expression, methylation-specific PCR analysis, and semiquantitative reverse transcription-PCR. The PCR-denaturing gradient gel electrophoresis did not detect variation in the whole coding sequence of the TGF beta RII gene, but the immunohistochemistry experiment revealed reduced or lost expression of the gene in 44% (19 of 43) of the tumor samples. The methylation analysis on the 19 pairs detected the frequent occurrence of methylated TGF beta RII promoter in tumor tissues, whereas most of the paracarcinoma tissues were free of methylation. The reduced TGF beta RII expression was highly significantly associated with the methylation event (P < 10(-4)). The reverse transcription-PCR analysis demonstrated a clear agreement between reduced TGF beta RII expression and decreased mRNA level of the gene in the tumor tissue samples.

TGF beta RII plays an important role as a tumor suppressor in NSCLC carcinogenesis. The defective expression may serve as one of most important molecular mechanisms in explaining progression of the disease. In particular, aberrant 5' CpG methylation of the gene has explained the down-regulation of the gene at a transcriptional level.

Overactive bladder in diabetes: a peripheral or central mechanism?

To study diabetic cystopathy with reference to overactive bladder (OAB). We retrospectively analyzed diabetic cystopathy in our digitized database that comprised 2300 case records, including data from a lower urinary tract symptoms questionnaire, data from a urodynamic study, and data from neurological examinations. Diabetic cystopathy was seen in 4% of cases (84 cases): 58 males, 26 females; mean age, 60.8 years; duration of diabetes, 143.5 months; HbA1C, 7.7 %. In addition to large post-void residual and decreased sensation, OAB, detrusor overactivity (DO), and increased bladder sensation were seen in 55%, 42%, and 14%, respectively. The frequency of DO in patients with increased bladder sensation was 58%. DO increased with age, but not with the duration of diabetes. A brain MRI was performed in 32 cases. The frequency of multiple cerebral infarction (MCI) in patients with DO was 76.5%. The remaining 23.5% of patients with DO had no MCI, and the remaining 42% with increased bladder sensation had no DO.

OAB commonly occurs in diabetic cystopathy. Both central and peripheral mechanisms are involved, e.g., MCI due to diabetic cerebral vasculopathy for the DO, and, to a lesser extent, peripheral nerve irritation for the DO and increased bladder sensation.

Is circulating Lp-PLA2 associated with high valvuloarterial impedance and low arterial compliance in patients with aortic valve bioprostheses?

We previously reported that plasma Lp-PLA2 was associated with aortic valve disease progression and degeneration of bioprostheses. Low systemic arterial compliance and high valvuloarterial impedance (Z(va)) are predictors of poor survival in patients with aortic valve disease. However, the prevalence of high Z(va) after AVR is largely unknown and whether Lp-PLA2 could predict Z(va) has not been documented. We investigated the relationships between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity and valvuloarterial impedance (Z(va)), an index of global LV hemodynamic load, in patients that underwent aortic valve replacement (AVR). A total of 195 patients with aortic bioprostheses underwent echocardiographic assessment of the prosthetic aortic valve function 8±3.4 years after AVR. Lp-PLA2 mass and activity were measured. In this group of patients, the mean Z(va) was elevated (5.73±1.21 mm Hg·ml(-1)·m(2)). In univariate analyses, Lp-PLA2 mass (p=0.003) and Lp-PLA2 activity (p=0.046) were associated with Z(va). After adjustment for covariates including age, gender, clinical risk factors, anti-hypertensive medications, body mass index and prosthesis size, Lp-PLA2 mass was associated with high Z(va) (≥4.5 mm Hg·ml(-1)·m(2)) (OR: 1.29, 95%CI: 1.10-1.53; p=0.005) and was inversely related with the systemic arterial compliance (β=-0.01, SEM=0.003; p=0.003).

An increased Z(va), an index of excessive hemodynamic load, was highly prevalent 8-year post-AVR and was independently related to circulating Lp-PLA2.

Does up-regulation of calcitonin gene-related peptide protect streptozotocin-induced diabetic hearts from ischemia/reperfusion injury?

Diabetic hearts are vulnerable to ischemia/reperfusion (I/R) injury. Pretreatment with exogenous calcitonin gene-related peptide (CGRP) exerts a cardioprotective effect against myocardial I/R injury. Our previous study found that the CGRP level was decreased in diabetic hearts. This study aimed to investigate whether up-regulation of CGRP could reduce I/R injury in diabetic hearts. Adenovirus encoding the CGRP gene (Ad-CGRP) was injected intramyocardially in mice with or without streptozotocin (STZ) treatment. Three days after injection, the hearts were subjected to in vivo and in vitro I/R. Myocardial infarct size, cardiac function, lactate dehydrogenase (LDH) level in plasma and effluents, and cell mitochondrial function were measured. After ischemia (30 min) and reperfusion (24h) in vivo, diabetes mellitus (DM) mice had greater myocardial infarct size than their nondiabetic counterparts, and released more LDH in plasma. However, CGRP gene transfer reduced myocardial infarct size and plasma LDH level in both non-DM and DM hearts. After 30 min global ischemia and 40 min reperfusion in vitro, the DM hearts demonstrated increased left ventricular end-diastolic pressure (LVEDP) and effluent LDH level, and decreased left ventricular developed pressure (LVDP), coronary flow (CF), as well as cell mitochondrial function, when compared with the non-DM hearts. Again, CGRP gene transfer could protect against I/R injury in both non-DM and DM hearts.

Adenovirus-mediated up-regulation of CGRP gene expression protects diabetic hearts against I/R injury.

Do the influence of concomitant triceps surae lengthening at the time of total ankle arthroplasty on postoperative outcomes?

Concomitant procedures are being performed with total ankle replacement (TAR) to improve alignment, function, and mobility. The purpose of this study was to examine the differences in outcomes between patients who had a concomitant triceps surae lengthening (gastrocnemius recession [GSR] or triple hemisection [TAL]) versus a group that underwent TAR alone preoperatively and 1 year after TAR. For this prospective, nonrandomized study, 229 patients (37 GSR, 22 TAL, and 170 TAR alone) were examined. Patient-reported outcomes, physical performance, and lower extremity gait mechanics were completed preoperatively and 1 year postoperatively. A series of repeated measures ANOVAs were used to determine significant differences (P < .05), and Tukey's post hoc testing was used to follow any significant ANOVA results. No difference existed in BMI, age, gender, or dorsiflexion (DF) angle at heel strike between the triceps surae lengthening groups or between preoperative and 1 year following TAR. Walking speed, the physical performance measures, the AOFAS Hindfoot Score, SF-36, peak plantar flexion angle, and the peak plantar flexion moment were significantly improved (P < .001) postoperatively with no differences between the triceps surae lengthening groups. The peak DF angle (P = .006) and the ankle range of motion (P = .014) demonstrated a greater improvement from preoperative to 1 year postoperatively in the triceps surae lengthening groups in comparison to the TAR alone group.

Significant improvements existed between preoperative and 1 year postoperatively for most of the variables of interest independent of the triceps surae lengthening group. This study demonstrated that the use of a concomitant triceps surae lengthening procedure (GSR or TAL) resulted in equivalent outcomes when compared with a group undergoing TAR alone.

Does laryngeal mask airway insertion require less propofol than endotracheal intubation in dogs?

To compare the doses of propofol required for insertion of the laryngeal mask airway (LMA) with those for endotracheal intubation in sedated dogs. Randomized prospective clinical study. Animals Sixty healthy dogs aged 0.33-8.5 (3.0 +/- 2.3, mean +/- SD) years, weighing 2.2-59.0 (23.4 +/- 13.6, mean +/- SD) kg, presented for elective surgery requiring inhalation anaesthesia. Animals were randomly assigned to receive either a LMA or an endotracheal tube. Pre-anaesthetic medication was intravenous (IV) glycopyrrolate (0.01 mg kg(-1)) medetomidine (10 microg kg(-1)) and butorphanol (0.2 mg kg(-1)). Repeated IV propofol injections (1 mg kg(-1) in 30 seconds) were given until LMA insertion or endotracheal intubation was achieved, when the presence or absence of laryngospasm, the respiratory rate (fr) and the total dose of propofol used were recorded. The total propofol dose (mean +/- SD) required for LMA insertion (0.53 +/- 0.51 mg kg(-1)) was significantly lower than for endotracheal intubation (1.43 +/- 0.57 mg kg(-1)). The LMA could be inserted without propofol in 47% of dogs; the remainder needed a single 1 mg kg(-1) bolus (n = 30). Endotracheal intubation was possible without propofol in 3.3% of the dogs, 47% needed one bolus and 50% required two injections (n = 30). The f(r) (mean +/- SD) was 18 +/- 6 and 15 +/- 7 minute(-1) after LMA insertion and intubation, respectively.

Laryngeal mask airway insertion requires less propofol than endotracheal intubation in sedated dogs therefore propofol-induced cardiorespiratory depression is likely to be less severe. The LMA is well tolerated and offers a less invasive means of securing the upper airway.

Can bariatric surgery improve cardiovascular risk factors in the metabolically healthy but morbidly obese patient?

Bariatric surgery has been shown to be effective in resolving co-morbid conditions even in patients with a body mass index (BMI)<35 kg/m(2). A question arises regarding the metabolic benefits of bariatric surgery in metabolically healthy but morbidly obese (MHMO) patients, characterized by a low cardiometabolic risk. The objective of this study was to assess the effects of bariatric surgery on cardiometabolic risk factors among MHMO and metabolically unhealthy morbidly obese (MUMO) adults. A nonrandomized, prospective cohort study was conducted on 222 severely obese patients (BMI>40 kg/m(2)) undergoing either laparoscopic roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy. Patients were classified as MHMO if only 1 or no cardiometabolic factors were present: high blood pressure, triglycerides, blood glucose (or use of medication for any of these conditions), decreased high-density lipoprotein-cholesterol (HDL-C) levels, and insulin resistance defined as homeostasis model assessment for insulin-resistance (HOMA-IR)>3.29. Forty-two (18.9%) patients fulfilled the criteria for MHMO. They were younger and more frequently female than MUMO patients. No differences between groups were observed for weight, BMI, waist and hip circumference, total and LDL-C. MHMO patients showed a significant decrease in blood pressure, plasma glucose, HOMA-IR, total cholesterol, LDL-C and triglycerides and an increase in HDL-C 1 year after bariatric surgery. Weight loss 1 year after bariatric surgery was similar in both groups.

Eighteen percent of patients with morbid obesity fulfilled the criteria for MHMO. Although cardiovascular risk factors in these patients were within normal range, an improvement in all these factors was observed 1 year after bariatric surgery. Thus, from a metabolic point of view, MHMO patients benefited from bariatric surgery.

Does orphan receptor small heterodimer partner suppress tumorigenesis by modulating cyclin D1 expression and cellular proliferation?

The small heterodimer partner (SHP; NROB2), a member of the nuclear receptor superfamily, contributes to the biological regulation of several major functions of the liver. However, the role of SHP in cellular proliferation and tumorigenesis has not been investigated before. Here we report that SHP negatively regulates tumorigenesis both in vivo and in vitro. SHP-/- mice aged 12 to 15 months old developed spontaneous hepatocellular carcinoma, which was found to be strongly associated with enhanced hepatocyte proliferation and increased cyclin D1 expression. In contrast, overexpressing SHP in hepatocytes of SHP-transgenic mice reversed this effect. Embryonic fibroblasts lacking SHP showed enhanced proliferation and produced increased cyclin D1 messenger RNA and protein, and SHP was shown to be a direct negative regulator of cyclin D1 gene transcription. The immortal SHP-/- fibroblasts displayed characteristics of malignant transformed cells and formed tumors in nude mice.

These results provide first evidence that SHP plays tumor suppressor function by negatively regulating cellular growth.

Does [ Total saponins of Clematis inhibit JAK2/STAT3 signal pathway of adjuvant-induced arthritis rats ]?

