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Does leonurine protect middle cerebral artery occluded rats through antioxidant effect and regulation of mitochondrial function?

Oxidative stress is known to be involved in ischemic stroke. Intense interest is drawn to the therapeutic potential of Chinese herbs on ischemic stroke because many of them contain antioxidant properties. Leonurine, 1 of the active compounds from purified Herba Leonuri, was studied to evaluate its possible therapeutic effects on ischemic stroke. Method-Middle cerebral artery occlusion was selected as our model of study. The animals were pretreated with Leonurine orally for 7 days and the surgery was done. One day after surgery, 2,3,5-triphenyltetrazolium chloride staining and neurological deficit score were carried out to evaluate the functional outcome of animals, whereas levels of superoxide dismutase, glutathione peroxidase, and malondialdehyde were analyzed for oxidative stress analysis. For mitochondrial studies, 3 hours after surgery, mitochondria were isolated for analysis of reactive oxygen species production, adenosine triphosphate biosynthesis, oxygen consumption, and respiratory control ratio value. Result-In in vivo experiments, Leonurine pretreatment reduced infarct volume, improved neurological deficit in stroke groups, increased activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase, and decreased levels from the lipid peroxidation marker malondialdehyde. In terms of mitochondrial modulation, Leonurine inhibited mitochondrial reactive oxygen species production and adenosine triphosphate biosynthesis. Animal studies also demonstrated that the mitochondrial function and redox state were restored by Leonurine treatment.

Leonurine has neuroprotective effects and carries a therapeutic potential of stroke prevention.

Are degenerative changes in the aortic valve an additional important marker of atherosclerosis?

Degenerative changes of the mitral annulus are associated with atherosclerotic disease. It has recently been suggested that degenerative changes in the aortic valve may also be associated with atherosclerosis. The intima-media thickness of the carotid arteries has been used as one of the best and earliest markers of atherosclerosis. The aim of this study was to evaluate whether the additional presence of degenerative changes in the aortic valve in coronary patients with mitral annular degenerative disease reflects different degrees of intima-media thickness as assessed by carotid ultrasonography. The study group included 55 patients admitted for myocardial infarction who presented with degenerative changes of the mitral annulus assessed by echocardiography. Exclusion criteria were moderate or severe valvular heart disease and chronic renal failure. All patients underwent echocardiography, cardiac Doppler and carotid ultrasonography. Based on the echocardiographic findings, two sub-groups were formed: 1--with degenerative changes of the aortic valve; and 2--without degenerative changes of the aortic valve. Carotid ultrasonography was performed with a 7.5-10 MHz linear transducer and the following parameters were evaluated: 1--bilateral measurement of intima-media thickness in the common carotid artery; 2-- incidence of atheromatous plaques in the carotid arteries, and 3--incidence of>50% lesion in the internal carotid arteries assessed by pulsed Doppler (Vmax>125 cm/s). Thirty-three patients (aged 71.6 +/- 7.1 years), 21 men and 12 women, did not present degenerative changes in the aortic valve. The other group consisted of 22 individuals (aged 72.9 +/- 6.8 years), 14 men and 8 women, who did have such changes. Differences in age and gender distribution between the two groups were not significant. Patients with degenerative aortic valve disease had greater intima-media thickness than the control group (1.6 +/- 0.3 mm versus 1.3 +/- 0.4 mm, p<0.001). Fifteen (68%) patients with aortic degenerative disease had plaques in the carotid arteries compared to 11 (33%) patients in the control group (p<0.05). No significant differences were found between the two groups regarding the incidence of>50% atherosclerotic lesion in the internal carotid artery (22% versus 12%; NS).

Patients with degenerative changes in the aortic valve presented significantly greater intima-media thickness and a higher incidence of atherosclerotic plaques than the control group, suggesting that their presence may constitute an additional important marker of severity of atherosclerotic disease.

Does the revised appropriate use criteria for echocardiography represent an improvement over the initial criteria?

The appropriateness use criteria (AUC) for the performance of transthoracic echocardiography were recently revised. The aims of this study were to evaluate the 2011 AUC for echocardiography for their ability to categorize indications not addressed by the older AUC and to identify trends in ordering unclassified and inappropriate studies when applying the new AUC. We reviewed 384 consecutive adult transthoracic echocardiographic studies performed at a tertiary care teaching hospital. The appropriateness of each study was determined applying both the 2007 and the 2011 AUC. Among the 384 studies evaluated, 212 (55.2%) were performed in men, 261 (67.9%) were inpatient studies, and 186 (48.4%) were ordered by cardiologists. Compared with the older 2007 AUC, applying the new 2011 AUC demonstrated a lower rate of unclassified studies (5.5% vs 12.5%), higher rates of appropriate (92.2% vs 86.7%) and inappropriate (1.8% vs 0.8%) studies, and no significant change in the rate of uncertain studies (0.5% vs 0.0%). Of the 5.5% of studies that continued to be unclassified despite the application of the more extensive 2011 AUC, common indications included preoperative evaluation for non-transplantation surgery in patients with coronary artery disease, postoperative assessment of thoracic aortic surgery in the absence of any clinical change, and reassessment of ventricular function after revascularization in the absence of acute coronary syndromes.

Compared with the 2007 AUC for transthoracic echocardiography, application of the recently revised 2011 criteria leads to a significant decrease in the number of studies that are not classified, demonstrating that the AUC revision was successful in achieving the goal of addressing more clinical indications.

Does epigenetic regulator MLL2 show altered expression in cancer cell lines and tumors from human breast and colon?

MLL2, an epigenetic regulator in mammalian cells, mediates histone 3 lysine 4 tri-methylation (H3K4me3) through the formation of a multiprotein complex. MLL2 shares a high degree of structural similarity with MLL, which is frequently disrupted in leukemias via chromosomal translocations. However, this structural similarity is not accompanied by functional equivalence. In light of this difference, and previous reports on involvement of epigenetic regulators in malignancies, we investigated MLL2 expression in established cell lines from breast and colon tissues. We then investigated MLL2 in solid tumors of breast and colon by immunohistochemistry, and evaluated potential associations with established clinicopathologic variables. We examined MLL2 at both transcript and protein levels in established cell lines from breast and colon cancers. Examination of these cell lines showed elevated levels of MLL2. Furthermore, we also identified incomplete proteolytic cleavage of MLL2 in the highly invasive tumor cell lines. To corroborate these results, we studied tumor tissues from patients by immunohistochemistry. Patient samples also revealed increased levels of MLL2 protein in invasive carcinomas of the breast and colon. In breast, cytoplasmic MLL2 was significantly increased in tumor tissues compared to adjacent benign epithelium (p < 0.05), and in colon, both nuclear and cytoplasmic immunostaining was significantly increased in tumor tissues compared to adjacent benign mucosa (p < 0.05).

Our study indicates that elevated levels of MLL2 in the breast and colon cells are associated with malignancy in these tissues, in contrast to MLL involvement in haematopoietic cancer. In addition, both abnormal cellular localization of MLL2 and incomplete proteolytic processing may be associated with tumor growth/progression in breast and colonic tissues. This involvement of MLL2 in malignancy may be another example of the role of epigenetic regulators in cancer.

Do social housing conditions influence morphine dependence and the extinction of morphine place preference in adolescent mice?

Adolescent opioid abuse is on the rise, and current treatments are not effective in reducing rates of relapse. Our previous studies demonstrated that social housing conditions alter the acquisition rate of morphine conditioned place preference (CPP) in adolescent mice. Specifically, the acquisition rate of morphine CPP is slower in morphine-treated animals housed with drug-naïve animals. Thus, here we tested the effect of social housing conditions on the development of morphine dependence and the extinction rate of an acquired morphine CPP. Adolescent male mice were group-housed in one of two housing conditions. They were injected for 6 days (PND 28-33) with 20 mg/kg morphine. Morphine only mice are animals where all four mice in the cage received morphine. Morphine cage-mate mice are morphine-injected animals housed with drug-naïve animals. Mice were individually tested for spontaneous withdrawal signs by quantifying jumping behavior 4, 8, 24, and 48 h after the final morphine injection. Then, mice were conditioned to acquire morphine CPP and were tested for the rate of extinction. Morphine cage-mates express less jumping behavior during morphine withdrawal as compared to morphine only mice. As expected, morphine cage-mate animals acquired morphine CPP more slowly than the morphine only animals. Additionally, morphine cage-mates extinguished morphine CPP more readily than morphine only mice.

Social housing conditions modulate morphine dependence and the extinction rate of morphine CPP. Extinction testing is relevant to human addiction because rehabilitations like extinction therapy may be used to aid human addicts in maintaining abstinence from drug use.

Is n-WASP highly expressed in hepatocellular carcinoma and associated with poor prognosis?

Neural Wiskott-Aldrich syndrome protein (N-WASP) mediates migration and invasion in cancer cells, but its expression and clinicopathologic and prognostic importance in hepatocellular carcinoma (HCC) remain unknown. The present study was designed to address these issues. N-WASP expression was first analyzed by Western blotting in 19 paired HCC and paratumoral liver (PTL) tissues. We further evaluated N-WASP expression immunohistochemically in samples from 119 patients with HCC. The clinicopathologic and prognostic importance of N-WASP expression were also investigated. Western blotting showed that N-WASP expression was up-regulated in 15 of 19 HCC tissues (79%), compared with PTL ones. The N-WASP-positive rate in immunohistochemical staining also was greater in HCC (63/119, 53%) than that in PTL tissues (8/119, 6%). The up-regulated N-WASP expression in HCC tissues was correlated with absence of capsule formation and predicted less overall and disease-free survival. Multivariate analysis demonstrated that N-WASP was an independent prognostic factor for overall survival and was marginally important for disease-free survival.

These data establish that N-WASP is highly expressed in HCC and its strong prognostic importance. Therefore, the gene/protein might serve as a potential therapeutic target for HCC.

Is intracardiac transvenous echocardiography superior to both precordial Doppler and transesophageal echocardiography techniques for detecting venous air embolism and catheter-guided air aspiration?

Venous air embolism (VAE) is a potentially fatal complication during surgical procedures with patients in the sitting position. Since methods for detection of persistent low-volume VAE and targeted air aspiration are limited, we tested the hypotheses that transvenous intracardiac echocardiography (ICE) 1) improves detection of small air emboli in comparison to transesophageal echocardiography (TEE) and precordial Doppler monitoring (PCD) techniques, and that 2) image-guided multiorifice central venous catheter manipulation improves air recovery in moderate and large VAE, when compared with aspiration with the multiorifice central venous catheter in a static position. Adult swine (73 +/- 4.6 kg, n = 7) were premedicated, anesthetized with propofol and fentanyl, endotracheally intubated, mechanically ventilated, and placed in a 45 degrees head-up position. First, nine different small volumes of air emboli (0.05-1 mL) were randomly injected via an ear vein, and VAE detection methods were applied in random order. For 378 small volume air injections, ICE had a much higher sensitivity (82.5%, P < 0.0001) on the analysis of VAE detection than TEE (52.8%) or PCD (46.8%), with no difference (P = 0.571) between TEE and PCD. An injected air volume as small as 0.15 mL was detected by ICE in 90% of injections performed, whereas PCD and TEE detected only half of the boluses of 0.25-0.30 mL of air, and required boluses of 0.4-1.0 mL to achieve 100% detection. Air recovery was assessed in a second series of moderate VAE (2, 5, 10 mL); image-guided aspiration-catheter manipulation recovered significantly more (34.1% vs 17.2%, P < 0.0001) intracardiac air than without catheter manipulation. In a third series of injections of large air volumes (25, 50, and 100 mL), air recovery was not significantly different with ultrasound-guided aspiration (41.3% vs 31.8%, P = 0.11).

Small air emboli are detected by ICE with much greater sensitivity compared with both PCD and TEE techniques. Furthermore, recovery of embolized air is enhanced by image-guided manipulation of a multiorifice central venous catheter. Clinical studies are required to assess this technique during surgery with patients in the sitting position.

Does protective immunity remain intact after antibody removal by means of proteasome inhibition?

Proteasome inhibition abrogates donor-specific anti-human leukocyte antigen (HLA) antibody (DSA) in patients posttransplant. However, its effects on protective humoral immunity to vaccine antigens remain unknown. Herein, we report on bortezomib's safety regarding protective immunity in patients who have experienced HLA antibody reduction/removal. Thirteen living donor renal transplant patients were treated with bortezomib one to two cycles (1.3 mg/m² × 4 doses) and plasmapheresis in 2008 to remove HLA antibodies posttransplant. Serial measurements of HLA antibody were conducted weekly before, during, and after treatment by means of single antigen bead on Luminex (One Lambda Inc., Canoga Park, CA). Measles and tetanus toxoid IgGs were measured quantitatively by using ELISA (American Research Products Inc., Belmont, MA). All patients treated with bortezomib/plasmapheresis resulted in a primary DSA reduction of more than 50%. In 10 of 13 patients, complete DSA removal (to below 1000 mean fluorescent intensity) occurred. At 1 year posttreatment, antibody intensity remains significantly depressed in the group as a whole. Despite the significant effect on antibody production, tetanus toxoid and measles IgG levels remained unchanged and above the level of protection at 1 year posttreatment.

These data indicate that proteasome inhibitors plus plasmapheresis results in prolonged reduction of HLA antibodies while leaving protective immunity intact.

Do effective teamwork and communication mitigate task saturation in simulated critical care air transport team missions?

Critical Care Air Transport Teams (CCATTs) are a critical component of the United States Air Force evacuation paradigm. This study was conducted to assess the incidence of task saturation in simulated CCATT missions and to determine if there are predictable performance domains. Sixteen CCATTs were studied over a 6-month period. Performance was scored using a tool assessing eight domains of performance. Teams were also assessed during critical events to determine the presence or absence of task saturation and its impact on patient care. Sixteen simulated missions were reviewed and 45 crisis events identified. Task saturation was present in 22/45 (49%) of crisis events. Scoring demonstrated that task saturation was associated with poor performance in teamwork (odds ratio [OR] = 1.96), communication (OR = 2.08), and mutual performance monitoring (OR = 1.9), but not maintenance of guidelines, task management, procedural skill, and equipment management. We analyzed the effect of task saturation on adverse patient outcomes during crisis events. Adverse outcomes occurred more often when teams were task saturated as compared to non-task-saturated teams (91% vs. 23%; RR 4.1, p < 0.0001).

Task saturation is observed in simulated CCATT missions. Nontechnical skills correlate with task saturation. Task saturation is associated with worsening physiologic derangements in simulated patients.

Are sympatho-inhibitory effects of gamma-l-glutamyl-l-dopa mediated by activation of dopamine-2 receptors in conscious rabbits?

To define the role of dopamine-2 receptors in the sympatho-inhibitory effects of gamma-l-glutamyl-l-dopa in conscious rabbits. gamma-l-glutamyl-l-dopa (gludopa) was infused iv at 25 and 100 micrograms.kg-1.min-1 with and without prior dopamine-2 receptor blockade by YM-09151-2 (50 micrograms.kg-1 iv) in conscious rabbits. Mean arterial pressure and heart rate remained unchanged while renal plasma flow increased. Arterial norepinephrine (NE) concentration, total and renal NE spillover rate were markedly decreased in a dose-related manner, which were not affected by prior dopamine-2 receptor blockade. Gludopa was detected in the whole brain (92 +/- 112 ng/g wet brain tissue) at the end of experiment although brain tissue levodopa, NE, and dopamine contents were not much different from those in the control group.

