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Is early assessment of metabolic response by 18F-FDG PET during concomitant radiochemotherapy of non-small cell lung carcinoma associated with survival : a retrospective single-center study?

We performed a retrospective single-center study to assess if midtreatment 18F-FDG PET/CT could predict local control and survival in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy. Thirty-one consecutive patients with unresectable or locally advanced lung cancer (T2-4 N0-3 M0) were treated with concurrent chemoradiotherapy in our center. Each patient received 18F-FDG PET/CT before treatment and at midtreatment time when a radiation therapy dose of 30 Gy was delivered. We assessed several PET/CT parameters as follows: SUV max, ΔSUV mean, ΔSUV max, variation of hypermetabolic tumor volume, and the variation of tumor total lesion glycolysis (ΔTLG). Univariate analysis was performed, and a stepwise procedure was used to define final multivariate model. The ΔTLG was statistically correlated to overall survival (OS) (P = 0.035), progression-free survival (P = 0.023), and local control (P = 0.043) in univariate analysis. A decrease in TLG over 15% was statistically correlated to a better OS (P = 0.007; hazards ratio [HR], 7.439; 95% confidence interval [CI], 1.168-28.897) and progression-free survival (P = 0.010; HR, 5.695; 95% CI, 1.506-21.537) in univariate analysis. In multivariate analysis, ΔTLG superior to -15% was significantly correlated to a worse OS (P = 0.020; HR, 5.973; 95% CI, 1.324-26.953).

Early assessment of TLG response by 18F-FDG PET/CT during concomitant radiochemotherapy of non-small cell lung cancer might be associated with survival.

Are adipocyte cell size , free fatty acids and apolipoproteins associated with non-alcoholic liver injury progression in severely obese patients?

Obesity is a modern pandemic with continuous expansion and represents an independent risk factor for non-alcoholic fatty liver disease (NAFLD), the most common liver disease in westernized countries. The crosstalk between adipose tissue and the liver is key to the development of NAFLD. Therefore, in an observational study blood, visceral adipose tissue and liver tissue were obtained from 93 severely obese patients with a mean age of 43 years and mean BMI of 52 kg/m2 at the time of weight loss surgery. In a subset of patients a follow-up blood sample was obtained 6 weeks after surgery to assess acute effects of weight loss. In addition to routine parameters of liver injury, serum samples were analyzed for leptin, adiponectin, free fatty acids (FFAs), and several apolipoproteins. The diameter of visceral adipocytes correlated to liver injury, serum markers of inflammation and serum adipokine levels. Liver injury assessed by serology (ALT, AST) and histology (NAFLD activity score, NAS) was independent of the BMI. However, serum levels of triglycerides and Apolipoprotein CIII (ApoCIII) were associated with NAS. Serum levels and composition of FFAs, especially long chain FFAs, also correlated with NAS. Analysis of serum samples six weeks after surgery revealed beneficial changes in serum triglycerides, levels of ApoCIII and several FFAs.

In severely obese patients beneficial effects on liver injury can been observed as early as six weeks after bariatric surgery. These effects may be explained by the observed changes in adipose tissue and lipid metabolism. Collectively, these findings underline the importance of the link between adipose tissue and the liver.

Is median nerve enlargement at the wrist associated with tremor in Parkinson disease?

Tremor is one of the cardinal features of Parkinson disease (PD) and may cause cumulative trauma-related injury to nerves of the hands. The aim of this study was to assess the electrodiagnostic and sonographic features of patients with PD and to assess the effect of tremor in PD on the median nerve. We studied 31 hands of healthy control participants (n = 16; mean age ± SD, 60.25 ± 14.67 years) and 81 hands of patients with PD (n = 42; 64.95 ± 11.13 years). Motor symptoms were measured by the Unified Parkinson's Disease Rating Scale III. Median nerve conduction studies and sonographic cross-sectional area measurements were performed in all participants. The median nerve cross-sectional area in patients with PD (10.71 ± 2.79 mm(2)) was significantly larger than that in the control group (7.40 ± 1.05 mm(2); P<.05). However, there was no significant difference in median nerve electrodiagnostic findings between the PD and control groups. The median nerve cross-sectional area was associated with the severity of the tremor but not with the Unified Parkinson's Disease Rating Scale motor score.

Tremor in PD is associated with median nerve enlargement but not with impairment of median nerve conduction.

Is psychological distress in men recently diagnosed with testicular cancer associated with their neuropsychological test performance?

To study the level of cancer-related distress (CRD) and variables associated with CRD in recently diagnosed testicular cancer patients (TCPs), and to explore associations between distress levels and neuropsychological test performance at the same time-point. As part of a prospective study of their psychological and cognitive functioning, 135 TCPs completed the Impact of Event Scale (IES) as a measure of CRD at a median of 37 days after diagnosis. They also completed the Hospital Anxiety and Depression Scale (HADS) and the Positive and Negative Affect Schedule (PANAS). Among 135 TCPs, 131 were interviewed and 129 were also tested with a neuropsychological battery. All investigations were done after orchidectomy but before any additional treatment. The associations between neuropsychological test-scores and IES, HADS and PANAS were examined. Twenty-four percent (95%CI 17%-31%) of the TCPs reported clinically significant CRD (IES-total score>26). No demographic or cancer-related variables were associated with the CRD-level. In univariate analyses, previous mental problems, sleeping problems, a higher level of neuroticism, daily smoking and hazardous alcohol-use were significantly associated with the CRD-level. In multivariate analysis neuroticism, smoking and alcohol-use remained significantly associated with CRD. Four out of 18 neuropsychological test-scores were significantly associated with at least one distress-measure. Increasing distress-levels were associated with decreasing test performance on some measures of attention, working memory and executive functions.

In newly diagnosed TCPs, the scores on neuropsychological tests should be considered in relation to co-existing mental distress. Future studies should consider adjustment for this on relevant tests.

Can radiographic morphometric parameters for the hip be assessed on MRI?

Although morphometric hip parameters measured on radiographs are valuable tools guiding diagnosis and therapy in patients with hip disorders, some clinicians use MRI for such measurements, although it is unclear whether the parameters assessed on MRI differ from those assessed on radiographs.QUESTIONS/ We asked whether the lateral center-edge angle (LCE), Tönnis angle, extrusion index, and anterior center-edge angle (ACE) are similar on MRI and radiography. We retrospectively reviewed the imaging data of 103 hips from 103 patients: 46 with femoroacetabular impingement and 57 with hip dysplasia. We manually measured the LCE, Tönnis angle, extrusion index, and ACE from radiographs and MRI in all 103 hips. Four straight coronal (Ant-10 mm, Ant-5 mm, Center, and Post-5 mm), three straight sagittal (S-Med-5 mm, S-Center, S-Lat-5 mm), and three 25º oblique sagittal (OS-Med-5 mm, OS-Center, OS-Lat-5 mm) reformats were reconstructed from a three-dimensional isotropic morphologic MRI sequence. MRI measurements were compared against the gold standard radiographic measurements. We found good agreement for the LCE angle, Tönnis angle, and extrusion index between radiographic and coronal slice MRI measurements. The mean differences between radiographic and MRI measurements were 5º or less or 5% or less (for the extrusion index) in all coronal MRI slices. However, the differences between ACE angles on sagittal MRI slices and radiographs ranged from 5° to 28º.

LCE, Tönnis angle, and extrusion index can be measured on MRI with comparable results to radiography. The ACE angle on radiographs cannot be estimated reliably from MRI.

Is genetic variation in CYB5R3 associated with methemoglobin levels in preterm infants receiving nitric oxide therapy?

In recent years, increasing numbers of preterm infants have been exposed to inhaled nitric oxide (iNO). This population has decreased methemoglobin (MetHb) reductase activity in their erythrocytes, which may increase the risk of MetHb toxicity. We sought to determine if genetic factors are associated with the observed variance in MetHb levels. A population of 127 preterm infants was genotyped for five single-nucleotide polymorphisms (SNPs) in the CYB5A and CYB5R3 genes. iNO dose and levels of MetHb were obtained by chart abstraction. ANOVA was performed to identify genetic associations with MetHb levels. An association was found between the heterozygous genotype (GA) of rs916321 in the CYB5R3 gene and the mean of the first recorded MetHb levels in Caucasian infants (P = 0.01). This result remained significant after adjustment for the iNO dose (P = 0.009), gender (P = 0.03), multiple gestation (P = 0.03), birth weight (P = 0.02), and gestational age (P = 0.02). No significant associations were found with the other SNPs.

We demonstrate a novel genetic association with neonatal MetHb levels. Identification of genetic risk factors may be useful in determining which preterm infants are most at risk of developing MetHb toxicity with the use of iNO.

Is helical computed tomography angiography the most efficient test to assess vascular calcifications in the iliac arterial sector in renal transplant candidates?

The increased scope of renal transplant indications has lead to a larger number of recipients with vascular problems due to arterial calcifications in the iliac region. Compared to magnetic resonance and conventional arteriography, helical computed tomography angiography (HCTA) accurately depicts arterial diseases, including the location and extent of arterial calcification. The objective of this study was to assess the value of HCTA with maximum-intensity-projection (MIP) reconstruction to evaluate iliac arterial calcifications and stenosis among candidates for renal transplantation. From December 1997 to March 2002, 114 HCTA scans with MIP reconstruction were performed in candidates for renal transplantation. Included patients fulfilled some of the following conditions: (a) older than 55 years, (b) diabetic, (c) second transplants, and (d) obvious vascular calcifications on plain abdominal x-ray. Among the 114 patients, 33 (29%) were excluded for transplantation due to universal calcification of the iliac arterial sector, and 81 (71%) were included on the waiting list due to the presence of calcium-free areas for the vascular anastomosis. Transplantation, which was attempted in 28 of the 81 patients, was successful in 25 using the area programmed after HCTA analysis. The transplants failed in three cases because no calcium-free area could be found upon surgical examination.

HCTA with MIP reconstruction makes it possible to draw an exact map of the arterial calcifications of the iliac arterial sector, allowing better recipient selection and accurate planning for the vascular anastomosis and placement of the renal graft.

Does loss of metacarpal bone density predict RA development in recent-onset arthritis?

Serum samples taken before the onset of RA suggest that one of the first features of RA is BMD loss. We determined the ability of radiographic BMD loss to predict RA development and arthritis persistency in patients with early undifferentiated arthritis (UA). Five hundred and seventeen patients with early UA, included in the Leiden Early Arthritis Clinic, were assessed. Of these, 101 had hand radiographs made at first visit as well as after 6 months. BMD loss was measured using digital X-ray radiogrammetry (DXR) online. The outcome measures fulfilled the 1987 ACR criteria for RA after 1 year and arthritis persistency during a mean follow-up of 7 years. Additionally, it was assessed whether BMD measurements improved predictions compared with a validated prediction rule. A total of 53.8% of UA patients developed RA and 67.5% had persistent disease after 7 years follow-up. Highly elevated BMD loss (≥2.5 mg/cm2/month) was present in 16.3% of patients and associated with RA development [odds ratio (OR) 6.1, 95% CI 1.2, 29.2, positive predictive value (PPV) 85%, negative predictive value (NPV) 52%, sensitivity 26%, specificity 95%]. BMD loss may have an independent effect of anti-CCP when tested in a logistic regression analysis (OR 4.1, 95% CI 0.8, 21.2), although the CI is large. All UA patients that were unclassified with the prediction rule and had highly elevated BMD loss progressed to RA. BMD loss was not significantly associated with arthritis persistency (HR = 0.56, 95% CI 0.14, 2.29).

Present data suggest that BMD loss predicts RA development. These findings need to be verified in larger studies.

Can peptide receptor radionuclide therapy be safely applied in florid bone metastases?

41 PRRT courses were performed in 11 patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET) and florid bone metastases (severely advanced widespread metastatic bone disease). A mean activity of 6.95 GBq 177Lu-octreotate was administered per treatment cycle, aimed at four courses with standard intervals of 3 months. Haematological parameters were determined prior to each treatment course, in 2-4 weeks intervals between the courses, 8-12 weeks after the last course of PRRT and in 3 monthly intervals thereafter. Toxicity was recorded using Common Terminology Criteria for Adverse Events v3.0. Restaging was performed 3 months after termination of PRRT with CT/MRI and functional imaging (modified MDA criteria). Significant (grade III-IV), reversible haematotoxicity occurred in 4 (35%) patients and after 10 (24%) administrations. It either resolved spontaneously (1 patient) or was controlled by supportive measures (3 patients), such as blood transfusions (3 patients) or deferral of the subsequent therapy cycle (1 patient). Patients returned to baseline blood values within up to 23 months after termination of PRRT. The observed treatment response of bone metastases consisted of a partial response in 2, a minor response in 1, stable disease in 7, and progressive disease in 1 patient. Of the 4 patients with metastatic bone pain, 1 experienced complete and 3 partial resolution of symptoms within 3-10 weeks after commencement of PRRT.

These preliminary data indicate that PRRT with 177Lu-octreotate can be safely applied even in florid bone metastases with extensive, severely advanced osseous replacement. The higher myelosuppression rate was not associated with serious complications and should not preclude patients from being treated and potentially experiencing remarkable treatment efficacy despite the very advanced stage.

Do alprazolam use and related harm among opioid substitution treatment clients - 12 months follow up after regulatory rescheduling?

Alprazolam, has been associated with disproportionate harms compared to other benzodiazepines, especially among people in opioid substitution treatment (OST). We examine the effect of the rescheduling of alprazolam in Australia, from Schedule 4 to Schedule 8 in February 2014 amongst a high-risk population of clients in OST. OST participants who reported recent (last month) alprazolam use were recruited from three Sydney clinics. Participants (n=57) were interviewed immediately prior to rescheduling and again three months and 12 months after rescheduling. We examined self-reported patterns of drug use, drug availability, mental and physical health. A linear mixed models approach was used to analyse changes in alprazolam and other benzodiazepine use. Mean days of alprazolam use in the past 28 days decreased from 13.7 to 7.1 days, and mean weekly alprazolam dose decreased from 15.1mg to 6.1mg at 12 months follow-up (p=0.001). Total weekly benzodiazepine use also reduced from a mean of 222mg diazepam equivalent to 157mg (p=0.044). Other substance use did not change significantly. Reported mode of cost price of street alprazolam doubled from $5 to $10 over the 12-month period.

Alprazolam rescheduling resulted in an overall reduction in alprazolam and total benzodiazepine use, without substitution with other drugs, in the short term. Unintended harms were not observed. Rescheduling appears to have been effective in reducing alprazolam use in this high-risk population.

Do eRK1/2 mediate wounding- and G-protein-coupled receptor ligands-induced EGFR activation via regulating ADAM17 and HB-EGF shedding?

Previous studies have shown that wounding of human corneal epithelial cells (HCECs) results in the release of G-protein-coupled receptor ligands such as ATP and lysophosphatidic acid (LPA), which in turn transactivate epidermal growth factor (EGF) receptor (EGFR) through ectodomain shedding of heparin-binding EGF-like growth factor (HB-EGF). In the present study, the role of extracellular signal-regulated kinases 1/2 (ERK1/2) in regulating EGFR transactivation was investigated. SV40-immortalized HCECs were wounded or stimulated with ATP and LPA. EGFR and ADAM17 activation was analyzed by immunoprecipitation followed by Western blot analysis with phospho-tyrosine or phospho-serine antibodies, respectively. Phosphorylation of ERK and AKT was analyzed by Western blot analysis. HB-EGF shedding was assessed by measuring the release of alkaline phosphatase (AP) in a stably transfected human corneal epithelial (THCE) cell line expressing HB-EGF-AP. ADAM17 and ERK interaction was determined by coimmunoprecipitation. Early, but not late, ERK1/2 phosphorylation in response to wounding, LPA, and ATP was EGFR independent, but sensitive to the inhibitors of calcium influx, protein kinase C and Src kinase. Wounding-, LPA-, and ATP-induced HB-EGF shedding and EGFR activation were attenuated by the MAPK/ERK kinase (MEK) inhibitors PD98059 and U0126, as well as by ADAM10 and -17 inhibitors. ADAM17 was found to be physically associated with active ERK and phosphorylated at serine residues in an ERK-dependent manner in wounded cells.

Taken together, our data suggest that in addition to functioning as an EGFR downstream effector, ERK1/2 also mediates ADAM-dependent HB-EGF shedding and subsequent EGFR transactivation in response to a variety of stimuli, including wounding and GPCR ligands.

Does cariporide ( HOE-642 ) improve cardiac allograft preservation in a porcine model of orthotopic heart transplantation?

Acute graft dysfunction caused by ischemia-reperfusion injury is recognized as a major source of morbidity and mortality following adult heart transplantation. The aim of this study was to determine whether treating the donor and recipient with cariporide, an inhibitor of the sodium-hydrogen exchanger, could reduce ischemia-reperfusion injury. A porcine model of donor brain death, hypothermic ischemic preservation, and orthotopic cardiac transplantation was used. Allografts in both the control group (CON, n=6) and treatment group (CAR, n=6) were arrested and stored for 4 hours in the extracellular crystalloid cardioplegia currently used in the clinical transplantation program at our institution. In addition, both the donor and recipient animals in the CAR group received a single intravenous dose of cariporide (2 mg/kg) 15 minutes before harvesting and reperfusion, respectively. The initial rate of troponin I release was significantly lower in recipients of CAR hearts than in recipients of CON hearts (P =0.020). All hearts were weaned successfully from bypass. More CAR hearts were weaned successfully at the first attempt, at 1 hour post-reperfusion, than CON hearts (6 of 6 vs 3 of 6), but this did not achieve statistical significance. Left ventricular contractility (preload recruitable stroke-work relationship) and left ventricular compliance (end-diastolic pressure-volume relationship) were significantly better preserved in CAR hearts than CON hearts (both P <0.0001).

Myocardial injury was reduced, and contractile function was better preserved in allografts that received cariporide, compared with allografts that received conventional preservation alone.

Does overexpression of a stabilized mutant form of the cyclin-dependent kinase inhibitor p27 ( Kip1 ) inhibit cell growth?