To evaluate the effect of total saponins of Clematis (TSC) on Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signal transduction pathway in adjuvant-induced arthritis (AIA) rats and investigate the probable mechanisms. Sixty male SD rats were randomized divided into six groups: normal group, model control group, (50, 100, 200 mg/kg) TSC group, and tripterygium glycosides tablet (10 mg/kg) group (10 rats in each group). Except the normal group, AA models were induced with Freund's complete adjuvant. Twelve days after modeling, corresponding drugs were given to rats by intragastric administration, q.d, for 16 days. Then, the effects of drugs on the body mass and paw swelling of AA rats were observed, and ankle-joint samples were taken to examine the degree of AA by HE staining. Moreover, real-time fluorescent quantitative PCR was performed to detect the expressions of JAK2 and STAT3 mRNA, and Western blotting to determine the expression of p-JAK2, JAK2, p-STAT3, and STAT3 protein. Compared with the model group, TSC not only effectively alleviated the body mass loss and significantly inhibited paw swelling in AA rats, but also significantly inhibited inflammatory cell infiltration, pannus formation and tissue proliferation. Furthermore, TSC treatment obviously decreased mRNA expressions of JAK2 and STAT3 as well as the relative expressions of p-JAK2/JAK2 protein and p-STAT3/STAT3 protein in synovial tissues.

TSC can inhibit JAK2/STAT3 signal pathway by decreasing the expressions of JAK2 and STAT3 mRNA and the relative expressions of p-JAK2/JAK2 protein and p-STAT3/STAT3 protein of synovial tissues in AA rats.

Does decision tree modeling predict effects of inhibiting contractility signaling on cell motility?

Computational models of cell signaling networks typically are aimed at capturing dynamics of molecular components to derive quantitative insights from prior experimental data, and to make predictions concerning altered dynamics under different conditions. However, signaling network models have rarely been used to predict how cell phenotypic behaviors result from the integrated operation of these networks. We recently developed a decision tree model for how EGF-induced fibroblast cell motility across two-dimensional fibronectin-coated surfaces depends on the integrated activation status of five key signaling nodes, including a proximal regulator of transcellular contractile force generation, MLC (myosin light chain) [Hautaniemi et al, Bioinformatics 21: 2027 {2005}], but we have not previously attempted predictions of new experimental effects from this model. In this new work, we construct an improved decision tree model for the combined influence of EGF and fibronectin on fibroblast cell migration based on a wider spectrum of experimental protein signaling and cell motility measurements, and directly test a significant and non-intuitive a priori prediction for the outcome of a targeted molecular intervention into the signaling network: that partially reducing activation of MLC would increase cell motility on moderately adhesive surfaces. This prediction was indeed confirmed experimentally: partial inhibition of the activating MLC kinase (MLCK) upstream using the pharmacologic agent ML-7 resulted in increased motility of NR6 fibroblasts. We further extended this exciting finding by showing that partial reduction of MLC activation similarly enhanced the transmigration of the human breast carcinoma cell line MDA-213 through a Matrigel barrier.

These findings specifically highlight a central regulatory role for transcellular contractility in governing cell motility, while at the same time demonstrating the value of a decision tree approach to a systems "signal-response" model in discerning non-intuitive behavior arising from integrated operation a cell signaling network.

Is regional brain injury on conventional and diffusion weighted MRI associated with outcome after pediatric cardiac arrest?

To assess regional brain injury on magnetic resonance imaging (MRI) after pediatric cardiac arrest (CA) and to associate regional injury with patient outcome and effects of hypothermia therapy for neuroprotection. We performed a retrospective chart review with prospective imaging analysis. Children between 1 week and 17 years of age who had a brain MRI in the first 2 weeks after CA without other acute brain injury between 2002 and 2008 were included. Brain MRI (1.5 T General Electric, Milwaukee, WI, USA) images were analyzed by 2 blinded neuroradiologists with adjudication; images were visually graded. Brain lobes, basal ganglia, thalamus, brain stem, and cerebellum were analyzed using T1, T2, and diffusion-weighted images (DWI). We examined 28 subjects with median age 1.9 years (IQR 0.4-13.0) and 19 (68 %) males. Increased intensity on T2 in the basal ganglia and restricted diffusion in the brain lobes were associated with unfavorable outcome (all P < 0.05). Therapeutic hypothermia had no effect on regional brain injury. Repeat brain MRI was infrequently performed but demonstrated evolution of lesions.

Children with lesions in the basal ganglia on conventional MRI and brain lobes on DWI within the first 2 weeks after CA represent a group with increased risk of poor outcome. These findings may be important for developing neuroprotective strategies based on regional brain injury and for evaluating response to therapy in interventional clinical trials.

Is plasma adiponectin a more specific marker of fatty liver than a marker of metabolic syndrome in Japanese men?

The association of plasma cardiovascular risk markers and metabolic syndrome (MetS) with non-alcoholic fatty liver disease (NAFLD) has not been well defined. Japanese men (n = 809) had standard anthropometric measurements done, and had their liver fat quantitated by ultrasound. Three groups were identified: (1) normal controls without significant disease, (2) preliminary-metabolic syndrome (pre-MetS) cases and (3) MetS cases. Plasma adiponectin, high sensitivity-C reactive protein (hs-CRP), HOMA-IR, lipids, lipoproteins and liver enzymes were evaluated among the three groups. The prevalence of fatty liver was 13% in controls, 39% in pre-MetS and 62% in MetS. Plasma adiponectin and high density lipoprotein cholesterol (HDL-C) were significantly decreased, and HOMA-IR, hs-CRP, TG, remnant lipoproteins (RLPs) and small dense-LDL-C (sd LDL-C) were significantly increased in subjects with fatty liver compared to those without fatty liver. Multivariate analyses of serum parameters associated with fatty liver revealed that adiponectin and hs-CRP were more strongly associated with the presence of fatty liver than waist circumference. However, HOMA-IR, HDL-C, TG, RLP-C, RLP-TG and sd LDL-C were more strongly associated with waist circumference than with fatty liver. Factor analysis revealed that adiponectin and HDL-C were linked to liver enzymes, lipoproteins and HOMA-IR associated with fatty liver, but not with waist circumference.

Adiponectin was found to be a more specific diagnostic marker for the presence of fatty liver regardless of MetS status, and was inversely correlated with liver enzyme concentrations. However, RLPs were found to be more specifically associated with the presence of MetS.

Is gravitational venous drainage significantly faster in patients with varicose veins?

It has been proposed that varicose veins may be caused by a degree of impeded proximal venous drainage (pelvic venous obstruction) in the same way that biological tubes dilate in response to an obstruction. The venous drainage index (VDI) of air-plethysmography (APG) was used to test this hypothesis. A dependency to elevation manoeuvre was used to provoke gravitational venous drainage. A rapid reduction in calf volume implied good drainage. This was a single centre, proof-of-concept study comparing gravitational venous drainage in varicose vein patients and controls. Leg filling and drainage manoeuvres (elevation to dependency and dependency to elevation) were performed three times per leg in 15 patients (7 male, 8 right) and 16 controls (3 male, 8 right). The VDI was measured in the same way the established venous filling index (VFI) is calculated to quantify filling: VDI = 90% of venous drainage volume (90VDV)/90% venous drainage time (VDT90). The patients were significantly older at 58 (41-75) years versus the controls 47 (18-58), p = 0.001. There was no significant difference between the groups in weight, height, BMI or common femoral vein diameter. The patients were (C2 = 8; C3 = 1, C4 = 6), VCSS 4 (1-11) with a median refluxing proximal thigh saphenous diameter of 6 (5-11) mm. The median (inter-quartile range) VFI and VDI (both in mL/s) in the control tests (n = 48) were 1.3 (0.9-1.9) and 33.8 (21.5-55), respectively. The VFI and VDI in the patient tests (n = 41) were significantly faster at 6.2 (3.5-9.4), p < 0.0005, and 47.1 (36.1-66.3), p = 0.002, respectively. Adjusted to a standard mean for each leg, the reproducibility limits (×3) of the VDI was very good at 39.7 (95% CI: 36.5-42.9) in controls and 52.9 (95% CI: 49.7-56.1) in patients.

The VDI was significantly greater in patients with varicose veins compared to controls. It is unlikely that impeded gravitational drainage is a significant factor in the pathophysiology of varicose veins.

Do polystyrene nanoparticles activate ion transport in human airway epithelial cells?

Over the last decade, nanotechnology has provided researchers with new nanometer materials, such as nanoparticles, which have the potential to provide new therapies for many lung diseases. In this study, we investigated the acute effects of polystyrene nanoparticles on epithelial ion channel function. Human submucosal Calu-3 cells that express cystic fibrosis transmembrane conductance regulator (CFTR) and baby hamster kidney cells engineered to express the wild-type CFTR gene were used to investigate the actions of negatively charged 20 nm polystyrene nanoparticles on short-circuit current in Calu-3 cells by Ussing chamber and single CFTR Clchannels alone and in the presence of known CFTR channel activators by using baby hamster kidney cell patches. Polystyrene nanoparticles caused sustained, repeatable, and concentration-dependent increases in short-circuit current. In turn, these short-circuit current responses were found to be biphasic in nature, ie, an initial peak followed by a plateau. EC(50) values for peak and plateau short-circuit current responses were 1457 and 315.5 ng/mL, respectively. Short-circuit current was inhibited by diphenylamine-2-carboxylate, a CFTR Cl(-) channel blocker. Polystyrene nanoparticles activated basolateral K(+) channels and affected Cl(-) and HCO(3) (-) secretion. The mechanism of short-circuit current activation by polystyrene nanoparticles was found to be largely dependent on calcium-dependent and cyclic nucleotide-dependent phosphorylation of CFTR Cl(-) channels. Recordings from isolated inside-out patches using baby hamster kidney cells confirmed the direct activation of CFTR Cl(-) channels by the nanoparticles.

This is the first study to identify the activation of ion channels in airway cells after exposure to polystyrene-based nanomaterials. Thus, polystyrene nanoparticles cannot be considered as a simple neutral vehicle for drug delivery for the treatment of lung diseases, due to the fact that they may have the ability to affect epithelial cell function and physiological processes on their own.

Is number of supernumerary vitrified blastocysts positively correlated with implantation and live birth in single-blastocyst embryo transfers?

To estimate whether live birth in single-blastocyst transfers is correlated with the number of sibling supernumerary vitrified blastocysts (embryos not transferred) generated from that same cycle. Retrospective cohort study. A large academic assisted reproduction clinic. All single-blastocyst transfers in 2010 graded as "good" embryos by Society for Assisted Reproductive Technologies (SART) criteria. None. Implantation and live birth. Of the 655 single-blastocyst transfers that met inclusion criteria, implantation occurred in 65% and live birth in 54% of cycles. In chi-square analysis, patients with supernumerary vitrified blastocysts had a statistically higher implantation rate (65% versus 50%) and live-birth rate (56% versus 41%) when compared with patients without supernumerary blastocysts. Univariate logistic regression demonstrated an increase in implantation (OR 1.09; 95% CI, 1.03-1.15) and live birth (OR 1.06; 95% CI, 1.02-1.09) with increasing number of supernumerary blastocysts. Multivariate logistic regression analysis demonstrated that patient age and the number of supernumerary blastocysts were statistically significantly associated with implantation and live birth.

The number of supernumerary vitrified blastocysts correlated positively with the odds of implantation and live birth in good quality single-blastocyst transfers. Patients with supernumerary blastocysts are good candidates for single-embryo transfer.

Does exogenous phosphatidylethanolamine induce apoptosis of human hepatoma HepG2 cells via the bcl-2/Bax pathway?