Gludopa decreased dose-dependently plasma NE concentration, and total and renal NE overflow to plasma, which were not mediated by activation of dopamine D2 receptors.

Is pancreatic cancer growth inhibited by blockade of VEGF-RII?

Angiogenesis is important in the development and progression of pancreatic cancer. Therefore antiangiogenic therapy targeting endothelial cells may represent a promising therapeutic option. The aim of the study was to evaluate antiangiogenic therapy as a potential therapeutic option in pancreatic cancer. Replication-deficient retroviruses encoding truncated VEGF-RII were used to block vascular endothelial growth factor (VEGF) signaling. Tumor growth of 3 pancreatic cancer cell lines was assayed in a nude mouse model in which each pancreatic cancer cell line was subcutaneously inoculated together with retrovirus-producing cells. Expression of VEGF was assayed by RT-PCR and by enzyme-linked immunosorbent assay. Oxygen tension in tumors was determined polarographically. All 3 pancreatic cancer cell lines expressed VEGF mRNA, with the highest VEGF secretion seen in MIA PaCa-2 cells. In vivo therapeutic intervention through dominant negative inhibition of VEGF-RII significantly reduced the growth rate of subcutaneous tumors and inhibited tumor neoangiogenesis. Tumor oxygenation, however, was not altered in xenograft tumors treated with dominant negative retroviruses.

The ligand/receptor system consisting of VEGF and VEGF-RII seems to be of biologic significance in the pathogenesis of pancreatic cancer growth. Therefore therapeutic intervention in this angiogenic system by a retroviral-based gene transfer technology represents a rational and feasible new technique to inhibit tumor growth.

Does mathematical modeling improve computed tomography diagnosis of traumatic aortic injury?

Acute traumatic aorta injuries (ATAIs) following blunt thoracic trauma require rapid and accurate diagnosis for institution of lifesaving treatment. The use of computed tomography (CT) in the diagnosis of such injuries continues to improve and has the potential to become the diagnostic modality of choice in many trauma centers. A standardized diagnostic model may contribute to improvements in radiologist interpretation of CT for ATAIs. The following diagnostic criteria were used to develop a diagnostic model for ATAIs: 11 areas of potential hematoma formation were identified in the mediastinum. Maximum short- and long-axis cross-sectional diameters of the aorta were measured. Qualitative morphologic information (contour change, intimal flap) was recorded. Smoothness of the aorta wall was assessed. These characteristics were quantified and analyzed for statistical significance, allowing for the development of an injury assessment model. The diagnostic model was used to score 69 blunt thoracic trauma patient cases. Average weighted kappa was 0.74, showing strong agreement among two observers and reproducibility of the model. The model improved injury assessment by classifying equivocal cases as either positive or negative. The ROC curve calculated from the original radiologist interpretation contained 86.1% area under the curve, while the curve for the new model contained 97.5%. The likelihood ratio increased from 30.06 to 48.67. The degree to which the new measure improved prediction over the original radiologist reading was tested using a nested model and yielded a reliable increment in model fit (chi2 analysis: Deltachi2(3) = 20.929, P < or = .0001). Finally, beta weights calculated from each variable were used to create a quantitative best-fit diagnostic model for future use.

We have developed a diagnostic tool that may help radiologists better evaluate CT for ATAIs.

Does recalls and safety alert involving pacemakers and implantable cardioverter-defibrillator generators?

Unanticipated pacemaker and implantable cardioverter-defibrillator (ICD) generator malfunctions sometimes warrant recall by the US Food and Drug Administration (FDA). Despite increasingly frequent device implantation, pacemaker and ICD recalls and safety alerts (advisories) remain poorly characterized. To determine pacemaker and ICD generator advisory rates in the United States, to identify trends in these rates, and to examine their clinical and financial implications. Analysis of weekly FDA Enforcement Reports issued between January 1990 and December 2000 to identify all advisories involving pacemaker or ICD generators in the United States. Recalls and safety alerts involving lead malfunctions were not included. Number of pacemakers and ICD generators in the United States subject to FDA recall or safety alert in 1990-2000; annual pacemaker and ICD advisory rates in the United States in 1990-2000; and estimated cost of device advisories. During the study period, 52 advisories (median [25th and 75th percentiles], 4 [4 and 7] per year) involving 408 500 pacemakers and 114 645 ICDs (523 145 total devices) were issued. Hardware malfunctions (35 advisories affecting 280 641 devices) and computer errors (10 advisories affecting 216 533 devices) accounted for 95% of device recalls. Implantable cardioverter-defibrillators were recalled more frequently than pacemakers (mean [SD], 16.4 [1.6] vs 6.7 [0.8] advisories per 100 person-years; P<.001). Between 1995 and 2000, the annual advisory rate increased for both pacemakers (P for trend <.001) and ICDs (P for trend =.02). An estimated 1.3 million device checks and analyses and 36 187 device replacements resulted from the advisories and cost approximately $870 million.

Pacemaker and ICD recalls and safety alerts occur frequently, affect many patients, and appear to be increasing in number and rate. With the growing number of device implants and expanding indications for device therapy, the number of patients affected by device advisories will likely continue to increase.

Does hepatic steatosis in patients with chronic hepatitis C virus genotype 2 or 3 affect viral response in patients treated with peginterferon alpha-2a ( 40KD ) ( PEGASYS ) plus ribavirin ( COPEGUS ) for 16 or 24 weeks?

Hepatic steatosis is common in patients infected with hepatitis C virus (HCV). The effect of steatosis on anti-HCV therapy efficacy is unclear. We studied host and viral factors associated with steatosis and the effect of steatosis on treatment efficacy using the database of a large prospective trial in patients with HCV genotypes 2 and 3. Out of 885 patients assessed for steatosis, a total of 614 patients or 69% had steatosis. Patients with genotype 3 were more likely to have steatosis than those with genotype 2 (79 vs. 59%, P<0.001). Using the logistic regression model, steatosis was associated with genotype 3 (P<0.0001), older age (P=0.0025), heavier weight (P<0.0001), higher HCV RNA (P<0.0001), and higher ALT levels (P=0.015). By univariate analysis, steatosis was associated with lower sustained virological response (SVR) in patients with genotype 3, but not in patients with genotype 2. When all factors associated with steatosis and SVR were evaluated by logistic regression analysis; genotype, age, bodyweight, histological diagnosis, ALT quotient, baseline HCV RNA and treatment duration were associated with the probability of SVR, but gender, race and steatosis were not. Further analysis showed that steatosis remained a non-significant factor while baseline viral load was significantly associated with the probability of an SVR.

Steatosis did not influence the efficacy of treatment in our study population. Baseline viral load is a confounding factor, particularly in patients infected with genotype 3 and once baseline viral load was accounted for, the association between steatosis and SVR was not relevant.

Is a genetic variation in the 5 ' flanking region of the UCP3 gene associated with body mass index in humans in interaction with physical activity?

In obese French Caucasian subjects we previously described a silent UCP3 Tyr99Tyr mutation, associated with body mass index. We hypothesised that an unknown polymorphism in the vicinity of the gene could contribute to obesity. Morbidly obese subjects were screened for mutations in 1 kb upstream from the UCP3 gene. Association studies were done between a variant and obesity in 401 morbidly obese and 231 control subjects. We detected three rare genetic variants and one polymorphism: a +5 G-->A in exon 1, a -155 C-->T, a -439 A insertion and a -55 C-->T located 6 bp from the putative TATA box. This variant was in linkage disequilibrium with the Tyr99Tyr polymorphism. Frequencies of the variant allele at the -55 locus were similar in the obese and control groups (0.23 vs 0.21). The -55 polymorphism was associated with BMI in the obese group (p = 0.0031): BMI was higher in TT than in CC or CT patients. Likewise control subjects with a TT genotype had a higher BMI (p = 0.03). In the obese group, homozygosity for this variant is a risk factor for high BMI (odds ratio: 1:75, p = 0.02). Obese patients were divided into tertiles according to physical activity. In the group with a wild C/C genotype, BMI was negatively associated with physical activity (p = 0.015).

The C-->T polymorphism in the 5' sequences of the UCP3 gene might contribute to the corpulence in obese and normal weight subjects and alter the benefit of physical activity. The UCP3 gene can be considered as a gene modifying corpulence.

Does sR48692 inhibit non-small cell lung cancer proliferation in an EGF receptor-dependent manner?

The mechanism by which SR48692 inhibits non-small cell lung cancer (NSCLC) proliferation was investigated. The ability of SR48692 to inhibit the proliferation of NSCLC cell lines NCI-H1299 and A549 was investigated in vitro in the presence or absence of neurotensin (NTS). The ability of NTS to cause epidermal growth factor receptor (EGFR) transactivation was investigated by Western blot using NSCLC cells and various inhibitors. The growth effects and Western blot results were determined in cell lines treated with siRNA for NTSR1. Treatment of A549 or NCI-H1299 cells with siRNA for NTSR1 reduced significantly NTSR1 protein and the ability of SR48692 to inhibit the proliferation of A549 or NCI-H1299 NSCLC cells. Treatment of A549 and NCI-H1299 cells with siRNA for NTSR1 reduced the ability of NTS to cause epidermal growth factor receptor (EGFR) transactivation. SR48692 or gefitinib (EGFR tyrosine kinase inhibitor) inhibited the ability of NTS to cause EGFR and ERK tyrosine phosphorylation. NTS transactivation of the EGFR was inhibited by GM6001 (matrix metalloprotease inhibitor), Tiron (superoxide scavenger) or U73122 (phospholipase C inhibitor) but not H89 (PKA inhibitor). NTS stimulates whereas SR48692 or gefitinib inhibits the clonal growth of NSCLC cells.

These results suggest that SR48692 may inhibit NSCLC proliferation in an EGFR-dependent mechanism.

Do implicit attitudes and explicit motivation prospectively predict physical activity?

Contemporary approaches to physical activity motivation and promotion focus on explicit motivational processes which regulate intentional physical activity. Less is known about the role of implicit processes, which may be instrumental in regulating habitual aspects of unintentional (i.e., incidental) physical activity (PA). To test the proposition that the routine nature of unintentional PA makes it amenable to control by implicit processes. Participants (N = 201) completed measures of explicit motivation (i.e., efficacy beliefs, outcome expectations, behavioral intentions, perceived behavioral control) and implicit attitudes toward physical activity, and then wore a pedometer for 1 week. Implicit attitudes positively predicted PA after controlling for well-established predictors of intentional physical activity.

PA motivation involves both explicit and implicit processes, and PA promotion efforts may be enhanced by attending to relevant implicit motivation processes.

Is downregulation of miR-342 associated with tamoxifen resistant breast tumors?

Tumor resistance to the selective estrogen receptor modulator tamoxifen remains a serious clinical problem especially in patients with tumors that also overexpress HER2. We have recently demonstrated that the clinically important isoform of HER2, HERΔ16, promotes therapeutically refractory breast cancer including resistance to endocrine therapy. Likewise additional breast tumor cell models of tamoxifen resistance have been developed that do not involve HER2 overexpression. However, a unifying molecular mechanism of tamoxifen resistance has remained elusive. Here we analyzed multiple cell models of tamoxifen resistance derived from MCF-7 cells to examine the influence of microRNAs (miRNAs) on tamoxifen resistance. We compared miRNA expression profiles of tamoxifen sensitive MCF-7 cells and tamoxifen resistant MCF-7/HER2Δ16 cells. We observed significant and dramatic downregulation of miR-342 in the MCF-7/HER2Δ16 cell line as well as the HER2 negative but tamoxifen resistant MCF-7 variants TAMR1 and LCC2. Restoring miR-342 expression in the MCF-7/HER2Δ16 and TAMR1 cell lines sensitized these cells to tamoxifen-induced apoptosis with a dramatic reduction in cell growth. Expression of miR-342 was also reduced in a panel of tamoxifen refractory human breast tumors, underscoring the potential clinical importance of miR-342 downregulation. Towards the goal of identifying direct and indirect targets of miR-342 we restored miR-342 expression in MCF-7/HER2Δ16 cells and analyzed changes in global gene expression by microarray. The impact of miR-342 on gene expression in MCF-7/HER2Δ16 cells was not limited to miR-342 in silica predicted targets. Ingenuity Pathways Analysis of the dataset revealed a significant influence of miR-342 on multiple tumor cell cycle regulators.

Our findings suggest that miR-342 regulates tamoxifen response in breast tumor cell lines and our clinical data indicates a trend towards reduced miR-342 expression and tamoxifen resistance. In addition, our results suggest that miR-342 regulates expression of genes involved in tamoxifen mediated tumor cell apoptosis and cell cycle progression. Restoring miR-342 expression may represent a novel therapeutic approach to sensitizing and suppressing the growth of tamoxifen refractory breast tumors.

Is dYT7 gene locus for cervical dystonia on chromosome 18p questionable?

A locus implicated in autosomal dominant cervical dystonia was assigned to chromosome 18p in 1 large family more than 15 years ago. This locus was designated DYT7. We reanalyzed the family clinically and genetically. Clinical reevaluation of all family members was performed. There was Sanger sequencing of candidate genes, SNP array analysis, and exome sequencing in definitely affected family members. Diagnosis of cervical dystonia was definite in 6 family members and possible in 12. Analysis of candidate genes in 18p revealed no alteration in definitely affected patients. There was no disease causing copy number variant in 18p. No potentially disease-causing mutations were detected in 18p by exome sequencing. The CIZ1 gene, mutated in some cases of cervical dystonia, was excluded.

Location of DYT7 on 18p in autosomal dominant cervical dystonia is questionable. We demonstrate genetic heterogeneity of this form of dystonia.

Is high density of peritumoral lymphatic vessels a potential prognostic marker of endometrial carcinoma : a clinical immunohistochemical method study?

The lymphatic system is a major route for cancer cell dissemination and also a potential target for antitumor therapy. To investigate whether increased lymphatic vessel density (LVD) is a prognostic factor for nodal metastasis and survival, we studied peritumoral LVD (P-LVD) and intratumoral LVD (I-LVD) in samples from 102 patients with endometrial carcinoma; Endometrial carcinoma tissues were analyzed for lymphatic vessels by immunohistochemical staining with an antibody against LYVE-1. Univariate analysis was performed with Kaplan-Meier life-table curves to estimate survival, and was compared using the log rank test. Prognostic models used multivariate Cox regression analysis for multivariate analyses of survival; Our study showed that P-LVD, but not I-LVD, was significantly correlated with lymph vascular space invasion (LVSI), lymph node metastasis, tumor stage, and CD44 expression in endometrial carcinoma. Moreover, P-LVD was an independent prognostic factor for progression-free survival and overall survival of endometrial carcinoma;

P-LVD may serve as a prognostic factor for endometrial carcinoma. The peritumoral lymphatics might play an important role in lymphatic vessel metastasis.

Do normal colon tissue and colon carcinoma show no difference in heparanase promoter methylation?

Heparanase, the sole heparan sulfate degrading enzyme, has a role in cellular invasion. Accordingly, a large number of studies have demonstrated an association between heparanase expression and tumor stage and patients' prognosis. In colon carcinoma, heparanase shows increased expression in tumor compared to normal tissue and its expression correlates with the presence of metastasis. One of the regulatory mechanisms of heparanase expression is de-methylation on its promoter. In the present study we evaluated the role of heparanase promoter methylation in colon carcinoma. Analysis of heparanase promoter methylation was done on 32 samples of colon carcinoma as well as 30 samples of normal colonic mucosa. DNA was extracted from FFPE tissue and subjected to bisulfite conversion. The relative fraction of methylated and unmethylated DNA was evaluated using quantitative real-time PCR. The fraction of methylated DNA was 1 ± 3.4% in the colon carcinoma group, and 2.5 ± 3.3% in the normal colon group (P=0.11). Only one case in the normal group and one case in the tumor group showed more than 10% methylation in the heparanase promoter.