The purpose of this study was to test the hypothesis that the expression of the mutant p27(Kip1) protein enhances cell growth inhibition and is more stable than that of the wild-type p27(Kip1). Site-directed mutagenesis was used to mutate threonine 187 to an alanine residue, generating the mutant p27(Kip1). To study the effects of the p27(Kip1) mutant on cell growth, luciferase assays were performed. Cells were transiently transfected with the Renilla luciferase reporter construct and empty vector, wild-type p27(Kip1), or mutant p27(Kip1) using Fugene 6. The transfected cells were lysed and assayed for luciferase activity 24 h later with a dual-luciferase reporter assay system. To further assess the effects of the p27(Kip1) mutant on cell growth, colony count assays were performed. The experiments were repeated in duplicate and a standard two-tailed Student t test was use to analyze the data. Wild-type p27(Kip1) protein has a half-life of approximately 2 h while the p27(Kip1) mutant has a half-life of greater than 12 h. Furthermore, the p27(Kip1) mutant retained the ability to inhibit CDK2-associated H1 kinase activity. Cells expressing the p27(Kip1) mutant had an 88% reduction in luciferase activity compared to cells expressing the wild-type p27(Kip1) (P = 0.001). Colony assays revealed that cells expressing the p27(Kip1) mutant had fewer colonies compared to cells expressing the wild-type p27(Kip1) (P = 0.04).

These data are consistent with the hypothesis that the mutated form of p27(Kip1) is more effective in cell growth inhibition than the wild-type p27(Kip1) protein.

Does parecoxib sodium have opioid-sparing effects in patients undergoing total knee arthroplasty under spinal anaesthesia?

This multicentre, double-blind, placebo-controlled study compared the opioid-sparing effectiveness and clinical safety of parecoxib sodium over 48 h, in 195 postoperative patients after routine total knee replacement surgery. Elective total primary knee arthroplasty was performed under spinal anaesthesia, with a single dose of spinal bupivacaine 10-20 mg, and intraoperative sedation with midazolam 0.5-1.0 mg i.v., or propofol <6 mg kg(-1)h(-1). Patients were randomized to receive either parecoxib sodium 20 mg twice daily (bd) i.v. (n=65), parecoxib sodium 40 mg bd i.v. (n=67), or placebo (n=63) at the completion of surgery, and after 12, 24, and 36 h. Morphine (1-2 mg) was taken by patient-controlled analgesia or by bolus doses after 30 min. Patients receiving parecoxib sodium 20 mg bd and 40 mg bd consumed 15.6% and 27.8% less morphine at 24 h than patients taking placebo (both P<0.05). Both doses of parecoxib sodium administered with morphine provided significantly greater pain relief than morphine alone from 6 h (P<0.05). A global evaluation of study medication demonstrated a greater level of satisfaction among patients taking parecoxib sodium than those taking placebo. Parecoxib sodium administered in combination with morphine was well tolerated. However, a reduction in opioid-type side-effects was not demonstrated in the parecoxib sodium groups.

Parecoxib sodium provides opioid-sparing analgesic effects in postoperative patients.

Do people really know what makes a family history of cancer?

Family history is often referred to as a family tree in casual everyday conservations, but it carries a different connotation in medicine. This study is the first to investigate people's understanding of 'family medical history' and the concept of 'family' in the context of inherited cancer. Three hundred and nine staff at the Faculty of Medicine and Health, University of Leeds completed an online web survey. Not all respondents understood or knew what makes a family history of cancer. Only 54% knew exactly the type of information required to make a family history. Apart from blood relatives, adopted and step-siblings, step parents, in-laws, spouses, friends and colleagues were also named as 'family' for family history taking. Personal experience of living with cancer and academic qualification were not significant in influencing knowledge of family history.

There is misunderstanding and poor knowledge of family history of cancer and the type of information required to make a family history even in a sample of people teaching and researching medicine and health issues. Public understanding of the value of family medical history in cancer prevention and management is important if informed clinical decisions and appropriate health care are to be delivered.

Is blunt assault associated with failure of nonoperative management of the spleen independent of organ injury grade and despite lower overall injury severity?

Nonoperative management (NOM) of blunt splenic injuries has become standard of care for its high success rate. We observe that many blunt assault (BA) patients fail NOM despite lower overall injury severity. We performed this study to determine whether BA is independently associated with failed initial NOM (FiNOM) of splenic injuries. Using the Trauma Registry at our level I center, we reviewed data of all patients with blunt splenic injuries, who did not undergo immediate operative management of the spleen, admitted from January 1, 1992 to December 31, 2007. Initial NOM was defined as any patient who did not undergo immediate (< or =12 hours after admission) operative intervention for the spleen or did not undergo operation for the spleen at any time during the admission. FiNOM was defined as any patient who underwent operative management of the spleen greater than 12 hours after admission. Logistic regression was performed to determine whether BA was independently associated with FiNOM. FiNOM occurred in 57 of the 419 (13.6%) patients initially managed nonoperatively. FiNOM decreased significantly in non-BA patients from 15.8% (1992-1999) to 6.2% (2005-2007) (p = 0.05) over time. This was not true for BA patients (33.3% vs. 30%) (p = 0.78). FiNOM for BA patients was 36.1% (13 of 36) versus 11.5% (44 of 383) for all other mechanisms combined. FiNOM was increased across all Organ Injury Scale scores for the spleen in BA patients. BA was independently associated with FiNOM.

BA is associated with FiNOM independent of severity of splenic injury. Despite an increasingly successful policy of NOM in all blunt splenic injuries, this does not apply for BA. BA should be an important factor considered when initial NOM is contemplated for blunt splenic injury because of the high failure rates compared with all other mechanisms.

Is albumin a better predictor of outcomes than body mass index following coronary artery bypass grafting?

Body mass index (BMI) influences risk in coronary artery bypass grafting (CABG) patients, but albumin level is not collected by the Society of Thoracic Surgeons database. We postulate that preoperative albumin is a better predictor of mortality than BMI following CABG. BMI from patients with serum albumin level within 6 months of isolated CABG during 1995-2010 from our institutional databases were identified. Patients were stratified by National Heart, Lung, and Blood Institute (NHLBI) BMI class, and by preoperative albumin. Regression models were used to assess predictors of morbidity and mortality. We analyzed 2,794 isolated CABG patients at our institution. Unadjusted mortality was highest with lowest BMI (P ≤ .05), and in patients with 2-3 g/dL albumin (P = .02). Ejection fraction (EF) and intra-aortic balloon pump (IABP) use were similar despite BMI; however, EF was lowest and IABP use highest in the 2-3 g/dL albumin group (P < .001, respectively). Unlike BMI groups, increasing albumin was associated with lower major complication rates (P = .001). Similarly, adjusted mortality was not influenced by BMI (AOR 0.97, 95% CI 0.93-1.02), but increasing albumin levels reduced the adjusted odds of death (AOR 0.61, 95% CI 0.42-0.90).

Albumin, more than body mass index, is associated with mortality and morbidity in isolated CABG recipients and may be a better indicator for outcomes.

Does pregnancy differentially impact performance of latent tuberculosis diagnostics in a high-burden setting?

Targeted screening for latent TB infection (LTBI) in vulnerable populations is a recommended TB control strategy. Pregnant women are at high risk for developing TB and likely to access healthcare, making pregnancy an important screening opportunity in developing countries. The sensitivity of the widely-used tuberculin skin test (TST), however, may be reduced during pregnancy. We performed a cross-sectional study comparing the TST with the QuantiFERON Gold In-tube (QGIT) in 401 HIV-negative women presenting antepartum (n = 154), at delivery (n = 148), or postpartum (n = 99) to a government hospital in Pune, India. A subset of 60 women enrolled during pregnancy was followed longitudinally and received both tests at all three stages of pregnancy. The QGIT returned significantly more positive results than the TST. Of the 401 women in the cross-sectional study, 150 (37%) had a positive QGIT, compared to 59 (14%) for the TST (p<0.005). Forty-nine (12%) did not have their TST read. Of 356 who had both results available, 46 (13%) were concordant positive, 91 (25%) were discordant (12 (3%) TST+/QGIT-; 79 (22%) TST-/QGIT+), and 206 (57%) concordant negative. Comparison by stage of pregnancy revealed that QGIT percent positivity remained stable between antepartum and delivery, unlike TST results (QGIT 31-32% vs TST 11-17%). Median IFN-γ concentration was lower at delivery than in antepartum or postpartum (1.66 vs 2.65 vs 8.99 IU/mL, p = 0.001). During postpartum, both tests had significantly increased positives (QGIT 31% vs 32% vs 52%, p = 0.01; TST 17% vs 11% vs 25%, p<0.005). The same trends were observed in the longitudinal subset.

Timing and choice of LTBI test during pregnancy impact results. QGIT was more stable and more closely approximated the LTBI prevalence in India. But pregnancy stage clearly affects both tests, raising important questions about how the complex immune changes brought on by pregnancy may impact LTBI screening.

Does attentional control mediate fearful responding to an ecologically valid stressor?

Attentional control (AC) is defined as the ability to voluntarily shift and disengage attention and is thought to moderate the relationship between preexisting risk factors for fear and the actual experience of fear. This longitudinal study elaborates on current models of AC by examining whether AC moderates or mediates effects of an ecologically valid stressor (a college examination) and also whether AC is predictive of state-like fear over longer timescales than previously reported. Based on previous findings, we hypothesized that AC would moderate the relationship between trait anxiety and affective distress in response to the examination stressor. We also tested a competing mediational model based on AC theory. These models were tested in two separate samples (sample 1, N = 219; sample 2, N = 129; Total N = 348) at two time points, at the beginning of a college semester in a large undergraduate class and 5 minutes prior to a college examination. Mediation but not moderation of anxiety by AC was supported in both samples using multiple dependent measures.

We conclude that AC may be useful in predicting affective distress in naturalistic settings, particularly in cases where anxiety is anticipatory.

Is white matter altered with parental family history of Alzheimer 's disease?

Brain alterations in structure and function have been identified in people with risk factors for sporadic type Alzheimer's disease (AD), suggesting that alterations can be detected decades before AD diagnosis. Although the effect of apolipoprotein E (APOE) varepsilon4 on the brain is well-studied, less is known about the effect of family history of AD. We examined the main effects of family history and APOE varepsilon4 on brain integrity, in addition to assessing possible additive effects of these two risk factors. Diffusion tensor imaging was performed in 136 middle-aged asymptomatic participants stratified on family history and APOE varepsilon4. Mean diffusivity and fractional anisotropy (FA) were entered in factorial analyses to test the effect of AD risk on microstructural brain integrity. We performed a post hoc analysis of the three principal diffusivities (lambda1, lambda2, lambda3) to provide potential additional insight on underlying tissue differences. Parental family history of AD was associated with lower FA in regions of the brain known to be affected by AD, including cingulum, corpus callosum, tapetum, uncinate fasciculus, hippocampus, and adjacent white matter. Contrary to previous reports, there was no main effect of APOE varepsilon4; however, there was an additive effect of family history and APOE varepsilon4 in which family history-positive participants who were also APOE varepsilon4 carriers had the lowest FA compared with the other groups.

The data indicate that unknown risk factors contained in family history are associated with changes in microstructural brain integrity in areas of the brain known to be affected by AD. Importantly, the results provide further evidence that AD pathology might be detected before cognitive changes, perhaps decades before disease onset.

Do signal transduction protein array analysis links LRRK2 to Ste20 kinases and PKC zeta that modulate neuronal plasticity?

Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease, however, the underlying pathogenic mechanisms are poorly understood. Several in vitro studies have shown that the most frequent mutation, LRRK2(G2019S), increases kinase activity and impairs neuronal survival. LRRK2 has been linked to the mitogen-activated protein kinase kinase kinase family and the receptor-interacting protein kinases based on sequence similarity within the kinase domain and in vitro substrate phosphorylation. We used an unbiased proteomic approach to identify the kinase signaling pathways wherein LRRK2 may be active. By incubation of protein microarrays containing 260 signal transduction proteins we detected four arrayed Ste20 serine/threonine kinase family members (TAOK3, STK3, STK24, STK25) as novel LRRK2 substrates and LRRK2 interacting proteins, respectively. Moreover, we found that protein kinase C (PKC) zeta binds and phosphorylates LRRK2 both in vitro and in vivo.

Ste20 kinases and PKC zeta contribute to neuronal Tau phosphorylation, neurite outgrowth and synaptic plasticity under physiological conditions. Our data suggest that these kinases may also be involved in synaptic dysfunction and neurite fragmentation in transgenic mice and in human PD patients carrying toxic gain-of-function LRRK2 mutations.

Does prevalence and correlate of probable adolescent mental health problems reported by parents in Vietnam?

The purpose of the present study was to estimate the prevalence of probable mental health problems in an epidemiologic study of Vietnamese adolescents. A secondary aim was to examine the correlates of probable mental health caseness. Interviewers visited 1,914 households that were randomly selected to participate in a multi-agency study of mental health in select provinces of Vietnam. Semi-structured interviews assessed adolescent mental health problems using the Strengths and Difficulties Questionnaire (SDQ) parent informant version, and additionally the interviewers collected information on demographic variables (age, gender, ethnic group, religious affiliation, social capital). The final sample included data on 1,368 adolescents (aged 11-18 years). The average score on the total problem composite of the SDQ scale was 6.66 (SD=4.89), and 9.1% of the sample was considered a case (n=124). Bivariate analyses were conducted to determine which demographic variables were related to the SDQ case/non-case score. All variables except gender were significant in bivariate analyses, and therefore were entered into a logistic regression. Results indicated that age, religion, and wealth remained significant predictors of probable caseness.

Overall, prevalence estimates of mental health problems generated by the SDQ were consistent with those reported in the US and other Western and non-Western samples. Results of the current study suggest some concordance of risk and protective factors between Western and Vietnamese youth (i.e., age and SES).

Is minichromosome maintenance protein 7 a risk factor for recurrence in patients with Dukes C colorectal cancer?

It has been hypothesized that minichromosome maintenance (MCM) proteins, which are replicative control factors, can be used to detect tumor proliferation. The aim of the present study was to investigate the expression of MCM in colorectal cancer tissues and correlate it to clinical outcomes. The study included 145 patients with colorectal cancer who underwent curative surgery, from January 2002 until December 2004, at the Kurume University Hospital in Fukuoka, Japan. The median follow-up duration was 87 months. The expression of MCM7 in tissues was studied by immuno-histochemical staining. The labeling index (LI) of MCM7 was calculated by dividing the number of positively-stained cells by the total number of cells counted. We divided samples into two groups: positive (MCM7 LI 76% or higher) and negative (MCM7 LI less than 76%). In patients with Dukes A and B, there were no significant differences in either overall survival (OS) or recurrence-free survival (RFS) between patents with MCM7-positive and those with MCM7-negative disease. On the other hand, in patients with Dukes C, there was significantly worse OS and RFS for patients with MCM7-positive compared to those with MCM7-negative disease.

We found that the expression of MCM7 is an independent risk factor for RFS in patients with Dukes C colorectal cancer. Further studies are required to investigate the validity of MCM7 protein expression for its potential clinical use in colorectal cancer therapy and prognosis.

Does overexpression of Hsp70 confer cytoprotection during gliadin exposure in Caco-2 cells?

In Celiac disease (CD), cytoskeletal integrity of intestinal cells is disrupted by gliadin exposure. This study investigates the role of heat shock protein (Hsp)70 during cytoskeletal recovery in CD by assessing its induction and effects on junctional proteins. Using an in-vitro model of CD, cytoskeletal injury and recovery was assessed in gliadin-exposed Caco-2 cells by measuring cellular distribution of ezrin, E-cadherin, and Hsp70 by differential centrifugation. Effects of Hsp70 were tested by an in-vitro repair assay, based on the incubation of injured or recovered cytoskeletal cellular fractions in noncytoskeletal supernatants containing low or high levels of Hsp70, or by transient transfection of Caco-2 cells with Hsp70. Cytoskeletal disruption of ezrin and E-cadherin was demonstrated in gliadin-exposed Caco-2 cells by their significant shift from the cytoskeletal pellet into the noncytoskeletal supernatant fraction. Recovery from gliadin exposure was associated with induction and cytoskeletal redistribution of Hsp70. The in-vitro repair assay delineated direct evidence for HSP-mediated repair by stabilization of junctional proteins by Hsp70. Overexpression of Hsp70 resulted in significantly increased cytoskeletal integrity.

Our results establish an essential role of HSP-mediated cytoskeletal repair in Caco-2 cells during recovery from in-vitro gliadin exposure.

Is subclinical elevation of high-sensitive troponin T levels at the convalescent stage associated with increased 5-year mortality after ST-elevation myocardial infarction?

It is unclear whether serum high-sensitive troponin T (hs-TnT) levels at the convalescent stage of ST-elevation myocardial infarction (STEMI) are associated with long-term mortality. This study enrolled a total of 2944 consecutive STEMI patients who were registered in the Osaka Acute Coronary Insufficiency Study between 2000 and 2009, and whose hs-TnT levels were evaluated at the convalescent stage. Patients were divided into four hs-TnT category groups according to the results of survival classification and regression tree (CART) analysis. The impact of hs-TnT levels on 5-year mortality was evaluated using multivariate Cox regression analysis. Only one patient had hs-TnT level below the detection limit of the assay (<0.003ng/mL). The median hs-TnT level was 0.025 (quartile 0.011-0.083)ng/mL. During the median follow-up period of 1782 days, 188 patients died. Survival CART analysis revealed that the 1st, 2nd, and 3rd discriminating hs-TnT levels to discern 5-year mortality were 0.028, 0.008, and 1.340ng/mL, respectively. The adjusted hazard ratios for the medium-low (0.009-0.028ng/mL), medium-high (0.029-1.340ng/mL), and high-risk (≥1.341ng/mL) groups were 3.03 (95% confidence interval 1.18-7.77, p=0.021), 4.29 (1.63-11.28, p=0.003), and 8.68 (2.20-34.27, p=0.002), respectively. Integrated discrimination improvement (IDI) analysis revealed that incorporation of this hs-TnT classification scheme with other clinical variables statistically improved the discriminatory accuracy for 5-year mortality, with a time-dependent IDI of 0.0076 (p=0.033).

hs-TnT levels at the convalescent stage were associated with long-term mortality in STEMI patients. Even subclinical elevation of hs-TnT levels was associated with increased 5-year mortality.

Is signal transducer and activator of transcription 3 involved in cell growth and survival of human rhabdomyosarcoma and osteosarcoma cells?