To investigate the signaling pathways implicated in phosphatidylethanolamine (PE)-induced apoptosis of human hepatoma HepG2 cells. Inhibitory effects of PE on human hepatoma HepG2 cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle, apoptosis and mitochondrial transmembrane potential (DeltaPsi m) were analyzed by flow cytometry. Immunocytochemical assay and Western blotting were used to examine Bcl-2, Bax and caspase-3 protein levels in HepG2 cells treated with PE. PE inhibited the growth of HepG2 cells in a dose- and time- dependent manner. It did not affect the cell cycle, but induced apoptosis. PE significantly decreased DeltaPsi m at 0.25, 0.5 and 1 mmol/L, respectively, suggesting that PE induces cell apoptosis by decreasing the mitochondrial transmembrane potential. The Bcl-2 expression level induced by different concentrations of PE was lower than that in control groups. However, the Bax expression level induced by PE was higher than that in the control group. Meanwhile, PE increased the caspase-3 expression in a dose- and time-dependent manner.

Exogenous PE induces apoptosis of human hepatoma HepG2 cells via the bcl-2/bax pathway.

Does cold cardioplegic arrest enhance heat shock protein 70 in the heat-shocked rat heart?

Myocardial content of the 70-kd heat shock protein has been found to correlate with improved cardiac recovery after ischemia, but the mechanisms and conditions that regulate its level, particularly under clinical conditions, are unclear. The aim of this study was to assess the effect of hypothermic cardioplegic arrest and reperfusion on the expression of 70-kd heat shock protein in a protocol mimicking conditions of preservation for cardiac transplantation. Heat-shocked and control hearts were subjected to 4 hours of cardioplegic arrest and global ischemia at 4 degrees C and then to 20 minutes of reperfusion. Hearts were freeze clamped at different time points-after 15 minutes of Langendorff perfusion, at the end of ischemia, and after 20 minutes of reperfusion, and analyzed for heat shock protein 70 content by Western blotting. Another set of hearts was subjected to 10 minutes of normothermic ischemia and 20 minutes of reperfusion followed by freeze clamping and analysis of heat shock protein 70 content as in cardioplegic arrest protocol. Cardiac function was measured by means of a left ventricular balloon at the end of reperfusion. Preischemic concentration of 70-kd heat shock protein was increased in heat-shocked hearts compared with control hearts. The content of 70-kd heat shock protein in heat-shocked hearts was further increased from 5.0 +/- 2.4 ng/microg at the end of ischemia to 11.0 +/- 4.9 ng/microg (n = 8, mean +/- SD; P <.05) at 20 minutes of reperfusion after cold cardioplegic arrest. No further rise in 70-kd heat shock protein of the heat-shocked hearts was observed after normothermic ischemia. Maximal developed pressure was 120.8 +/- 13.4 mm Hg in control hearts compared with 164.7 +/- 22.5 mm Hg in heat-shocked hearts (n = 5, mean +/- SD; P =.037) after cardioplegic arrest. By contrast, after normothermic ischemia, maximum developed pressure was 111.2 +/- 10.9 mm Hg in control hearts compared with 139.2 +/- 11.0 mm Hg in heat-shocked hearts (n = 4, mean +/- SD; P =.031).

Hypothermic cardioplegic arrest but not short normothermic ischemia triggered a further increase in the level of 70-kd heat shock protein in heat-shocked rat hearts, which may enhance endogenous cardiac protection.

Does gatekeeping control costs for privately insured children?

Gatekeeping requirements were widely adopted by health insurers in an attempt to control costs in the mid-1990s, but empirical evidence demonstrating decreased health expenditures for children enrolled in such plans is lacking. We analyzed data from 3254 children with private health insurance sampled in the 1996 Medical Expenditure Panel Survey (MEPS) to compare total per capita health expenditures among gatekeeping versus indemnity plan enrollees. This sample represents 40.4 million privately insured American children. Total expenditures were defined as payments from all sources, including third-party and out-of-pocket payments, but excluding administrative costs. MEPS data are based on information provided by patients, health care providers, and hospitals. Gatekeeping plans included all children enrolled in health maintenance organizations or other plans requiring a primary care gatekeeper. All others were considered indemnity plan enrollees. Mean total per capita annual expenditures for children in gatekeeping versus indemnity plans differed by<1% (887 dollars vs 881 dollars, respectively). Third-party payments by gatekeeping plans on behalf of their beneficiaries were 636 dollars versus 595 dollars by indemnity plans. Out-of-pocket payments were on average 62 dollars less for gatekeeping enrollees than for indemnity enrollees. After multivariate adjustment, mean per capita expenditures were approximately 4% lower for gatekeeping enrollees than for indemnity enrollees.

In 1996, total per capita annual health expenditures for children in gatekeeping plans were approximately 8 dollars less than for those in indemnity plans. These data indicate that gatekeeping is not an effective cost-containment method for children.

Are previous treatment interruptions associated with higher viral rebound rates in patients with viral suppression?

We investigated whether previous treatment interruptions are associated with a raised risk of viral rebound in individuals who have attained virological suppression. All patients achieving an undetectable viral load while on therapy were followed until viral rebound or the time of the last viral load. Poisson regression was used to describe the independent impact of treatment interruptions on rebound rates. A total of 12,977 patients from the United Kingdom Collaborative HIV Cohort (UK CHIC) Study achieved a viral load of less than 50 copies/ml. These patients contributed a total of 37,314 person-years of follow-up. The overall rebound rate was 8.07 (7.78, 8.36) per 100 person-years. In adjusted analyses, rates of viral rebound were up to 64% higher (rate ratio 1.64; 1.43, 1.88) in those who had previously interrupted therapy compared with those who had not. Patients who had interrupted at detectable viral loads had up to a 74% (1.74; 1.42, 2.14) higher chance of rebounding compared with those who had not interrupted with a detectable viral load. We found no evidence to suggest interrupting treatment at an undetectable viral load was associated with viral rebound.

Among patients with an undetectable viral load, having previously interrupted therapy while the viral load was detectable is associated with a raised risk of rebound.

Does transplantation of cryopreserved human ovarian tissue result in follicle growth initiation in SCID mice?

To determine the long-term survival of frozen-thawed human ovarian tissue as xenografts in severe-combined-immunodeficiency (SCID) mice. Animal study. Animal and laboratory facilities at an academic center. Ovarian tissue obtained from a 27-year-old woman. Grafting of frozen-thawed ovarian tissue in SCID mice for 22 weeks. Follicle counts and growth by morphology and PCNA staining in frozen-thawed grafts and fresh controls. All three grafts were recovered intact after 22 weeks. Their stroma was devoid of necrotic cells and contained healthy follicles. The ratio of primordial-total follicles decreased significantly after grafting (0.94 +/- 0.02 to 0.87 +/- 0. 01, control vs. grafting). Compared with controls, after 22 weeks of grafting, a higher percentage of follicles had initiated growth (5.6 +/- 2.4 vs. 12.5 +/- 1.9), but there was still a significant number of primordial follicles/graft (75 +/- 6.8). Follicle stages were similar between two groups; only primordial and one-layer follicles were seen in the xenografts. In the controls, except for one two-layer follicle, the most advanced follicle was at the one-layer stage.

Human primordial follicles survive freeze-thaw and long-term xenografting procedures and retain their capacity to initiate growth. These findings encourage future attempts for human autologous ovarian transplantation.

Does activation of serotonin 5-HT2A receptors inhibit high compulsive drinking on schedule-induced polydipsia?

Schedule-induced polydipsia (SIP) is an established model for studying compulsive behaviour in rats. Serotoninergic drugs effectively reduce compulsive drinking on SIP, and high compulsive drinker rats selected by SIP have shown differences in serotoninergic brain activity. However, the specific serotoninergic receptors that modulate compulsive SIP remain unclear. We investigated the functional role of serotonin 5-hydroxytryptamine 2A or C (5-HT2A/C) receptors in compulsive SIP behaviour. Rats were selected for low (LD) versus high drinking (HD) behaviour on SIP. The effects of the systemic administration of the selective serotonin reuptake inhibitor citalopram, selective norepinephrine reuptake inhibitor atomoxetine, serotonin 5-HT2A/C receptor agonist DOI hydrochloride ((±)-2,5-dimethoxy-4-iodoamphetamine), serotonin 5-HT2C receptor antagonist SB242084, serotonin 5-HT2A receptor antagonist ketanserin and M100907 were assessed on SIP. Subsequently, the effects of DOI were tested after the pre-administration of SB242084, ketanserin and M100907 on SIP. Citalopram and DOI reduced compulsive drinking in HD compared with LD rats on SIP. In contrast, SB242084 increased compulsive drinking in HD compared with LD rats on SIP. Atomoxetine, ketanserin and M100907 had no effect on SIP. The reduction in water intake produced by DOI was blocked by ketanserin and M100907, but not by SB242084 administration, in HD rats.

These findings highlight the contribution of serotoninergic 5-HT2A/C receptors compared with noradrenergic mechanisms on SIP and reveal the "therapeutic" activation of serotonin 5-HT2A in the inhibition of the compulsive drinking behaviour in HD rats. Thus, it may represent a potentially new marker of vulnerability and provides additional insight for potential treatments on compulsive behaviours in neuropsychiatric populations.

Is aberrant obturator artery a common arterial variant that may be a source of unidentified hemorrhage in pelvic fracture patients?

Similar to all pelvic arteries, the aberrant obturator artery (AOA) and its branches are at risk for injury when the pelvic ring is fractured; however, because of its unique origin, bleeding from this artery may be unrecognized and, thus, treatment ineffective. The purpose of this study was to describe the incidence of the AOA using angiography and determine the sensitivity of 64-slice computed tomography angiography (CTA) at identifying the AOA. Imaging from patients undergoing pelvic angiography, for any reason, during 2009 was retrospectively reviewed to determine the incidence of the AOA. The angiographically determined arterial anatomy was the compared with CTA findings. Pelvic angiography, performed in 174 patients, identified the AOA in 60.0% of males, 52.3% of females, 55.1% of all patients, and 38.4% of hemipelvises. The sensitivity/specificity of CTA at identifying the AOA is 90.0%/100% and 63.6%/92.3% in nonpelvic fracture and pelvic fracture patients, respectively; the sensitivity difference being significant (p=0.0351). Three of the 13 (23.1%) AOA identified in pelvic fracture patients demonstrated extravasation when the inferior epigastric artery was cannulated; however, flush angiography failed to demonstrate the extravasation.

The AOA is a common arterial variant occurring in more than half of the population and, if present in pelvic fracture patients, commonly injured. Although CTA is effective at identifying the AOA in nonpelvic trauma patients, it is not as effective in pelvic fracture patients. Failure to consider this arterial variant may result in untreated arterial bleeding with the attendant consequences.

Does chondrocalcinosis affect Knee Society scores and range of motion after TKA?

Chondrocalcinosis is manifested by crystalline deposits of calcium commonly found during primary TKA for osteoarthritis. Its frequency among patients undergoing TKA is poorly defined, as is its influence on pain or function after TKA.QUESTIONS/ The purposes of this study are to (1) determine the prevalence of chondrocalcinosis in patients undergoing TKA for osteoarthritis; (2) evaluate the effect of chondrocalcinosis on ROM and The Knee Society scores; (3) determine if patients with chondrocalcinosis and severe synovitis who underwent synovectomy are at risk for lower postoperative Knee Society scores and less ROM; and (4) assess if chondrocalcinosis is associated with increased rates of revision surgery. We retrospectively reviewed the medical records of 1500 primary TKAs performed by one surgeon. The minimum followup for patients was 24 months (average, 57 months; range, 24-120 months). There were 511 men and 934 women with an average age of 70 years. Fifty-five patients underwent bilateral knee replacements. Crystal deposition was graded prospectively during surgery using a subjective visual scale. A thorough synovectomy was performed on patients with severe synovitis and apparent crystalline deposition suggestive of calcium pyrophosphate dihydrate (CPPD) deposition (n = 50). The Knee Society scores, ROM, and revision rates were compared between patients with visible chondrocalcinosis with those without and between patients with mild chondrocalcinosis with those with severe chondrocalcinosis. Chondrocalcinosis was found in 173 male patients (34%) undergoing TKAs during this period compared with 224 female patients (24%) (p < 0.001). The Knee Society scores for knee rating and function were similar in patients with or without chondrocalcinosis undergoing TKA. However, patients with visible CPPD deposition who underwent synovectomy for proliferative synovitis had diminished final ROM and Knee Society knee rating scores (107(o) versus 115(o) knee flexion, p < 0.001 and 87 versus 94 points, p = 0.001). We cannot determine whether this result is because of the synovectomy or severity of the disease, and therefore we cannot recommend a synovectomy at this time. Revision rates were no different among patients with chondrocalcinosis compared with those without it (3.6% versus 2.2%, p = 0.2).