We did not find any significant difference in heparanase promoter methylation between colon carcinoma and normal colonic mucosa, suggesting that heparanase overexpression in colon carcinoma is mediated by other mechanisms.

Is fatigue associated with raised inflammatory markers in multiple sclerosis?

The pathogenesis of fatigue in patients with MS is poorly understood. To test the hypothesis that fatigue in MS is related to inflammatory disease activity as measured by systemic markers of inflammation. Fatigue as assessed by the Fatigue Questionnaire Scale (FQS) and Krupp's Fatigue Severity Scale (KFSS) was correlated with several inflammatory markers in 38 patients with MS (16 relapsing-remitting [RR; 7 of whom had benign MS), 9 secondary progressive [SP], 13 primary progressive [PP]). The markers included daily urinary neopterin excretion, a marker of interferon-gamma-activated macrophage activity, and serum C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) levels. Urinary neopterin excretion was measured daily for 2 weeks. No correlation was found between urinary neopterin excretion, CRP, or sICAM-1 and the fatigue scores. However, patients with a raised serum CRP level had higher KFSS, but not FQS, scores than patients with normal CRP levels (KFSS, 50 +/- 8 vs 41 +/- 14, p = 0.05; FQS, 13 +/- 4 vs 11 +/- 5, p = NS). When assessed using the FQS, patients with RR and SP MS were more fatigued than patients with PP MS (RR = 12.5 [4 to 23] vs SP = 13 [8 to 18] vs PP = 9 [7 to 14], p = 0.02). The patients with benign MS were as fatigued as patients with nonbenign disease.

The pathogenesis of fatigue in MS is complex and does not appear to be directly related to systemic markers of inflammatory disease activity. Interestingly, patients with PP MS were less fatigued than patients with RR disease.

Does body mass index predict outcome of ureteroscopy-assisted retrograde nephrostomy for percutaneous nephrolithotomy?

Several clinical series of retrograde nephrostomy for percutaneous nephrolithotomy (PCNL) have been published over the past 30 years demonstrating good outcomes and safety. We previously reported our adaptation of the Lawson technique, wherein we deploy the puncture wire through a flexible ureteroscope. We herein aim to clarify the performance characteristics of this nephrostomy creation technique. Institutional Review Board approval and informed consent were obtained. A ureteroscopy-assisted retrograde nephrostomy (UARN) procedure was performed as described previously. Data were collected prospectively. Multiple patient and operative factors were evaluated for association with UARN success and nephrostomy creation time: body mass index (BMI), skin-to-stone distance, Guy's score, Clinical Research of the Endourological Society nephrolithometric score, hydronephrosis, stone burden, location of nephrostomy, exit from a stone-bearing calix, and use of holmium laser to access calix. Nephrostomy was successful in 49/52 UARN procedures (94%). Only single access was placed: upper-18, mid-27, and lower-7. Median BMI was 29 kg/m(2) and median time for nephrostomy creation was 39 minutes. Fluoroscopy time for the entire PCNL including nephrostomy creation was 84 and 16 seconds for case numbers 1-25 and 26-52, respectively. By stepwise linear regression, variables correlating with nephrostomy creation time were BMI (r(2)=0.219), stone burden (r(2)=0.094), use of holmium laser to access calix (r(2)=0.104), and total r(2) linear=0.416.

UARN is an intuitive safe procedure that offers dramatic reductions in fluoroscopy times. UARN is best suited to cases requiring only one nephrostomy tract. Upper pole access is commonly performed with a subcostal technique to navigate the puncture wire below the ribs. Increasing BMI best predicts longer nephrostomy creation times; procedure failure was associated with BMI exceeding 40 kg/m(2). UARN is a robust technique for nephrostomy creation in appropriately selected patients.

Is expression of glypican-3 highly associated with pediatric hepatoblastoma : a systemic analysis?

Glypican-3 (GPC3) is reported to be an oncofetal protein that is a useful diagnostic immunomarker for hepatoblastoma. However, the results are not inclusive. This study systemically investigated the association between expression of GPC3 and pediatric hepatoblastoma. Clinical studies evaluating the association were identified using a predefined search strategy. GPC3 immunohistochemistry was applied in the pathological diagnosis of hepatoblastoma using the monoclonal antibodies with formalin-fixed and paraffin-embedded specimens. Positive predictive rates for the association between expression of GPC3 and pediatric hepatoblastoma were calculated. Specimens from four clinical studies which including 134 patients with pediatric hepatoblastoma tested by GPC3 immunohistochemistry were considered eligible for inclusion. Systemic analysis showed that, in all patients, pooled positive predictive rate of the association between expression of GPC3 and pediatric hepatoblastoma was 95.5% (128/134).

This systemic analysis suggests that the expression of glypican-3 is highly associated with the diagnosis of pediatric hepatoblastoma.

Is a non-synonymous polymorphism in IL-23R Gene ( rs1884444 ) associated with reduced risk to schistosomiasis-associated Immune Reconstitution Inflammatory Syndrome in a Kenyan population?

Human Immunodeficiency Virus (HIV) and Schistosomiasis co-infection is common among residents at the shores of Lake Victoria in Kenya. About 36% of this population initiating antiretroviral therapy (ART) experience Immune Reconstitution Inflammatory Syndrome (IRIS) that complicates recovery. Several IL-23R alleles have been associated with susceptibility to both autoimmune and inflammatory diseases through T-helper type 17 (TH17) cells. However, whether or not variants within the IL-23R increase susceptibility to IRIS in western Kenya is unknown. The objective of the current study was to determine the association between IL-23R gene polymorphisms, CD4+ cell counts and HIV RNA levels and IRIS in HIV and Schistosoma mansoni co-infected patients undergoing highly active anti-retroviral therapy (HAART). A three-month case-control study was conducted on antiretroviral naïve schistosomiasis/HIV co-infected fishermen starting HAART in Uyoma Rarieda, Siaya County, Kenya. Seventy one patients were sampled at baseline and followed up for three months, to establish if they developed Schistosoma-related IRIS. In addition, the CD4+ cell counts and HIV RNA levels were determined in pre- and post-administration of HAART. Variations at five polymorphic sites of IL-23R (rs1884444, rs11465754, rs6682925, rs7530511 and rs7539625) based on >10% minor allele frequency in Yoruban reference population was determined using Allelic Discrimination Assay. The association between the five variants and susceptibility to IRIS was determined using logistic regression while controlling for potential confounders. In addition, the functional differences between the baseline CD4 + Cell counts and viral loads were determined using medians while across IL-23R genotypes were determined using Kruskal-Wallis tests. Overall, 26 (36.6%) patients developed schistosomiasis-associated IRIS at a median age of 35.5 years. Carriage of the TT genotype at the non-synonymous rs1884444 T > G relative to GG, was associated with a decreased risk of schistosomiasis-associated IRIS (OR, 0.25, 95% CI, 0.07-0.96, P = 0.043) while both baseline CD4+ cell counts and viral loads had no association with IRIS.

These findings indicate that the non-synonymous variant rs1884444 T > G of IL-23R is associated with a decreased risk to schistosomiasis-associated IRIS. However, additional studies in a larger cohort and with an all inclusive polymorphic variants in the synonymous and non-synonymous regions need to be evaluated.

Do immunohistochemical findings after LASIK confirm in vitro LASIK model?

To compare immunohistochemical findings in human donor corneas after successful laser in situ keratomileusis (LASIK) without clinical complications with a recently established human LASIK in vitro model. Donor corneas with prior LASIK treatment were investigated. Cryostat sections were stained immunohistochemically for collagen types I, III, and VI and laminin and fibronectin. With light microscopy, the interface of the LASIK flap could hardly be detected. In all samples, fibronectin was consistently detected along the entire extent of the surgical wound. In contrast, collagen type III and laminin only stained the superficial portion of the LASIK incision site. Staining for collagen types I and VI showed no changes after LASIK.

Histologic findings in donor corneas with prior LASIK treatment confirm histologic observations in a recently introduced human organ culture LASIK model. This strengthens the reliability of the latter LASIK model for further studies concerning wound healing after LASIK surgery.

Does patient-centric blood pressure-targeted cardiopulmonary resuscitation improve survival from cardiac arrest?

Although current resuscitation guidelines are rescuer focused, the opportunity exists to develop patient-centered resuscitation strategies that optimize the hemodynamic response of the individual in the hopes to improve survival. To determine if titrating cardiopulmonary resuscitation (CPR) to blood pressure would improve 24-hour survival compared with traditional CPR in a porcine model of asphyxia-associated ventricular fibrillation (VF). After 7 minutes of asphyxia, followed by VF, 20 female 3-month-old swine randomly received either blood pressure-targeted care consisting of titration of compression depth to a systolic blood pressure of 100 mm Hg and vasopressors to a coronary perfusion pressure greater than 20 mm Hg (BP care); or optimal American Heart Association Guideline care consisting of depth of 51 mm with standard advanced cardiac life support epinephrine dosing (Guideline care). All animals received manual CPR for 10 minutes before first shock. Primary outcome was 24-hour survival. The 24-hour survival was higher in the BP care group (8 of 10) compared with Guideline care (0 of 10); P = 0.001. Coronary perfusion pressure was higher in the BP care group (point estimate +8.5 mm Hg; 95% confidence interval, 3.9-13.0 mm Hg; P < 0.01); however, depth was higher in Guideline care (point estimate +9.3 mm; 95% confidence interval, 6.0-12.5 mm; P < 0.01). Number of vasopressor doses before first shock was higher in the BP care group versus Guideline care (median, 3 [range, 0-3] vs. 2 [range, 2-2]; P = 0.003).

Blood pressure-targeted CPR improves 24-hour survival compared with optimal American Heart Association care in a porcine model of asphyxia-associated VF cardiac arrest.

Does peripartum infection increase the incidence of cerebral palsy in extremely low birthweight infants?

This study was undertaken to determine the perinatal predictors of cerebral palsy in extremely low birthweight infants (<1000 g). A case control study of infants with birthweight of less than 1000 g (19 with cerebral palsy and 38 controls) who survived beyond 18-22 months of corrected age was performed. Outcome variables included maternal demographics, obstetric complications, and neonatal outcome (gestational age at delivery, birthweight, Apgar scores, intrauterine growth restriction, respiratory distress syndrome, intraventricular hemorrhage, and neonatal sepsis). Data analysis consisted of t tests, chi2, and analysis of variance when appropriate. There were no significant differences between cerebral palsy and control groups with regard to mode of delivery, Apgar scores, preeclampsia, antenatal vaginal bleeding, or the use of magnesium sulfate. However, male gender (odds ratio 3.70; 95% CI 1.05-12.5), primigravid status (odds ratio 5.52; 95% CI 1.67-18.3), early neonatal sepsis (odds ratio 12.9; 95% CI 2.94-57.2) and chorioamnionitis, both clinical and histologic (odds ratio 3.71; 95% CI 1.16-11.9) were significantly associated with the development of cerebral palsy. The strong association between cerebral palsy and chorioamnionitis, as well as early neonatal sepsis, remain significant after adjustment for primigravid status and male gender.

In extremely low birthweight infants, cerebral palsy was strongly associated with chorioamnionitis, early neonatal sepsis, male gender, and primigravid status.

Does the incorporation of platelet-rich plasma into calcium phosphate cement enhance bone regeneration in osteoporosis?

Polymethyl methacrylate (PMMA) bone cement is widely used for osteoplasty. However, previous studies have demonstrated the adverse effects of PMMA due to its excessive stiffness and heat production. Recently, calcium phosphate cement (CPC) that overcomes those negative effects has been successfully applied in osteoplasty. The potential problem of CPC is markedly less initial stiffness. It leads to progressive, repeated collapse in the treated vertebra before CPC has been replaced by new bone that would provide substantial improvement in compressive strength and stiffness. The activated platelets in platelet-rich plasma (PRP) release a high concentration of growth factors which play an important role in bone healing. To investigate whether PRP could accelerate the osteoconduction of CPC and enhance the bone strength of the treated vertebra in an animal model. Controlled animal study. Laboratory animal study, Thirty-two female Sprague-Dawley rats were ovariectomized at 8 weeks of age. After 3 months, they were randomly divided into 4 groups and received cement augmentation in the fifth caudal spine with different filler materials; sham-operated rats (S), PMMA (P), CPC (C), and CPC + PRP (CP). Bone mineral density (BMD) and trabecular type-associated morphological parameters, including trabecular bone volume fraction and trabecular thickness in the augmented caudal spine, were evaluated by micro-computed tomography (mirco-CT) 2 weeks after the cementoplasty. Histological analysis was also performed to compare the bone regeneration. The trabecular bone volume fraction in the CP group was significantly greater than those of all the other groups. Trabecular thickness was higher in the CP group than the S and P groups. This augmented trabecular structure in the CP group accordingly showed higher BMD. Histological evaluations showed significantly more bone regeneration in the CP group.

There has been a concern that the effect of PRP would be dependent on the species, and might show different results in humans. Baseline values of micro-CT analysis were not measured, which could have provided exact evidence of the changes in trabecular micro-architecture parameters and cement resorption profiles. Finally, caudal vertebrae with filler materials used in biological study should have been compared by their mechanical properties using biomechanical evaluations for a more coherent study, which was not possible due to technical problems.

Is the tissue availability of circulating insulin-like growth factor I involved in organ damage and glucose regulation in hypertension?

Besides its capacity to regulate organ and tissue growth, the insulin-like growth factor I exerts biologic actions that resemble those of insulin. Tissue access of the factor depends on the distribution of the circulating bound factor between its binding protein 3 that remains within the intravascular space and its binding protein 1 that is able to cross the endothelium. To investigate whether the distribution of the circulating factor between its binding proteins is altered in patients with essential hypertension and whether this is related to changes in organ damage and glucose regulation in these patients. The study subjects were 30 never-treated patients with essential hypertension and 27 age- and sex-matched normotensive controls. Serum insulin-like growth factor I-binding proteins 3 and 1 and plasma insulin-like growth factor I levels were determined by specific radioimmunoassays. Insulin-like growth factor I levels were significantly higher in the hypertensive patients than they were in the normotensive controls. Whereas the serum level of binding protein 1 was significantly higher in hypertensives than it was in controls, we found no differences in the level of binding protein 3 between the two groups. With the upper 100% confidence limit of the normotensive population as the cut-off point, a subgroup of 16 hypertensives had an abnormally high serum level of binding protein 1. Compared with patients with normal binding protein 1 levels, patients with increased binding protein 1 levels were characterized by the following: lower fasting glucose and insulin levels, lower insulin: glucose ratios, lower triglyceride levels, higher left ventricular mass indexes, higher creatinine clearances and higher urinary albumin excretion rates. The serum binding protein 1 level was correlated inversely to the plasma insulin level for the whole group of hypertensives.

These results show that the distribution of circulating insulin-like growth factor I between its binding proteins 1 and 3 is altered in essential hypertension. Thus, there is a subgroup (53%) of hypertensive patients with increased serum levels of insulin-like growth factor I-binding protein 1. Access of the circulating factor to tissues is more easily achieved in these patients. The clinical characteristics of this subgroup of patients suggest that the tissue availability of insulin-like growth factor I is a determinant of organ damage and insulin sensitivity in essential hypertension.