Stat3 has been classified as a proto-oncogene and constitutive Stat3 signaling appears to be involved in oncogenesis of human cancers. However, whether constitutive Stat3 signaling plays a role in the survival and growth of osteosarcomas, rhabdomyosarcomas, and soft-tissue sarcomas is still unclear. To examine whether Stat3 is activated in osteosarcomas, rhabdomyosarcomas and other soft-tissue sarcomas we analyzed sarcoma tissue microarray slides and sarcoma cell lines using immunohistochemistry and Western blot analysis, respectively, with a phospho-specific Stat3 antibody. To examine whether the activated Stat3 pathway is important for sarcoma cell growth and survival, adenovirus-mediated expression of a dominant-negative Stat3 (Y705F) and a small molecule inhibitor (termed STA-21) were used to inhibit constitutive Stat3 signaling in human sarcoma cell lines expressing elevated levels of Stat3 phosphorylation. Cell viability was determined by MTT assays and induction of apoptosis was analyzed by western blotting using antibodies that specifically recognize cleaved caspases-3, 8, and 9. Stat3 phosphorylation is elevated in 19% (21/113) of osteosarcoma, 27% (17/64) of rhabdomyosarcoma, and 15% (22/151) of other soft-tissue sarcoma tissues as well as in sarcoma cell lines. Expression of the dominant-negative Stat3 and treatment of STA-21 inhibited cell viability and growth and induced apoptosis through caspases 3, 8 and 9 pathways in human sarcoma cell lines expressing elevated levels of phosphorylated Stat3.

This study demonstrates that Stat3 phosphorylation is elevated in human rhabdomyosarcoma, osteosarcomas and soft-tissue sarcomas. Furthermore, the activated Stat3 pathway is important for cell growth and survival of human sarcoma cells.

Endocervical crypt involvement by high-grade cervical intraepithelial neoplasia after large loop excision of transformation zone: do we need a different follow-up strategy?

The aim of this study was to determine the effect of endocervical crypt involvement in specimens with clear margins on recurrence following large loop excision of transformation zone (LLETZ). This was an observational cohort study. In the colposcopy unit in a university teaching hospital we prospectively collected data for women who underwent LLETZ treatment for high-grade cervical intraepithelial neoplasia (CIN) between 2003 and 2004. We determined the difference in recurrence rate and need for repeat treatment between groups with and without crypt involvement in the primary histology. We prospectively collected data of follow up until 2010. The recurrence was analyzed using Cox regression. A total of 309 women had complete excision of the margins following LLETZ treatment for CIN 2 or 3. There was no significant difference in age between groups with (30.2) and without (29.7) crypt involvement (P<0.25). There was a significant difference in the prevalence of abnormal smear results before and after LLETZ between groups with or without crypt involvement (P=0.043). The need to perform a repeated treatment was significantly different between groups with and without crypt involvement (P<0.024). A full model significantly predicted recurrence of cervical pathology (P<0.009) that necessitated treatment when crypt involvement was present. The odds ratio for repeat treatment with crypt involvement was 2.67 (confidence interval, 1.27-5.64).

Our study showed that positive involvement of endocervical crypt by CIN in a cervical loop excision specimen increases the frequency of subsequent episodes of treatment.

Is operant responding for conditioned and unconditioned reinforcers in rats differentially enhanced by the primary reinforcing and reinforcement-enhancing effects of nicotine?

Nicotine self-administration in rats is modest when response-contingent nicotine infusions are delivered alone (primary reinforcement) but robust when nicotine infusions are combined with a mildly reinforcing non-pharmacological stimulus. Furthermore, response-independent (non-contingent) nicotine administration also elevates responding for that same non-pharmacological stimulus, suggesting that in addition to primary reinforcement, nicotine can enhance the incentive value of other reinforcers. In this study, we tested the hypothesis that the reinforcement-enhancing effects of non-contingent nicotine are more dependent on the reinforcing strength of the non-pharmacological stimulus than are the effects of contingent nicotine. A weakly reinforcing light-tone stimulus was established as a conditioned reinforcer by repeated pairings with sucrose for some rats, or by delivery in an explicitly unpaired design with sucrose to other rats. Subsequently, both groups lever pressed for the stimulus with contingent nicotine, non-contingent nicotine (0.06 mg kg(-1) per infusion, freebase), or non-contingent saline, according to fixed ratio and progressive ratio reinforcement schedules. Compared to sucrose-unpaired training, repeated association with sucrose established the light-tone stimulus as a robust conditioned reinforcer. Contingent and non-contingent nicotine equally elevated responding for this conditioned stimulus. Conversely, for the less reinforcing (sucrose-unpaired) stimulus contingent nicotine more effectively elevated behavior compared to non-contingent nicotine.

The reinforcement-enhancing effect of nicotine increases behavior controlled by both conditioned and unconditioned reinforcers; however, for less salient stimuli associative processes derived from the primary reinforcing effects of contingent nicotine may also be important. These data suggest that nicotine present in tobacco may differentially modulate stimulus-driven behavior in smokers.

Does the subspecialty of the surgeon performing primary colonic resection influence the outcome of patients with hepatic metastases referred for resection?

To compare resection rates and outcome of patients subsequently referred with hepatic metastases whose initial colon cancers were resected by surgeons with different specialty interests. Variation in practice among noncolorectal specialist surgeons has led to recommendations that colorectal cancers should be treated by surgeons trained in colorectal surgery or surgical oncology. The resectability of metastases, the frequency and pattern of recurrence after resection, and the length of survival were compared in patients referred to a single center for resection of colorectal hepatic metastases. The patients were divided into those whose colorectal resection had been performed by general surgeons (GS) with other subspecialty interests (n = 108) or by colorectal specialists (CS; n = 122). RESULTS No differences were observed with respect to age, sex, tumor stage, site of primary tumor, or frequency of synchronous metastases. Comparing the GS group with the CS group, resectable disease was identified in 26% versus 66%, with tumor recurrence after a median follow-up of 19 months in 75% versus 44%, respectively. Recurrences involving bowel or lymph nodes accounted for 55% versus 24% of all recurrences, with respective median survivals of 14 months versus 26 months.

Fewer patients referred by general surgeons had resectable liver disease. After surgery, recurrent tumor was more likely to develop in the GS group; their overall outcome was worse than that of the CS group. This observation is partly explained by a lower local recurrence rate in the CS group.

Viable malignant germ cell tumor in the postchemotherapy retroperitoneal lymph node dissection specimen: can it be predicted using clinical parameters?

The presence of viable tumor in the surgical specimen after postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) is associated with an increased risk of disease progression. The objective of this study was to determine whether the presence of viable tumor in the surgical specimen could be predicted. Between 1980 and 2003, 236 patients underwent PC-RPLND for clinical Stage IIA or III nonseminomatous germ cell tumors (NSGCT). The authors retrospectively reviewed the medical records of those patients for pertinent clinical and treatment-related outcomes. A multivariate logistic regression analysis was used to evaluate whether clinical parameters were capable of predicting the presence of viable tumor in the surgical specimen. International Germ Cell Consensus Classification (IGCCC) risk categories could be assigned to 218 patients, with 101 patients in the good-risk category, 32 patients in the intermediate-risk category, and 85 patients in the poor-risk category. The incidence of viable tumor in the good-risk, intermediate-risk, and poor-risk categories was similar (17.8%, 15.6%, and 15.3%, respectively); however, the risk categories predicted disease-specific and recurrence-free survival (P = .022 and P<.0001, respectively). On multivariate analysis, an elevated serum alpha-fetoprotein (AFP) level prior to PC-RPLND (P = .05) and the size of the retroperitoneal mass on pathology review (P = .02) were predictive of viable tumor in the surgical specimen.

Although IGCCC risk categories were correlated with disease-related outcomes, the risk groups had similar incidences of viable tumor. Elevated serum AFP levels prior to surgery and the size of the retroperitoneal mass in the resected specimen may help to predict viable tumor in the PC-RPLND specimen.

Getting Started with Minimally Invasive Pancreaticoduodenectomy: Is It Worth It?

This study evaluates the safety and cost of introducing minimally invasive pancreaticoduodenectomy (MIPD) to a surgeon's practice. All MIPDs performed between December 2011 and July 2013 were compared with open pancreaticoduodenectomy (OPD) cases by the same surgeon. The primary outcomes were mortality, major morbidity, and re-operation. Secondary outcomes were perioperative and oncologic outcomes and cost. MIPD include total laparoscopic pancreaticoduodenectomy (TLPD) and laparoscopic-assisted pancreaticoduodenectomy (LAPD), where a small incision is used for reconstruction. Bivariate comparisons of outcomes were performed using nonparametric tests. In total, 44 pancreaticoduodenectomies were performed: 15 MIPDs (2 TLPDs and 13 LAPDs) and 29 OPDs. One death occurred in each group. Major complication rates were not significantly different (33% for MIPD versus 17% for OPD); however, there was a trend toward more re-operation after MIPD compared with OPD (20% versus 3%; P = .07). The incidence of pancreatic leak (20% for MIPD versus 14% for OPD), biliary leak (0% versus 7%, respectively), abscess formation (27% versus 14%, respectively), and intraabdominal hemorrhage (13% versus 3%, respectively) were not significantly different. MIPD achieved equivalent oncologic outcomes as OPD with 100% R0 margin and adequate lymph node retrieval. There was no statistical difference in median operative time (342 minutes for MIPD versus 358 minutes for OPD), length of stay (8 versus 9 days, respectively), operating room expenses (Canadian) ($7246.0 versus $6912.0, respectively), or total cost (Canadian) per case ($15,034.0 versus $18,926.0, respectively).

MIPD and OPD had similar safety and cost in this introductory series. However, a trend toward a higher rate of re-operation for pancreatic leak suggests the need for caution in introducing this novel technique.

Is the ECEL1-related strabismus phenotype consistent with congenital cranial dysinnervation disorder?

Congenital cranial dysinnervation disorders (CCDDs) are phenotypes of congenital incomitant strabismus and/or ptosis related to orbital dysinnervation. CCDDs have been associated with dominant or recessive monogenic mutations in at least 7 different genes (CHN1, SALL4, HOXA1, KIF21A, PHOX2A, TUBB3, ROBO3) that cause phenotypes such as Duane retraction syndrome, congenital fibrosis of the extraocular muscles, and horizontal gaze palsy with progressive scoliosis. Recently, arthrogryposis with or without strabismus has been shown to be caused by recessive mutations in ECEL1, a gene likely involved in neuromuscular junction formation. The strabismus phenotype in ECEL1-related cases has not always been detailed but may be a form of CCDD. To better define the ECEL1-related ophthalmic phenotype, we detail ophthalmic findings in 4 affected siblings from a consanguineous family and review documented ophthalmic findings for other reported mutation-positive cases. Affected family members were prospectively examined and the relevant literature was reviewed. Ophthalmic findings were present in 3 of the 4 siblings with ECEL1-related distal arthrogryposis: bilateral ptosis with bilateral congenital fibrosis of the extraocular muscles, right ptosis with ipsilateral Y exotropia (exotropia increasing in upgaze), and right ptosis with ipsilateral Duane retraction syndrome. The fourth affected sibling, who had the mildest arthrogryposis, had no ophthalmic abnormalities. Of 26 other reported recessive ECEL1 mutation cases (14 families), all had arthrogryposis, 19 had documented ptosis, and 4 had documented complex strabismus. One of these cases had both documented ptosis and complex strabismus.

Our clinical findings are consistent with recessive ECEL1 mutations causing variably penetrant orbital dysinnervation phenotypes (ptosis and/or complex strabismus with abnormal synkinesis) in the context of arthrogryposisis, that is, with the ECEL1-related ophthalmic phenotype being a form of CCDD.

Do imipenem-resistant Pseudomonas aeruginosa strains carry metallo-beta-lactamase gene bla ( VIM ) in a level I Iranian burn hospital?

In this study, we aimed to determine the distribution of bla(VIM) and bla(IMP) transferable genes in Pseudomonas aeruginosa isolates from infected burn wounds in an Iranian level I burn care center. These genes confer imipenem resistance and increase the mortality rate of burn patients. P. aeruginosa isolates from burn patients were tested for antibiotic susceptibility with Kirby-Bauer disk diffusion method and for production of metallo-beta-lactamase (MBL) by EDTA disk method. DNA was purified from isolates with positive MBL results and underwent PCR for detection of bla(VIM) and bla(IMP) genes. MBL was produced by 23 imipenem-resistant isolates and bla(VIM) gene was detected in all of these isolates. None of the isolates carried bla(IMP) gene. Mortality rate of infection with MBL-producing Pseudomonas strains was 82.6% in this hospital while the mortality rate for non-MBL-producing Pseudomonas was 22.7%.

We found that all MBL-producing isolates in this hospital carry bla(VIM) gene. This result is similar to the previous Iranian study and emphasizes the importance of VIM family of MBLs in Iran. Timely identification of these strains and strict isolation methods can prevent spread of this transferable gene to other Gram-negative bacteria and prevent the subsequent outbreak of high mortality.

Are plasma levels of leptin associated with the plasma levels of LDL conjugated dienes in children?

Plasma leptin has been suggested to be involved in the proatherogenic process by increasing oxidative stress. We investigated the relationship between leptin and plasma conjugated diene formation, a measure of LDL oxidation in vivo in schoolchildren. We measured blood lipid profiles, plasma antioxidant vitamins, leptin and diene conjugation in LDL of 118 Korean children (35 overweight-obese vs. 83 normal weight children). The overweight-obese children showed significantly higher levels of leptin (p < 0.0001), conjugated dienes (p = 0.02), total cholesterol (p < 0.05), triglyceride (p < 0.005) and LDL cholesterol (p < 0.01) and a significantly lower level of plasma lycopene (p < 0.0001) compared with the normal weight children. When all the subjects were classified into the three groups by tertiles of leptin levels, significant differences in circulating conjugated dienes (p < 0.05), lipid-corrected lycopene (p < 0.05), total cholesterol (p < 0.05), triglyceride (p < 0.05) and LDL cholesterol (p < 0.05) were found among the three groups.

Our results showed that leptin was positively associated with the LDL conjugated diene formation, which might be related to the proatherogenic process in schoolchildren.

Is autonomic reflex dysfunction in patients presenting for elective surgery associated with hypotension after anesthesia induction?

Autonomic reflex dysfunction in patients with diabetes is associated with an increased incidence of hypotension after induction of anesthesia. Whether this finding can be extrapolated to patients with autonomic dysfunction from other causes (e.g., advanced age, hypertension, altered ventricular function) has not been established. The authors investigated whether autonomic reflex dysfunction in a more generalized patient group (26 consecutively consenting day-surgery patients older than 39 yr) was similarly associated with the occurrence of hypotension after induction. Preoperative tests of autonomic function included: Valsalva maneuver, change in heart rate with forced breathing, change in heart rate and blood pressure with standing, and spectral analysis of heart rate variability. Anesthesia was induced with 3-5 mg/kg thiopental, 2 micrograms/kg fentanyl, and 60% N2O; 0.1 mg/kg vecuronium was used for paralysis; 0-1.5% isoflurane was added for maintenance of anesthesia after intubation. Noninvasive measurements of mean blood pressure were obtained every minute for 10 min after induction and then every 3 min until skin incision. Twelve patients developed hypotension (mean blood pressure < 70 mmHg), and 14 patients did not. Measurements of autonomic reflex function were significantly more abnormal in the patients who developed hypotension (P < 0.006 for Valsalva measurements, heart rate variability parameters, and change in heart rate with forced breathing). Using critical test values for autonomic tests, the incidence of hypotension was 67-83% in patients with autonomic nervous system dysfunction versus 9-17% in other patients.

The results document that: (1) some degree of autonomic reflex dysfunction is not uncommon in patients older than 39 yr presenting for elective surgery, and (2) such dysfunction is associated with an increased incidence of hypotension when using the described induction technique.

Is persistent diastolic flow reversal in abdominal aortic Doppler-flow profiles associated with an increased risk of necrotizing enterocolitis in term infants with congenital heart disease?

Diastolic runoff in the abdominal aorta, with subsequent circulatory mesenteric insufficiency, has been postulated as a cause of necrotizing enterocolitis in term infants with congenital heart disease. With this study we sought to determine whether Doppler-flow characteristics in the abdominal aorta can predict which infants are at specific risk, independent of gestational age and type of congenital heart disease. We conducted a case-control study of term infants with congenital heart disease and proven necrotizing enterocolitis (n = 18) compared with gestational age-matched and diagnosis-matched control subjects (n = 20). Abdominal aortic Doppler velocities, time intervals, and reversals were analyzed. Groups were compared, and independent risk factors for necrotizing enterocolitis were determined. The groups were similar with regard to weight, pulse pressure, use of prostaglandins or inotropes, presence of a patent ductus arteriosus, and systolic function. However, 47% of the case subjects with necrotizing enterocolitis had persistent retrograde diastolic flow in the abdominal aorta compared with 15% of the control subjects. When adjusting for multiple risk factors, persistent diastolic flow reversal remained the only factor significantly associated with necrotizing enterocolitis.

Persistent diastolic flow reversal in the abdominal aortic Doppler profile is associated with an increased risk of necrotizing enterocolitis in term infants with congenital heart disease irrespective of gestational age or anatomic type of congenital heart disease.

Are fetal breathing movements in oligohydramnios increased by aminoinfusion?

To determine whether fetal breathing movements (FBM) in pregnancies with oligohydramnios change with restoration of amniotic fluid volume. A prospective experimental study. Fetal Medicine Unit, tertiary referral hospital. 16 women with singleton pregnancies complicated by severe oligohydramnios. Restoration of amniotic fluid volume by transabdominal amnioinfusion. Controls comprised pregnancies in which infused fluid leaked vaginally, so that oligohydramnios was not corrected. Change in total breathing movements, change in FBM incidence derived from 40 min recordings immediately before and after amnioinfusion. There was no significant difference in the change in total breathing movements or in the change in incidence of FBM between the 10 pregnancies in which amniotic fluid volume was restored, and the other six in which fluid leaked after infusion and volume was not restored. In both groups, there was no significant change with infusion in number of FBM (mean change -72, 95% CI -218 to +74 in the fluid-retained group and -64, 95% CI -273 to +145 in the fluid-leaked group) and incidence of FBM (median change -2.5%, range -27 to +10 in the fluid retained group and -4.5%, range -34 to +15 in the fluid-leaked group).

This study suggests that restitution of amniotic fluid volume in human pregnancies complicated by severe oligohydramnios does not acutely alter the incidence of FBM. These data support an increasing literature suggesting that impairment of fetal breathing is not the mechanism for oligohydramnios-related pulmonary hypoplasia.

Is collagen triple helix repeat containing 1 a new promigratory marker of arthritic pannus?