Chondrocalcinosis is common among patients undergoing TKA for osteoarthritis. The presence of CPPD deposition does not appear to affect the ROM and Knee Society scores of patients with CPPD but without severe synovitis. However, patients with severe synovitis and visible CPPD who underwent thorough synovectomy may be at risk for having decreased postoperative ROM and pain develop.

Is haemostasis biological screening always useful before performing a neuraxial blockade in children?

Because of the lack of controlled studies, there is no consensus of opinion about the practice of routine haemostasis tests before neuraxial blockade in children. The purpose of this study was to compare the influence of two different strategies of coagulation evaluation on the incidence of diagnosed coagulopathies leading to a modification of the preoperative or anaesthetic management in children who were scheduled for caudal, epidural or intrathecal block. For a 24-month period (period 1, retrospective study, n=751), haemostasis screening was undertaken only after family and personal history and physical examination in all patients. For the following 24 months (period 2, prospective study, n=958), a standardized questionnaire was used. In addition, routine tests (prothrombin, partial thromboplastin time, platelet count) were performed in children who where not yet walking. In older children, coagulation tests were undertaken as in period 1. Overall, 26 significant abnormalities were diagnosed. Coagulation tests were performed in 16.2% (period 1) and 78.2% (period 2) of the children, who were not yet walking. Routine tests did not improve the diagnosis of haemostasis abnormalities justifying a modification of the preoperative and anaesthetic management (2.2% from 406 children in period 1 vs 4.1% from 266 children in period 2). The predictive positive value of routine tests (period 2) was 19%, vs 45% for specific tests (period 1) (P<0.001). In older children, the use of a standardized form increased the number of haemostasis screenings without improvement of diagnosis leading to modified preoperative management (0.3% from 315 children in period 1 vs 0.5% from 628 children in period 2).

When routine testing is performed in nonwalking children, the screening number increases without leading to a higher number of anaesthetic management changes, suggesting that routine testing does not seem to provide much extra information in the absence of a positive history.

Is an imbalance between physical capacity and exposure to work-related physical factors associated with low-back, neck or shoulder pain?

This study investigates whether an imbalance between physical capacity and exposure to work-related physical factors is associated with low-back, neck, or shoulder pain. Data of the longitudinal study on musculoskeletal disorders, absenteeism, stress, and health (SMASH), with a follow-up of 3 years (N=1789), were used. At baseline, physical capacity (isokinetic lifting strength, static muscle endurance, and mobility of the spine) and exposure to work-related physical factors were assessed. During the follow-up, low-back, neck, and shoulder pain were self-reported annually. "Imbalance" was defined as lower than median capacity combined with higher than median exposure, "high balance" was high capacity and high exposure, and "low balance" was low capacity and low exposure. For both the low-back and neck, imbalance between static endurance and working with flexed postures was a risk factor for pain [relative risk (RR) 1.35, 95% confidence interval (95% CI) 1.08-1.68, and RR 1.36, 95% CI 0.96-1.91, respectively]. Low balance was also associated with low-back pain (RR 1.29, 95% CI 1.04-1.68). Furthermore, low balance between isokinetic lifting strength and lifting exposure was a risk factor for low-back and neck pain [RR between 1.22 (95% CI 0.99-1.49) and 1.35 (95% CI 1.03-1.79)]. No associations were found with shoulder pain.

Some relationship between low-back and neck pain and combined measures of physical capacity with exposure to work-related physical factors seems to exist, but an imbalance between physical capacity and exposure was not found to yield higher risks than high balance or low balance.

Hospital discharge in the day following open Roux-en-Y gastric bypass: is it feasible and safe?

Roux-en-Y gastric bypass (RYGBP) either laparoscopic or open has been increasingly employed in the treatment of patients with morbid obesity. Laparoscopic approach is believed to be superior over open approach in terms of shorter hospital stay and easier recovery. We aimed to assess feasibility and safety of open RYGBP with short stay in comparison with laparoscopic RYGBP. One hundred and ninety consecutive patients were assigned to open (n=103) or laparoscopic (n=87) RYGBP. The first 20 patients of the laparoscopic arm were excluded due to procedure learning curve. Patients were treated by a multidisciplinary team focused on successfully RYGBP with short stay (1 day). Short stay was reached by 90% of patients operated with open approach and 81% by laparoscopy (P=0.070). Discharge in the second day was reached by 97% of patients in both groups. Procedure length [(median (IQR)] was faster for open RYGBP [103 (70-180 min) vs. 169 (105-248 min); P<0.0001]. Thirty-day readmission rate was similar between groups (3% vs. 7%; P=0.266). There was no death in either group.

Short stay (1 day) following open gastric bypass was a feasible and safe procedure. This approach might have economic impact and might increase patient acceptance for open RYGBP.

Does broader autism phenotype in mothers predict social responsiveness in young children with autism spectrum disorders?

The aim of this study was to identify phenotypes in mothers and fathers that are specifically associated with disturbances in reciprocal social interactions and communication in their young children with autism spectrum disorder (ASD) in a Japanese sample. Autistic traits in parents were evaluated using the Autism-spectrum Quotient (AQ), the Empathy Quotient (EQ) and the Systemizing Quotient (SQ) in 88 parents (44 mothers and corresponding fathers) of children with ASD and in 60 parents (30 mothers and corresponding fathers) of typically developing (TD) children. For the measurement of autistic traits in children, we employed the Social Responsiveness Scale (SRS). In two of the five AQ subscales (social skills and communication), the parents of ASD children scored significantly higher than did the parents of TD children, regardless of whether the parent was a mother or a father. In addition, in mothers of ASD children, there were significant positive correlations between two of the five AQ subscales (attention-switching and communication) and the SRS T-score in their children.

This is the first study to demonstrate that the social skills and communication subscales in the AQ are more sensitive as autism traits in a Japanese sample and to demonstrate that some autistic traits in mothers are specifically associated with disturbances in the social ability of their young children with ASD, as measured by the SRS score. Further study is necessary to determine whether these results were caused by genetic or environmental factors.

Is sacral nerve stimulation a valid approach in fecal incontinence due to sphincter lesions when compared to sphincter repair?

Anal sphincter lesions represent the major cause of fecal incontinence, particularly in women. Sphincteroplasty with overlap is the traditional treatment, but a significant reduction in benefits within 5 years of surgery has been reported. More recently, sacral nerve stimulation has been suggested following sphincteroplasty or as primary treatment. Overall, 24 women with fecal incontinence in the presence of anal sphincter lesions underwent sphincteroplasty (14 patients, mean age 47.6 +/- 15.6 years, range 26-70) or definitive implant of sacral nerve stimulation (10 patients, mean age 60.7 +/- 17.6 years, range 26-73), using identical selection criteria. At baseline, patients were studied with clinical evaluation, 3-dimensional endoanal ultrasound, and anorectal manometry (ARM), repeated at follow-up (median 60.0 months, range 6-96 in sphincteroplasty group; median 33.0 months, range 6-84 in sacral nerve stimulation group). At baseline, both groups presented similar characteristics. Two sphincteroplasty patients (14.3%) experienced relapse of fecal incontinence at 6 and 19 months after treatment, whereas good to excellent continence was observed in all of the sacral nerve stimulation patients. Compared to baseline, both groups showed a significant improvement in clinical parameters, and ARM data remained unchanged. In 12 of 14 sphincteroplasty patients, the repaired sphincter at endoanal ultrasound was found to overlap. At follow-up, comparison between sphincteroplasty and sacral nerve stimulation showed no significant differences in clinical and ARM parameters, if related to lesion of internal, external, or both sphincters.

These data appear to confirm that sacral nerve stimulation could represent a valid alternative in the treatment of fecal incontinence patients presenting with sphincter lesion that was not preceded by sphincteroplasty.

Is hypoalbuminemia at admission associated with increased incidence of in-hospital complications in geriatric trauma patients?

Elderly patients are at an increased risk of protein-energy malnutrition (PEM) which increases the risk of morbidity/mortality. We evaluated the association between hypoalbuminemia at the time of emergency department (ED) admission and in-hospital complications among geriatric trauma patients. This was an ambidirectional cohort study of geriatric (≥55 years) trauma patients treated at a Level I trauma center between May 2013 and March 2014. The exposure of interest was albumin level at ED admission (<3.6 g/dL [PEM] or ≥3.6 g/dL (No PEM)]. The outcome of interest was 30-day incidence of complications. A total of 130 patients met study eligibility. Of these, 85 (65%) patients were in the PEM group. After adjusting for tube feeding and injury severity score, PEM at admission was associated with a 2-fold increase in the risk of 30-day overall hospital complications (hazard ratio 2.1, 95% confidence interval 1.1 to 3.8).

Serum albumin level at ED admission, but not prealbumin level, is a significant predictor of in-hospital complications in geriatric trauma patients.

Is expression of hNP22 altered in the frontal cortex and hippocampus of the alcoholic human brain?

Human neuronal protein (hNP22) is a gene with elevated messenger RNA expression in the prefrontal cortex of the human alcoholic brain. hNP22 has high homology with a rat protein (rNP22). These proteins also share homology with a number of cytoskeleton-interacting proteins. A rabbit polyclonal antibody to an 18-amino acid epitope was produced for use in Western and immunohistochemical analysis. Samples from the human frontal and motor cortices were used for Western blots (n = 10), whereas a different group of frontal cortex and hippocampal samples were obtained for immunohistochemistry (n = 12). The hNP22 antibody detected a single protein in both rat and human brain. Western blots revealed a significant increase in hNP22 protein levels in the frontal cortex but not the motor cortex of alcoholic cases. Immunohistochemical studies confirmed the increased hNP22 protein expression in all cortical layers. This is consistent with results previously obtained using Northern analysis. Immunohistochemical analysis also revealed a significant increase of hNP22 immunoreactivity in the CA3 and CA4 but not other regions of the hippocampus.

It is possible that this protein may play a role in the morphological or plastic changes observed after chronic alcohol exposure and withdrawal, either as a cytoskeleton-interacting protein or as a signaling molecule.

Is iL-8 an angiogenic factor in human coronary atherectomy tissue?

Interleukin-8 (IL-8), a CXC chemokine that induces the migration and proliferation of endothelial cells and smooth muscle cells, is a potent angiogenic factor that may play a role in atherosclerosis. Previously, IL-8 has been reported in atherosclerotic lesions and circulating macrophages from patients with atherosclerosis. Therefore, we sought to determine whether IL-8 plays a role in mediating angiogenic activity in atherosclerosis. Homogenates from 16 patients undergoing directional coronary atherectomy (DCA) and control samples from the internal mammary artery (IMA) of 7 patients undergoing bypass graft surgery were assessed for IL-8 content by specific ELISA, immunohistochemistry, and in situ hybridization for IL-8 mRNA. The contribution of IL-8 to net angiogenic activity was assessed using the rat cornea micropocket assay and cultured cells. IL-8 expression was significantly elevated in DCA samples compared with IMA samples (1.71+/-0.6 versus 0.05+/-0.03 ng/mg of total protein; P<0.01). Positive immunolocalization of IL-8 was found exclusively in DCA tissue sections, and it correlated with the presence of factor VIII-related antigen. In situ reverse transcriptase polymerase chain reaction revealed the expression of IL-8 mRNA in DCA tissue. Corneal neovascular response, defined by ingrowth of capillary sprouts toward the implant, was markedly positive with DCA pellets, but no constitutive vessel ingrowth was seen with IMA specimens. Neutralizing IL-8 attenuated both the in vivo corneal neovascular response and the in vitro proliferation of cultured cells.

The results suggest that, in human coronary atherosclerosis, IL-8 is an important mediator of angiogenesis and may contribute to plaque formation via its angiogenic properties.