Does loss of fatty acid synthase inhibit the `` HER2-PI3K/Akt axis '' activity and malignant phenotype of Caco-2 cells?

Fatty acid synthase (FASN) is frequently activated and overexpressed in human cancers, and plays a crucial role in the carcinogenesis of various cancers. In this study, our aims were to explore the role of FASN in regulating the "HER2-PI3K/Akt axis" activity and malignant phenotype of colorectal cancer. Caco-2 cells with a high expression of both HER2 and FASN were selected for functional characterization. Caco-2 cells were transfected with either the FASN specific RNAi plasmid or the negative control RNAi plasmid, followed by the RT-qPCR and western blot to examine the expression of FASN, HER2, PI3K and Akt. The MTT and colony formation assays were used to assess the proliferation potential. The migration was investigated by the transwell, and the apoptosis and cell cycle were assayed by the flow cytometry. Notably, the expression of FASN, HER2, PI3K and Akt were downregulated upon a silence of FASN. The proliferation was decreased after a downregulation of FASN, which was consistent with an increased apoptosis rate. The migration was also impaired in FASN-silenced cells.

A downregulation of FASN effectively inhibits the activity of "HER2-PI3K/Akt axis" and alters the malignant phenotype in colorectal cancer cells.

Is expression of cysteine-rich 61 correlated with poor prognosis in patients with esophageal squamous cell carcinoma?

Cysteine-rich 61 (Cyr61), a secreted protein belonged to the CCN family, was involved in the progression of many cancers. The purpose of this study was to explore the clinical significance of Cyr61 expression in esophageal squamous cell carcinoma (ESCC). Cyr61 expression was detected on tissue microarrays of ESCC samples in 372 cases by using immunohistochemical staining. Survival analysis was assessed by the Kaplan-Meier analysis. Relative risk was evaluated by the multivariate Cox proportional hazards model. The staining pattern of Cyr61 was heterogeneous and varied from negative to intense expression in a cytoplasmic distribution. Kaplan-Meier analysis revealed that expression of Cyr61 was related to poor survival of ESCC patients (P = 0.001). Further analysis revealed that Cyr61 high-expression was related to poorer overall survival of patients in stage I/II (P = 0.001); but did not effect the overall survival of patients in stage III/IV. Univariate and multivariate analysis suggested that Cyr61 expression status was an independent prognostic factor for ESCC (P = 0.001).

Cyr61 might play important roles in the progression of ESCC. Cyr61 is a new biomarker to predict the prognosis of ESCC patients.

Is optimization of codon usage required for effective genetic immunization against Art v 1 , the major allergen of mugwort pollen?

As the major allergen of mugwort pollen, Art v 1 is an important target for specific immunotherapy. However, both recombinant protein as well as a gene vaccine for Art v 1 failed to be immunogenic in mice. In order to improve immunogenicity we focused on genetic immunization because interspecific differences of codon usage have been shown as an obstacle for effective induction of immune responses with gene vaccines encoding infectious pathogens. In order to find out, whether codon usage might also be used to improve genetic immunization with allergen genes, the response against a gene vaccine expressing the wild-type gene of Art v 1 (pCMV-wtArt) was compared with a synthetic codon-optimized vector with human codon usage (pCMV-humArt). Balb/c mice were injected intradermally with pCMV-wtArt or pCMV-humArt. In vitro expression levels of both constructs were compared in transfection experiments. Total immunoglobulin G (IgG), IgG1, IgG2a and IgE antibodies were analyzed by enzyme-linked immunosorbent assay and the anaphylactic activity of the sera was determined by allergen-specific degranulation of rat basophil leukemia-2H3 cells. No immune response was detectable with the gene vaccine expressing the wildtype Art v 1, but immunization with pCMV-humArt revealed a strong and allergen-specific induction of antibody responses. The antibodies recognized both the recombinant as well as the purified natural (glycosylated) Art v 1 molecule. The response type was Th1-biased, as indicated by high levels of IgG2a antibodies. Expression analysis with B16 mouse melanoma cells transfected with pCMV-humArt or pCMV-wtArt revealed an impaired expression of the wild-type vector but normal translation after recoding.

The results demonstrate that optimization of codon usage offers a simple way to improve immunogenicity and therefore should be routinely considered in the development of gene vaccines for the treatment of allergy.

Is high apoptotic index in urine cytology associated with high-grade urothelial carcinoma?

The significance of apoptosis and its association with high-grade urothelial carcinoma (HGUC) in urine cytology has yet to be determined. A computerized search of the study laboratory information system was performed over a 3-year period for all urine cytology specimens processed using the SurePath liquid-based preparation technique. Only those cases with correlating surgical pathology obtained within 6 months after the urine cytologic samples were included in the current study. Cases from ileal conduit samples were excluded. A semiquantitative numerical scoring system (apoptotic index) was used to assess the amount of pyknosis or karyorrhexis, with 0 indicating none, 1 indicating < 10 per 10 high-power fields, 2 indicating 10 to 30 per 10 high-power fields, and 3 indicating > 30 per 10 high-power fields. Statistical analysis using the Pearson chi-square test was performed. A total of 228 cases including 105 benign cases, 79 cases of HGUC, and 44 cases of low-grade urothelial carcinoma (LGUC) diagnosed on follow-up surgical pathology were selected. A score of 0 was observed in 70 benign, 11 HGUC, and 8 LGUC cases; a score of 1 was observed in 31 benign, 21 HGUC, and 23 LGUC cases; a score of 2 was observed in 3 benign, 27 HGUC, and 9 LGUC cases; and a score of 3 was observed in 1 benign, 20 HGUC, and 4 LGUC cases.

Excluding ileal conduit urine specimens, the finding of a high apoptotic index (score ≥ 2) with the presence of pyknosis or karyorrhexis in ≥10 per 10 high-power fields in the urine cytology appears to be significantly associated with HGUC (P<.05). Cancer Cytopathol 2016;124:546-51. © 2016 American Cancer Society.

Does cultural and demographic factors influencing noise exposure estimate from use of portable listening devices in an urban environment?

This study examined listening levels and duration of portable listening devices (PLDs) used by people with diversity of ethnicity, education, music genre, and PLD manufacturer. The goal was to estimate participants' PLD noise exposure and identify factors influencing user behavior. This study measured listening levels of 160 adults in 2 New York City locations: (a) a quiet college campus and (b) Union Square, a busy interchange. Participants completed a questionnaire regarding demographics and PLD use. Ordinary least squares regression was used to explore the significance of demographic and behavioral factors. Average listening level was 94.1 dBA, with 99 of 160 (61.9%) and 92 of 159 (57.5%) exceeding daily (L A8hn) and weekly (L Awkn) recommended exposure limit, respectively. African American participants listened at the highest average levels (99.8 dBA).

A majority of PLD users exceeded recommended exposure levels. Factors significant for higher exposure were ethnicity and age; factors not significantly associated with exposure were gender, education, location, awareness of possible association between PLD use and noise-induced hearing loss, mode of transportation, device manufacturer, and music genre. Efforts to effect behavior changes to lessen noise-induced hearing loss risk from PLD use should be sensitive to the cultural differences within the targeted population.

Does anterolateral rectopexy for correction of rectoceles lead to good anatomical but poor functional results?

Several different surgical repair procedures for symptomatic rectocele have been described with variable results. In our clinic, a modified anterolateral rectopexy is used. In this article we evaluate our results, with emphasis on patient satisfaction. From 2001 until 2003, twenty patients with a symptomatic rectocele were treated by anterolateral rectopexy. The preoperative dynamic defecogram and anorectal complaints were analyzed and compared to postoperative outcome via a standardized questionnaire. After surgery, all rectoceles were restored as shown by postoperative defecogram. Anorectal symptoms (incomplete evacuation, continuous urge, prolapse, digital evacuation) were improved in 40%. As new-onset symptoms, dyspareunia (50%), digital support (55%) and incomplete evacuation (75%) were mentioned frequently. Most of the patients with larger rectoceles (>3.5 cm) had increased anorectal complaints after surgery.

Anterolateral rectopexy for treatment of rectocele give limited improvement of anorectal complaints. Besides, many patients developed new complaints postoperatively and hence overall satisfaction was low.

Does experience with intraoperative neuromonitoring of the recurrent laryngeal nerve improve surgical skills and outcomes of non-monitored thyroidectomy?

Intraoperative neuromonitoring (IONM) can serve as a tool to increase skills in recurrent laryngeal nerve (RLN) identification and complete removal of thyroid tissue. The aim of this study was to validate this hypothesis. This prospective study involved 632 patients (1161 RLNs at risk) who underwent thyroid surgery in 2011-2014. Although IONM was not used until 2012, this prospective study started on 1 January 2011. The three participating surgeons knew about the study before that date and that the rate of RLN identification would be carefully measured in total and near-total surgery. Solely, visual identification of the RLN was used throughout 2011. IONM was introduced as a training tool in 2012-2014 for the first 3 months of each year. In the remaining months, thyroid operations were performed without IONM. Outcomes of non-monitored thyroid operations were compared before (01-12/2011) vs. after (04-12/2012-2014) 3 months of exposure to IONM yearly (01-03/2012-2014). The rate of RLN identification was assessed in total and near-total thyroidectomies and in totally resected lobes in Dunhill's operation. The prevalence of RLN injury and the utilization of total thyroidectomy were evaluated. In 2011, the rate of successful RLN visual identification in total and near-total thyroidectomies and in totally resected lobes in Dunhill's operation was 45.71 %. After the introduction of IONM in 2012-2014, in the procedures performed without IONM, the rate was 86.66, 90.81, and 91.3 %. The prevalence of RLN injury in 2011 was 6.8 %, while in the years following the introduction of IONM, it was 3.61, 2.65, and 1.45 %. Utilization of total thyroidectomy increased from 47.9 % in 2011 to 100 % in 2014.

Experience with IONM led to an increase in RLN identification (p < 0.0001), a decrease of RLN injury (p < 0.05), and an increase in the safe utilization of total thyroidectomy (p < 0.0001) in non-monitored thyroid operations. IONM is a valuable tool for surgical training.

Central lymph node dissection as a secondary procedure for papillary thyroid cancer: Is there added morbidity?

Routine central lymph node dissection (CLND) for papillary thyroid cancer (PTC) at the time of initial thyroidectomy has been advocated with a demonstrated decrease in post-ablation serum thyroglobulin compared to total thyroidectomy alone. Patients now present with central compartment metastatic disease after initial thyroid cancer surgery, or with a diagnosis of PTC after diagnostic lobectomy requiring completion thyroidectomy, and an undissected central compartment. Our aim was to compare the clinical outcomes in patients with PTC who underwent CLND as a secondary event with those having initial CLND. A retrospective cohort study of 193 patients who underwent CLND for PTC between June 2002 and November 2007 was undertaken. Data gathered included patient demographics, number of lymph nodes excised, lymph node involvement, and incidence of postoperative complications. One-hundred and seventy (M/F: 28/142) patients (Grp A) had a CLND as part of their primary surgical procedure while 23 (M/F: 10/13) patients (Grp B) underwent CLND as a secondary procedure (12 therapeutic/11 prophylactic procedures). The mean number of lymph nodes sampled and the % involved in the 2 groups A and B were 9.2 vs 10.2 and 64% vs 61%, respectively. Similarly, the incidence of temporary hypocalcemia (12% vs 9%), permanent hypoparathyroidism (1.8% vs 0%), temporary recurrent laryngeal nerve (RLN) paresis (3% vs 4%), permanent RLN paresis (0.6% vs 0%), and wound infection (0.6% vs 4.3%) was comparable in groups A and B.

This study demonstrates that there is no additional morbidity when CLND is performed as a secondary procedure for patients with PTC. Secondary CLND should be performed in patients with proven central compartment metastatic disease after previous thyroidectomy and can be offered safely as a prophylactic procedure to patients at high risk for central lymph node metastasis when CLND has not been performed at initial primary operation for PTC.

PGE(2) receptor (EP(4)) agonists: potent dilators of human bronchi and future asthma therapy?

Asthma and chronic obstructive pulmonary disease are characterized by inappropriate constriction of the airway smooth muscle. In this context, the physiological response of the human airways to selective relaxant agonists like PGE(2) is highly relevant. The aim of this study was thus to characterize the PGE(2) receptor subtypes (EP(2) or EP(4)) involved in the relaxation of human bronchial preparations. Human bronchial preparations cut as rings were mounted in organ baths for isometric recording of tension and a pharmacological study was performed using selective EP(2) or EP(4) ligands. In the presence of a thromboxane TP receptor antagonist and indomethacin, PGE(2) induced the relaxation of human bronchi (E(max) = 86 ± 04% of papaverine response; pEC(50) value = 7.06 ± 0.13; n = 6). This bronchodilation was significantly blocked by a selective EP(4) receptor antagonist (GW627368X, 1 and 10 μmol/L) with a pK(B) value of 6.38 ± 0.19 (n = 5). In addition, the selective EP(4) receptor agonists (ONO-AE1-329; L-902688), but not the selective EP(2) receptor agonist (ONO-AE1-259), induced potent relaxation of bronchial preparations pre-contracted with histamine or anti-IgE.

PGE(2) and EP(4) agonists induced potent relaxations of human bronchial preparations via EP(4) receptor. These observations suggest that EP(4) receptor agonists could constitute therapeutic agents to treat the increased airway resistance in asthma.

Does thapsigargin induce a calmodulin/calcineurin-dependent apoptotic cascade responsible for the death of prostatic cancer cells?

New agents are required for the treatment of androgen-independent prostate cancer. Due to the low rate of proliferation of these malignant cells, agents which can activate the apoptotic death of these cells without requiring the cells being in the proliferative cell cycle are critically required. Thapsigargin (TG), via its ability to perturb intracellular free calcium [Ca(2+)](i), is such a cell proliferation-independent cytotoxic agent. The present study focuses on more completely describing the biochemical cascade during the apoptotic death of androgen-independent prostate cancer cells induced by TG and on the mechanistic requirements for this death. A variety of cell and molecular biology techniques (e.g., time-lapse video, fluorescence image analysis, Northern and Western blotting) were used to examine the temporal relationship between changes in [Ca(2+)](i), GADD 153 transcription, translocation of the NFATc transcription factor to the nucleus, translocation of BAD from the cytosol to the mitochondria, caspase 9 activation, DNA fragmentation, and the loss of clonogenic survival induced by TG treatment of both human TSU-prl and rat AT3.1 prostate cancer cells in vitro. Additional studies using both microinjection of inhibitors of calmodulin and DNA transfections to induce expression of Ca(2+) binding proteins, e.g., calbindin, were performed to evaluate the causal relationship between [Ca(2+)](i) elevation, calmodulin/calcineurin activation, and apoptosis of prostate cancer cells. Using simultaneous fluorescence ratiometric and phase contrast image analysis in individual cells followed longitudinally for several days, it was documented that TG induced early (1-12 hr) moderate (i.e., <500 nM) elevation in [Ca(2+)](i). During this early rise in [Ca(2+)](i), genes like GADD 153 are induced at the transcriptional level. This early rise is followed by a return of [Ca(2+)](i) to baseline (i.e., approximately 50 nM) before the induction of a delayed (i.e., >12 hr) secondary rise ( approximately 10 microM) in [Ca(2+)](i). During the secondary rise in [Ca(2+)](i), Ca(2+) binds to calcineurin and calmodulin, allowing these proteins to form a complex which activates calcineurin's latent phosphatase activity. Once activated, calcineurin dephosphorylates NFATc and BAD, allowing translocation of these proteins to the nucleus and mitochondria, respectively. BAD translocation induces the release of cytochrome C from the mitochondria into the cytoplasm, which results in activation of caspase 9 and DNA fragmentation. If the TG-induced rise in [Ca(2+)](i) is blocked by overexpressing calbindin, or if calmodulin function is inhibited, these apoptotic events are prevented.