The formation of destructive hypercellular pannus is critical to joint damage in rheumatoid arthritis (RA). The collagen triple helix repeat containing 1 (CTHRC1) protein expressed by activated stromal cells of diverse origin has previously been implicated in tissue remodeling and carcinogenesis. We recently discovered that the synovial Cthrc1 mRNA directly correlates with arthritis severity in mice. This study characterizes the role of CTHRC1 in arthritic pannus formation. Synovial joints of mice with collagen antibody-induced arthritis (CAIA) and human RA-fibroblast-like synoviocytes (FLS) were immunostained for CTHRC1, FLS and macrophage-specific markers. CTHRC1 levels in plasma from patients with RA were measured using sandwich ELISA. The migratory response of fibroblasts was studied with a transwell migration assay and time-lapse microscopy. Velocity and directness of cell migration was analyzed by recording the trajectories of cells treated with rhCTHRC1. Immunohistochemical analysis of normal and inflamed synovium revealed highly inducible expression of CTHRC1 in arthritis (10.9-fold). At the tissue level, CTHRC1-expressing cells occupied the same niche as large fibroblast-like cells positive for α-smooth muscle actin (α-SMA) and cadherin 11 (CDH11). CTHRC1 was produced by activated FLS predominantly located at the synovial intimal lining and at the bone-pannus interface. Cultured RA-FLS expressed CDH11, α-SMA, and CTHRC1. Upon treatment with exogenous rhCTHRC1, embryonic fibroblasts and RA-FLS significantly increased migration velocity, directness, and cell length along the front-tail axis (1.4-fold, p < 0.01).

CTHRC1 was established as a novel marker of activated synoviocytes in murine experimental arthritis and RA. The pro-migratory effect of CTHRC1 on synoviocytes is considered one of the mechanisms promoting hypercellularity of the arthritic pannus.

Is thyroxine transfer from cerebrospinal fluid into choroid plexus and brain affected by brefeldin A , low sodium , BCH , and phloretin , in ventriculo-cisternal perfused rabbits?

Thyroxine (T4) hormone is synthesized by the thyroid gland and then released into the systemic circulation where it binds to a number of proteins. Dysfunction in T4 transport mechanisms has been demonstrated in multiple central nervous system (CNS) diseases including Alzheimer's disease. In the presence of different compounds that inhibit potential T4 transport mechanisms, this study investigated the transfer of T4 from cerebrospinal fluid (CSF) into Choroid Plexus (CP) and other brain tissues. The compounds used were brefeldin A, low sodium artificial CSF (aCSF), BCH, phloretin, and taurocholate (TA). Radiolabeled T4 ((125)I-T4) was perfused continuously into the CSF and was assessed in several brain compartments with reference molecule (14)C-mannitol and blue dextran, using the in vivo ventriculo-cisternal perfusion (V-C) technique in the rabbit. The aCSF containing the drug of interest was infused after 1 h of perfusion. Drugs were applied independently to the aCSF after 1 h of control perfusion. Of interest, in presence of low sodium or BCH, the percentage recovery of (125)I-T4, was increased compared to controls, with concomitant increase in T4 clearance. Conversely, brefeldin A, phloretin, and TA did not exert any significant effect on the recovery and clearance of (125)I-T4 assessed in aCSF. On the other hand, the uptake of (125)I-T4 into CP was raised by 18 fold compared to controls in the presence of brefeldin A. In addition, low sodium, BCH, or phloretin alone, enhanced the uptake of (125)I-T4 by almost 3-fold, whereas TA did not show any significant effect. Finally, the uptake and distribution of (125)I-T4 into other brain regions including ependymal region (ER) and caudate putamen (CAP) were significantly higher than in controls.

Our study suggests the involvement of different mechanisms for the transfer of (125)I-T4 from CSF into CP and other brain regions. This transfer may implicate sodium-dependent mechanisms, amino acid "L" system, or organic anion transporting polypeptide (OATP).

Do conicity Index and Waist-to-Hip Ratio Are Superior Obesity Indices in Predicting 10-Year Cardiovascular Risk Among Men and Women?

Central obesity has been recognized as a main risk factor for cardiovascular (CV) events. Three popular central obesity indices are waist circumference, waist-to-hip ratio (WHR), and waist-to-height ratio; abdominal volume index and conicity index are 2 recent novel obesity indices. The main aim of this study is to determine the performance of these indices to best predict 10-year CV events. Some obesity indices can be used to predict cardiovascular risk. In total, 3199 subjects (age range, 40-79 years) were enrolled in this cross-sectional study. The American College of Cardiology/American Heart Association and Framingham risk score tools were used to estimate the 10-year CV events. Receiver operating characteristic curve analysis was used to determine the optimal discriminator(s) among the central obesity measures in the estimation of a 10-year risk of CV events ≥7.5%, ≥10%, and ≥20% separately. Among the 5 central obesity indices, conicity index showed the most discriminatory power in estimation of a 10-year CV risk. In men, based on the American College of Cardiology/American Heart Association tool, the areas under the curve (AUCs) were from 0.671 to 0.682 based on the 3 above thresholds, whereas with the Framingham tool, AUCs were from 0.651 to 0.659. In women, all AUCs were >0.7. Our results also showed WHR to be an almost comparable discriminator of CV disease risk in the Iranian study population.

Conicity index and WHR had a more discriminatory accuracy for 10-year CV events compared with the other obesity indices.

Do cPU86017-RS attenuate hypoxia-induced testicular dysfunction in mice by normalizing androgen biosynthesis genes and pro-inflammatory cytokines?

Downregulation of androgen biosynthesis genes StAR (steroidogenic acute regulatory) and 3β-HSD (3β-hydroxysteroid dehydrogenase) contributes to low testosterone levels in hypoxic mice and is possibly related to increased expression of pro-inflammatory cytokines in the testis. The aim of this study is to investigate the effects of CPU86017-RS that block Ca(2+) influx on hypoxia-induced testis insult in mice. Male ICR mice were divided into 5 groups: control group, hypoxia group, hypoxia group treated with nifedipine (10 mg/kg), hypoxia groups treated with CPU86017-RS (60 or 80 mg/kg). Hypoxia was induced by placing the mice in a chamber under 10%±0.5% O2 for 28 d (8 h per day). The mice were orally administered with drug in the last 14 d. At the end of experiment the testes of the mice were harvested. The mRNA and protein levels of StAR, 3β-HSD, connexin 43 (Cx43), matrix metalloprotease 9 (MMP9), endothelin receptor A (ET(A)R) and leptin receptor (OBRb) were analyzed using RT-PCR and Western blotting, respectively. The malondialdehyde (MDA), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH) and acid phosphatase (ACP) levels were measured using biochemical kits. Serum testosterone concentration was measured with radioimmunoassay. Hypoxia significantly increased the MDA level, and decreased the LDH, ACP and SDH activities in testes. Meanwhile, hypoxia induced significant downregulation of StAR and 3β-HSD in testes responsible for reduced testosterone biosynthesis. It decreased the expression of Cx43, and increased the expression of MMP9, ETAR and OBRb, leading to abnormal testis function and structure. These changes were effectively diminished by CPU86017-RS (80 mg/kg) or nifedipine (10 mg/kg).

Low plasma testosterone level caused by hypoxia was due to downregulation of StAR and 3β-HSD genes, in association with an increased expression of pro-inflammatory cytokines. These changes can be alleviated by CPU86017-RS or nifedipine.

Robot-assisted epicardial ablation of the pulmonary veins: is a completed isolation necessary?

To study the feasibility and electrophysiological efficacy of minimally invasive beating heart ablation of the pulmonary veins (PVs) via a robot-assisted single-sided approach. PV isolation by minimally invasive epicardial ablation may offer a new treatment for patients with lone atrial fibrillation (AF). However, complete PV isolation has been shown to be difficult to obtain. In 14 mongrel dogs, robot-assisted epicardial microwave ablation was performed on the beating heart by a single-sided right chest approach. Isolation of all PVs was performed in two steps to study the effect of an incomplete and a complete isolation on AF. AF was studied by random and burst pacing. Incremental pacing was performed to study conduction characteristics across the lesions. Opening of the pericardial reflections, introduction of the catheter and ablation were robotically feasible by a single-sided approach in 11 dogs. The AF duration decreased from 6.6+/-4.1 to 1.3+/-0.8 s (P=0.03) and 1.6+/-1.6 s (P=0.04 compared with control) after incomplete and completed isolation of the PVs. The AF cycle length increased from 134+/-5 to 141+/-5 and 145+/-8 ms (P=0.03) after incomplete and complete isolation, respectively. Several incomplete lesions showed 2:1 exit and/or entrance block during incremental pacing. After complete isolation, AF was no longer inducible from the PVs.

Epicardial PV isolation can be successfully performed by a single-sided robot-assisted approach. The effect of PV ablation on AF is not an all or none phenomenon. Incomplete isolation already decreases AF duration and lengthens the AF cycle length. However, complete isolation is necessary to prevent AF induction by triggering from the isolated area.

Does pramipexole reduce the prevalence of fatigue in patients with Parkinson 's disease?

The aim of this multicenter cross-sectional study was to assess the relation between fatigue in a large number of Japanese patients with Parkinson's disease (PD) and drugs taken to treat PD. We used the 16-item Parkinson Fatigue Scale (PFS-16), which was designed to assess fatigue exclusively associated with PD. Multiple logistic regression analyses were used to assess the relation between antiparkinson drugs and fatigue in PD. A total of 350 non-demented PD patients were enrolled. Fatigue (PFS score of ≥4) was revealed in 319 patients (91%). Pramipexole was administered to 24% of PD patients. Multiple logistic regression analysis revealed that the administration of Pramipexole was significantly related to low rates of fatigue in PD patients with Hoehn and Yahr stage <3 (p=0.011, odds ratio=5.23, 95% confidence interval; 1.47-18.63).

The reduced fatigue in PD patients was observed in taking Pramipexole.

Does hepatocyte growth factor gene therapy accelerate regeneration in cirrhotic mouse livers after hepatectomy?

Impaired regeneration and dysfunction of the cirrhotic liver following partial hepatectomy (PHx) are the most serious risk factors for postoperative liver failure. Using naked hepatocyte growth factor (HGF) plasmid by the electroporation (EP) in vivo method, we investigated HGF for its role and mechanism of proliferation and restoration of liver mass in cirrhotic mice following PHx. Eight week old female mice were used. HGF plasmid 50 micro g was injected intramuscularly and transferred by EP in vivo once a week for three weeks. After establishment of carbon tetrachloride induced cirrhosis, mice underwent PHx. The HGF treated group was given naked HGF plasmid four days before PHx, and additional HGF was given once a week until they were killed, while a control group was given only empty plasmid. Mice were killed 2, 4, 10, and 14 days after PHx. Morphological and functional restoration of the liver were examined, as well as activation of mitogen activated protein kinase (MAPK) and mRNA levels of HGF activator (HGFA). The HGF treated group demonstrated a continuous threefold increase in HGF levels in plasma. Therapy with HGF in cirrhotic PHx resulted in effective liver regeneration via restoration of HGFA and activation of MAPK p44/p42, accelerated normalisation of liver function, and increased collagen degradation.

HGF gene therapy by in vivo EP may be useful for hepatic resection in cirrhotic livers by stimulating liver proliferative and collagenolytic capacities, as well as accelerating functional recovery.

Are hemoglobin Area and Time Index Above 90 g/L Associated with Improved 6-Month Functional Outcomes in Patients with Severe Traumatic Brain Injury?

There is conflicting data on the relationship between anemia and outcomes in patients with traumatic brain injuries (TBI). The objective of this study was to determine if the proportion of time and area under the hemoglobin-time curve of ≥90 g/L are independently associated with 6-month functional outcomes. Retrospective cohort study of 116 patients with a severe TBI who underwent invasive neuromonitoring between June 2006 and December 2013. Hemoglobin area (HAI) and time (HTI) indices were calculated by dividing the total area, or time, under the hemoglobin-time curve at 90 g/L or above by the total duration of monitoring. Multivariable log-binomial regression was used to model the association between HAI or HTI and 6 month favorable neurologic outcome (Glasgow Outcome Score 4 or 5). Patients had a mean age of 38 years (SD 16) with a median admission Glasgow Coma Scale of 6 (IQR 4-7). There were 1523 hemoglobin measurements and 523 monitoring days. Patients had a hemoglobin ≥90 g/L for a median of 70 % (IQR 37-100) of the time. Each 10 g/L increase in HAI (RR 1.23, 95 %CI 1.04-1.44, P = 0.011), and 10 % increase in HTI (1.10, 95 %CI 1.04-1.16, P < 0.001) were associated with improved neurologic outcome. Thirty-one patients (27 %) received a transfusion with the median pre-transfusion hemoglobin being 81 g/L (IQR 76-87).

In patients with severe TBI, increased area under the curve and percentage of time that the hemoglobin concentration was ≥90 g/L, were associated with improved neurologic outcomes.

Does insulin enhance metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2?

Insulin is tightly associated with cancer progression; however, mechanistic insights into such observations are poorly understood. Recent studies show that metabolic transformation is critical to cancer cell proliferation. Here, we attempt to understand the role of insulin in promotion of cancer metabolism. To this end, the role of insulin in regulating glycolytic enzyme pyruvate kinase M2 (PKM2) was examined. We observed that insulin up-regulated PKM2 expression, through PI3K/mTOR mediated HIF1α induction, but significantly reduced PKM2 activity independent of this pathway. Drop in PKM2 activity was attributed to subunit dissociation leading to formation of low activity PKM2 oligomers, as assessed by density gradient centrifugation. However, tyrosine 105 phosphorylation of PKM2, known for inhibiting PKM2 activity, remained unaffected on insulin treatment. Interestingly, insulin-induced ROS was found responsible for PKM2 activity reduction. The observed changes in PKM2 status led to augmented cancer metabolism. Insulin-induced PKM2 up-regulation resulted in enhanced aerobic glycolysis as confirmed by PKM2 knockdown studies. Further, PKM2 activity reduction led to characteristic pooling of glycolytic intermediates and increased accumulation of NADPH; suggesting diversion of glucose flux towards macromolecular synthesis, necessary for cancer cell growth.

The study identifies new PKM2-mediated effects of insulin on cancer metabolism, thus, advancing the understanding of insulin's role in cancer.

Are patient experiences of caring and person-centredness associated with perceived nursing care quality?

To explore the extent to which patient ratings of perceived caring and person-centredness are associated with perceived nursing care quality in an acute hospital sample of inpatients. Self-reported patient experiences have had limited attention in conceptualizations of healthcare quality as described in policy and national standards, as well as in health and nursing care practice. The impact of central nursing concepts such as caring and person-centredness on patient ratings of nursing care quality is largely unknown. A descriptive non-experimental correlational design was used to collect and analyse data from a sample of Australian acute hospital inpatients (n = 210) in December 2012. The study collected self-report patient data through a study survey including demographic data and the Caring Behaviours Inventory, the Person-centred Climate Questionnaire, the SF-36 and the Distress thermometer. Descriptive statistics together with Pearson correlation and hierarchical linear regression were used. Perceived caring behaviours of staff and the person-centredness of wards were significantly associated with nursing care quality as evidenced by Pearson correlations being significant and exceeding the pre-set cut-off of r > 0·5. Staff caring behaviours and ward person-centredness also accounted for more than half of the total variance in perceived nursing care quality as evidenced by the final regression model. Knowledgeable and communicable staff, timeliness of assistance and environmental support stood out as most significantly related to patient perceived nursing care quality.

Patient experiences of caring and person-centredness seem to have an influential role in the extent to which patients experience the quality of nursing care. Knowledgeable and communicable staff, timeliness of assistance and environmental support stand out as most significantly related to patient-perceived nursing care quality.

Do psychiatric sequelae to the loss of an adolescent peer to suicide?

This study was designed to learn whether friends and acquaintances of suicide victims were at increased risk for depression, post-traumatic stress disorder, and suicidal behavior after exposure to suicide. The social networks of 26 adolescent suicide victims, consisting of 146 adolescents, were interviewed 7 months after the death of the suicide victim and compared with 146 matched, unexposed controls. The rates of these disorders that had onset after exposure were elevated in the exposed group vs. controls: major depression, post-traumatic stress disorder, suicidal ideation with a plan or an attempt, but not suicidal attempts. Almost all of those exposed youth who developed new-onset suicidality did so in the context of a new-onset depressive episode. The majority of these new-onset depressive disorders began within 1 month of exposure.

Postvention programs not only should focus on the prevention of imitation of suicidal behavior, but also should provide longer term follow-up for potentially bereaved and depressed youth exposed to suicide.

Does dilatation and curettage fail to detect most focal lesions in the uterine cavity in women with postmenopausal bleeding?

To determine the prevalence of focally growing lesions in the uterine cavity in women with postmenopausal bleeding and endometrium > or = 5 mm and the extent to which such lesions can be correctly diagnosed by D&C. In a prospective study, 105 women with postmenopausal bleeding and endometrium > or = 5 mm at transvaginal ultrasound examination underwent diagnostic hysteroscopy, D&C and hysteroscopic resection of any focally growing lesion still left in the uterine cavity after D&C. Twenty-four women also underwent hysterectomy. If the histological diagnosis differed between specimens from the same patient, the most relevant diagnosis was considered the final one. Eighty percent (84/105) of the women had pathology in the uterine cavity, and 98% (82/84) of the pathological lesions manifested a focal growth pattern at hysteroscopy. In 87% of the women with focal lesions in the uterine cavity, the whole or parts of the lesion remained in situ after D&C. D&C missed 58% (25/43) of polyps, 50% (5/10) of hyperplasias, 60% (3/5) of complex atypical hyperplasias, and 11% (2/19) of endometrial cancers. The agreement between the D&C diagnosis and the final diagnosis was excellent (94%) in women without focally growing lesions at hysteroscopy.

If there are focal lesions in the uterine cavity, hysteroscopy with endometrial resection is superior to D&C for obtaining a representative endometrial sample in women with postmenopausal bleeding and endometrium > or = 5 mm.

Do cD57 ( high ) neuroblastoma cells have aggressive attributes ex situ and an undifferentiated phenotype in patients?

Neuroblastoma is thought to originate from neural crest-derived cells. CD57 defines migratory neural crest cells in normal development and is expressed in neuroblastoma. We investigated the role of CD57 expression in neuroblastoma cells ex situ and in situ. Compared to CD57(low) U-NB1 neuroblastoma cells, CD57(high) cells developed tumors with decreased latency after orthotopic transplantation into adrenal glands of mice. In addition, CD57(high) U-NB1 and SK-N-BE(2)-C neuroblastoma cells were also more clonogenic, induced more spheres and were less lineage-restricted. CD57(high) cells attached better to endothelial cells and showed enhanced invasiveness. While invasion of U-NB1 cells was inhibited by blocking antibodies against CD57, neither invasion of SK-N-BE(2)-C cells nor adhesion of U-NB1 and SK-N-BE(2)-C cells was attenuated. After tail vein injection only CD57(high) cells generated liver metastases, while overall metastatic rate was not increased as compared to CD57(low) cells. In stroma-poor neuroblastoma of patients CD57(high) cells were associated with undifferentiated tumor cells across all stages and tended to be more frequent after chemotherapy.