Does gABAergic system gene expression predict clinical outcome in patients with neuroblastoma?

Neuroblastoma (NB) is a common childhood malignancy characterized by heterogeneous clinical behavior. The purpose of this study was to identify potential NB biomarkers that may improve outcome prediction. The suppression subtractive hybridization (SSH) technique was used to identify the genes differentially expressed between NB and control tissue. RNA isolated from 235 primary NB tumor samples obtained from the Children's Cancer Group was evaluated for expression of the candidate markers using quantitative reverse transcriptase polymerase chain reaction (Taqman assays). The association between the mRNA expression levels in the identified candidate genes and clinical outcome was evaluated. SSH analysis identified differential expression of members of the GABAergic gene family in NB. Lower levels of gamma-aminobutyric acid (GABA) receptor-associated protein (GABARAP) gene expression predict decreased survival among all patients. GABA(A) delta receptor subunit gene expression was predictive of a poor outcome among Evans stage IV-S patients. An index of five coexpressed GABA(A) receptor subunits was identified (GABA(A) profile [GAP score]). Patients with a higher GAP score (> -1) had a survival advantage. Multivariate analysis showed that GABARAP and GABA(A) alpha2 receptor subunit gene expression levels and GAP score remained predictors of clinical outcome after accounting for current prognostic indicators.

Dysregulation of the GABAergic system may constitute a fundamental event in the development of NB, and assessment of GABAergic system gene expression could provide improved patient stratification and potential new therapies.

Does transcutaneous iontophoresis of methadone provoke local flushing and thermal hyperalgesia?

To investigate whether the introduction of methadone into the skin of the human forearm produces wheals, cutaneous vasodilatation or thermal hyperalgesia and, if so, to determine whether these responses are mediated by opioid receptors. Healthy adults. In Experiment 1 (N = 11), the increase in local blood flow (monitored with a laser Doppler flowmeter) was greater after the iontophoresis of methadone than saline (mean increase +/- S.D. 12.6 +/- 8.8 versus 2.2 +/- 1.9 times greater than baseline, p < 0.01). Flushing did not spread into surrounding skin and wheals did not form. In Experiment 2, pre-treatment with naloxone (N = 12) prevented increases in blood flow to methadone whereas saline pre-treatment (N = 14) did not. The heat pain threshold was lower at the site of methadone administration than at an untreated site (42.8 +/- 2.3 degrees C versus 44.6 +/- 1.7 degrees C, p < 0.001), and this effect was inhibited by naloxone pre-treatment. However, naloxone pre-treatment also antagonized an inhibitory effect of methadone on the pain generated by a 7-second pulse of 45 degrees C heat. In Experiment 3 (N = 11), the iontophoresis of methadone was repeated after an interval of 1.5 h. Vasodilatation to methadone persisted after the second iontophoresis, and sensitivity to heat was greater at a site of methadone administration than at a site of saline administration or an untreated control site.

Stimulation of mu-opioid receptors dilated cutaneous blood vessels, and evoked local thermal analgesia and hyperalgesia at different stimulus intensities. However, stimulation of mu-opioid receptors did not produce wheals or flares.

Is gram-negative bacterial carriage in chronic rhinosinusitis with nasal polyposis associated with more severe inflammation?

We have previously demonstrated that persistent symptoms following functional endoscopic sinus surgery for chronic rhinosinusitis (CRS) is associated with Gram-negative bacterial carriage. Mechanisms for this remain unknown. We wished to determine whether Gram-negative carriage in patients with CRS with nasal polyposis is associated with a more severe inflammatory phenomenon. Three hundred and thirty-seven patients with CRS with nasal polyposis (CRSwNP) previously phenotyped for genetic association studies with questionnaire, serum biomarkers, and endoscopically-obtained swab cultures were studied. These were separated according to the presence (wGN) or absence (sGN) of Gram-negative bacterial carriage; demographic parameters and available serum biomarkers (complete blood count [CBC], total immunoglobulin E [IgE]) were then compared. Subgroup analysis for Pseudomonas aeruginosa (GNwPa) and non-Pseudomonas Gram-negative bacteria (GNsPs) was performed in order to explore potentially differential roles of these bacteria. Gram-negative bacterial carriage was not associated with a difference in demographic parameters or serum biomarkers. However, P. aeruginosa carriage was associated with a higher self-reported incidence of asthma (GNwPa 79%, sGN 57%; p = 0.048). Interestingly, serum IgE was increased in the non-Pseudomonas Gram-negative population (GNsPs: 338 IU/mL, sGN: 195 IU/mL; p = 0.026).

CRSwNP patients colonized with Gram-negative bacteria have a similar pattern of inflammation as assessed by serum biomarkers to those colonized with Gram-positive ones. Gram-negative bacteria may contribute to development of a T helper 2 (Th2) phenotype via other mechanisms, possibly via Toll-like receptor 4 (TLR4)-mediated interleukin 33 (IL-33) production. Differences in phenotype associated with Pseudomonas species carriage suggest a different behavior than other Gram-negative bacteria, supporting their importance as disease modifiers in CRSwNP.

Does apolipoprotein A-V variant ( T-1131 > C ) affect plasma levels of non-high-density lipoprotein cholesterol in Caucasians?

The importance of apolipoprotein A-V (APOAV) gene variants in the determination of plasma triglyceride levels in humans has been proven in several population studies. To investigate whether APOAV gene variants are associated with the different plasma cholesterol fractions. The influence of APOAV polymorphisms (T-1131>C, Ser19>Trp and Val153>Met) on plasma cholesterol fractions was evaluated in 1191 men and 1368 women representatively selected from the Czech population. Low-density lipoprotein cholesterol, non-high-density lipoprotein (non-HDL) cholesterol and HDL cholesterol levels were analyzed. The T-1131>C variation in the APOAV gene was found to affect plasma non-HDL cholesterol, showing significantly higher levels in C-1131 carriers than in T/T-1131 homozygotes. This association was observed in both men (4.61+/-1.09 mmol/L in C-1131 carriers versus 4.47+/-1.07 mmol/L in T/T-1131 homozygotes; P<0.01) and women (4.46+/-1.22 mmol/L in C-1131 carriers versus 4.24+/-1.17 mmol/L in T/T-1131 homozygotes; P<0.01). Interestingly, when low-density lipoprotein cholesterol (obtained by the Friedewald formula) or HDL cholesterol levels were analyzed, no significant association was detected.

The APOAV gene variant T-1131>C may play a role not just in the genetic determination of triglyceride levels but may also influence plasma levels of non-HDL cholesterol.

Are sex and pain-related psychological variables associated with thermal pain sensitivity for patients with chronic low back pain?

Biologic and psychological associations with evoked pain sensitivity have been extensively studied in healthy subjects but not among subjects with clinical pain syndromes. This study involved patients with chronic low back pain and investigated whether: 1) sex differences existed for thermal pain sensitivity; and 2) sex, fear-avoidance beliefs, and/or pain catastrophizing influenced thermal pain sensitivity. Thirty-three consecutive patients enrolled in a pain rehabilitation program completed self-report questionnaires and underwent quantitative sensory testing with an established protocol for thermal stimuli. Women had elevated pain sensitivity for measures of tolerance and temporal summation but not for first pulse response. In the multivariate models predicting thermal pain sensitivity, sex was associated with tolerance, and fear-avoidance beliefs were associated with first pulse response. Sex and pain catastrophizing were associated with temporal summation of thermal pain. Future studies involving clinical samples are necessary to replicate these findings and to explore the involvement of cortical structures.

This study suggests that sex, fear-avoidance beliefs, and pain catastrophizing were associated with thermal pain sensitivity for patients with chronic low back pain. These results corroborated sex differences in tolerance and temporal summation observed in the experimental pain literature for healthy subjects. These results also suggest the potential for these specific pain-related beliefs to be associated with a sensitized state because previous studies have demonstrated their association to clinical pain reports, and this study demonstrated associations with thermal pain sensitivity.

Do increasing rates of preterm twin births coincide with improving twin pair survival?

To examine trends in twin gestational age over time, with adjustment for potential confounding factors, and to assess twin pair mortality and respiratory support over time. Rates of preterm births, respiratory support, and neonatal mortality were calculated for 21,569 twin pairs born from 1980 to 2005 in Washington State, using birth certificate and hospital discharge data. Fetal death risks were determined on a "per-pair-at-risk" basis. While the proportion of twins born at 24-31 weeks remained stable at 8%, the proportion born at 32-36 weeks increased from 28% to 48%, and the proportion at 37-42 weeks declined from 64% to 44% (P<0.0001). Controlling individually for a variety of factors, such as maternal age, race, parity, and mode of delivery did not diminish the highly significant trend of increasing preterm births (P<0.0001 for each). Twin pair neonatal mortality decreased significantly through time (P<0.0001); however, the rate of pairs with one or both infants requiring oxygen or ventilation increased significantly through time (P<0.0001). Fetal death risks declined for term twins.

The proportion of twins born at 32-36 weeks' gestation has increased over time, along with requirement for respiratory support. Twin pair mortality decreased from 1980 to 2005.

Does intraocular penetration of vancomycin eye drop after application to the medial canthus with closed lids?

To investigate the intraocular penetration of vancomycin eye drops and to compare the conventional method of drop instillation to the lower cul de sac with applying drops to the medial canthus with closed lids. This prospective randomised trial evaluated 53 eyes of 53 patients who had undergone extracapsular cataract extraction (ECCE) with intraocular lens implantation. Vancomycin (50 mg/ml) eye drops were applied to either the lower cul de sac with open lids (conventional method), or to the medial canthus with the patient in a supine position and with closed lids. After paracentesis performed during ECCE, an aqueous humour sample was taken and vancomycin concentration was measured using the TDX vancomycin assay (fluorescence polarisation immunoassay). Vancomycin concentration in the anterior chamber were above the minimal inhibitory concentration for Gram positive bacteria in the two methods of drop instillation examined (2.04 (SD 1.9) microg/ml and 1.49 (1.1) microg/ml in the open and closed methods, respectively (p =0.202)).

Vancomycin (50 mg/ml) reaches therapeutic concentration in the anterior chamber after topical drop application. Comparable concentrations were reached when drops were applied in either the lower cul de sac or to the medial canthus with closed lids. The latter method is proposed as likely to improve patient compliance.

Is the inflammatory C-reactive protein increased in both liver and adipose tissue in severely obese patients independently from metabolic syndrome , Type 2 diabetes , and NASH?

C-Reactive Protein (CRP), a nonspecific marker of inflammation that is moderately elevated in obesity, metabolic syndrome (MS), and type 2 diabetes, has been proposed as a surrogate marker of nonalcoholic steatohepatitis (NASH). Its clinical usefulness in the diagnosis of NASH was evaluated in severely obese patients without or with MS, diabetes, and NASH and the potential roles of the liver and of the adipose tissue in CRP production were characterized. Severely obese patients without NASH (without MS [N = 13], with MS [N = 11], or with MS and diabetes [N = 7]) and with NASH (without [N = 8] or with [N = 7] MS) were studied. For each patient, liver and adipose tissue biopsies were collected during a bariatric surgery and were used to determine the CRP gene expression by real-time PCR. The role of interleukin-6 (IL6) and lipopolysaccharide in CRP expression was also evaluated in subcutaneous adipose tissue obtained during cosmetic abdominoplasty. Plasma CRP levels were elevated in severely obese patients independently from the presence or absence of MS, diabetes, or NASH. CRP gene expression was not only increased in livers but also in adipose tissues of obese patients compared with controls subjects. In human adipose tissue, CRP mRNA levels were positively correlated with those of IL-6 and the CRP expression was enhanced in vitro by IL-6 and lipopolysaccharide.

Plasma CRP levels are not predictive of the diagnosis of NASH in severely obese patients. The liver but also the adipose tissue can produce CRP, a process which could be dependent on IL6. Therefore, both tissues might contribute to the elevated plasma CRP levels found in obesity. In addition, the large amount of body fat may well produce an important part of the circulating CRP, further limiting its clinical usefulness in the evaluation of NASH in severely obese patients.