TG induces the apoptotic death of prostate cancer cells via the activation of a reversible signaling phase induced by a transient nanomolar rise in [Ca(2+)](i), which involves new gene transcription and translation. This reversible signaling phase is followed by an irreversible commitment to undergo the execution phase which is induced by a secondary micromolar rise in [Ca(2+)](i). This secondary [Ca(2+)](i) rise irreversibly commits the cell to a calmodulin/calcineurin-dependent cascade, which results in DNA and cellular fragmentation into apoptotic bodies.

Is second-look endoscopy associated with better clinical outcomes after gastric endoscopic submucosal dissection : a prospective , randomized , clinical trial analyzed on an as-treated basis?

The efficacy of routine second-look endoscopy (SLE) to detect or prevent bleeding after gastric endoscopic submucosal dissection (ESD) has not yet been validated. The aim of this study was to determine whether SLE affects clinical outcomes including bleeding and morbidity after gastric ESD. A prospective, randomized, controlled study with consecutive data analyzed on an as-treated basis. A single, tertiary-care referral center. A total of 182 patients. Gastric ESD and SLE. Incidence of and risk factors related to bleeding after ESD and outcomes by univariate or multivariate analysis. Among 182 patients enrolled, 74 and 81 patients were assigned to the SLE and no-SLE groups, respectively. Two groups were observed closely for 4 weeks. Bleeding occurred after ESD in 21 patients (13.5%). Hemoglobin loss (≥2.0 g/dL) was observed in 20 patients, and melena developed in 1 patient after ESD. However, only 1 patient needed a transfusion. Twelve patients (16.2%) in the SLE group and 9 in the no-SLE group (11.1%) experienced bleeding after ESD. The frequency of bleeding after ESD was not significantly different between the 2 groups (P = .66). There were no risk factors related to bleeding after ESD.

Single-center analysis.

Does intravenous delivery of adipose-derived mesenchymal stromal cells attenuate acute radiation-induced lung injury in rats?

Radiation-induced lung injury (RILI) commonly occurs in patients with thoracic cancer. However, an effective treatment option has not yet been established. Adipose-derived mesenchymal stromal cells (Ad-MSCs) have significant potential for clinical use, but their role in RILI is currently unknown. We aimed to evaluate the therapeutic capacity of Ad-MSCs to heal acute RILI in rats. Sprague-Dawley rats were used in this study. Rat Ad-MSCs were delivered through the tail veins of rats 2 h after thorax irradiation. Lung histopathologic findings, pulmonary levels of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-10 and tumor necrosis factor-α), pro-fibrotic factors (transforming growth factor [TGF]-β1, connective tissue growth factor, α-smooth muscle actin and type 1 collagen), pro- or anti-apoptotic mediators (Bcl-2, Bax and caspase-3) and the multifunctional factor hepatocyte growth factor were evaluated after Ad-MSC transplant. Intravenous delivery of Ad-MSCs attenuated acute RILI. Further studies showed that Ad-MSCs had anti-inflammation and anti-fibrotic effects and maintained lung epithelium integrity, as indicated by reduced serum levels of the pro-inflammatory cytokines IL-1, IL-6 and tumor necrosis factor-α, increased levels of the anti-inflammatory cytokine IL-10, and downregulated transforming growth factor -β1, α-smooth muscle actin and type 1 collagen levels in irradiated lung tissues. Ad-MSCs also regulated the expression of pro- and anti-apoptotic mediators (Bcl-2, Bax and caspase-3) to protect lung cells from apoptosis.

Intravenous Ad-MSC delivery attenuated acute RILI through anti-inflammation, anti-fibrosis and anti-apoptosis mechanisms.

Does monoclonal antibody against transforming growth factor Beta 1 influence liver regeneration after resection in large animal experiments?

Steatohepatitis is a type of histopathological liver injury that can be caused by chemotherapy [chemotherapy-associated steatohepatitis (CASH)] and can progress to liver fibrosis or cirrhosis. CASH impairs liver functions, including liver regeneration. Impaired liver regeneration reduces the number of patients who can undergo liver resection and reduces opportunities for curative therapies. Transforming growth factor-beta (TGFβ) is a potent mitotic inhibitor that participates during the last phase of liver regeneration. TGFβ has been studied as a potential solution to the development of liver fibrosis or hepatocellular carcinoma. The first aim of our study was to establish a large animal model of toxic liver injury and test the ability of a monoclonal antibody against TGFβ (MAB-TGFβ) to increase liver-regeneration capacity. The second aim was to evaluate the degree to which early preoperative administration of MAB-TGFβ influenced hepatic parenchyma regeneration following healthy liver resection in a swine experimental model. Toxic liver injury was induced by alcohol consumption and regular intraperitoneal administration of carbon tetrachloride (CCl4) to piglets for 10 weeks. After 10 weeks, the piglets underwent liver resection of the left lateral and left medial liver lobes. Twenty-four hours after liver resection, MAB-TGFβ was administered to the experimental group (10 piglets) and a physiological solution to the control group (10 piglets) through an implemented port-a-cath. In the second part of the study, either MAB-TGFβ or a saline solution control were administered at 12 and 4 days prior to resection of the right lobes of healthy liver (six experimental and 10 control group subjects). Observation and follow-up was performed throughout the entire experiment. Ultrasound and biochemical tests (for albumin, cholinesterase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, bilirubin, urea, creatinine and ammonia levels) were performed on postoperative days 1, 3, 7, 10 and 14. A histopathological examination was performed after sacrificing the animals on the 14th postoperative day. No significant differences were observed between groups when using ultrasound volumetry to assess the regenerative volume of the liver in both experiments. The only significant differences found when comparing biochemical parameters between groups were higher serum levels of both creatinine and γ-glutamyl transferase in the experimental group with preoperative administration of MAB-TGFβ. There were no differences in the histological analyses of hepatic lobule cross-sectional area nor in the proliferative index between animals receiving MAB-TGFβ and those treated with physiological saline solution before resection. Hepatocytic cross-sectional areas were larger in animals treated with physiological solution versus those treated with MAB-TGFβ on the operative day; however, these values were comparable between groups by 14 days following resection.

We established a large animal model of toxic liver injury that is comparable with CASH. The toxic injury that was induced without pause between administrations was probably more extensive than occurs in CASH, and there was no effect of MAB-TGFβ administration on liver regeneration. MAB-TGFβ administration did not lead to any observable side-effects, indicating that it could be a promising solution for use as an oncologic-targeted treatment.

Does severity of hypoalbuminemia predict response to intradialytic parenteral nutrition in hemodialysis patients?

Intradialytic parenteral nutrition (IDPN) is used infrequently to correct hypoalbuminemia in maintenance hemodialysis (MHD) patients. We hypothesized that the severity of baseline hypoalbuminemia correlates with the success rate of IDPN therapy in MHD patients. In a prospective and contemporary cohort of 196 hypoalbuminemic MHD patients who received IDPN through Pentec Health (Boothwyn, PA), predictors of IDPN response were examined using multivariate logistic regression. Of 196 hypoalbuminemic MHD patients, 134 had severe hypoalbuminemia, defined as a baseline serum albumin level of less than 3.0 g/dL. The average period of IDPN therapy was 5.8 +/- 2.4 months, S.D. The baseline level of serum albumin was lower in MHD patients who responded to IDPN (2.68 +/- 0.47 g/dL, S.D.). A multivariate logistic regression analysis adjusted the associations for age, gender, diabetes, and IDPN time. The presence of severe hypoalbuminemia (serum albumin, <3.0 g/dL) at baseline was associated with a 2.5 times higher chance of responding to IDPN (95% confidence interval, 1.3 to 4.9; P = .006). The same severe hypoalbuminemia was associated with a 3.5 times increased likelihood of serum albumin correction by at least 0.5 g/dL (95% confidence interval, 1.8 to 6.8; P < .001).

Improvement of hypoalbuminemia occurs in most hypoalbuminemic MHD patients who receive IDPN therapy. The likelihood and magnitude of the response to IDPN are associated with the severity of baseline hypoalbuminemia. These associations need to be verified in controlled trials.

Do incidence and outcome of operatively treated achilles tendon rupture in the elderly?

Very little has been published about Achilles tendon rupture in the elderly. Optimal therapy is controversial with conservative treatment generally recommended. The purpose of our study was to find the incidence and outcome of operatively treated Achilles tendon ruptures in the elderly. We determined the incidence of a closed complete Achilles tendon rupture in a period from 1991 to 2000 in two centers caring for 572,929 people with 108,668 people over 60 years of age. In a 10-year period there were 434 ruptures, all of which were treated operatively: 146 in an open fashion and 288 percutaneously. The average incidence was 7.6 ruptures per 100,000 people. The average age of patients was 38.7 years, with a male-to-female ratio of 16.7:1. There were 14 ruptures in 13 patients older than 60 years, with the incidence of 1.28 ruptures per 100,000 people. Seven of the ruptures were operated on in an open way under spinal anesthesia and seven percutaneously under local anesthesia. The average age of the patients was 67.9 years, with a male-to-female ratio of 1.6:1 and the mean ASA score 1.64. There were no major complications in either group. One patient in the percutaneous group had transient sural nerve injury and one patient in the open group had a superficial infection. All of the patients returned to their previous activities, four of them with some limitations. The average AOFAS score was 93.1 points.

Achilles tendon rupture in the elderly is a rare injury. Operative treatment can yield a successful outcome.

Do the use of frequency compression by cochlear implant recipients with postoperative acoustic hearing?

The number of cochlear implant (CI) recipients who have usable acoustic hearing in at least one ear is continuing to grow. Many such CI users gain perceptual benefits from the simultaneous use of acoustic and electric hearing. In particular, it has been shown previously that use of an acoustic hearing aid (HA) with a CI can often improve speech understanding in noise. To determine whether the application of frequency compression in an HA would provide perceptual benefits to CI recipients with usable acoustic hearing, either when used in combination with the CI or when the HA was used by itself. A repeated-measures experimental design was used to evaluate the effects on speech perception of using a CI either alone or simultaneously with an HA that had frequency compression either enabled or disabled. Eight adult CI recipients who were successful users of acoustic hearing aids in their nonimplanted ears participated as subjects. The speech perception of each subject was assessed in seven conditions. These required each subject to listen with (1) their own HA alone; (2) the Phonak Naida HA with frequency compression (SoundRecover) enabled; (3) the Naida with SoundRecover disabled; (4) their CI alone; (5) their CI and their own HA; (6) their CI and the Naida with SoundRecover enabled; and (7) their CI and the Naida with SoundRecover disabled. Test sessions were scheduled over a period of about 10 wk. During part of that time, the subjects were asked to use the Phonak Naida HA with their CIs in place of their own HAs. The speech perception tests included measures of consonant identification from a closed set of 12 items presented in quiet, and measures of sentence understanding in babble noise. The speech materials were presented at an average level of 60 dB SPL from a loudspeaker. Speech perception was better, on average, in all conditions that included use of the CI in comparison with any condition in which only an HA was used. For example, consonant recognition improved by approximately 50 percentage points, on average, between the HA-alone listening conditions and the CI-alone condition. There were no statistically significant score differences between conditions with SoundRecover enabled and disabled. There was a small but significant improvement in the average signal-to-noise ratio (SNR) required to understand 50% of the words in the sentences presented in noise when an HA was used simultaneously with the CI.

Although each of these CI users readily accepted the Phonak Naida HA with SoundRecover frequency compression, no benefits related specifically to the use of SoundRecover were found in the particular tests of speech understanding applied in this study. The relatively high levels of perceptual performance attained by these subjects with use of a CI by itself are consistent with the finding that the addition of an HA provided little further benefit. However, the use of an HA with the CI did provide better performance than the CI alone for understanding sentences in noise.

Acute coronary syndrome and stable coronary artery disease: are they so different?

Patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) are known to have poorer short-term prognosis compared to stable coronary artery (CAD) patients undergoing elective PCI. Few studies have made direct comparison of long-term mortality between ACS and stable CAD patients undergoing PCI. The aim of our study was to compare the long-term mortality following PCI between patients with ACS and those with stable CAD. We examined consecutive patients undergoing PCI with stenting at a tertiary referral hospital. Clinical, angiographic and biochemical data were collected and analysed. The primary outcome was all-cause mortality retrieved from the Statewide Death Registry database. Included were 1923 consecutive PCI patients (970 stable CAD and 953 ACS). The mean follow-up time was 4.1 years ± 1.8 years. In-hospital mortality was 1.4% overall, seen exclusively in patients with ACS (n=28, 2.9%). Post-discharge mortality was 6.7% among patients with stable CAD and 10.5% for ACS (P<0.01). Multivariate predictors of post-discharge deaths for both groups included age (HR 1.08 per year, P<0.001) and impaired renal function (HR 2.49, P<0.001). Following adjustment for these factors, an ACS indication for PCI was not associated with greater post-discharge mortality (adjusted HR 1.18: 0.85-1.64, P=0.32).

Patients undergoing PCI following an ACS have higher long-term mortality to those with stable CAD, which is potentially explained by a greater prevalence of comorbidities. This suggests that for the ACS population, contemporary interventional and medical management strategies may effectively and specifically counter the adverse prognostic impact of coronary instability and myocardial damage.

Do intermittent Short Sleep Results in Lasting Sleep Wake Disturbances and Degeneration of Locus Coeruleus and Orexinergic Neurons?

Intermittent short sleep (ISS) is pervasive among students and workers in modern societies, yet the lasting consequences of repeated short sleep on behavior and brain health are largely unexplored. Wake-activated neurons may be at increased risk of metabolic injury across sustained wakefulness. To examine the effects of ISS on wake-activated neurons and wake behavior, wild-type mice were randomized to ISS (a repeated pattern of short sleep on 3 consecutive days followed by 4 days of recovery sleep for 4 weeks) or rested control conditions. Subsets of both groups were allowed a recovery period consisting of 4-week unperturbed activity in home cages with littermates. Mice were examined for immediate and delayed (following recovery) effects of ISS on wake neuron cell metabolics, cell counts, and sleep/wake patterns. ISS resulted in sustained disruption of sleep/wake activity, with increased wakefulness during the lights-on period and reduced wake bout duration and wake time during the lights-off period. Noradrenergic locus coeruleus (LC) and orexinergic neurons showed persistent alterations in morphology, and reductions in both neuronal stereological cell counts and fronto-cortical projections. Surviving wake-activated neurons evidenced persistent reductions in sirtuins 1 and 3 and increased lipofuscin. In contrast, ISS resulted in no lasting injury to the sleep-activated melanin concentrating hormone neurons.

Collectively these findings demonstrate for the first time that ISS imparts significant lasting disturbances in sleep/wake activity, degeneration of wake-activated LC and orexinergic neurons, and lasting metabolic changes in remaining neurons most consistent with premature senescence.

Does exercise training lower plasma visfatin concentrations in patients with type 1 diabetes?