Strong expression of CD57 correlates with aggressive attributes of U-NB1 and SK-N-BE(2)-C neuroblastoma cells and is linked with undifferentiated neuroblastoma cells in patients.

Does s100P enhance the chemosensitivity of human gastric cancer cell lines?

The effect of the protein S100P on biological characteristics of cancer is not clear, especially in gastric cancer. We previously showed that S100P positive gastric cancer patients have a better cumulative survival than S100P negative patients. To study the possible mechanisms of S100P enhanced the chemosensitivity to oxaliplatin in gastric cancer cell lines. S100P was overexpressed in vitro by plasmid transfection and downregulated by siRNA transfection in the BGC823 and SGC7901 gastric cancer cell lines. Cell survival rate, changes in the chemoresistance gene, such as GST-π, MDR1, MRP1, Topo-II, MVP and BCRP, intake of anticancer drug were measured after oxaliplatin treatment. In SGC7901 cells, MTT assay indicated that increased S100P expression levels decreased the survival rate and decreased S100P expression levels increased the survival rate. In BGC823 and SGC7901 cell lines, mRNA of MDR1, a chemoresistance genes, was decreased in cells that overexpressed S100P, and increased in cells with downregulation of S100P. Intracellular accumulation of platinum increased in cells with overexpressed S100P, and decreased in cells with S100P downregulation.

S100P contributes to oxaliplatin chemosensitivity in gastric cell lines by increasing drug inflow. It might also be a novel independent prognostic factor in gastric cancer patients who receive adjuvant chemotherapy with oxaliplatin.

Is jaw-stretch reflex weaker in patients after orthognathic surgery?

The jaw-stretch reflex (JSR) was studied in both patients and healthy participants in order to investigate the possible long-term impact of orthognathic surgery on the motor function of the masticatory system. JSR was measured in patients before surgery (PC), 1year after surgery (PS) and in healthy controls (HC) (N=31 in each group). JSR was evoked by a standardized stretch device and recorded bilaterally from masseter and anterior temporalis muscles using surface electromyography (EMG). The peak-to-peak amplitude (which was normalized to pre-stimulus EMG activity) of JSRs in PC and PS were significantly smaller than in HC (P<0.001; P<0.001). The onset latency in PS was significantly longer compared with HC (P<0.05). The duration of JSR in PS was significantly longer than in HC and PC (P<0.001; P<0.05).

Patients with dentofacial deformities are characterized by reduced JSR amplitude. The delayed onset and elongated duration of JSR might be potential indicators of a long-term surgical impact on the motor function of the masticatory system.

Is cancer stem cell marker Bmi-1 expression associated with basal-like phenotype and poor survival in breast cancer?

The purpose of present study was to examine the expression of cancer stem cell marker Bmi-1 in breast cancer tissue and to evaluate the clinical implication of Bmi-1 expression for these patients. A total of 171 breast cancer patients who received surgical treatment in our hospital were enrolled in this study. Bmi-1 expression in breast cancer tissue was assayed by immunohistochemistry. Statistical analyses were applied to test the relationship between expression of Bmi-1 and clinicopathologic features and patient survival. The relationship between Bmi-1 and the basal-like phenotype of breast cancer also was analyzed in this study. Positive Bmi-1 expression was detected in 89 of 171 (52%) invasive breast cancers patients. The Bmi-1 status was significantly correlated to histological grade III (p = 0.001) and basal-like phenotype (p < 0.001). The 5 year overall survival of the patients with Bmi-1-positive and -negative cancers were 78 and 91.9%, respectively (p = 0.03). Histological grade (p = 0.046) and Bmi-1 status (p = 0.012) were detected as the independent prognostic factors in the Cox regression test.

Bmi-1 status is an independent prognostic factor, which also is associated with tumor histological grade and basal-like phenotype. The high proportions of positive Bmi-1 expression in basal-like breast cancer may be related to the high aggressiveness behavior of this subtype of breast cancer.

Does the placement of a FRECA gastrostomy at the time of laparoscopic fundoplication impact on outcome?

This is retrospective study of a single surgeon's experience of laparoscopic fundoplications over a decade. Patient details were retrieved form a Microsoft Excel database and demographic, operative, and performance measures analysed. Of a series of 67 laparoscopic fundoplications, 20 with neurological compromise underwent FP placement at the time of surgery. Mean age was 3.37 years with a male to female ratio of 1.1:1. A size 9 French FRECA was placed in patients less than 10 kg (12) with larger patients (8) having a size 15 device. A Watson anterior wrap was performed in 16 cases with the rest having a Nissen fundoplication. Seven of these cases had pre-existing FPs which were taken down before replacement post fundoplication. Feeding was resumed the next morning except in three with delayed gastric emptying. Other complications (3) were seen but were not PEG related. The median stay for the series was 4 days (SD 3) and patients were followed up for a mean of 684 days. Over this period four patients relapsed and resumed medical treatment. A single mortality occurred in a syndromic 3-year-old a year later from problems unrelated to surgery. FPs were changed to a button device under general anaesthetic 3-24 months following placement.

FP placement at the time of laparoscopic fundoplication does not appear to compromise the outcome of surgery. Neither the size of patient nor the type of wrap is an impediment to its placement and the device can be used shortly after surgery in the majority allowing for an early discharge. Complications are infrequent; however, change to a button device within 2 years of initial placement requires general anaesthetic.

Clinical interpretation for the pressure-flow relationships in extrinsic allergic alveolitis and in interstitial lung disease pulmonary hypertension patients. Should we care for the lung, the pulmonary artery pressure or both?

We sought to analyze exercise-derived mean pulmonary artery pressure (mPAP)-cardiac index (CI) relationship to expand the concepts regarding its nature and to better identify pulmonary hemodynamic responders to acute oxygen breathing (AO2B-99.5%) and to hydralazine (H) in extrinsic allergic alveolitis (EAA) and chronic interstitial lung disease (CILD) pulmonary hypertension (PH) patients. mPAP/CI and extrapolated pressure (Pext) to zero flow were obtained while breathing room air (BRA) and under AO2B-99.5% in 38 stable (EAA (n = 14) and CILD (n = 24)) patients with resting and exercising PH. Hemodynamic characteristics were analyzed for the entire cohort and separate for EAA and CILD patients. AO2B-99.5% was tested in cohorts, H only in CILD and the effect of long-term corticosteroid treatment in EAA patients. Lung biopsies (LB) were obtained to evaluate the inflammatory-fibrosis stage and the degree of vascular lesion in the entire cohort. LB studies reveal a predominant stage of inflammation associated with grade-I vascular lesion for EAA patients. A predominant stage for fibrosis (although moderate) over inflammation associated with grade-II vascular lesions were documented for CILD patients. mPAP/CI abnormal location were associated with hypoxemia/decreased mixed venous-PO2 and lung mechanics abnormalities for both cohorts. An abnormal slope (Sp: 4.13; 95% CI: 3.42-4.84 mmHg/L/min/m2) and a normal Pext value (7 +/- 1.9 mmHg) were found for EAA patients. On the contrary, a normal slope (Sp: 1.22; 95% CI: 0.47-1.99 mmHg/L/min/m2) and an abnormal Pext value (19.7 +/- 3.5 mmHg) were found for CILD patients. Hemodynamic conditions that did not change for the Sp (4.0; 95% CI: 3.18-4.82 mmHg/L/min/m2); however, were associated with a statistical significant decrease in parallel for mPAP/CI during AO2B-99.5% when compared to BRA (p<0.01), although not to normal slope values (0.96; 95% CI: 0.41-1.37) or mPAP/CI location. For CILD patients, during AO2B-99.5% no change for the slope, for Pext and mPAP/CI location in relation to BRA were observed. Under the effect of H, no change for the previous mentioned hemodynamic findings were found in relation to the control condition for CILD patients. After long-term corticosteroid treatment, normalization for mPAP/CI location and for the slope value (1.6; 95% CI: 0.91-2.29 mmHg/L/min/m2) were associated with lung mechanics and blood-gas exchange normalization were documented in EAA patients.

When mPAP/CI exercise derived is analyzed, valuable information for linear-pulmonary vascular resistance-(LPVR) could be obtained for EAA and CILD-PH patients. mPAP/CI-r abnormalities not always reflect "pure arteriolar" increased LPVR for EAA and CILD patients. H is not useful as an adjunct vasodilator therapy for CILD-PH patients. AO2B-99.5% decrease right ventricular afterload for EAA patients, although not to normal. Complete reversibility for PH could result after long-term corticosteroid treatment. We conclude that treatment should focus mainly on the lung and not in the pulmonary artery pressure in interstitial lung disease PH patients.

Is metronomic oral cyclophosphamide prednisolone chemotherapy an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure?

There is currently no standard of treatment for patients with hormone refractory prostate cancer (HRPC) after failure of docetaxel-based chemotherapy. The purpose of this study was to assess the anticancer activity and tolerance of metronomic cyclophosphamide prednisolone combination in this setting. From 2005 to 2010, patients with HRPC who failed at least docetaxel-based chemotherapy were proposed metronomic cyclophosphamide-prednisolone regimen, and were prospectively registered. Twenty-three patients received 50 mg cyclophosphamide and 10 mg prednisolone per os daily until disease progression. Treatment tolerance and efficacy on PSA decrease and pain were studied. Metronomic cyclophosphamide prednisolone was safe, well tolerated, and demonstrated interesting clinical activity, yielding a prostate specific antigen decrease by ≥50% in 26% of patients and decrease by ≥30% in 48% of patients, but also favorable palliative effects on pain in 43% of patients. The median progression-free survival was 6 months (95% CI: 4-8 months) and the median overall survival was 11 months (95% CI: 7-19 months).

For this patient population, low dose metronomic cyclophosphamide prednisolone might be a viable alternative. Its convenient oral administration, low cost, and lack of toxicity justify further studies alone, or in combination with other agents in HRPC patients.

Are longer durations of antitumour necrosis factor treatment associated with reduced risk of cardiovascular events in patients with rheumatoid arthritis?

To assess the effects of treatment with antitumour necrosis factor (TNF) agents, methotrexate, or other non-biological disease-modifying antirheumatic drugs (DMARDs) on cardiovascular event risks among patients with rheumatoid arthritis (RA). We conducted a retrospective study using data from the MarketScan claims database. Patients with RA with ≥1 prescription for an index drug were included. Each patient's use of an index drug was calculated cumulatively as a time-varying exposure. The incidence of cardiovascular events among patients with RA was determined. Associations between drug exposures and occurrence of cardiovascular events were assessed with Cox proportional hazards models. Of 113 677 patients identified, 35.8%, 41.1% and 23.1% received anti-TNF agents, methotrexate and other DMARDs, respectively. Patients were treated for an average of 7.6 months; 2138 patients (1.9%) had a cardiovascular event following their index prescription. Each additional 6 months of anti-TNF therapy use versus non-use reduced the risk (HR; 95% CI) for any cardiovascular event by 12% (0.88; 0.81 to 0.95, p=0.002). Anti-TNF therapy was associated with a 13% and 12% reduction in cardiovascular events in patients aged ≥50 years (0.87; 0.80 to 0.95, p=0.002) and in those without prior methotrexate use (0.88; 0.78 to 0.99, p=0.04), respectively. Cumulative use of 1, 2 or 3 years of anti-TNF therapy versus non-use is expected to reduce cardiovascular event risks by 21%, 38% and 51%, respectively.

Anti-TNF therapy was associated with a significantly lower risk of cardiovascular events among patients with RA, older patients with RA and patients without prior exposure to methotrexate.

Is fibroblast growth factor 2 of prognostic value for patients with locally advanced squamous cell carcinoma of the head and neck?

Patients with locally advanced SCCHN have a poor prognosis. This study investigated the prognostic value of the tumor cell expression of the fibroblast growth factor 2 (FGF-2) in patients treated with surgery followed by radiotherapy. The impact of FGF-2-expression and 11 additional potential prognostic factors on loco-regional control (LRC), metastases-free survival (MFS), and overall survival (OS) was retrospectively evaluated in 146 patients. Additional factors included age, gender, performance status, pre-radiotherapy hemoglobin levels, tumor site, histologic grade, T-category, N-category, human papilloma virus (HPV) status, extent of resection, and chemotherapy. Univariate analyses were performed with the Kaplan-Meier method and the log-rank test, multivariate analyses with the Cox proportional hazard model. On multivariate analysis, improved LRC was significantly associated with FGF-2-negativity [risk ratio (RR): 7.33; 95%-confidence interval (CI): 2.88-19.05; p<0.001], lower T-category (RR: 2.42; 95%-CI: 1.47-4.33; p<0.001), lower N-category (RR: 12.36; 95%-CI: 3.48-78.91; p<0.001), and pre-radiotherapy hemoglobin levels ≥ 12 g/dl (RR: 4.18; 95%-CI: 1.73-10.53; p=0.002). No factor was significantly associated with improved MFS. Lower T-category showed a trend (RR: 1.59; 95%-CI: 0.97-2.82; p=0.069). Better OS was significantly associated with FGF-2-negativity (RR: 5.10; 2.22-11.80; p<0.001), lower T-category (RR: 2.17; 95%-CI: 1.38-3.68; p < 0.001), lower N-category (RR: 3.86; 95%-CI: 1.60-10.85; p=0.002), and pre-radiotherapy hemoglobin levels ≥ 12 g/dl (RR: 3.20; 95%-CI: 1.46-7.30; p=0.004). HPV-positivity showed a trend (RR: 2.36; 95%-CI: n.a.; p=0.054).

Tumor cell expression of FGF-2 proved to be an independent prognostic factor for LRC and OS. This factor can help personalize treatment and stratify patients in future trials.

Does addition of eGFR and Age improve the Prognostic Absolute Renal Risk-Model in 1,134 Norwegian Patients with IgA Nephropathy?

Predicting outcome in individual patients with IgA nephropathy (IgAN) is difficult but important. For this purpose, the absolute renal risk (ARR) model has been developed in a French cohort to calculate the risk of end-stage renal disease (ESRD) and death. ARR (0-3) is scored in individual IgAN patients based on the presence of proteinuria ≥1 g/24 h, hypertension, and severe histopathological lesions (1 point per risk factor). We have validated the ARR model in a Norwegian cohort of IgAN patients and tested whether adding data on initial estimated glomerular filtration rate (eGFR) and age improved prediction. IgAN patients diagnosed between 1988 and 2012 were identified in the Norwegian Kidney Biopsy Registry, and endpoints were identified by record linkage with the Norwegian Renal Registry (ESRD) and the Population Registry (deaths). We identified 1,134 IgAN patients. The mean duration of follow-up was 10.2 years (range 0.0 to 25.7 years). Two hundred and fifty one patients developed ESRD and there were 69 pre-ESRD deaths. The ARR model significantly stratified the IgAN cohort according to risk of ESRD/death. The inclusion of eGFR and age significantly improved the ARR prognostic model; in the receiver operator characteristics (ROC) analysis, area under the curve (AUC) at 10-years of follow-up increased from 0.79 to 0.89, p < 0.001.

ARR is a suitable prognostic model for stratifying IgAN patients according to the risk of ESRD or death. Including initial eGFR and age in the model substantially improved its accuracy in our nationwide cohort.

Is reluctance to undergo follow-up screening for head and neck cancer associated with income , gender , and tobacco use?

To determine the factors associated with reluctance to undergo head and neck cancer follow-up screening. We surveyed 813 individuals for their medical history, income, behavior habits, and willingness to participate in phone or physical examination follow-up screening for head and neck cancer. Association of reluctance to undergo follow-up screening with the other aforementioned factors was assessed. Overall, 10.9% (95% CI: 8.9-13.3%) of participants were reluctant to undergo follow-up screening. Patients with a history of cigar/pipe use (OR = 1.86, 95% CI: 1.1-3.3, p = 0.03) or low income (under USD 30,000; OR = 1.71, 95% CI: 1.0-2.9, p = 0.04) were more reluctant to undergo phone follow-up. Males (OR = 2.0, 95% CI: 1.0-4.1, p = 0.05) and those with low income (OR = 2.1, 95% CI: 1.1-4.0, p = 0.02) were more reluctant to undergo physical examination follow-up.

Lower income, male gender, and tobacco use are associated with reluctance to undergo follow-up screening for head and neck cancer.

Is coronary artery atherosclerosis related to reduced regional left ventricular function in individuals without history of clinical cardiovascular disease : the Multiethnic Study of Atherosclerosis?

We investigated whether regional coronary calcium score by computed tomography is related to regional left ventricular systolic function measured by MRI tagging in participants of the Multiethnic Study of Atherosclerosis. The Multiethnic Study of Atherosclerosis is a prospective observational study of men and women without a history of previous heart disease from 4 ethnic groups. Calcium scores were measured separately for the left anterior descendent (LAD), left circumflex (LCX), and right (RCA) coronary arteries. Left ventricular strain and strain rate were determined by tagged MRI in the corresponding vascular territories of the coronary vessels in 509 participants. Greater coronary calcification in the LAD, LCX, and right RCA coronary arteries were related to worse function in their respective perfusion. Anterior wall strain rate was -1.37+/-0.41 when LAD calcium was zero versus -1.17+/-0.24 1/s in the highest quartile of calcium score (P<0.001). Similar relationships were evident in the LCX and RCA regions. Participants with 1- and 2-vessel coronary artery calcium had better myocardial function in the remote area compared with the territory supplied by the diseased artery.

High-local calcium score is related to regional dysfunction in the corresponding coronary territory among individuals without a history of previous heart disease. These results indicate a link between atherosclerosis and subclinical regional left ventricular dysfunction.

Can fetal ultrasound result in prenatal diagnosis of Prader-Willi syndrome?

To define fetal ultrasound characteristics triggering an antenatal diagnosis of Prader Willi syndrome (PWS). Retrospective analysis of sonographic characteristics retrieved from obstetric ultrasound records. All children (n=11) had a postnatal genetically confirmed diagnosis of PWS. All patients (n=11) showed at least one aspecific abnormality on prenatal ultrasound. Ten out of eleven (90.9 %) had decreased fetal movements, 7 (63.6%) presented in breech position, 7 (63.6%) had severe intra-uterine growth restriction (<5th centile) and 4 (36.4%) showed a polyhydramnios. Immobile flexed limbs and clenched hands were seen in one patient (9.1%). Severe growth restriction combined with polyhydramnios favors the diagnosis in 3/11 cases.