Is re-expression of SPR1 in breast cancer cells by phorbol 12-myristate 13-acetate ( PMA ) or UV irradiation mediated by the AP-1 binding site in the SPR1 promoter?

Invasive tumor cells are characterized by multiple phenotypic changes as a result of the large number of cDNAs being differentially expressed in tumor cells compared to normal progenitors. Expression genetics focuses on changes at the RNA level with the aim of identifying functionally important genes whose aberrant expression in cancer cells is regulated at the level of transcription. These genes were named class II genes and are distinguished from class I genes, which are characterized by genomic mutations, deletions, or other alterations. Reversal of the tumor cell phenotype accompanying normalization of the expression of such genes may be exploited therapeutically if gene expression can be specifically modulated by drugs or other treatments. Considering that genes are coordinately regulated in complex networks, it is likely that the expression of multiple genes can be simultaneously modulated in tumor cells by drugs acting on the signal transduction pathway that regulates their expression. The SPR1 gene is associated with differentiation and its expression is down-regulated or inactivated in malignant cells. Analysis of the SPR1 promoter showed that down-regulation of SPR1 expression in breast tumor cells occurs at the level of transcription. SPR1 presents an example of class II genes, since its expression was up-regulated in tumor cells by phorbol 12-myristate 13-acetate (PMA) or by ultraviolet (UV) irradiation. The SPR1 gene was identified by differential display on the basis of its reduced or absent expression in human breast tumor cell lines compared to normal mammary epithelial cell strains. Differential expression was confirmed by Northern blot analysis employing multiple normal and tumor cell lines. The promoter region -619 to +15 of the SPR1 gene was sequenced and analyzed by CAT assays, deletion analysis, and mutagenesis. Up-regulation of SPR1 expression by PMA and UV irradiation was monitored by Northern analysis and analyzed by CAT assays. The mechanism of down-regulation of SPR1 expression in breast tumor cells was investigated. It was found that the -619 to +15 upstream promoter region is sufficient for SPR1 expression in normal breast cells, but it is transcriptionally silent in most breast tumor cell lines. By deletion analysis and mutagenesis, two upstream cis-acting promoter elements were identified. Our data indicate that the AP-1 element located between -139 and -133 acts as a major enhancer of SPR1 transcription only in normal mammary epithelial cells but not in corresponding tumor cells, whereas the sequences flanking the AP-1 site do not affect its promoter enhancing activity. In addition, a transcriptional repressor was identified that binds unknown factor(s) and is active in both normal and tumor breast cells. Inhibitor function was mapped to a 35-bp element located from -178 to -139 upstream of the human SPR1 mRNA start site. The expression of SPR1 could be induced in the 21MT-2 metastatic breast tumor cell line by PMA treatment or by short UV irradiation via a transcriptional mechanism. AP-1 is the cis element mediating the transcriptional activation of SPR1 by PMA, which induces the expression of AP-1 factors in 21MT-2 cells. Mutation of the AP-1 site abolishes the induction of SPR1 expression by PMA.

Our results demonstrate that loss of SPR1 expression in breast tumor cells results from impaired transactivation through the AP-1 site in the SPR1 promoter, as well as from the presence of a negative regulatory element active in both normal and tumor cells. Furthermore, our results provide a basis for therapeutic manipulation of down-regulated genes, such as SPR1, in human cancers.

Is laparoscopic partial splenectomy safe and effective in patients with focal benign splenic lesion?

Traditionally, splenectomy is considered as the treatment for splenic lesions. The risk of early and late complications and the awareness of immunologic function of spleen have pushed the development of spleen sparing techniques. This study aimed to evaluate the safety and feasibility of laparoscopic partial splenectomy in selected patients. From May 2011 we initiated performing laparoscopic partial splenectomy in patients with focal benign splenic lesion. The main surgical procedure consisted of four steps: 1. Mobilizing the perisplenic ligaments. 2. Ligating and dissecting the vessels which supplying the involved spleen. 3. Dissecting the spleen along the demarcation. 4. Hemostasis was achieved by bipolar energy device. The perioperative data were collected and analyzed. The follow-up including quality of life and splenic regrowth was routinely undergone 6 months after surgery. From May 2011 to December 2013, laparoscopic partial splenectomy had been performed on 11 patients aged from 13 to 57 (mean 33). The indications included nonparasitic cyst (n = 6), lymphangioma (n = 3), and hemangioma (n = 2). The mean operative time was 148 min (range 110-200 min). The mean estimated blood loss was 189 ml (range 100-400 ml). One patient converted to total splenectomy because of hemorrhaging. Two patients suffered from postoperative complications: the one who converted to total splenectomy suffered from portal vein thrombosis, the other one underwent partial splenectomy suffered from fluid collection around splenic recess. There was no blood transfusion and postoperative mortality. All patients discharged uneventfully. Seven patients finished the follow-up including evaluation of CT scan and quality of life 6 month after surgery. The results demonstrated all these patients had different degree of splenic regrowth and gained a good quality of life.

Laparoscopic partial splenectomy is safe and effective in patients with focal benign splenic lesion. Meanwhile, this technique potentially retains some splenic function, and confers the benefit of a minimal access technique.

Does iNG4 regulate JWA in angiogenesis and their prognostic value in melanoma patients?

We previously showed that inhibitor of growth family member 4 (ING4) inhibits melanoma angiogenesis, and JWA suppresses the metastasis of melanoma cells. As angiogenesis is essential for tumour metastasis, further investigation of the function of ING4 and JWA in melanoma angiogenesis is needed, and their prognostic value are of great interest. Western blot, tube-formation assays and luciferase assays were used to investigate the correlation between ING4 and JWA in melanoma angiogenesis. JWA and integrin-linked kinase (ILK) expression was determined on a tissue microarray constructed from 175 biopsies. ING4 promoted JWA expression by activating JWA promoter. Furthermore, the regulation of growth and tube formation of endothelial cells by ING4 was partially JWA dependent. Also, ING4 inhibited the ILK-induced angiogenesis signalling pathway via JWA. Moreover, reduced JWA, or increased ILK, expression was closely associated with 5-year disease-specific survival of melanoma patients (P=0.001 and 0.007, respectively). There was also a positive correlation between ING4 and JWA yet a negative correlation between ING4 and ILK. Importantly, their concomitant expressions were significantly related to 5-year survival of melanoma patients (P=0.002 and 0.003, respectively).

JWA has an important role in ING4-regulated melanoma angiogenesis, and ING4/JWA/ILK are promising prognostic markers and may be used as anti-angiogenic therapeutic targets for melanoma.

Does intermittent reloading attenuate muscle atrophy through modulating Akt/mTOR pathway?

The aim of this study is to investigate the effects of intermittent reloading during hindlimb unloading (HU) on the changes in intracellular signaling pathways in skeletal muscle. Male Wister rats were divided randomly into one of three experimental groups: 1) nonsuspended control, 2) HU for 7 d, and 3) HU with intermittent reloading (HU/IR) for 4 h.d(-1). After each experimental period, the antigravitational soleus muscle was analyzed. After 7 d of HU treatment, muscle fiber atrophy (decrease in relative muscle mass: 0.28 mg.g(-1) in the HU group vs 0.36 mg.g(-1) in the control group, P < 0.05; decrease in fiber CSA: 1682.6 microm2 in the HU group vs 2673.0 microm2 in the control group, P < 0.05) and a decrease in phosphorylation levels of anabolic signaling pathway (Akt and mTOR) were observed. Additionally, expressions of two types of muscle-specific E3 ubiquitin ligase mRNA (muscle atrophy F-box (MAFbx), and muscle ring finger 1 (MuRF1)) were upregulated during muscle atrophy. Increases in binding activities of nuclear factor kappa B (NFkappaB) were also determined. In contrast, IR treatment attenuated the muscle fiber atrophy (0.33 mg.g(-1) and 2067.5 microm2) and partially increased the phosphorylation levels of anabolic signaling molecules. Expression of MAFbx and MuRF1 mRNA were returned to the control level, and binding activities of nuclear NFkappaB was suppressed with the effects of IR.

These results suggest that IR-induced attenuation of skeletal muscle atrophy is achieved by the synergy between increased anabolic and decreased catabolic signaling mechanisms.

Is preoperative positron emission tomography with fluorine-18-fluorodeoxyglucose predictive of prognosis in patients with hepatocellular carcinoma after resection?

Hepatocellular carcinomas (HCCs) accumulate fluorine-18 fluorodeoxyglucose (FDG) to various degrees. The standardized uptake values (SUVs) of FDG-positron emission tomography (PET) in high-grade HCCs are significantly higher than those in low-grade HCCs. The aim of this study was to evaluate the possible usefulness of FDG-PET in predicting the prognosis of HCC patients after resection. We analyzed the relationship between the tumor to non-tumor SUV ratios (SUV ratio) and surgical outcome in 31 patients. Of the 31 cases of HCC studied, seven (23%) exhibited SUV ratios greater than 2, as the cutoff value. The percentage of patients with poorly differentiated HCC was greater in the higher SUV ratio group (SUV ratio >2) than in the lower SUV ratio group (SUV ratio <2) (57 vs. 32%). The overall survival was significantly longer in the lower SUV ratio group than in the higher SUV ratio group (5-year-survival rate: 63 vs. 29% P = 0.006) (median survival time: 2310 vs.182 days).

The SUV ratio was related significantly to disease-related death as well as other predictive factors, including the number of tumors, the size, stage, and involvement of vessels, and the involvement of the capsule. Consequently, we conclude that the SUV ratio provides information of prognostic relevance in patients with HCC before surgery.

Growth in use of lipid-lowering therapies: are we targeting the right patients?

Prescription drug spending has been rising at>10% per year, with volume of use (rather than price) being the primary driver for that growth. Concern exists that industry marketing has led to increased use of medications by patients with marginal indications. To determine whether the increase in the number of patients receiving lipid-lowering therapy represents a shift away from treatment of patients at highest cardiovascular (CV) risk towards patients in lower risk categories. Cardiovascular risk criteria adapted from guidelines were applied to an administrative database of medical and pharmaceutical claims for 1997 and 1999 that included managed care plan enrollees in 22 states. Patients were assigned to 1 of 7 categories representing CV risk based on documentation of CV disease/risk factors, with category 1 and 2 indicating the highest risk group (secondary prevention). The odds of the treated population being in the highest risk during 1997 versus 1999 were calculated, adjusting for age and sex. Patients treated with lipid medications in the study population increased from 5% in 1997 to 8% in 1999. During the same period, the percentage of treated patients in categories 1 through 6 rose from 17% to 21%. The odds of the treated population being in the highest risk group did not differ significantly between the 2 years (odds ratio (OR) = 0.99; 95% confidence interval, (CI) 0.96-1.01; P = .40).

Despite an increase in the percentage of patients receiving lipid-lowering therapy from 1997 to 1999, treatment rates rose modestly across all categories. Greater overall use did not appear to be associated with a shift in use towards patients with less CV risk.

Is early repolarization associated with symptoms in patients with type 1 and type 2 long QT syndrome?

Early repolarization (ER) is associated with an increased risk for death from cardiac causes. Recent evidence supports ER's role as a modifier and/or predictor of risk in many cardiac conditions. The purpose of this study was to determine the prevalence of ER among genotype-positive patients with long QT syndrome (LQTS) and evaluate its utility in predicting the risk of symptoms. ER was defined as QRS slurring and/or notching associated with ≥1-mV QRS-ST junction (J-point) elevation in at least 2 contiguous leads, excluding the anterior precordial leads. The ECG with the most prominent ER was used for analysis. Major ER was defined as ≥ 2-mm J-point elevation. Symptoms of LQTS included cardiac syncope, documented polymorphic ventricular tachycardia (VT), and resuscitated cardiac arrest. One hundred thirteen patients (mean age 41 ± 19 years; 63 female) were reviewed, among whom 414 (mean 3.7 ± 1.5) ECGs were analyzed. Of these, 30 patients (27%) with a history of symptoms. Fifty patients (44%) had ER, and 19 patients (17%) had major ER. Patients with major ER were not different from patients without major ER with respect to age, sex, long QT type, longest QTc recorded, number of patients with QTc >500 ms, or use of beta-blockade. Univariate and independent predictors of symptom status included the presence of major ER, longest QTc recorded >500 ms, and female sex.