Exercise training exerts beneficial effects on metabolic and vascular risk factors in patients with type 1 diabetes mellitus (T1DM). It is unknown whether training also influences concentrations of visfatin, a novel insulin-mimetic adipocytokine. In this study, we have investigated whether plasma visfatin concentrations are altered by training in patients with T1DM. Fasting plasma visfatin concentrations and metabolic parameters were measured in 18 patients with T1DM who participated in a supervised aerobic exercise program for 4 months. Three subjects discontinued training prematurely after 2 months. Samples were obtained before and during training and 8 months after the end of regular exercise. Fourteen healthy young subjects served as controls. At baseline, patients with T1DM had higher visfatin concentrations than controls (64.1 +/- 12.0 vs. 1.3 +/- 0.0 ng/ml, P < 0.01). Exercise reduced visfatin after 2 and 4 months to 27.8 +/- 2.6 (n = 18) and 17.5 +/- 3.4 ng/ml (n = 15), respectively (P < 0.001 for n = 15 subjects who participated in all visits, ANOVA). This effect was maintained 8 months after cessation of training, with visfatin concentrations of 19.7 +/- 5.0 ng/ml (n = 15). Metabolic parameters were not affected by the training program.

Elevated visfatin concentrations in patients with T1DM can be lowered by regular physical exercise. It is unknown whether glucose tolerance is affected by changes in visfatin concentrations.

Is intrauterine instillation of trichloroacetic acid effective for the treatment of dysfunctional uterine bleeding?

To evaluate the effectiveness of trichloroacetic acid (TCA) instillation into uterine cavity for the treatment of dysfunctional uterine bleeding (DUB). Prospective clinical study. A university research hospital. Ninety women participated who had dysfunctional uterine bleeding. Ninety-five percent of TCA was instilled into uterine cavity for endometrial ablation in women with dysfunctional uterine bleeding who want conservative treatment. Participants in group 1 received only TCA; participants in group 2 received a single dose of gonadotropin-releasing hormone analogue 1 month before the procedure. All participants underwent an evaluation that included cycle history, body mass index measurement, and transvaginal ultrasonography of pelvis, diagnostic hysteroscopy and endometrial biopsy. At the end of 12 months of the treatment, amenorrhea rates in group 1 and group 2 were 26.7% vs. 31.1%, with pooled amenorrhea, hypomenorrhea, and eumenorrhea rates of 95.6% vs. 97.8%, respectively. There was no significant difference between the groups vis-a-vis postprocedure results. More than 90% of women who have this procedure are satisfied with the results. There were no observed negative effects or related complications with this treatment.

An instillation of TCA into uterine cavity produces acceptable results and provides conservative management of DUB.

Does metformin improve lipid metabolism disorders through reducing the expression of microsomal triglyceride transfer protein in OLETF rats?

This study aimed to investigate the role of MTP on lipid metabolism disorders in insulin-resistant rats and the potential mechanism through which metformin can improve lipid metabolism disorders. 30 OLETF rats served as research subjects and 18 LETO rats of the same strain served as the control group (LETO group). After the first oral glucose tolerance test (at 8-week-old), 6 rats were randomly killed from each group. The remaining 24 OLETF rats were randomly divided into untreated group (OLETF group) and treated group (OLETF/M group, cured with metformin). By the end of the 10th and 20th week of treatment, MTP in the liver was measured for all rats in the study. All OLETF rats exhibited diabetic phenotypes at 18-week-old, with their triglyceride level higher than in LETO rats at the same age. In OLETF rats, MTP level in the liver was higher than in LETO rats at 18-week-old, and the difference was significant at 28-week-old [(13.79±1.47) vs. (8.20±1.14), p<0.05]. Treatment with metformin for 20weeks decreased triglyceride [(1.06±0.23) vs. (2.20±0.62) mmol/L, p<0.05] and total cholesterol [(1.90±0.19) vs. (2.36±0.14) mmol/L, p<0.05] in OLETF rats. Metformin also decreased MTP level in the liver [(7.65±1.31) vs. (13.79±1.47), p<0.01].

MTP may be associated with the lipid metabolism disorder in OLETF rats and metformin could improve lipid metabolism through reducing the expression of MTP.

Does the mind map learning strategy facilitate information retrieval and critical thinking in medical students?

A learning strategy underutilized in medical education is mind mapping. Mind maps are multi-sensory tools that may help medical students organize, integrate, and retain information. Recent work suggests that using mind mapping as a note-taking strategy facilitates critical thinking. The purpose of this study was to investigate whether a relationship existed between mind mapping and critical thinking, as measured by the Health Sciences Reasoning Test (HSRT), and whether a relationship existed between mind mapping and recall of domain-based information. In this quasi-experimental study, 131 first-year medical students were randomly assigned to a standard note-taking (SNT) group or mind map (MM) group during orientation. Subjects were given a demographic survey and pre-HSRT. They were then given an unfamiliar text passage, a pre-quiz based upon the passage, and a 30-minute break, during which time subjects in the MM group were given a presentation on mind mapping. After the break, subjects were given the same passage and wrote notes based on their group (SNT or MM) assignment. A post-quiz based upon the passage was administered, followed by a post-HSRT. Differences in mean pre- and post-quiz scores between groups were analyzed using independent samples t-tests, whereas differences in mean pre- and post-HSRT total scores and subscores between groups were analyzed using ANOVA. Mind map depth was assessed using the Mind Map Assessment Rubric (MMAR). There were no significant differences in mean scores on both the pre- and post-quizzes between note-taking groups. And, no significant differences were found between pre- and post-HSRT mean total scores and subscores.

Although mind mapping was not found to increase short-term recall of domain-based information or critical thinking compared to SNT, a brief introduction to mind mapping allowed novice MM subjects to perform similarly to SNT subjects. This demonstrates that medical students using mind maps can successfully retrieve information in the short term, and does not put them at a disadvantage compared to SNT students. Future studies should explore longitudinal effects of mind-map proficiency training on both short- and long-term information retrieval and critical thinking.

Is drug safety a barrier to the discovery and development of new androgen receptor antagonists?

Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk.

Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs.

Does elevated body temperature independently contribute to increased length of stay in neurologic intensive care unit patients?

Elevated temperature results in worse outcome in experimental models of cerebral ischemia and brain trauma. In critically ill neurologic and neurosurgical patients, elevated body temperature is common and is associated with neurologic deterioration and poor outcome. We sought to determine whether, after controlling for age, severity of illness, and complications, elevated body temperature remained an important predictor of intensive care unit (ICU) and hospital length of stay, mortality rate, and hospital disposition in a large cohort of patients emergently admitted to a neurologic ICU. Prospectively collected data (demographics, diagnosis, Acute Physiology and Chronic Health Evaluation II score, Glasgow Coma Scale score, daily maximum temperature, complications, disposition) were retrospectively reviewed. A 20-bed neurology/neurosurgery ICU in a tertiary care academic, level I trauma, referral center. From 6,759 admissions, those admitted after an elective procedure with length of stay < or = 1 day, those <18 yrs old, and those with incomplete data were excluded, leaving 4,295 patients for this analysis. First, a hierarchical multiple regression analysis was performed to determine whether elevated body temperature was an independent predictor of length of stay. Second, a path analysis was performed to define the relationships among elevated body temperature, complications, and length of stay. Finally, a matched, weighted sample was developed to quantify the difference in length of stay. None. We measured ICU and hospital length of stay, mortality rate, and discharge disposition. The presence of elevated body temperature was associated with a dose-dependent longer ICU and hospital length of stay, higher mortality rate, and worse hospital disposition. The most important predictor of ICU length of stay was the number of complications (beta =.681) followed by elevated body temperature (beta =.143). In the matched, weighted population, the presence of elevated body temperature was associated with 3.2 additional ICU days and 4.3 additional hospital days.

In a large cohort of neurologic ICU patients, after we controlled for severity of illness, diagnosis, age, and complications, elevated body temperature was independently associated with a longer ICU and hospital length of stay, higher mortality rate, and worse outcome.

Are src Family Kinases Regulated in Multiple Myeloma Cells by Phosphatase of Regenerating Liver-3?

Phosphatase of regenerating liver-3 (PTP4A3/PRL-3) is a dual specificity phosphatase that is up-regulated in various types of cancers and is related to poor prognosis and aggressive tumor behavior. The expression level of PRL-3 is elevated in response to several anti-apoptotic cytokines, including interleukin-6 (IL6), in cancer cells from patients with multiple myeloma (MM) and can promote survival and migration. Here it is demonstrated that PRL-3 activates Src kinase in the IL6-dependent MM cell line INA-6. Inhibition of PRL-3 by a small-molecule inhibitor of PRL-3 or by shRNA resulted in inactivation of Src. In addition to activation of Src, PRL-3 also activated the Src family kinase (SFK) members LYN and HCK in INA-6 cells. Forced expression of catalytically inactive mutant PRL-3 decreased the activation of these three SFK members while the total level of HCK and FYN remained elevated. Inhibitors of Src increased sensitivity of cells overexpressing PRL-3 to the PRL-3 inhibitor through joint downregulation of both PRL-3 and Mcl-1. In conclusion, PRL-3 protected MM cells against apoptosis by dysregulating both the total levels and the activation levels of specific SFK members that are important for IL6 signal transduction in MM cells. Eventually, this led to increased levels of Mcl-1.

This study suggests PRL-3 and Src family kinases (SFK) are key mediators of the IL6-driven signaling events and points to both PRL-3 and SFK members as potential targets for treatment of MM.

Do cigarette warning labels reduce smoking?

To examine the association between adolescents knowledge of cigarette warning labels and actual smoking behavior. Cohort analytic study. Four public high schools in northern California. Seventeen hundred forty-seven ninth graders (mean age, 14.9 years). Students from 2 of the schools (n = 803) were observed for approximately 3 months. Self-reported knowledge of warning labels was assessed at baseline. Self-reports of smoking behavior were completed at baseline and at follow-up. Greater knowledge of cigarette package warning labels was significantly associated with higher levels of smoking. Knowledge of warning labels on magazine and billboard advertisements did not differ significantly by level of smoking. In the longitudinal sample, greater knowledge of cigarette package warning labels was significantly associated with a subsequent increase in smoking, controlling for the baseline level of smoking, sex, ethnicity, and knowledge of warning labels on cigarette advertisements (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.02-1.46). Knowledge of warning labels on cigarette advertisements was not associated with a significant change in smoking behavior (OR, 1.06; 95% CI, 0.82-1.35).

Sizable proportions of adolescent smokers are not seeing, reading, or remembering cigarette warning labels. In addition, knowledge of warning labels on cigarette packages and advertisements is not associated with reduced smoking. The current warning labels are ineffective among adolescents.

Is there a high incidence of hysterectomy and other nonbladder surgeries before and after onset of interstitial cystitis/bladder pain syndrome?

The objective of the study was to compare with controls the incidence of nonbladder pelvic surgeries in the months before and after the onset of interstitial cystitis/bladder pain syndrome (IC/BPS). The design of the study used an existing database from a retrospective case-control study of 312 incident IC/BPS cases and matched controls plus a longitudinal study of the cases that examined lifetime approximated annual incidence of surgeries with that in the months before and after the onset of IC/BPS. In cases, in the month before the onset of IC/BPS, the approximated annual incidence of nonbladder pelvic surgeries was 15 times higher and of hysterectomy 25 times higher than the incidences of previous years and similarly higher than controls. This rate declined to preindex levels over the first 2 years of IC/BPS.

There may be a very high incidence of nonbladder surgeries just before IC/BPS onset that decreases to historical levels over the first years of the syndrome.

Is chronic administration of losartan , an angiotensin II receptor antagonist , effective in reducing portal pressure in patients with preascitic cirrhosis?

Plasma angiotensin II (ANG II) concentrations are elevated in cirrhosis and have been implicated as a cause of portal hypertension. We aimed to study both the systemic and portal hemodynamics, and tolerability after chronic administration of losartan, an ANG II receptor antagonist. Twelve patients with preascitic cirrhosis were studied: mean age of 53.8 +/- 3.3 yr; average Child-Pugh score of 5.8 +/- 0.3; alcohol etiology (5), hepatitis B/C (1/3), primary biliary cirrhosis (3). No patients were on diuretics or vasoactive medication. Hemodynamic measurements were performed at baseline and 4 weeks after daily administration of 25 mg losartan. There was no significant change in the hepatic venous pressure gradient (15.4 +/- 1.5 to 13.6 +/- 1.6 mmHg, -11.7%, p = NS), despite a significant reduction in the wedge hepatic venous pressure (20.3 +/- 1.8 to 17.3 +/- 1.8 mmHg, -14.8%, p < 0.05). Cardiac output, hepatic blood flow, systemic vascular resistance, creatinine clearance, and natriuresis were unaffected. The plasma renin activity increased significantly from 2.7 +/- 0.4 to 5.2 +/- 1.1 ng/ml/h (p < 0.05). There was a significant reduction in the mean arterial pressure from 96.9 +/- 3.3 to 89.3 +/- 3.5 mmHg, -7.8 +/- 3.0% (p = 0.02), with 1 patient experiencing symptomatic hypotension.

Chronic administration of low-dose losartan does not lead to a significant reduction in the portal pressure gradient. Losartan is unlikely to be useful in the management of patients with early cirrhosis, who are at risk of variceal bleeding.

Can highly active antiretroviral therapy reduce the spread of HIV?

Calls have been made for the large-scale delivery of highly active antiretroviral therapy (HAART) to people infected with HIV in developing countries. If this is to be done, estimates of the number of people who currently require HAART in high HIV prevalence areas of sub-Saharan Africa are needed, and the impact of the widespread use of HAART on the transmission and, hence, spread of HIV must be assessed. To estimate the proportion of people eligible for combination antiretroviral therapy and to evaluate the potential impact of providing HAART on the spread of HIV-1 under World Health Organization (WHO) guidelines in a South African township with a high prevalence of HIV-1. A community-based cross-sectional study in a township near Johannesburg, South Africa, of a random sample of approximately 1000 men and women aged 15 to 49 years. Background characteristics and sexual behavior were recorded by questionnaire. Participants were tested for HIV-1, and their CD4 cell counts and plasma HIV-1 RNA loads were measured. The proportion of people whose CD4 cell count was less than 200 cells/mm and who would be eligible to receive HAART under WHO guidelines was estimated. The potential impact of antiretroviral drugs on the spread of HIV-1 in this setting was determined by estimating among the partnerships engaged in by HIV-1-positive individuals the proportion of spousal and nonspousal partnerships eligible to receive HAART and then by calculating the potential impact of HAART on the annual risk of HIV-1 transmission due to sexual contacts with HIV-1-infected persons. The results were compared with those obtained using United States Department of Health and Human Services (USDHHS) guidelines. The overall prevalence of HIV-1 infection was 21.8% (19.2%-24.6%), and of these people, 9.5% (6.1%-14.9%) or 2.1% (1.3%-3.3%) of all those aged 15 to 49 years would be eligible for HAART (ranges are 95% confidence limits). In each of the next 3 years 6.3% (4.6%-8.4%) of those currently infected with HIV-1 need to start HAART. Among the partnerships in which individuals were HIV-1-positive, only a small proportion of spousal partnerships (7.6% [3.4%-15.6%]) and nonspousal partnerships (5.7%, [3.0%-10.2%]) involved a partner with a CD4 cell count below 200 cells/mm and would have benefited from the reduction of transmission due to the decrease in plasma HIV-1 RNA load under HAART. Estimates of the impact of HAART on the annual risk of HIV-1 transmission show that this risk would be reduced by 11.9% (7.1%-17.0%). When using USDHHS guidelines, the proportion of HIV-1-positive individuals eligible for HAART reached 56.3% (49.1%-63.2%) and the impact of HAART on the annual risk of HIV-1 transmission reached 71.8% (64.5%-77.5%).