Prenatal sonographic phenotype of PWS includes decreased fetal movements, fetal malpresentation, severe intra-uterine growth restriction and polyhydramnios. These findings are not specific to PWS, but the combination of some of them (especially severe intra-uterine growth restriction and polyhydramnios) can prompt clinicians to perform invasive testing leading to a molecular cytogenomic diagnosis prenatally.

Does collateral flow prevent unintentional myocardial ischemia during antegrade cardioplegia in patients undergoing coronary artery bypass grafting?

We evaluated, in the prevention of perioperative unintentional myocardial ischemia, the role of coronary collateral flow in patients with left anterior descending coronary artery stenosis or occlusion who underwent elective coronary artery bypass grafting. Coronary lesions and collaterals were assessed by coronary angiography in 21 patients. Anteroseptal myocardial viability was evaluated by dobutamine echocardiography. Antegrade perfusion of cardioplegic solution was assessed by myocardial contrast echocardiography. Time-intensity curves were generated from the anteroseptal region. Twelve parameters were measured and averaged in the following four groups of patients: those with stenosis of the left anterior descending artery and poor collaterals; those with stenosis of the left anterior descending artery and good collaterals; those with occlusion of the left anterior descending artery and good collaterals; and those with occlusion of the left anterior descending artery and poor collaterals. Time-intensity curves were significantly different in patients with stenosis versus occlusion of the left anterior descending artery (p < 0.005); multiple comparisons with Bonferroni's correction showed that this difference was mainly a result of the impact of collateral circulation (p < 0.01). However, the role of collaterals was nonsignificant within the groups with stenosis and occlusion of the left anterior descending artery. Patients with occlusion of the left anterior descending artery and good collaterals had perfusion parameters similar to those of patients with stenosis of the left anterior descending artery (p = not significant), except for the ascending slope and time to peak values (p < 0.05 and p < 0.01, respectively), which reflected a higher flow resistance in the collateral circulation. Regional systolic function after coronary artery bypass grafting was depressed in patients with poor collaterals and poor perfusion of cardioplegic solution, as compared with findings in other subgroups.

Incomplete myocardial protection may impair the early recovery of function after coronary artery bypass grafting.

Does Helicobacter pylori Exacerbate Gastric Mucosal Injury in Users of Nonsteroidal Anti-Inflammatory Drugs?

The interaction between nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori remains controversial. We retrospectively investigated whether H. pylori infection exacerbates severe gastric mucosal injury among chronic NSAID users. From January 2010 to December 2013, a total of 245 long-term NSAID (including low-dose aspirin) users who had undergone an esophagogastroduodenoscopy and had been evaluated for H. pylori infection were enrolled at Okayama University Hospital and Tsuyama Chuo Hospital. The degree of gastric mucosal injury was assessed according to the modified Lanza score (MLS). Severe gastric mucosal injury was defined as an MLS ≥4. Univariate and multivariate logistic regression analyses were performed. In the univariate analysis, age ≥75 years (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.3 to 4.2), H. pylori-positivity (OR, 2.0; 95% CI, 1.2 to 3.5), and the concomitant use of proton pump inhibitors (PPIs) (OR, 0.48; 95% CI, 0.26 to 0.86) were significantly associated with severe gastric mucosal injury. The multivariate analysis was adjusted by age and sex and demonstrated that H. pylori-positivity (OR, 1.8; 95% CI, 1.0 to 3.3) and the concomitant use of PPIs (OR, 0.53; 95% CI, 0.28 to 0.99) significantly contributed to severe gastric mucosal injury.

H. pylori infection exacerbates severe gastric mucosal injury among chronic NSAID users.

Can zinc deficiency be used as a marker for the diagnosis of celiac disease in Turkish children with short stature?

It is generally accepted that celiac disease (CD) must always be considered when dealing with growth failure in children. Therefore, it is important to develop screening tests for detecting patients that need an intestinal biopsy. The aim of the present study was to investigate the value of plasma zinc levels for the diagnosis of monosymptomatic CD in short-statured children. Fourty-nine children with a short stature and 34 healthy controls were investigated. Plasma zinc levels were assayed by atomic absorption spectrophotometry in short-statured children and controls. All patients with short stature underwent endoscopic small intestinal biopsy. Duodenal mucosal histopathology was normal in 25 children. Low plasma zinc values were observed in 54.2% of patients with CD, 32.0% of patients with idiopathic short stature and 14.8% of controls. The mean values of plasma zinc levels were not significantly different among the three groups. Sensitivity, specificity and the positive and negative predictive values for plasma zinc were 45.8, 76.0, 64.7 and 59.4%, respectively.

These results indicate that zinc deficiency is an important problem in CD children with short stature; however, plasma zinc levels are not useful as a screening test for selecting patients for jejunal biopsy.

Is nitric oxide required for the auxin-induced activation of NADPH-dependent thioredoxin reductase and protein denitrosylation during root growth responses in arabidopsis?

Auxin is the main phytohormone controlling root development in plants. This study uses pharmacological and genetic approaches to examine the role of auxin and nitric oxide (NO) in the activation of NADPH-dependent thioredoxin reductase (NTR), and the effect that this activity has on root growth responses in Arabidopsis thaliana. Arabidopsis seedlings were treated with auxin with or without the NTR inhibitors auranofin (ANF) and 1-chloro-2, 4-dinitrobenzene (DNCB). NTR activity, lateral root (LR) formation and S-nitrosothiol content were measured in roots. Protein S-nitrosylation was analysed by the biotin switch method in wild-type arabidopsis and in the double mutant ntra ntrb. The auxin-mediated induction of NTR activity is inhibited by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO), suggesting that NO is downstream of auxin in this regulatory pathway. The NTR inhibitors ANF and DNCB prevent auxin-mediated activation of NTR and LR formation. Moreover, ANF and DNCB also inhibit auxin-induced DR5 : : GUS and BA3 : : GUS gene expression, suggesting that the auxin signalling pathway is compromised without full NTR activity. Treatment of roots with ANF and DNCB increases total nitrosothiols (SNO) content and protein S-nitrosylation, suggesting a role of the NTR-thioredoxin (Trx)-redox system in protein denitrosylation. In agreement with these results, the level of S-nitrosylated proteins is increased in the arabidopsis double mutant ntra ntrb as compared with the wild-type.

The results support for the idea that NTR is involved in protein denitrosylation during auxin-mediated root development. The fact that a high NO concentration induces NTR activity suggests that a feedback mechanism to control massive and unregulated protein S-nitrosylation could be operating in plant cells.

Is inhibition of gastric carcinogenesis by the hormone gastrin mediated by suppression of TFF1 epigenetic silencing?

Epigenetic alterations have been correlated with field cancerization in human patients, but evidence from experimental models that specific epigenetic changes can initiate cancer has been lacking. Although hormones have been associated with cancer risk, the mechanisms have not been determined. The peptide hormone gastrin exerts a suppressive effect on antral gastric carcinogenesis. N-methyl-N-nitrosourea (MNU)-dependent gastric cancer was investigated in hypergastrinemic (INS-GAS), gastrin-deficient (GAS(-/-)), Tff1-deficient (Tff1(+/-)), and wild-type (WT) mice. Epigenetic alterations of the trefoil factor 1 (TFF1) tumor suppressor gene were evaluated in vitro and in vivo. Human intestinal-type gastric cancers in the antrum exhibited progressive TFF1 repression and promoter hypermethylation. Mice treated with MNU exhibited a field defect characterized by widespread Tff1 repression associated with histone H3 lysine 9 methylation and H3 deacetylation at the Tff1 promoter in epithelial cells. In MNU-induced advanced cancers, DNA methylation at the Tff1 promoter was observed. Tumor induction and Tff1 repression were increased in MNU-treated mice by Helicobacter infection. Hypergastrinemia suppressed MNU-dependent tumor initiation and progression in a manner that correlated with gene silencing and epigenetic alterations of Tff1. In contrast, homozygous gastrin-deficient and heterozygous Tff1-deficient mice showed enhanced MNU-dependent field defects and cancer initiation compared with WT mice. In gastric cancer cells, gastrin stimulation partially reversed the epigenetic silencing in the TFF1 promoter.

Initiation of antral gastric cancer is associated with progressive epigenetic silencing of TFF1, which can be suppressed by the hormone gastrin.

Does developmental instability predict individual variation in verbal memory skill after caffeine ingestion?

To determine the mediating effects of developmental instability on individual differences in response to caffeine. Individual variation of drug effects might reflect broad genomic factors as well as the direct effects of specific alleles. The current study tested the hypothesis that individual differences in developmental instability, in part determined by genomic characteristics, would predict individual variation in the magnitude of caffeine-induced verbal memory deficits. Minor physical anomalies and fluctuating asymmetry were used as measures of developmental instability. One hundred participants were (1) administered one version of the Rey Auditory Verbal Learning Test; (2) given a dose of caffeine determined by body weight (3 mg/kg); (3) assessed for minor physical anomalies and fluctuating asymmetry; and (4) given an alternate randomized version of the Rey Auditory Verbal Learning Test. Consistent with predictions, a composite measure of developmental instability predicted the magnitude of caffeine-induced memory decrements.

These results may have important implications for the genetic underpinnings of individual differences in drug effects.

The gender-neutral timed obstacle course: a valid test of police fitness?

In the light of the Winsor review, UK police forces have been urged to use fitness tests as large-scale cost-effective measures of officers' fitness to work. One test is the Gender-Neutral Timed Obstacle Course (GeNTOC), which must be completed within 3min 45 s, regardless of sex. To investigate if obstacle courses, mimicking a range of police-type activities, can provide a suitable and valid basis for identifying fit and unfit officers and if any other factors may influence test performances. Five years of GeNTOC records were randomly sampled, providing data for 1701 officers. Pass/fail rates were analysed alongside demographics and obstacle performance. Of 1701 candidates, 24% (397) failed GeNTOC (7 and 42% of males and females, respectively). Females failed in two specific obstacles significantly more often than males: the 'body drag' and 'gate weave'. Errors made on these obstacles alone accounted for 49% of obstacle errors made by females. GeNTOC success was significantly associated with candidates who were male, younger, taller, heavier and of lower body mass index (BMI). Of all candidates, 42% were overweight, and 8% were obese.

The GeNTOC was not a useful screening tool and worked independently of BMI groups. Too few candidates were appropriately screened out; too many of those failing were female; and too many who passed were overweight or obese. GeNTOC was unfair to female candidates and favoured overweight or obese males. Recommendations are made to adopt alternative fitness tests or to modify the GeNTOC obstacles, testing procedures and data collection.

Does safflor yellow A protect neonatal rat cardiomyocytes against anoxia/reoxygenation injury in vitro?

To investigate the effects of safflor yellow A (SYA), a flavonoid extracted from Carthamus tinctorius L, on cultured rat cardiomyocytes exposed to anoxia/reoxygenation (A/R). Primary cultured neonatal rat cardiomyocytes were exposed to anoxia for 3 h followed by reoxygenation for 6 h. The cell viability was measured using MTT assay. The releases of lactate dehydrogenase (LDH) and creatine kinase (CK), level of malondialdehyde (MDA), and activities of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were analyzed. Hoechst 33258 staining and changes in Bcl-2/Bax ratio and caspase 3 activity were used to examine A/R-induced apoptosis. The A/R exposure markedly decreased the viability of cardiomyocytes, suppressed the activities of SOD, GSH, CAT and GSH-Px, and Bcl-2 protein expression. Meanwhile, the A/R exposure markedly increased the release of LDH and CK, and MDA production in the cardiomyocytes, and increased the rate of apoptosis, caspase 3 activity, Bax protein expression. Pretreatment with SYA (40, 60 and 80 nmol/L) concentration-dependently blocked the A/R-induced changes in the cardiomyocytes. Pretreatment of the cardiomyocytes with the antioxidant N-acetylcysteine (NAC, 200 μmol/L) produced protective effects that were comparable to those caused by SYA (80 nmol/L).

SYA protects cultured rat cardiomyocytes against A/R injury, maybe via inhibiting cellular oxidative stress and apoptosis.

Is personality the missing link in understanding recruitment and retention of rural general practitioners?

Little is known about the role of personality and related constructs in general practitioners' (GPs) choices of geographic location of medical practice. There is however some theory suggesting a role for personality in career decision making and some limited empirical evidence that this applies in medical career decisions. The aim of this study is to gain insight into whether personality plays a role in GPs' decisions to work in rural areas and the length of time that they intend to remain as a rural practitioner. Samples of rural (n=372) and urban (n=100) GPs from New South Wales (Australia) completed the Neuroticism, Extraversion, Openness--Five Factor Inventory (NEO-FFI) and Adjective Checklist personality instruments and answered questions about demographics and rural upbringing. Rural GPs scored, on average, more highly than urban GPs with respect to conscientiousness and agreeableness but lower on openness, which can also be taken to mean a more 'down-to-earth' personality. Personality together with age, gender, experience as a GP, time in current location and rural childhood yield an area under the receiver operating characteristic curve of 0.81 in discriminating rural from urban GPs. Among rural GPs openness (P=0.007) was positively correlated with intended longevity as a rural doctor as was nurturing (P=0.06).

Personality appears to play some role both in discriminating rural from urban GPs and in how long existing rural GPs intend to remain as rural GPs. Consideration of personality might assist in selection of individuals who will better fit the professional and social environment of rural life.

Synovitis and radiographic progression in non-erosive and erosive hand osteoarthritis: is erosive hand osteoarthritis a separate inflammatory phenotype?

To compare the prevalence of synovitis, pain and radiographic progression in non-erosive and erosive hand osteoarthritis (HOA), and to explore whether the different rate of disease progression is explained by different levels of synovitis and structural damage. We included 31 and 34 participants with non-erosive and erosive HOA at baseline, respectively. Using Generalized Estimating Equations, we explored whether participants with erosive HOA had more synovitis (by MRI, ultrasound and clinical examination) independent of the degree of structural damage. Similarly, we explored whether pain at baseline and radiographic progression after 5 years were higher in erosive HOA, independent of the levels of synovitis and structural damage. All analyses were adjusted for age and sex. Power Doppler activity was found mainly in erosive HOA. Participants with erosive HOA demonstrated more moderate-to-severe synovitis, assessed by MRI (OR = 1.73, 95% CI 1.11-2.70), grey-scale ultrasound (OR = 2.02, 95% CI 1.25-3.26) and clinical examination (OR = 1.80, 95% CI 1.44-2.25). The associations became non-significant when adjusting for more structural damage. The higher frequency of joint tenderness in erosive HOA was at least partly explained more structural damage and inflammation. Radiographic progression (OR = 2.53, 95% CI 1.73-3.69) was more common in erosive HOA independent of radiographic HOA severity and synovitis (here: adjusted for grey-scale synovitis by ultrasound).

Erosive HOA is characterized by higher frequency and more severe synovitis, pain and radiographic progression compared to non-erosive HOA. The higher rate of disease progression was independent of baseline synovitis and structural damage.

Does high mobility group box 1 activate Toll like receptor 4 signaling in hepatic stellate cells?

The aim of the present study was to investigate the effect of high mobility group box 1 (HMGB1), a damage pattern molecule that signals the presence of necrosis, on TLR4 signaling in hepatic stellate cells (HSC). Immortalized mouse HSC lines JS1, JS2, and JS3 that were either TLR4(+/+), TLR4(-/-), or MyD88(-/-) were transfected with NF-κB or AP-1 responsive luciferase reporter plasmids, followed by stimulation with 100 ng/ml lipopolysacchride (the exogenous TLR4 ligand) or 100 ng/ml HMGB1. The activation of NF-κB or AP-1 activities was determined by a dual-luciferase reporter assay system. The cells were also stimulated with LPS or HMGB1 and collected for the determination of chemotactic cytokine MCP-1 mRNA or proteins secretion. In a separate experiment, the cells were co-stimulated with 10 μg/ml TGF-β1 and LPS or HMGB1 and collected for assessment of fibrogenic mRNA and protein expression. HMGB1 stimulation markedly up-regulated MCP-1 mRNA expression and protein secretion, and enhanced TGF-β1-stimulated collagen α2(I) and α-SMA expression in JS1 cells. This was associated with enhanced activation of NF-κB and AP-1 responsive luciferase reporters. On the contrary, JS2 and JS3 cells were hyporesponsive to both LPS and HGMB1 stimulation compared to JS1 cells.

As an endogenous ligand of TLR4, HMGB1 activates TLR4 signaling in HSCs to enhance their inflammatory phenotype, indicating that TLR4 signaling need not rely solely on gut-derived LPS for activation during liver injury. HMGB1 also has a synergistic effect with TGF-β1 to stimulate fibrogenic protein expression, which is likely to be TLR4 dependent.

Does 3,5-diiodothyronine ( 3,5-T2 ) reduce blood glucose independently of insulin sensitization in obese mice?

Thyroid hormones regulate metabolic response. While triiodothyronine (T3) is usually considered to be the active form of thyroid hormone, one form of diiodothyronine (3,5-T2) exerts T3-like effects on energy consumption and lipid metabolism. 3,5-T2 also improves glucose tolerance in rats and 3,5-T2 levels correlate with fasting glucose in humans. Presently, however, little is known about mechanisms of 3,5-T2 effects on glucose metabolism. Here, we set out to compare effects of T3, 3,5-T2 and another form of T2 (3,3-T2) in a mouse model of diet-induced obesity and determined effects of T3 and 3,5-T2 on markers of classical insulin sensitization to understand how diiodothyronines influence blood glucose. Cell- and protein-based assays of thyroid hormone action. Assays of metabolic parameters in mice. Analysis of transcript and protein levels in different tissues by qRT-PCR and Western blot. T3 and 3,5-T2 both reduce body weight, adiposity and body temperature despite increased food intake. 3,3'-T2 lacks these effects. T3 and 3,5-T2 reduce blood glucose levels, whereas 3,3'-T2 worsens glucose tolerance. Neither T3 nor 3,5-T2 affects markers of insulin sensitization in skeletal muscle or white adipose tissue (WAT), but both reduce hepatic GLUT2 glucose transporter levels and glucose output. T3 and 3,5-T2 also induce expression of mitochondrial uncoupling proteins (UCPs) 3 and 1 in skeletal muscle and WAT respectively.

3,5-T2 influences glucose metabolism in a manner that is distinct from insulin sensitization and involves reductions in hepatic glucose output and changes in energy utilization.

Is down-regulation of TRF1 , TRF2 and TIN2 genes important to maintain telomeric DNA for gastric cancers?