ER ≥2 mm was the strongest independent predictor of symptom status related to LQTS, along with female sex and QTc >500 ms.

Does endothelin receptor antagonist combined with a calcium channel blocker attenuate renal injury in spontaneous hypertensive rats with diabetes?

To investigate the effects of the mixed endothelin receptor antagonist, bosentan, combined with the long-acting calcium channel blocker, amlodipine, compared to the angiotensin-converting enzyme inhibitor, cilazapril, on the progressive renal injury in spontaneous hypertensive rats (SHR) with diabetes. Diabetic hypertensive rats (SHR-DM) were induced by streptozotozin injected in male SHR (7-week-old),and divided into an untreated and three treated groups: 1) cilazapril treated group; 2) bosentan+amlodipine treated group; and 3) amlodipine treated group. Wistar Kyoto rats (WKY) and SHR rats served as normotensive and hypertensive control, respectively. The mean arterial blood pressure, renal function, endothelin and angiotensin II levels as well as the protein expression of renal extracellular matrix components and transforming growth factor (TGF)-beta1 were determined at the end of the 4th week. Mean arterial blood pressure significantly increased in SHR and SHR-DM rats compared to WKY rats. All the therapies reduced the blood pressure to normal levels. However, the enhanced urinary protein excretion, the decreased creatinine clearance as well as the increased plasma and intrarenal endothelin and angiotens in II levels were found in the untreated SHR-DM and prevented by treatment with bosentan+amlodipine and cilazapril. Similarly, these two kinds of therapies in SHR-DM abolished the overexpression of renal TGF-beta1 by Western blot analysis and reduced the accumulation of collagen type IV, laminin and fibronectin proteins by an immunochemical approach. Amlodipine monotherapy had no detectable effects on the above parameters.

Bosentan combined with amlodipine can offer similar renoprotective effects on that of cilazapril and may be a potent therapy to attenuate renal injury by reducing renal protein levels of TGF-beta1 in diabetes with a hypertensive state.

Is prognosis important in decisionmaking in Dutch nursing home patients with dementia and pneumonia?

To explore how physicians treating nursing home residents with dementia and pneumonia in the Netherlands consider prognosis in their treatment decision. Survey study with data collected between July 2006 and March 2008. Physicians (n = 69) from 54 nursing homes in the Netherlands completed a questionnaire on symptoms, treatment, and prognosis for their next dementia patient newly diagnosed with pneumonia. They were also asked a general question regarding withholding antibiotic treatment and prognosis. Outcome was assessed at least two months afterwards. Two-week mortality risk if treated with antibiotics was calculated with a validated prognostic score. The patients not treated with antibiotics had high (92%) actual 2-week mortality while only 12% of patients treated with antibiotics died. Physicians believed that mortality risk was high in the untreated group and would have been only slightly lower if treated with antibiotics (mean estimated risk 73%), which was higher than predicted from the risk score (42%). In general, three-quarters of physicians considered withholding antibiotics appropriate for mortality risks between 75% and 90%.

Prognosis is an important consideration when Dutch nursing home physicians make antibiotic treatment decisions for patients with dementia and pneumonia. This suggests they prefer not to treat with antibiotics when to do so is probably futile. Physicians in other countries may hold different views on futility, which should be addressed in larger, cross-national comparative studies.

Is why Congo red binding specific for amyloid proteins - model studies and a computer analysis approach?

The complexing of Congo red in two different ligand forms - unimolecular and supramolecular (seven molecules in a micelle) - with eight deca-peptides organized in a b-sheet was tested by computational analysis to identify its dye-binding preferences. Polyphenylananine and polylysine peptides were selected to represent the specific side chain interactions expected to ensure particularly the stabilization of the dye-protein complex. Polyalanine was used to verify the participation of non-specific backbone-derived interactions. The initial complexes for calculation were constructed by intercalating the dye between the peptides in the middle of the beta-sheet. The long axis of the dye molecule (in the case of unimolecular systems) or the long axis of the ribbon-like micelle (in the case of the supramolecular dye form) was oriented parallel to the peptide backbone. This positioning maximally reduced the exposure of the hydrophobic diphenyl (central dye fragment) to water. In general the complexes of supramolecular Congo red ligands appeared more stable than those formed by individual dye molecules. Specific interactions (electrostatic and/or ring stacking) dominated as binding forces in the case of the single molecule, while non-specific surface adsorption seemed decisive in complexing with the supramolecular ligand. Both the unimolecular and supramolecular versions of the dye ligand were found to be likely to form complexes of sufficient stability with peptides. The low stability of the protein and the gap accessible to penetration in the peptide sheet seem sufficient for supramolecular ligand binding, but the presence of positively charged or hydrophobic amino acids may strengthen binding significantly.

The need for specific interaction makes single-molecule Congo red binding rather unusual as a general amyloid protein ligand. The structural feature of Congo red, which enables specific and common interaction with amyloid proteins, probably derives from the ribbon-like self-assembled form of the dye.

Does functional appliance treatment truly improve stability of mandibular vertical distraction osteogenesis in hemifacial microsomia?

Ten children were treated by a combined orthodontic-distraction treatment, seven by distraction only. Only the vertical changes in the mandible and maxilla in the panoramic and postero-anterior cephalometric X-rays were measured. All of the patients showed a gradual return of the asymmetry with growth. Occlusal plane correction and, to a much lesser extent, mandibular vertical ramus height correction were better maintained over 5 years post-DO in the orthopaedic group.

Although orthopaedic treatment allows for a more stable occlusal plane and for a slower return of the mandibular vertical asymmetry, it has mainly a dento-alveolar effect. Therefore, the decision of applying an orthopaedic treatment associated with distraction, should be taken by surgeon and orthodontist together, considering both the advantages and the disadvantages of this treatment.

Does 18β-Glycyrrhetinic acid protect against methotrexate-induced kidney injury by up-regulating the Nrf2/ARE/HO-1 pathway and endogenous antioxidants?

18β-glycyrrhetinic acid (18β-GA) has multiple beneficial and therapeutic effects. However, its protective roles on methotrexate (MTX)-induced renal injury are not well defined. In the present study, we investigated the possible protective effects of 18β-GA against MTX-induced nephrotoxicity in rats. 18β-GA (50 and 100 mg/kg) was administered for 7 days either before or after MTX. The rats were decapitated and kidney and serum samples were collected. MTX-induced renal injury in rats was evidenced by the significant (p < 0.001) increase in circulating kidney function markers and tumor necrosis factor alpha (TNF-α), as well as the histopathological alterations. MTX-induced rats exhibited significantly increased lipid peroxidation (p < 0.05) and nitric oxide (p < 0.001) levels, with concomitant marked (p < 0.001) decline in the antioxidant defenses. 18β-GA, administered either before or after MTX, produced a significant amelioration of circulating kidney function markers, TNF-α, kidney lipid peroxidation, nitric oxide, and antioxidant defenses. In addition, 18β-GA supplementation significantly up-regulated the mRNA abundance of both nuclear factor-erythroid 2-related factor 2 (Nrf2) and hemoxygenase 1 (HO-1) in the kidney of MTX-induced rats.

These results indicate that 18β-GA has a protective effect on MTX-induced nephrotoxicity with possible mechanisms of attenuating oxidative stress and inflammation through up-regulating the Nrf2/ARE signaling. These findings make 18β-GA candidate as a potent agent in preventing MTX-induced kidney injury.

Does hippocampal expression of murine IL-4 result in exacerbation of amyloid deposition?

Pro-inflammatory stimuli, including cytokines like Interleukin-1β, Interleukin-6 and Interferon-γ, in the brain have been proposed to exacerbate existing Alzheimer's disease (AD) neuropathology by increasing amyloidogenic processing of APP and promoting further Aβ accumulation in AD. On the other hand, anti-inflammatory cytokines have been suggested to be neuroprotective by reducing neuroinflammation and clearing Aβ. To test this hypothesis, we used adeno-associated virus serotype 1 (AAV2/1) to express an anti-inflammatory cytokine, murine Interleukin-4 (mIL-4), in the hippocampus of APP transgenic TgCRND8 mice with pre-existing plaques. mIL-4 expression resulted in establishment of an "M2-like" phenotype in the brain and was accompanied by exacerbated Aβ deposition in TgCRND8 mice brains. No change in holo APP or APP C terminal fragment or phosphorylated tau levels were detected in mIL-4 expressing CRND8 cohorts. Biochemical analysis shows increases in both SDS soluble and insoluble Aβ. mIL-4 treatment attenuates soluble Aβ40 uptake by microglia but does not affect aggregated Aβ42 internalization by microglia or soluble Aβ40 internalization by astrocytes.

Short term focal mIL-4 expression in the hippocampus leads to exacerbation of amyloid deposition in vivo, possibly mediated by acute suppression of glial clearance mechanisms. Given that recent preclinical data from independent groups indicate engagement of the innate immune system early on during disease pathogenesis may be beneficial, our present study strongly argues for a cautious re-examination of unwarranted side-effects of anti-inflammatory therapies for neurodegenerative diseases, including AD.

Do nonspecific focal EEG slowing and epileptiform abnormalities favor one hemisphere?

Several EEG-based studies suggest that epileptiform activity originates from the left more than the right hemisphere. In contrast, other pathophysiologies such as stroke lateralize relatively symmetrically. Study of focal slowing and other EEG abnormalities allows assessment of favoring as well as referral and interpretation bias. The 1,331 consecutive adult EEG reports were reviewed for epileptiform discharges (EDs) and nonepileptiform focal slowing. Side of slowing or EDs, interpreting electoencephalographer, and whether the patient was undergoing long-term monitoring or routine EEG were tallied. Results were statistically analyzed. Focal slowing occurred symmetrically; EDs favored the left hemisphere (p<0.01).

The left hemisphere may be more prone to epileptiform abnormalities in adults, but not to the nonspecific pathophysiologic processes that cause slowing. These findings suggest that potential interpretation bias does not influence left hemispheric favoring of EDs and instead may implicate a biologic etiology.

Initial experience with a new biodegradable airway stent in children: Is this the stent we were waiting for?

To report our experience with a new type of biodegradable airway stent in the setting of severe tracheobronchial obstruction in children. We conducted a retrospective and prospective (since June 2014) study of pediatric patients with severe airway obstruction treated with biodegradable stents in our institution between 2012 and 2015. The following data were collected: demographics, indication for stenting, bronchoscopic findings, insertion technique complications, clinical outcome, stent related complications, re-stenting, and time of follow-up. Thirteen custom-made polydioxanone stents were placed in four infants (mean age, 4 months) with severe tracheobronchial obstruction: tracheomalacia (two patients), bronchomalacia (1), and diffuse tracheal stenosis (1). All the stents were bronchoscopically inserted uneventfully. Immediate and maintained clinical improvement was observed in every case. No major stent related complications have occurred and only mild or moderate granulation tissue was observed during surveillance bronchoscopy. Two patients required repeated stenting as expected. All the patients are alive and in a good respiratory condition with a follow-up ranging from 5 to 40 months.

Biodegradable airway stents seem to be safe, effective, and cause fewer complications than other types of stents. They can be an alternative to the classic metallic or plastic stents for severe tracheal stenosis or malacia in small children. More experience is needed in order to establish the definite clinical criteria for their use in pediatric patients. Pediatr Pulmonol. 2016;51:607-612. © 2015 Wiley Periodicals, Inc.

Does [ Time-density curve of 16-slice spiral CT quantitatively distinguish true from false lumen of aortic dissection ]?