The population impact of HAART on reducing sexual transmission of HIV-1 is likely to be small under WHO guidelines, and reducing the spread of HIV-1 will depend on further strengthening of conventional prevention efforts. A much higher impact of HAART is to be expected if USDHHS guidelines are used.

Esophagogastric dissociation in the neurologically impaired: an alternative to fundoplication?

Gastroesophageal reflux is common in children with severe neurological impairment. Fundoplication may produce symptomatic improvement but has a high failure rate. Esophagogastric dissociation (EGD) is an alternative procedure for treatment of gastroesophageal reflux. The aim of this study is to evaluate the results of EGD in our institution and compare them with a neurologically matched group of children who had Nissen fundoplication. Twenty consecutive patients who had EGD were retrospectively evaluated and the results were compared with a neurologically matched group of 20 consecutive patients who had Nissen fundoplication. Twenty patients had EGD, 17 as a primary procedure. There was no operative mortality but 5 have died of other causes. Resolution of reflux-associated symptoms occurred in all patients. Of the 15 survivors, 5 remain on antireflux medication. Twenty patients had fundoplication. There was no operative mortality, but 8 patients have died of other causes. Failure occurred in 5 patients necessitating further surgery. Of the 10 unreoperated survivors, 6 remain on antireflux medication.

Esophagogastric dissociation is an effective antireflux procedure when compared with fundoplication. It has a lower failure rate. We recommend EGD as a primary procedure in selected children with severe neurological impairment.

Assessment for rest home subsidy: are the elderly getting a fair deal?

A 47 item questionnaire was completed by the geriatric service at the time of assessment of elderly people in the community or in rest homes. Of 280 assessments, 100 were from private homes, 180 from rest homes. Sixty-three per cent in rest homes were referred only because private funds were exhausted, 33% for a change in dependency category. These two groups plus those at home were used as a basis for comparison in subsequent analysis. Of those at home: 30% already had a rest home bed arranged; 77% remembered being consulted about rest home care, but only 38% were sure they wanted to go into such care. The proportion of those too independent or too sick for rest home care was: private homes 14%, rest home resident requiring subsidy 6%, rest home requiring change in category status 11%. Twenty three percent of those at home could continue there with or without additional support. No significant difference was found in dependency between those in rest homes only seeking funding, and those at home, but both of these groups were significantly less dependent than those seeking an increase in subsidy. There was only a moderate correlation (rs = 0.778) between the geriatric service assessment of dependency and the composite dependency score.

Many elderly people do not feel properly consulted about rest home placement, and some could be supported at home for longer. It is likely that many who can afford rest home fees are entering too early and then asking for a subsidy when their funds are exhausted. By then it is almost impossible to insist on alternatives in the community. A policy of geriatric service assessment for all seeking entry into rest home care should ensure independent consultation and consideration of alternative strategies. More research is required to examine cost implications of unrestricted movement into rest homes.

Is osteoporosis associated with the risk of colorectal adenoma in women?

Recently, it was reported that postmenopausal women with lower bone mineral density have an increased risk of colorectal cancer. An association between lower bone mineral density and colorectal cancer suggests that colorectal adenoma, which is a precursor of colorectal cancer, may also be associated with lower bone mineral density. The aim of this study was to determine the association between colorectal adenoma and osteoporosis. We conducted a retrospective cross-sectional study between January 2007 and May 2011. Women older than 50 years of age who underwent dual-energy x-ray absorptiometry for bone mineral density and screening colonoscopy at Gangdong Kyung Hee University Hospital in Korea during a routine health checkup were eligible for this study. We performed multivariate analysis adjusted for age, family history of colorectal cancer, alcohol consumption, current smoking, regular aspirin use, exercise, menopause, and postmenopausal hormone use to identify independent predictors for the presence of colorectal adenoma. The primary outcome measured was the prevalence of colorectal adenoma according to the bone mineral density level. A total of 992 women older than 50 years were assigned to an osteoporosis group (n = 231) or a control group (n = 231) after menopause matching. In univariate analysis, the proportion of colorectal adenoma was significantly higher in the osteoporosis group than in the control group (29.9% vs 20.8%, p = 0.025). Furthermore, osteoporosis (OR = 1.592, 95% CI = 1.004-2.524, p = 0.048) was found to be an independent risk factor for the presence of colorectal adenoma.

Osteoporosis is associated with an increased risk of colorectal adenoma in women older than 50 years.

Does exposure to organic solvents used in dry cleaning reduce low and high level visual function?

To investigate whether exposure to occupational levels of organic solvents in the dry cleaning industry is associated with neurotoxic symptoms and visual deficits in the perception of basic visual features such as luminance contrast and colour, higher level processing of global motion and form (Experiment 1), and cognitive function as measured in a visual search task (Experiment 2). The Q16 neurotoxic questionnaire, a commonly used measure of neurotoxicity (by the World Health Organization), was administered to assess the neurotoxic status of a group of 33 dry cleaners exposed to occupational levels of organic solvents (OS) and 35 age-matched non dry-cleaners who had never worked in the dry cleaning industry. In Experiment 1, to assess visual function, contrast sensitivity, colour/hue discrimination (Munsell Hue 100 test), global motion and form thresholds were assessed using computerised psychophysical tests. Sensitivity to global motion or form structure was quantified by varying the pattern coherence of global dot motion (GDM) and Glass pattern (oriented dot pairs) respectively (i.e., the percentage of dots/dot pairs that contribute to the perception of global structure). In Experiment 2, a letter visual-search task was used to measure reaction times (as a function of the number of elements: 4, 8, 16, 32, 64 and 100) in both parallel and serial search conditions. Dry cleaners exposed to organic solvents had significantly higher scores on the Q16 compared to non dry-cleaners indicating that dry cleaners experienced more neurotoxic symptoms on average. The contrast sensitivity function for dry cleaners was significantly lower at all spatial frequencies relative to non dry-cleaners, which is consistent with previous studies. Poorer colour discrimination performance was also noted in dry cleaners than non dry-cleaners, particularly along the blue/yellow axis. In a new finding, we report that global form and motion thresholds for dry cleaners were also significantly higher and almost double than that obtained from non dry-cleaners. However, reaction time performance on both parallel and serial visual search was not different between dry cleaners and non dry-cleaners.

Exposure to occupational levels of organic solvents is associated with neurotoxicity which is in turn associated with both low level deficits (such as the perception of contrast and discrimination of colour) and high level visual deficits such as the perception of global form and motion, but not visual search performance. The latter finding indicates that the deficits in visual function are unlikely to be due to changes in general cognitive performance.

Are prior suicide attempts less common in suicide decedents who died by firearms relative to those who died by other means?

Suicide prevention efforts often center on the identification of risk factors (e.g., prior suicide attempts); however, lists of risk factors without consideration of context may prove incapable of impacting suicide rates. One contextual variable worth considering is attempt method. Utilizing data from the National Violent Death Reporting System (2005-2012), I examined suicide deaths (n=71,775) by firearms and other means to determine whether prior suicide attempts were more common in one group versus the other. Significantly fewer suicide decedents who died by firearms reported a prior history of suicide attempts (12.10%) than did decedents who died by other means (28.66%). This result was further replicated within each state that contributed data to the NVDRS.

Only 17 states have contributed to the NVDRS thus far and, within those states, not all suicide deaths were reported. Due to the nature of the data, I was unable to test proposed mediators within our model.

Tumor size on computed tomography scans: is one measurement enough?

Bidimensional tumor measurements are used routinely as surrogates for tumor volume. The purpose this study was to determine whether there is any added benefit in bidimensional or tridimensional measurements over a unidimensional measurement. Sixty-nine colorectal hepatic metastases on 19 computed tomography scans (1-8 lesions per scan) from 9 patients were analyzed. Five patients contributed 2-4 scans each (mean, 3 scans). The standard volume of these lesions was determined by the "summation of areas" technique. The maximum axial dimension, the product of the greatest axial dimensions, and several volume estimates (based on the volumes of a sphere, an ellipsoid, and a cube) each were correlated with the standard volume. The maximum axial dimension and the product of the greatest axial dimensions correlated equally with tumor volume (correlation coefficient = 0.93). Surrogate measures based on the equations for a sphere and an ellipsoid underestimated tumor volume, whereas the equation for a cube overestimated volume.

When reporting tumor size, there is no significant added benefit in reporting bidimensional or tridimensional measurements over the maximum axial dimension.

Is platelet transfusion during liver transplantation associated with increased postoperative mortality due to acute lung injury?

Platelet transfusions have been identified as an independent risk factor for survival after orthotopic liver transplantation (OLT). In this study, we analyzed the specific causes of mortality and graft loss in relation to platelet transfusions during OLT. In a series of 449 consecutive adult patients undergoing a first OLT, the causes of patient death and graft failure were studied in patients who did or did not receive perioperative platelet transfusions. Patient and graft survival were significantly reduced in patients who received platelet transfusions, compared with those who did not (74% vs 92%, and 69% vs 85%, respectively at 1 yr; P < 0.001). Lower survival rates in patients who received platelets were attributed to a significantly higher rate of early mortality because of acute lung injury (4.4% vs 0.4%; P = 0.004). There were no significant differences in other causes of mortality between the two groups. The main cause of graft loss in patients receiving platelets was patient death with a functioning graft.

These findings suggest that platelet transfusions are an important risk factor for mortality after OLT. The current study extends previous observations by identifying acute lung injury as the main determinant of increased mortality. The higher rate of graft loss in patients receiving platelets is related to the higher overall mortality rate and does not result from specific adverse effects of transfused platelets on the grafted liver.

Trans-obturator urethral sling for the surgical correction of female stress urinary incontinence: outside-in (Monarc) versus inside-out (TVT-O). Are the two ways reassuring?

In 2001, the trans-obturator route was proposed for the surgical positioning of tape with a view to avoiding the retropubic space and its disadvantages. The route, originally described outside-in by Delorme was presented inside-out by de Leval. Since then, anatomical discussions have attempted to prove that one technique is safer than the other. Demonstrating the safety of the two techniques through personal and published experience. Non-randomized, prospective, observational, open-label, longitudinal study of 100 female patients (50 tension-free vaginal tape (TVT)-O and 50 Monarc). All the female patients presented with isolated stress urinary incontinence. Only four patients presented with mixed incontinence in the Monarc (MON) group. Sphincter incompetence was observed four times in the MON group and three times in the TVT-O group. Almost all the patients were undergoing their first procedure. All the patients underwent surgery under assisted local anesthesia in a day-hospital setting. All the patients underwent a full gynecological examination and a urodynamic assessment. Only those patients presenting with patent established urinary incontinence, corrected by the TVT test, underwent surgery. Post-operative control was conducted at 3 months and 1 year when a physical examination and urodynamic assessment were implemented. All the patients underwent control up to time point 12 months. The duration of hospitalization was 10h for 48 patients in the MON group and 49 in the TVT-O group. The duration of hospitalization was 24h for one patient in each group and 4 days for one patient in the TVT-O group due to transient urine retention. The only per-operative complication was a vaginal perforation in the lateral angle of the vagina for a MON patient. Tape repositioning was necessary. Early post-operative complications were observed in the MON group: three cases of urinary tract infection, one of transient urine retention, three of pain in the thighs spontaneously resolving within 4 days and one of permanent pain in one leg at time 1 year, which remained bearable. For the TVT-O group the post-operative complications consisted in: one case of urinary tract infection, one of transient retention and four of pain in the thigh. No hematoma was reported in either group. Amongst the late complications, the de novo symptoms included one case of imperious urges to urinate in the TVT-O group and objective dysuria in two cases in the MON group versus seven in the TVT-O group. There was no statistically significant between-group difference in the complications. No tape exposure was observed. Overall, the recovery rate was 90% at 1 year for MON versus 94% for TVT-O (p=NS) with two cases of recurrence between 3 months and 1 year in that series. Mixed incontinence was corrected at time point 1 year in 75% of cases for MON, with one case of recurrence in the year. For the patients presenting with sphincter incompetence, competence was maintained at 3 months and 1 year in all cases in the MON group. The three TVT-O were cured at 3 months, but two recurrences were observed at 1 year. Almost all the patients were satisfied or very satisfied at time point 1 year and those who had sexual relations (54%) did not report any disorder at time point 1 year. The outside-in technique necessitates more marked peri-urethral dissection and vesical complications are possible. The cadaveric studies by the outside-in partisans show a vascular and nervous risk, which has little reflection in terms of complications in the literature. Post-operative leg pains are encountered with both techniques and are usually only transient. All the studies of the two routes report a recovery rate of over 90% for pure stress incontinence.

The author's experience, like that reported in the literature, shows that the two trans-obturator access routes are equally safe and do not require per-operative cystoscopic control. The clinical results would appear to be equivalent, in terms of recovery, to the rates obtained with retropubic TVT. Attempting to find anatomical or etiological arguments in order to prove one technique superior to the other appears somewhat parochial.

Do mesenchymal stem cells facilitate fracture repair in an alcohol-induced impaired healing model?

Clinical studies have shown alcohol to be a risk factor for traumatic orthopaedic injuries and for nonunion. Data from animal studies suggest that alcohol exposure inhibits fracture healing. This report presents a novel rodent model of impaired fracture healing caused by repeated alcohol exposure. Using this model, we examined the regenerative effects of an intravenously administered population of isolated and expanded mesenchymal stem cells (MSCs) on fracture healing. Bone marrow-derived MSC were isolated from transgenic green fluorescent protein C57BL/6 mice, and culture expanded using a lineage depletion protocol. Adult wild-type C57BL/6 mice were subjected to a 2-week binge alcohol exposure paradigm (3 days during which they received daily intraperitoneal injections of a 20% alcohol/saline solution followed by a 4-day rest period and another binge cycle for 3 consecutive days). At completion of the second binge cycle, mice were subjected to a mid-shaft tibia fracture while intoxicated. Twenty-four hours after the fracture, animals were administered an intravenous transplant of green fluorescent protein-labeled MSC. Two weeks after the fracture, animals were euthanized and injured tibiae were collected and subjected to biomechanical, histologic, and microcomputed tomography analysis. Pre-injury binge alcohol exposure resulted in a significant impairment in biomechanical strength and decrease in callus volume. MSC transplants restored both fracture callus volume (P < 0.05) and biomechanical strength (P < 0.05) in animals with alcohol-impaired healing. In vivo imaging demonstrated a time-dependent MSC migration to the fracture site.

These data suggest that a 2-week binge alcohol exposure significantly impairs fracture healing in a murine tibia fracture model. Intravenously administered MSC were capable of specifically homing to the fracture site and of normalizing biomechanical, histologic, and microcomputed tomography parameters of healing in animals exposed to alcohol. Understanding MSC recruitment patterns and functional contributions to fracture repair may lead to their use in patients with impaired fracture healing and nonunion.

Does α-Lipoic acid attenuate transplacental nicotine-induced germ cell and oxidative DNA damage in adult mice?