The maintenance of telomeres may be required for long-term proliferation of tumors. Activity of telomerase, a ribonucleoprotein complex that elongates telomeres, has been found in almost all human tumors but not in adjacent normal cells. Several factors which regulate telomere length, TRF1 and 2, TIN2, tankyrase and Rap1, have been identified. TRF1, TRF2 and TIN2 are negative regulators of telomere length, while tankyrase and Rap1 act as positive regulators. In this study, we quantitated the mRNA of these five genes in gastric cancers to clarify the mechanism by which cancer cells maintain telomere length. The expression of these five genes transcription was determined using a quantitative RT-PCR. TRF1, TRF2 and TIN2 mRNAs were significantly down-regulated in cancers compared to non-cancerous mucosa. Neither tankyrase nor Rap1 was upregulated in cancers.

Down-regulation of TRF1, TRF2 and TIN2 gene expression may be important to maintain telomeres in gastric cancer.

Does the redox enzyme p66Shc contribute to diabetes and ischemia-induced delay in cutaneous wound healing?

The redox enzyme p66Shc produces hydrogen peroxide and triggers proapoptotic signals. Genetic deletion of p66Shc prolongs life span and protects against oxidative stress. In the present study, we evaluated the role of p66Shc in an animal model of diabetic wound healing. Skin wounds were created in wild-type (WT) and p66Shc(-/-) control and streptozotocin-induced diabetic mice with or without hind limb ischemia. Wounds were assessed for collagen content, thickness and vascularity of granulation tissue, apoptosis, reepithelialization, and expression of c-myc and beta-catenin. Response to hind limb ischemia was also evaluated. Diabetes delayed wound healing in WT mice with reduced granulation tissue thickness and vascularity, increased apoptosis, epithelial expression of c-myc, and nuclear localization of beta-catenin. These nonhealing features were worsened by hind limb ischemia. Diabetes induced p66Shc expression and activation; wound healing was significantly faster in p66Shc(-/-) than in WT diabetic mice, with or without hind limb ischemia, at 1 and 3 months of diabetes duration and in both SV129 and C57BL/6 genetic backgrounds. Deletion of p66Shc reversed nonhealing features, with increased collagen content and granulation tissue thickness, and reduced apoptosis and expression of c-myc and beta-catenin. p66Shc deletion improved response to hind limb ischemia in diabetic mice in terms of tissue damage, capillary density, and perfusion. Migration of p66Shc(-/-) dermal fibroblasts in vitro was significantly faster than WT fibroblasts under both high glucose and hypoxia.

p66Shc is involved in the delayed wound-healing process in the setting of diabetes and ischemia. Thus, p66Shc may represent a potential therapeutic target against this disabling diabetes complication.

Are asymmetric and symmetric dimethylarginine associated with coronary artery lesions in Kawasaki disease?

To determine whether 3 biomarkers, L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA), can predict outcomes in patients with Kawasaki disease (KD). Plasma levels of L-arginine, ADMA, and SDMA were measured in 39 patients with KD and 27 febrile control patients. Plasma L-arginine, ADMA, and SDMA levels were lower in patients with KD than in control patients before treatment with intravenous immunoglobulin (IVIG; P=.027, P<.001, and P<.001, respectively). After treatment with IVIG, L-arginine, ADMA, L-arginine/ADMA ratios, and arginine methylation ([ADMA+SDMA]/L-arginine) increased significantly (P<.001, P=.001, P=.014, and P=.001, respectively). Compared with control patients, persistent lower SDMA and higher ADMA/SDMA ratios existed in patients with KD. Furthermore, a lesser magnitude of change in terms of L-arginine and ADMA/SDMA ratios after IVIG treatment was associated with the formation of coronary dilation (P=.025, and .029, respectively).

Levels of L-arginine, ADMA, and SDMA appear to be associated with KD. Lower L-arginine levels and ADMA/SDMA after treatment with IVIG was associated with coronary artery abnormalities patients with KD.

Is clinical remission following treatment with tumour necrosis factor-alpha antagonists accompanied by changes in asymmetric dimethylarginine in patients with rheumatoid arthritis?

Rheumatoid arthritis (RA) is characterised by impaired endothelial function which contributes to increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and contributes to endothelial dysfunction. The aim of the present longitudinal study was to investigate the effects of tumour necrosis factor alpha (TNFα) antagonists on serum concentrations of ADMA in RA patients. Thirty-five patients (age (mean ± SD) 55 ± 15 years, 21 women) who qualified for anti-TNFα therapy were included in the study. ADMA was measured by ELISA in all patients prior to starting anti-tumour necrosis factor alpha treatment, and 2 weeks and 3 months after initiation of treatment. Generalised estimating equations were used to analyse the change in a range of factors after the treatment commenced, and to test the relationship between ADMA and various inflammatory parameters. Anti-tumour necrosis factor alpha therapy significantly reduced ESR, CRP, fibrinogen and disease activity score 28 (all p<0.001). ADMA levels did not change significantly following 2 weeks or 3 months treatment using three different tumour necrosis factor alpha inhibitors, despite the fact that CRP (p=0.016), and DAS28 (p=0.025) were found to be significantly associated with ADMA levels after treatment with TNFα antagonists.

ADMA levels do not change significantly during anti-TNF therapy, despite the fact that they associate with CRP and DAS28, which are significantly reduced during such treatment in patients with rheumatoid arthritis. Levels of inflammation after treatment with TNFα antagonists are significantly associated with ADMA levels in patients with rheumatoid arthritis.

Does lazaroid improve intestinal blood flow in the rat during hyperdynamic bacteraemia?

Intestinal mucosal hypoperfusion and loss of barrier function during sepsis may contribute to maintaining the septic state. Free radicals are produced during sepsis and antioxidants improve survival from experimental sepsis. It is unclear whether endothelial cell injury from free radicals results in altered microvascular reactivity. Lazaroids are antioxidants which scavenge radicals and block lipid radical chain reactions. The authors sought to determine whether lazaroids altered the intestinal microvascular responses to sepsis. In vivo video microscopy was used to study the ileal microcirculation of the rat. A1 (inflow) arteriolar diameter and flow, A3 (premucosal) arteriolar diameters, and cardiac output were measured. Lazaroid or vehicle was infused before a bolus injection of live Escherichia coli or saline. Lazaroid alone had no effect on the intestinal vessels or haemodynamics. E. coli caused vasoconstriction (A1, -21 per cent, A3, -19 per cent of baseline) and hypoperfusion (-36 per cent) despite increased cardiac output (+31 per cent). Lazaroid significantly attenuated both constriction (A1, -11 per cent; A3, 10 to -1 per cent) and hypoperfusion (-15 per cent), but did not increase cardiac output (30 per cent).

E. coli bacteraemia led to intestinal vasoconstriction and hypoperfusion. Lazaroid reduced this effect without altering central haemodynamic responses, suggesting that free radicals have a deleterious effect on the intestinal microcirculation during bacteraemia.

Does twenty-four-week treatment with extended release methylphenidate improve emotional symptoms in adult ADHD?

Treatment investigations with methylphenidate in adults with ADHD focus preferentially on the classical psychopathology: inattention, hyperactivity and impulsivity. ADHD-associated emotional symptoms, which are frequently present at least in ADHD subpopulations, were studied rarely. The vast majority of the placebo-controlled trials had observation periods between 4 and 8 weeks. To assess the medium- to long-term effects of extended release methylphenidate (MPH-ER) on emotional symptoms and other psychopathology frequently seen in ADHD patients, we conducted a large-scale, multicenter treatment study. We performed a randomised, 24-week, double-blind, placebo-controlled study in adults with ADHD. The diagnosis was made on the basis of the DSM-IV criteria, which were confirmed by clinical history and a structured psychopathological interview and the use of rating instruments. 363 patients were randomized to MPH-ER or placebo at a ratio of 2:1. The duration of the titration period was 5 weeks followed by a maintainance phase of 19 weeks. The efficacy measures were the observer rated 10-item Emotional Dysregulation Scale (EDS) derived from the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) and a self-report, six-item Emotional Lability Scale (ELS) extracted from the long version of the Conners Adult ADHD Self Report Scale (CAARS:S:L). In addition we used the SCL-90-R for the assessment of ADHD associated and comorbid psychopathology. MPH-ER was statistically superior to placebo in reducing emotional symptoms as assessed by the EDS and the ELS. Obsessive-compulsive symptoms and those of problems with self-concept declined until the end of the observation period. The decline was more pronounced in MPH-ER treated individuals. The effects remained robust during the entire maintenance period until week 24. Symptoms of anxiety, depression, anger and hostility, phobia, paranoid ideations and psychoticism were not improved.

MPH-ER appears to be an efficacious treatment for emotional symptoms with ADHD. Also obsessive-compulsive symptoms and problems with self-concept were affected positively.

Does gene expression analysis of forskolin treated basilar papillae identify microRNA181a as a mediator of proliferation?

Auditory hair cells spontaneously regenerate following injury in birds but not mammals. A better understanding of the molecular events underlying hair cell regeneration in birds may allow for identification and eventually manipulation of relevant pathways in mammals to stimulate regeneration and restore hearing in deaf patients. Gene expression was profiled in forskolin treated (i.e., proliferating) and quiescent control auditory epithelia of post-hatch chicks using an Affymetrix whole-genome chicken array after 24 (n = 6), 48 (n = 6), and 72 (n = 12) hours in culture. In the forskolin-treated epithelia there was significant (p<0.05; >two-fold change) upregulation of many genes thought to be relevant to cell cycle control and inner ear development. Gene set enrichment analysis was performed on the data and identified myriad microRNAs that are likely to be upregulated in the regenerating tissue, including microRNA181a (miR181a), which is known to mediate proliferation in other systems. Functional experiments showed that miR181a overexpression is sufficient to stimulate proliferation within the basilar papilla, as assayed by BrdU incorporation. Further, some of the newly produced cells express the early hair cell marker myosin VI, suggesting that miR181a transfection can result in the production of new hair cells.

These studies have identified a single microRNA, miR181a, that can cause proliferation in the chicken auditory epithelium with production of new hair cells.

Could the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) be a valid measure of disease activity in patients with psoriatic arthritis?

To determine whether the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) could be a valid indicator of disease activity in psoriatic arthritis (PsA). Patients with PsA identified from a disease-register and case-note review answered a questionnaire by mail (n = 133); some patients (n = 86) consented to examination. In a second sample of 47 consecutive clinic attendees with PsA, logistic regression examined the independent contribution of BASDAI to disease activity, as judged by treatment decisions at that time. BASDAI correlated highly with patient perception of disease activity (r = 0.739) and there was no significant effect of the pattern of disease (axial or peripheral) on this relationship. However, only physician perception of disease activity was significantly associated with high or low disease activity (odds ratio 18.4, 95% confidence interval 2.9-118.3). BASDAI, patient perception, and erythrocyte sedimentation rate failed to contribute significantly to the model.

BASDAI performs similarly for axial and peripheral PsA but does not correlate well with external indicators of disease activity, such as treatment decisions.

Does sleep EEG provide evidence that cortical changes persist into late adolescence?

To examine developmental changes in the human sleep electroencephalogram (EEG) during late adolescence. A 4-bed sleep laboratory. Fourteen adolescents (5 boys) were studied at ages 15 or 16 (initial) and again at ages 17 to 19 (follow-up). N/A. All-night polysomnography was recorded at each assessment and scored according to the criteria of Rechtschaffen and Kales. A 27% decline in duration of slow wave sleep, and a 22% increase of stage 2 sleep was observed from the initial to the follow-up session. All-night spectral analysis of 2 central and 2 occipital leads revealed a significant decline of NREM and REM sleep EEG power with increasing age across frequencies in both states. Time-frequency analysis revealed that the decline in power was consistent across the night for all bands except the delta band. The decreases in power were most pronounced over the left central (C3/A2) and right occipital (O2/A1) derivations.

Using longitudinal data, we show that the developmental changes to the sleeping EEG that begin in early adolescence continue into late adolescence. As with early adolescents, we observed hemispheric asymmetry in the decline of sleep EEG power. This decline was state and frequency nonspecific, suggesting that it may be due to the pruning of synapses known to occur during adolescence.

Does desflurane accelerate patient response during the wake-up test for scoliosis surgery?

To evaluate if desflurane possesses a shorter wake-up onset time and less incidence of recall than fentanyl-based anesthesia. Forty ASA class I-II adolescents, were enrolled into either a desflurane (DES) group, or a fentanyl (FEN) group for scoliosis surgery. Bispectral index (BIS) was monitored continuously in all patients throughout the procedure; the relationship between the wake-up time and BIS value was evaluated. Patients in the DES group had a significantly shorter wake-up onset than patients in the FEN group (4.1 +/- 0.6 vs 8.9 +/- 2.1 min, P < 0.01). No recall occurred during the wake-up test in the DES group, while five patients had recall in the FEN group, including two patients who recalled a given colour. Extubation time was significantly shorter in the DES group than in the FEN group (7.2 +/- 0.6 vs 16 +/- 11.9 min, P < 0.01). BIS values were significantly higher in the FEN group than in the DES group during anesthesia. (62 +/- 4.5 vs 42 +/- 5.3, P < 0.05) BIS after the wake-up test was similar in both groups (90 +/- 2.9 vs 93.8 +/- 2.5). There was a latency period (3.3 +/- 1.2 min) between the maximal BIS value and wake-up time in the FEN group but not in the DES group.

DES provides a significantly shorter onset time during the wake-up test and a rapid emergence after scoliosis surgery. BIS monitoring during the wake-up test was more informative when anesthesia was maintained with DES compared to FEN infusion.

Does acute hyperglycaemia in the forearm induce vasodilation that is not modified by hyperinsulinaemia?

To evaluate whether acute elevations of local plasma glucose concentrations could influence forearm blood flow (FBF) and how this interacts with local hyperinsulinaemia in healthy volunteers. Using the perfused forearm technique, in random order, glucose 20% or saline 0.9% as a control was infused in three dose steps (0.3, 1.0, and 3.0 ml/min) for 5 min each in eight healthy men. The infusion experiments were repeated, in random order, during local hyperinsulinaemia by intra-arterial infusion of insulin 0.05 mU/kg/min. The ratio of FBF of the infused over the FBF in the control arm (FR) was measured at 15-sec intervals during the infusions. Glucose infusion increased the FR dose-dependently by 172%+/-39% (M+/-SE) at the highest dose (P < 0.01). During hyperinsulinaemia the glucose-induced increase in FR was significantly (P < 0.01) less, 96%+/-26%, however, when changes in FR or forearm vascular resistance were related to the plasma glucose concentrations both glucose infusions were equipotent. The saline infusions induced small increases in FR of 27+/-5% (P < 0.01) and 24+/-11% (P > 0.05), without or with insulin respectively. The changes in FR during the saline infusions were much smaller than during the glucose infusions (P < 0.01). During the glucose infusions small but significant increases in FBF and venous plasma glucose in the non-infused forearm appeared, indicating carry-over effect and the possibility of a very low threshold for glucose-induced vascular effects.

High, local levels of glucose in the forearm have a vasodilator effect on resistance vessels in skeletal muscle of the forearm that is not modified by local hyperinsulinaemia. Indications were found that the threshold for this glucose-induced vasodilation may be remarkably low, but this needs to be studied more formally.

Is yY1 overexpression associated with poor prognosis and metastasis-free survival in patients suffering osteosarcoma?

The polycomb transcription factor Yin Yang 1 (YY1) overexpression can be causally implicated in experimental tumor growth and metastasization. To date, there is no clinical evidence of YY1 involvement in outcome of patients with osteosarcoma. Prognosis of osteosarcoma is still severe and only few patients survive beyond five years. We performed a prospective immunohistochemistry analysis to correlate YY1 immunostaining with metastatic development and survival in a selected homogeneous group of patients with osteosarcoma. We studied 41 patients suffering from osteosarcoma (stage II-IVa). Multivariate analysis was performed using Cox proportional hazard regression to evaluate the correlation between YY1 expression and both metastasis development and mortality. YY1 protein is not usually present in normal bone; in contrast, a high number of patients (61%) showed a high score of YY1 positive cells (51-100%) and 39% had a low score (10-50% positive cells). No statistical difference was found in histology, anatomic sites, or response to chemotherapy between the two degrees of YY1 expression. Cox regression analysis demonstrated that the highest score of YY1 expression was predictive of both low metastasis-free survival (HR = 4.690, 95%CI = 1.079-20.396; p = 0.039) and poor overall survival (HR = 8.353, 95%CI = 1.863-37.451 p = 0.006) regardless of the effects of covariates such as age, gender, histology and chemonecrosis.

Overexpression of YY1 in primary site of osteosarcoma is associated with the occurrence of metastasis and poor clinical outcome.

Is serum secreted phospholipase A2 associated with abdominal aortic aneurysm presence but not progression?

Secretory phospholipase A(2) (sPLA(2)) has been implicated in rodent models of abdominal aortic aneurysm (AAA). The aim of this study was to assess whether serum sPLA(2) activity was associated with AAA presence and progression. Serum sPLA(2) activity was measured using a fluorometric assay in 1002 men of whom 310 had an AAA. 272 of the men had repeat ultrasound surveillance of their AAA for a median of 5.5 years. The association of sPLA(2) activity with AAA was assessed using multiple regression analysis to adjust for other risk factors. Median serum sPLA(2) activity was 21.67 in men with AAA and 18.32 U/ml in men without AAA, p<0.001. Men with sPLA(2) activity ≥ median (19.20 U/ml) had a 1.40-fold (95% CI 1.04-1.87, p=0.027) increased prevalence of AAA independent of other risk factors. Serum sPLA(2) activity was not associated with AAA growth.

Serum sPLA(2) activity is elevated in men with small AAAs but is not associated with AAA progression.

Does smad7 dependent expression signature highlight BMP2 and HK2 signaling in HSC transdifferentiation?

To analyse the influence of Smad7, antagonist of transforming growth factor (TGF)-β canonical signaling pathways on hepatic stellate cell (HSC) transdifferentiation in detail. We systematically analysed genes regulated by TGF-β/Smad7 in activated HSCs by microarray analysis and validated the results using real time polymerase chain reaction and Western blotting analysis. We identified 100 known and unknown targets underlying the regulation of Smad7 expression and delineated 8 gene ontology groups. Hk2, involved in glycolysis, was one of the most downregulated proteins, while BMP2, activator of the Smad1/5/8 pathway, was extremely upregulated by Smad7. However, BMP2 dependent Smad1 activation could be inhibited in vitro by Smad7 overexpression in HSCs.