To use the time-density curves (TDCs) to quantitatively distinguish the true from false lumen of aortic dissection (AD). 28 cases with AD underwent the dynamic scanning of 16-slice spiral computer tomography (SCT). We used the CT Dynamic Evaluation software to determine the circulation times of the true and false lumens of the AD and got the TDCs, and then analyzed the circulation times and CT values of the true and false lumens by using matched t-test for dependent samples. The TDCs of the true and false lumens of the AD were achieved in all 28 patients. The peak CT values [(71.87 +/- 35.14) HU] of the true lumen were higher than those [(45.58 +/- 24.00) HU] of false lumen (P < 0.05); while the time to peak [(23.43 +/- 5.73) s] of the true lumen were earlier than that [(29.46 +/- 6.27) s] of false lumen (P < 0.05). The patterns of TDCs of the true lumen appeared to be rapid rise followed by rapid decline in 22 cases (78.6%) and rapid rise with gradual decline in 6 (21.4%), while the patterns of TDCs of the false lumen showed gradual rise followed by gradual decline in 18 cases (64.3%) and rapid rise with gradual decline in 10 (35.7%).

The TDCs of the true and false lumens showed: the peak CT values of the true lumen were higher than those of false lumen; while the time to peak of the true lumen were earlier than that of false lumen. So, the time-density curve, is used as an original and quantitative method to distinguish the true from false lumen in AD.

Is abnormal colour vision a handicap to playing cricket but not an insurmountable one?

Two studies have reported that abnormal colour vision is under-represented among cricketers, presumably because cricketers with abnormal colour vision have difficulty seeing the red ball against the green grass of the cricket field and the green foliage around it. We have previously reported on the difficulties of five cricketers with abnormal colour vision but we have also reported that one of Australia's finest cricketers was a protanope. This survey was undertaken to confirm the under-representation of abnormal colour vision among cricketers and to ascertain whether those playing tend to be (1) those with a mild colour vision deficiency, (2) bowlers rather than batsman and (3) prefer to field close to the batsman rather than in the outfield. The colour vision of 293 members of seven Melbourne Premier cricket clubs was tested using the Ishihara test. Those who failed were examined further to confirm their abnormal colour vision, to assess its severity with the Farnsworth D15 test and to classify it as either protan or deutan using the Medmont C100 test. A questionnaire about cricketing ability and problems playing cricket was administered. Twenty-six (8.9 per cent) of the cricketers had abnormal colour vision, of whom six played in the First Grade (6.7 per cent of First Grade players). The proportion of cricketers with a severe deficiency was significantly less than expected for the First Grade players. There were only two protans. Bowlers were not over-represented among the colour vision defective cricketers but those preferring to field close to the batsman were significantly over-represented.

Abnormal colour vision is a modest handicap to playing cricket, especially at the higher levels of the game. It may impede batting and the ability to field in the outfield.

Is neuronal calcium sensor synaptotagmin-9 involved in the regulation of glucose homeostasis or insulin secretion?

Insulin secretion is a complex and highly regulated process. It is well established that cytoplasmic calcium is a key regulator of insulin secretion, but how elevated intracellular calcium triggers insulin granule exocytosis remains unclear, and we have only begun to define the identities of proteins that are responsible for sensing calcium changes and for transmitting the calcium signal to release machineries. Synaptotagmins are primarily expressed in brain and endocrine cells and exhibit diverse calcium binding properties. Synaptotagmin-1, -2 and -9 are calcium sensors for fast neurotransmitter release in respective brain regions, while synaptotagmin-7 is a positive regulator of calcium-dependent insulin release. Unlike the three neuronal calcium sensors, whose deletion abolished fast neurotransmitter release, synaptotagmin-7 deletion resulted in only partial loss of calcium-dependent insulin secretion, thus suggesting that other calcium-sensors must participate in the regulation of insulin secretion. Of the other synaptotagmin isoforms that are present in pancreatic islets, the neuronal calcium sensor synaptotagmin-9 is expressed at the highest level after synaptotagmin-7. In this study we tested whether synaptotagmin-9 participates in the regulation of glucose-stimulated insulin release by using pancreas-specific synaptotagmin-9 knockout (p-S9X) mice. Deletion of synaptotagmin-9 in the pancreas resulted in no changes in glucose homeostasis or body weight. Glucose tolerance, and insulin secretion in vivo and from isolated islets were not affected in the p-S9X mice. Single-cell capacitance measurements showed no difference in insulin granule exocytosis between p-S9X and control mice.

Thus, synaptotagmin-9, although a major calcium sensor in the brain, is not involved in the regulation of glucose-stimulated insulin release from pancreatic β-cells.

Intraoperative placement of the nasoenteric feeding tube: a practical alternative?

The provision of early postoperative enteral feeding may be enhanced by the placement of enteral feeding access during celiotomy, but surgeons are often reluctant to pursue this option because of the extra effort required. We conducted a retrospective review of our 2-year experience with 60 sequential intraoperative nasoenteric feeding-tube placements and included data on demographics, diagnosis, surgery, type of feeding tube, formula, tolerance, and complications. Our surgeons placed intraoperative nasoenteric feeding tubes at their discretion in a variety of subjects who were undergoing elective or urgent celiotomies. The surgeries largely involved the upper gastrointestinal tract, and feeding-tube placements were readily accomplished. The majority of patients received enteral feedings within 3 postoperative days and achieved feeding rates of 50 mL/h or greater. The average duration of feeding-tube use was 1 week, accounting for 399 feeding days overall. There were no serious complications attributable to feeding-tube placement or use, but inadvertent tube removal by patients or staff was a limitation.

Intraoperative placement of the nasoenteric feeding tube may be a reasonable option for treating the surgical patient at nutritional risk who faces a limited course of impaired oral intake postoperatively.

Do protein phosphatase 1 β paralogs encode the zebrafish myosin phosphatase catalytic subunit?

The myosin phosphatase is a highly conserved regulator of actomyosin contractility. Zebrafish has emerged as an ideal model system to study the in vivo role of myosin phosphatase in controlling cell contractility, cell movement and epithelial biology. Most work in zebrafish has focused on the regulatory subunit of the myosin phosphatase called Mypt1. In this work, we examined the critical role of Protein Phosphatase 1, PP1, the catalytic subunit of the myosin phosphatase. We observed that in zebrafish two paralogous genes encoding PP1β, called ppp1cba and ppp1cbb, are both broadly expressed during early development. Furthermore, we found that both gene products interact with Mypt1 and assemble an active myosin phosphatase complex. In addition, expression of this complex results in dephosphorylation of the myosin regulatory light chain and large scale rearrangements of the actin cytoskeleton. Morpholino knock-down of ppp1cba and ppp1cbb results in severe defects in morphogenetic cell movements during gastrulation through loss of myosin phosphatase function.

Our work demonstrates that zebrafish have two genes encoding PP1β, both of which can interact with Mypt1 and assemble an active myosin phosphatase. In addition, both genes are required for convergence and extension during gastrulation and correct dosage of the protein products is required.

Are different groups of patients with stroke more likely to be excluded from the new UK general medical services contract?

In April 2004, an incentive based contract was introduced to UK primary care. An important element of the new contract is the ability to exclude individuals from quality indicators for a variety of reasons (known as 'exception reporting'). Exception of patients with stroke or TIA from the recording and achievement of quality indicators may have important consequences in terms of stroke recurrence and mortality. A cross-sectional retrospective analysis of anonymised patient data was performed using 312 Scottish primary care practices. Patients recorded as unsuitable for inclusion in the contract were more likely to be female (odds ratio (OR) 1.51, 95% confidence interval (CI) 1.36-1.68), older (>75 years:OR 3.15, 95%CI 2.69-3.69), and have dementia (OR 4.40, 95%CI 3.57-5.43) when compared to those patients without such a code. Patients were less likely to be older (>75 years:OR 0.70, 95%CI 0.56-0.87) and were more likely to be from the most deprived areas of Scotland (Quintile 5: OR 2.02, 95%CI 1.50-2.70) if they refused to attend for review or did not reply to letters asking for attendance at primary care clinics. Patients with multiple co-morbidities were more likely to have exclusions for achieving diagnostic clinical targets such as cholesterol control (3 or more co-morbidities: OR 3.37, 95%CI 2.50-4.50).

Scottish practices have appeared to use exception reporting appropriately by excluding patients who are older or have dementia. However, younger or more socio-economically deprived patients were more likely to be recorded as having refused to attend for review or not replying to letters asking for attendance at primary care clinics. It is important for primary care practices to identify and monitor these individuals so that all patients fully benefit from the implementation of an incentive based contract and receive appropriate clinical care to prevent stroke recurrence, further disability and mortality.

Does n-acetyl-l-cysteine decrease intra-abdominal adhesion formation through the upregulation of peritoneal fibrinolytic activity and antioxidant defenses?

Intraperitoneal adhesions occur in more than 94% of patients after abdominal surgery. Mechanisms that decrease oxidative stress and upregulate peritoneal fibrinolysis reduce adhesions. N-acetyl-l-cysteine (NAC) is a clinically relevant antioxidant whose effect on peritoneal fibrinolysis and ability to decrease adhesions has not been established. The aims of this study were to determine if NAC reduces adhesions and to characterize its potential mechanism(s) of action. Male Wistar rats (n = 92) received 0.9% saline (OP Control), intraperitoneal NAC (150 mg/kg, OP + NAC), or oral NAC (1200 mg/kg) twice daily on preoperative day 1, day of operation, and postoperative day 1. Adhesions were induced on the day of operation using our previously described ischemic button model. Animals were killed on postoperative day 7 for adhesion scoring. Peritoneal tissue and fluid from the intraperitoneal NAC group were measured at 24 hours for fibrinolytic activity, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), total glutathione, and 8-isoprostane (8-IP). The effect of NAC on tPA and PAI-1 production was tested in vitro in human mesothelial cells. The effect of NAC on intestinal wound healing was measured using colonic anastomotic burst pressures. Intraperitoneal NAC reduced adhesions by 53% (P < .001) compared to OP Controls without affecting anastomotic wound healing. NAC increased the tPA/PAI-1 protein ratio and peritoneal fibrinolytic activity by 69% and 127%, respectively, compared to OP Controls (P < .05). NAC did not restore total glutathione levels in peritoneal adhesion tissue but decreased 8-IP by 46% and 65% (P < .05) in peritoneal tissue and fluid, respectively, compared to OP Controls. Human mesothelial cells incubated with NAC exhibited a concentration-dependent increase in the tPA/PAI-1 ratio, which supported in vivo observations (P < .05). Oral NAC did not decrease adhesions.

NAC administered intraperitoneally decreased adhesion formation while upregulating peritoneal fibrinolytic activity and antioxidant defenses without affecting normal anastomotic wound healing. These data suggest a potential new therapeutic use for NAC in adhesion prevention.

Does recombinant LPG3 stimulate IFN-Γ and TNF-Α Secretion by Human NK Cells?

Natural killer (NK) cells play an important role in early stages of innate immune responses against viral and tumoral attacks. Activation of NK cells by leishmaniasis results in secretion of cytokines such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, which enhance the phagocytosis and clearance of parasite. Lipophosphoglycan 3 (LPG3), the Leishmania homologous with GRP94 (glucose regulated protein 94), a member of HSP90 family, contributes to LPG assembly as the most abundant macromolecule on the surface of Leishmania promastigotes. We purified NK cells from healthy individuals (n=10) using magnetic-activated cell sorting (MACS) technology. Purified NK cells were co-incubated with different concentrations of recombinant LPG3 (rLPG3), and its N-terminal (NT) and C-terminal (CT) fragments. Finally, the production of IFN-γ and TNF-α by NK cells were measured by ELISA. Recombinant LPG3 but not its fragments (CT and NT), could significantly enhance the production of TNF-α by NK cells (P<0.05). Moreover, rLPG3, CT, and NT fragments were markedly stimulated the secretion of IFN-γ by NK cells (P<0.001).

The Leishmania LPG3 antigen could effectively activate NK cells, in vitro. Leishmania LPG3 participates in the innate immunity against leishmaniasis and thereby improves the effective parasite destruction. However, its efficiency should be tested in vivo.