We conclude (1) the existence of a tight crosstalk of TGF-β and BMP2 pathways in HSCs and (2) a Smad7 dependently decreased sugar metabolism ameliorates HSC activation probably by energy withdrawal.

Do rewetting drops containing surface active agents improve the clinical performance of silicone hydrogel contact lenses?

The purpose of this study was to investigate the impact of using a rewetting drop (RWD) containing surface active agents (OPTI-FREE RepleniSH; Alcon, Fort Worth, TX) on the clinical performance and protein deposition when using a continuous-wear (CW) silicone hydrogel (SH) contact lens. Subjects wore lotrafilcon A SH lenses on a 30-day CW basis for two consecutive 1-month periods while inserting either 0.9% unpreserved unit-dose saline (control) or multidose OPTI-FREE RepleniSH (test RWD). Subjective comfort and symptoms were assessed after 2 and 4 weeks with each product. After 1 month of wear with each product, lenses were collected and analyzed in the laboratory for total protein, total lysozyme, and percentage of denatured lysozyme. Symptoms of dryness and comfort varied across the day regardless of drop type (p < 0.001) with dryness being maximal on waking, least in the middle of the day, and increased towards the evening. The test RWD provided greater comfort on insertion (p = 0.02), better visual quality (p < 0.01), and less mucous discharge on waking (p = 0.02) than the control product. Lysozyme deposition was significantly reduced after the use of the test RWD as compared to saline (0.73 +/- 0.5 microg/lens vs. 1.14 +/- 0.7 microg/lens; p < 0.001) as was total protein deposition (1.17 +/- 0.7 microg/lens vs. 1.86 +/- 0.8 microg/lens; p < 0.001). Lysozyme denaturation was also reduced with the use of the test RWD compared with the control (76 +/- 10% vs. 85 +/- 7%; p < 0.01).

The use of a RWD containing surface active agents provided greater subjective satisfaction, reduced lysozyme and total protein deposition, and reduced denatured lysozyme than a RWD containing saline alone.

Does pRBC-derived plasma induce non-muscle myosin type IIA-mediated neutrophil migration and morphologic change?

Neutrophils are the primary effector cells in the pathogenesis of transfusion-related acute lung injury or multiple organ failure after blood transfusion. We aimed to investigate the effect of fresh (1 day preparation) and aged (42 day preparation) PRBC-derived plasma on neutrophil morphology, migration and phagocytosis. We evaluated the production of reactive oxygen species (ROS) and the expression of non-muscle myosin heavy chain IIA (MYH9) in neutrophils treated with PRBC-derived plasma. We used western blots and antibody arrays to evaluate changes in signal transduction pathways in plasma-treated neutrophils. Aged PRBC-derived plasma elicited a stronger oxidative burst in neutrophils when compared with fresh PRBC-derived plasma (p < 0.05). Antibody arrays showed increased phosphorylation of NF-ĸB proteins (p105, p50 and Ikk) in aged PRBC-derived plasma-treated neutrophils. The expression of non-muscle myosin IIA (MYH9), a cytoskeleton protein involved in immune cell migration and morphological change, was also significantly upregulated in neutrophils treated with aged PRBC-derived plasma compared to fresh plasma (p < 0.05). Pretreatment of neutrophils with blebbistatin (a specific type II myosin inhibitor), ascorbic acid (an antioxidant), or staurosporine (a protein tyrosine kinase inhibitor), effectively abrogated the morphological changes, neutrophil migration, and phagocytosis induced by aged PRBC-derived plasma.

Upregulation of MYH9 in neutrophils treated with aged PRBC-derived plasma and abrogation of neutrophil migration in blebbistatin-treated neutrophils suggested a functional role of MYH9 in the directional migration of immune cells. Our data help elucidate the cellular and molecular mechanisms of transfusion-related injury.

Does long-term ethanol feeding selectively impair the attachment of rat perivenous hepatocytes to extracellular matrix substrates?

We have previously shown that long-term ethanol consumption by rats results in a profound decrease in hepatocyte attachment to various extracellular matrix substrates. The present study investigated whether differences in attachment exist between cells isolated from either the periportal or perivenous regions of the liver. Rats received long-term ethanol, and hepatocytes were selectively isolated by the digitonin-collagenase perfusion method. The ability of periportal and perivenous cells isolated from ethanol-fed and pair-fed control rats to attach to plates coated with either laminin, fibronectin, or type I collagen was then assayed. With all substrates, the attachment of perivenous hepatocytes isolated from ethanol-fed animals was significantly impaired. Time-course studies showed that although the rate of attachment of perivenous cells from ethanol-fed animals was only slightly reduced, a dramatic decrease in absolute attachment was observed. Furthermore, the perivenous cells isolated from ethanol-fed animals detached more readily from the substrate-coated plates than the corresponding periportal cells or either periportal or perivenous cells from pair-fed controls.

Long-term ethanol consumption impairs hepatocyte-extracellular matrix interactions more severely in the perivenous region of the liver. This finding could be relevant to the pathological changes observed in alcoholic liver injury.

Does a Polymorphism in RNF213 be a Susceptibility Gene for Intracranial Atherosclerosis?

Both intracranial atherosclerotic stenosis (ICAS) and moyamoya disease (MMD) are prevalent in Asians. We hypothesized that the Ring Finger protein 213 gene polymorphism (RNF213), a susceptibility locus for MMD in East Asians, is also a susceptibility gene for ICAS in patients whose diagnosis had been confirmed by conventional angiography (absence of basal collaterals) and high-resolution MRI (HR-MRI, presence of plaque). We analyzed 532 consecutive patients with ischemic events in the middle cerebral artery (MCA) distribution and relevant stenotic lesion on the distal internal carotid artery or proximal MCA, but no demonstrable carotid or cardiac embolism sources. Additional angiography was performed on 370 (69.5%) patients and HR-MRI on 283 (53.2%) patients. Based on angiographic and HR-MRI findings, 234 patients were diagnosed with ICAS and 288 with MMD. The RNF213 variant was observed in 50 (21.4%) ICAS patients and in 119 (69.1%) MMD patients. The variant was observed in 25.2% of patients with HR-MRI-confirmed ICAS. Similarly, 15.8% of ICAS patients in whom MMD was excluded by angiography had this variant. Among the ICAS patients, RNF213 variant carriers were younger and more likely to have a family history of MMD than non-carriers were. Multivariate testing showed that only the age of ICAS onset was independently associated with the RNF213 variant (odds ratio, 0.97; 95% CI, 0.944-0.99).

RNF213 is a susceptibility gene not only for MMD but also for ICAS in East Asians. Further studies are needed on RNF213 variants in ICAS patients outside East Asian populations.

Is irritable pouch syndrome characterized by visceral hypersensitivity?

Irritable pouch syndrome (IPS) is a functional disorder in patients with ileal pouch-anal anastomosis (IPAA), which presents with symptoms in the absence of structural abnormalities of the pouch. Thus, it resembles other functional disorders, such as irritable bowel syndrome characterized by visceral hypersensitivity in the presence of normal rectal biomechanics. The aim was to assess pouch biomechanics and perception of balloon distension in different groups of subjects with IPAA and to correlate the findings with clinical features. Pouch tone, compliance, and sensation to balloon distension were measured in 18 patients with IPS, 11 patients with active pouch inflammation (pouchitis or Crohn's disease of the pouch), and 12 asymptomatic subjects with normal pouches. All patients were recruited from a subspecialty Pouchitis Clinic. Scores of sensation of gas, urge to defecate, and pain measured by visual analog scales at various distension pressures were significantly higher in IPS than pouchitis and normal pouch patients. Pouch tone was comparable among the groups and compliance was reduced in the pouchitis group. The visual analog scale showed a trend of correlation with the Pouchitis Disease Activity Index symptom scores in IPS.

IPS, like other gut functional disorders, is characterized by visceral hypersensitivity, with normal pouch biomechanics.

Is poor vitamin C status associated with increased depression symptoms following acute illness in older people?

Vitamin C has important physical and mental health benefits and plasma concentrations reflect recent intakes. Inflammation associated with any acute illness can lead to poor appetite and low food intake in older people. The aims of this report were to assess the prevalence and clinical significance of vitamin C deficiency among hospitalized acutely-ill older patients. Three hundred and twenty two patients (152 [47%] female), aged 65 yrs. and over who took part in a randomized, double blind, placebo-controlled trial had their nutritional status assessed from anthropometric, hematological and biochemical data at baseline, and after 6 weeks and 6 months. Vitamin C was measured using a fluorimetric technique and logistic regression analysis was performed to determine the influence of a number of clinical indicators, including tissue inflammation measured using C-reactive protein on vitamin C concentrations. Clinical outcome measures including symptoms of depression were also compared between patients with vitamin C deficiency and those with normal levels. At baseline, 116 (36%) patients had a vitamin C concentration below 11 µmol/L indicating biochemical depletion. The figures at 6 weeks and 6 months were 28 (22%) and 44 (28%) patients, respectively. Older age, male gender, smoking, increased dependency and tissue inflammation were associated with lower vitamin C concentrations. Patients with vitamin C biochemical depletion had significantly increased symptoms of depression compared with those with higher concentrations at baseline (p=0.035) and at 6 weeks (p=0.028).

A high proportion of older patients had sub-optimal vitamin C status and this was associated with increased symptoms of depression.

Is Mycoplasma genitalium in women the "New Chlamydia?

The role of Mycoplasma genitalium in pelvic inflammatory disease is unclear. We conducted a cohort study to determine the prevalence and predictors of M. genitalium infection in female students, to explore its role in pelvic inflammatory disease and to estimate its annual incidence and persistence rate. Two thousand three hundred seventy-eight multiethnic, sexually active female students (mean age, 21 years) provided duplicate self-taken vaginal samples for a chlamydia screening trial. From this population, 2246 (94%) were followed up after 12 months and assessed for incidence of clinical pelvic inflammatory disease. In addition, 900 women (38%) returned follow-up samples via the postal service 11-32 months after recruitment. Stored samples were tested for M. genitalium. The prevalence of M. genitalium at baseline was 3.3% (78 of 2378 women; 95% confidence interval [CI], 2.6%-4.1%). Infection was more common in women reporting ≥ 2 sexual partners in the previous year, those with bacterial vaginosis, women aged<18 years, women of black ethnicity, and smokers. Multiple partners and bacterial vaginosis were independent risk factors for M. genitalium (adjusted risk ratio, 2.23 [95% CI, 1.39-3.58] and 2.54 [95% CI, 1.61-4.01], respectively). The incidence of pelvic inflammatory disease over 12 months was 3.9% (3 of 77 women) among women with M. genitalium infection, compared with 1.7% (36 of 2169 women) among those without infection (risk ratio, 2.35; 95% CI, 0.74-7.46; P = .14). Annual incidence of M. genitalium infection in 873 women without M. genitalium infection at baseline who returned samples via the postal service was 0.9% (95% CI, 0.5%-1.6%). Seven (26%; 95% CI, 9%-43%) of 27 women with M. genitalium infection at baseline remained positive after 12-21 months; genotyping results suggest that these were persistent infections.

M. genitalium infection is unlikely to be a major risk factor for clinical pelvic inflammatory disease in this population.

Can circuit lifetime be a quality indicator in continuous renal replacement therapy in the critically ill?

Continuous renal replacement therapy (CRRT) is frequently used in critically ill patients with acute renal failure and sepsis. Frequent circuit changes increase nursing workload, blood loss and costs, and also compromise achievement of the filtration rate goal. Circuit downtime is the most important factor that compromises the cumulative filtration goal. We used continuous venovenous hemodiafiltration (Prismaflex, Gambro, Meyzieu Cedex, France) in our 12-bed medical intensive care unit (ICU). Circuit lifetimes, indication to start CRRT anticoagulation protocol, reason for circuit change, and location of the vascular access were prospectively documented for 12 months in consecutive patients. Unfractionated heparin was the first choice for anticoagulation. No anticoagulation was used in patients with severe coagulation abnormalities or hepatic failure; regional citrate-based anticoagulation (CBA) was used in patients with recurrent circuit clotting or with bleeding predisposition. Our aim was to assess the suitability of circuit lifetime as a quality indicator, evaluated by survival analysis. Median circuit lifetime was significantly longer for CBA (log rank chi2 = 8.08; p = 0.018). This is consistent with the literature. There were no differences in vascular access site, proportion of sepsis, or vasopressor dependency between the three anticoagulation groups.

In addition to monitoring the complication rate, the evaluation of circuit lifetime using survival analysis stratified by anticoagulation strategy is a simple and feasible means of assessing the quality of CRRT in the ICU.

Does neuregulin repellent signaling via ErbB4 restrict GABAergic interneurons to migratory paths from ganglionic eminence to cortical destinations?

Cortical GABAergic interneurons (INs) are generated in the medial ganglionic eminence (MGE) and migrate tangentially into cortex. Because most, if not all, migrating MGE-derived INs express the neuregulin (NRG) receptor, ErbB4, we investigated influences of Nrg1 isoforms and Nrg3 on IN migration through ventral telencephalon (vTel) and within cortex. During IN migration, NRG expression domains and distributions of ErbB4-expressing, MGE-derived INs are complementary with minimal overlap, both in vTel and cortex. In wild-type mice, within fields of NRG expression, these INs are focused at positions of low or absent NRG expression. However, in ErbB4-/- HER4(heart) mutant mice in which INs lack ErbB4, these complementary patterns are degraded with considerable overlap evident between IN distribution and NRG expression domains. These findings suggest that NRGs are repellents for migrating ErbB4-expressing INs, a function supported by in vitro and in vivo experiments. First, in collagen co-cultures, MGE-derived cells preferentially migrate away from a source of secreted NRGs. Second, cells migrating from wild-type MGE explants on living forebrain slices from wild-type embryonic mice tend to avoid endogenous NRG expression domains, whereas this avoidance behavior is not exhibited by ErbB4-deficient cells migrating from MGE explants and instead they have a radial pattern with a more uniform distribution. Third, ectopic NRG expression in the IN migration pathway produced by in utero electroporation blocks IN migration and results in cortex distal to the blockade being largely devoid of INs. Finally, fewer INs reach cortex in ErbB4 mutants, indicating that NRG-ErbB4 signaling is required for directing IN migration from the MGE to cortex.

Our results show that NRGs act as repellents for migrating ErbB4-expressing, MGE-derived GABAergic INs and that the patterned expression of NRGs funnels INs as they migrate from the MGE to their cortical destinations.

Are the antigen-bearing eye and the spleen indispensable in maintaining anterior chamber-associated immune deviation?

To investigate the role of the eye and the spleen in maintaining suppression of delayed-type hypersensitivity (DTH) after anterior chamber (AC) inoculation of allogeneic splenocytes. Suppression of DTH response was tested in BALB/c mice after AC inoculation of allogeneic B10.D2 splenocytes. Seven days after AC injection, the antigen-inoculated eyes were enucleated or the spleens were removed. After enculeation or splenectomy at different time intervals, DTH responses in groups of the BALB/c mice were examined. Spleen components obtained from BALB/c mice that had been primed by B10.D2 splenocytes in the AC 7 days earlier were transferred intravenously to groups of naive syngeneic acceptors. At various intervals after adoptive transfer, variations of DTH responses were tested. Inoculation of B10.D2 splenocytes to the AC of BALB/c mice induced antigen-specific suppression of DTH. Either enucleation of the antigen-inoculated eyes or splenectomy weakened the DTH-suppressive effect within 5 weeks and abolished it within 9 weeks, whereas the mice retaining both antigen-inoculated eyes and spleens maintained longstanding DTH suppression. Adoptive transfer of spleen components to syngeneic acceptors demonstrated DTH suppression for only 3 weeks.

The antigen-inoculated eye and spleen are required for long-standing suppression of DTH after AC inoculation of allogeneic splenocytes.

Are psychiatric diagnoses in patients with fibromyalgia related to health care-seeking behavior rather than to illness?

To compare the frequency of lifetime psychiatric disorders among 3 groups of subjects: patients with fibromyalgia syndrome (FMS) from a tertiary care setting, community residents with FMS who had not sought medical care for their FMS symptoms ("FMS nonpatients"), and healthy controls. We used the Computerized Diagnostic Interview Schedule to assess lifetime psychiatric diagnoses, as well as the Center for Epidemiological Studies Depression scale and the Trait Anxiety Inventory to assess current psychological distress, among 64 patients with FMS, 28 FMS nonpatients, and 23 healthy individuals. Patients with FMS, relative to FMS nonpatients and healthy controls, were characterized by a significantly greater number of lifetime psychiatric diagnoses (P = 0.002). Nonpatients did not differ from controls in psychiatric diagnoses. Patients also exhibited higher psychological distress levels than nonpatients, and nonpatients showed greater distress than controls. Differences in psychological distress between patients and nonpatients were eliminated after controlling for pain threshold and fatigue ratings.

Psychiatric disorders are not intrinsically related to the FMS syndrome. Instead, multiple lifetime psychiatric diagnoses may contribute to the decision to seek medical care for FMS in tertiary care settings.

Is serum cystatin C superior to serum creatinine as a marker of kidney function : a meta-analysis?

Serum cystatin C (Cys C) has been proposed as a simple, accurate, and rapid endogenous marker of glomerular filtration rate (GFR) in research and clinical practice. However, there are conflicting reports regarding the superiority of Cys C over serum creatinine (Cr), with a few studies suggesting no significant difference. We performed a meta-analysis of available data from various studies to compare the accuracy of Cys C and Cr in relation to a reference standard of GFR. A bibliographic search showed 46 articles until December 31, 2001. We also retrieved data from eight other studies presented and published in abstract form. The overall correlation coefficient for the reciprocal of serum Cys C (r = 0.816; 95% confidence interval [CI], 0.804 to 0.826) was superior to that of the reciprocal of serum Cr (r = 0.742; 95% CI, 0.726 to 0.758; P < 0.001). Similarly, receiver operating characteristic (ROC)-plot area under the curve (AUC) values for 1/Cys C had greater identity with the reference test for GFR (mean ROC-plot AUC for Cys C, 0.926; 95% CI, 0.892 to 0.960) than ROC-plot AUC values for 1/Cr (mean ROC-plot AUC for serum Cr, 0.837; 95% CI, 0.796 to 0.878; P < 0.001). Immunonephelometric methods of Cys C assay produced significantly greater correlations than other assay methods (r = 0.846 versus r = 0.784; P < 0.001).

In this meta-analysis using currently available data, serum Cys C is clearly superior to serum Cr as a marker of GFR measured by correlation or mean ROC-plot AUC.