Smoking during pregnancy is associated with numerous fetal and developmental complications and reproductive dysfunctions in the offspring. Nicotine is one of the key chemicals of tobacco responsible for addiction. The present study was aimed to investigate the protective role of α-lipoic acid (ALA) during the transplacental nicotine-induced germ cell and DNA damage in the offspring of Swiss mice. Pregnant mice were treated with nicotine (20 mg/kg/day) in drinking water from 10 to 20 days of gestation period, and ALA (120 mg/kg/day) was administered orally for the same period. Endpoint of evaluation includes general observations at delivery and throughout the study, litter weight and size, sperm count and sperm head morphology, while structural damages and protein expression were assessed by histology and immunohistochemistry, respectively. Maternal nicotine exposure led to decreased growth rate, litter and testicular weight, testosterone level, 3β-HSD expression and sperm count as well as increased sperm head abnormalities, micronucleus frequency and 8-oxo-dG positive cells, and the effects have been restored by ALA supplementation.

The present study clearly demonstrated that ALA ameliorates nicotine-associated oxidative stress, DNA damage and testicular toxicity in the offspring by improving steroidogenesis, spermatogenesis and sperm count.

Do jAB1 and phospho-Ser10 p27 expression profile determine human hepatocellular carcinoma prognosis?

To elucidate the clinicopathological significance and the role of Jun Activation Domain-Binding Protein 1 (JAB1), Ser10-phosphorylated p27 (p27S10), and total p27 in human hepatocellular carcinoma (HCC) prognosis. We evaluated the expression of JAB1 and p27S10 in tissues by immunohistochemical and immunoblot analyses. p27 Ser10 phosphorylation and Ser10 phosphorylation-dependent p27-JAB1 interaction were demonstrated in proliferating Huh7 cells following transfection of pEGFP-p27WT/p27S10A/p27S10D plasmids and pcDNA3.1-p27WT/p27S10A/p27S10D-Myc plasmids. Univariate and multivariate analysis were used to determine their role in HCC prognosis. JAB1 and p27S10 are overexpressed in HCC samples compared with paired normal tissues. There was a strong correlation between JAB1 and p27S10 expression (P < 0.001), and expression of both inversely correlated with total p27 levels (P < 0.001). High JAB1 and p27S10 expression correlated with histological grade, vascular invasion, and serum α-fetoprotein (AFP) level (all P < 0.01). Total p27 expression also correlated with histological tumor grade (P = 0.048) and AFP level (P = 0.015). The p27S10(high)/JAB1(high)/p27(1ow) profile was the most reliable indication of poor prognostic. Ser10 phosphorylation increased and total p27 levels decreased in a time-dependent manner in serum-starved Huh7 cells following addition of serum. Immunoprecipitation analysis revealed that p27 Ser-to-Asp substitution at position 10 (S10D) markedly enhanced the interaction between JAB1 and p27, but replacement of S10A reduced binding.

This study revealed that combined JAB1, p27S10, and total p27 expression may serve as a prognostic marker for HCC.

Do PFNA devices and Intertan nails both have the same effects in the treatment of trochanteric fractures?

To clinically and radiologically compare third-generation intramedullary nails used in the treatment of trochanteric hip fractures and to determine their efficacy. Seventy-five of 88 patients admitted to our hospital with trochanteric fractures were enrolled in the study; 43 were treated with PFNA devices and 32 with Intertan nails. The amount of compression applied during the procedure, duration of the procedure, amount of subsequent shortening in the proximal femoral area, subsequent backup of proximal screws, and changes in the tip-apex and tip-cortex distances were compared between groups. The postoperative change in the varus angle of the proximal femur and times to mobilization, full weight bearing, and fracture union were also evaluated. On early postoperative radiographs, the tip-apex distance was ≤25 mm in 86 % of patients in the PFNA group and 96.9 % of those in the Intertan group. Twelve months postoperatively, the tip-apex distance did not differ between groups. No cut-out of the screws into the coxofemoral joint was observed. Fracture healing was achieved in all patients. At 12 months postoperatively, the rates of proximal screw backup, proximal femoral shortening, and decrease in the varus angle of the proximal femur were significantly higher in the PFNA group than in the Intertan group.

Trochanteric fractures may be treated effectively with PFNA devices or Intertan nails. During the healing period, the rates of reverse displacement of the proximal screw, shortening of the proximal femur, and decrease in the varus angle of the proximal femur were significantly higher in the PFNA group than in the Intertan group. Surgical technique, implant positioning, and the choice of implant play roles in the successful treatment of trochanteric fractures.

Should noncardiac chest pain be treated empirically?

Chest pain is a common clinical problem, but up to 30% of patients who present with chest pain lack coronary disease. Subsequent investigation often reveals an esophageal source for the pain, with gastroesophageal reflux disease identified most frequently. Controversy exists regarding whether to establish the cause or to empirically treat as reflux. To assess the cost-effectiveness of empirical treatment in patients with noncardiac chest pain. Decision analysis was used to compare a strategy of empirical treatment as reflux using an H-blocker or proton pump inhibitor with initial investigation for gastrointestinal causes over a period of up to 16 weeks and over a period of more than a year. The prototype patient was an outpatient with chest pain and a normal coronary angiogram. Gastrointestinal investigations included an upper gastrointestinal tract series, endoscopy, manometry, 24-hour pH monitoring, and provocation tests. The main outcome measure was direct medical costs per case treated from a third-party payer perspective. Total medical costs were $2,187 per case treated for the initial investigation arm and $849 for the empirical treatment arm in the 8- to 16-week model. One-way sensitivity analyses revealed that the model was robust; the treatment arm was less expensive in all cases. At just over a year empirical treatment remained dominant.

An initial therapeutic trial with antisecretory agents for patients with noncardiac chest pain is cost-effective compared with investigation for gastrointestinal causes in the short term of weeks, with cost savings persisting beyond a year.

Patient-centredness, self-rated health, and patient empowerment: should providers spend more time communicating with their patients?

Patient-centred communication is often employed as a strategy for empowering patients. The purpose of this study was to investigate the relationship between a direct measure of patient empowerment, feeling that one is in control of one's own health and patient satisfaction with communication. A cross-sectional survey of family medicine patients was used to test the theory that, in primary care patients, empowerment is related to satisfaction with several aspects of communication after adjusting for health status, age and gender. Interviews were completed with 680 adult patients for whom complete data were available. Multiple logistic regression analysis revealed that being highly satisfied with overall communication [adjusted odds ratio (AOR)=2.08], explanations (AOR=2.04), listening (AOR=2.63), use of understandable words (AOR=2.41) and involvement in decisions (2.34) were positively associated with empowerment. Self-rated health was more strongly related to empowerment than satisfaction with communication in every model tested (AORs ranged from 2.8 to 3.0).

Reliance solely on patient-centred communication to promote empowerment may be insufficient as well as costly. Instead, improved one-to-one communication between patients and providers should be reserved for clinically complex and urgent situations. For other health matters, referral of patients to community health promotion and education programmes should be considered because this may offer a lower-cost approach to empowerment.

Does choice of radiotherapy planning modality influence toxicity in the treatment of locally advanced esophageal cancer?

Three-dimensional computed tomography-based radiotherapy planning (3DCTP) is increasingly employed in the treatment of esophageal cancer. It is unknown whether a 3DCTP approach influences outcomes compared to two-dimensional planning (2DP). This study compares clinical outcomes for homogeneously treated patient cohorts stratified by planning modality. A retrospective chart review was conducted on patients with T3/4 and/or node-positive esophageal carcinoma treated at the Cleveland Clinic between July 1, 2003 and May 31, 2006 who were managed with an institutional regimen consisting of preoperative radiotherapy, whether 3DCTP or 2DP [30 Gy/20 fractions/1.5 Gy twice daily over 2 weeks], with concurrent cisplatin and 5-fluorouracil the first week. Following definitive resection, an identical postoperative course of concurrent chemoradiotherapy (CRT) was delivered. One hundred and forty-one patients completed preoperative CRT and were available for review. The median follow-up of living patients is 21.7 months. Fifty-five percent underwent 3DCTP and 45% had 2DP. The treatment groups were similar, with the exception of clinical stage group, with 2DP having more stage II and fewer stage III patients than 3DCTP (p = 0.02). 3DCTP plans had significantly smaller field sizes by area (p < 0.0001). Pathologic response, locoregional control, distant control, and overall survival were equivalent between the two planning modalities. Esophagitis was significantly less common with a 3D approach compared to 2D planning (49% vs. 71%, p = 0.0096), with other toxicities equivalent between the groups.

3DCTP reduces acute esophagitis in patients receiving multimodality therapy for esophageal cancer without compromising clinical outcomes.

Is the Psychotic Depression Assessment Scale a useful diagnostic tool?

The Psychotic Depression Assessment Scale (PDAS) has been validated as a method of assessing the severity and treatment outcomes of psychotic depression (PD). We aimed to compare the results of the PDAS in PD and non-psychotic depression (non-PD) patients and validate the PDAS as a diagnostic tool for PD. We included 53 patients with PD and 441 with non-PD who participated in the Clinical Research Center for Depression study in South Korea. In addition to the PDAS, psychometric tools including the HAMD17, HAMA, BPRS, CGI-S, SOFAS, SSI-Beck, WHOQOL-BREF, AUDIT, and FTND were used to assess, respectively, depression, anxiety, overall symptoms, global severity, social functioning, suicidal ideation, quality of life, alcohol use, and nicotine use. After adjusting for age and total HAMD17 score, PD patients had higher scores for depressive mood, hallucinations, unusual thought content, suspiciousness, blunted affect, and emotional withdrawal on the PDAS and higher total scores on the SSI-Beck than non-PD patients. Binary logistic regression identified hallucinatory behavior and emotional withdrawal as predictors of PD. Receiver operating characteristic analysis showed that emotional withdrawal could be used to differentiate psychotic from non-psychotic depression. The inter-rater reliability for psychometric assessments was not evaluated.

In addition to assessing the severity and treatment outcomes of PD, PDAS can help in the diagnosis of PD.

Does halothane increase smooth muscle protein phosphatase in airway smooth muscle?

Halothane relaxes airway smooth muscle, in part, by decreasing the force produced for a given intracellular [Ca(2+)] (i.e., Ca(2+) sensitivity) during muscarinic stimulation, an effect produced by a decrease in regulatory myosin light-chain (rMLC) phosphorylation. The authors tested the hypothesis that halothane reduces rMLC phosphorylation during muscarinic stimulation at constant intracellular [Ca(2+)] by increasing smooth muscle protein phosphatase (SMPP) activity, without changing myosin light-chain kinase (MLCK) activity. Enzyme activities were assayed in beta-escin permeabilized strips of canine tracheal smooth muscle. Under conditions of constant intracellular [Ca(2+)], the rate of rMLC phosphorylation was measured by Western blotting during inhibition of SMPP with microcystin-LR (to assay MLCK activity) or during inhibition of MLCK by wortmannin and adenosine triphosphate depletion (to assay SMPP activity). The effect of halothane (0.8 mm) on enzyme activities and isometric force during stimulation with 0.6 microm Ca(2+) and 10 microm acetylcholine was determined. Halothane produced a 14 +/- 8% (mean +/- SD) decrease in isometric force by significantly reducing rMLC phosphorylation (from 32 +/- 9% to 28 +/- 9%). Halothane had no significant effect on any parameter of a monoexponential relation fit to the data for the MLCK activity assay. In contrast, halothane significantly decreased the half-time for rMLC dephosphorylation in the SMPP activity assay (from 0.74 +/- 0.28 min to 0.44 +/- 0.10 min), indicating that it increased SMPP activity.

Halothane decreases Ca(2+) sensitivity and rMLC phosphorylation in airway smooth muscle during muscarinic receptor stimulation by increasing SMPP activity, without affecting MLCK, probably by disrupting receptor G-protein signaling pathways that inhibit SMPP.

Key gaps in pathologic reporting for appendiceal mucinous neoplasms: time for universal synoptic reporting?

The prognosis of appendiceal mucinous neoplasms (AMN) is directly related to their histopathology. Existing classification schemes encompass tumors with widely divergent clinical behaviors within a single diagnosis, making it difficult for clinicians to interpret pathology reports to counsel patients on optimal management. We sought to examine pathology reports generated for AMN for inclusion of essential histologic features. Pathology reports of appendectomy specimens with a diagnosis of AMN (2002-2015) at our center ("internal") and from referring institutions ("external") were retrospectively reviewed for inclusion of the following 5 essential items: layer of invasion, mucin dissection (low grade neoplasms only), perforation, margins, and serosal implants. Sixty-nine patients were included, 54 with external reports available. Benign/low grade tumors comprised 29.0% and 27.8% of internal and external reports, respectively. Thirty-seven internal reports (53.6%) were signed out by specialist gastrointestinal pathologists. External reports were 66.7% complete for layer of invasion, 26.7% for mucin dissection, 64.8% for perforation, 68.5% for margins, 53.7% for serosal implants, and 18.5% for all items. Internal reports were 75.4% complete for layer of invasion, 40.0% for mucin dissection, 40.6% for perforation, 82.6% for margins, 69.6% for serosal implants, and 17.4% for all items. Eight external (14.8%) and 24 internal (34.8%) reports were synoptic. Synoptic reports were more likely to be complete for all key items both external and internal.

Most pathology reports are incomplete for essential features needed for management and discussion of AMN with patients. Synoptic reports improve completeness of reporting for these tumors.

Is postoperative infliximab associated with an increase in adverse events in Crohn 's disease?

Infliximab is effective treatment for Crohn's disease and has been associated with rare, but serious infectious complications. Emerging data suggest a benefit of infliximab in preventing postoperative Crohn's disease recurrence. It is not known whether administration of infliximab shortly after resective surgery for Crohn's disease increases postoperative complications. To evaluate the risk of developing postoperative complications among Crohn's disease patients receiving infliximab within 4 weeks of intestinal resection. As part of a randomized placebo-controlled infliximab postoperative prevention study, adverse events were prospectively monitored. Crohn's disease patients undergoing intestinal resection were randomized to placebo or infliximab 2-4 weeks after surgery. Study infusions were administered at 0, 2, and 6 weeks then every 8 weeks for 1 year. To evaluate whether infliximab increased postoperative complications, we analyzed all adverse events for 1 year after surgery. Twenty-four patients were randomized to infliximab or placebo after intestinal resection for Crohn's disease. Mean time to first postoperative infusion was 20 days (range 14-25 days). Over the course of 1 year, there were 22 total adverse events, but no difference between infliximab and placebo patients (12 versus 10, respectively, P = 1.0). In the immediate postoperative period, within 8 weeks of surgery, the number of adverse events was also similar between the two groups (3 infliximab and 5 placebo patients, P = 0.68). There were no serious adverse events and no complications related to wound healing or infection.

Initiation of infliximab within 4 weeks of intestinal resection was not associated with postoperative complications.

Does revised staging classification improve outcome prediction for small intestinal neuroendocrine tumors?

Small intestinal (SI) neuroendocrine tumors (NETs) have heterogeneous outcomes. The NET societies have recently proposed a TNM staging classification. In this study, we used population-based data to assess the validity of the staging system. We identified patients with SI-NETS diagnosed between 1988 and 2009 from the Surveillance, Epidemiology, and End Results registry. We used Kaplan-Meier analysis to assess disease-specific survival according to TNM status. Cox models were constructed to evaluate differences in prognosis after controlling for potential confounders. We identified 6,792 patients with SI-NET. Although the current staging system was predictive of prognosis, there was overlap among some groups (stage I/IIA, P = .36; stage IIB/IIIB, P = .70). Additionally, stage IIIB patients had better survival than stage IIIA patients (P < .001). Adjusted analyses showed similar outcomes for T1 versus T2 disease (hazard ratio [HR], 1.02; 95% CI, 0.63 to 1.66). Patients with T3 (HR, 3.60; 95% CI, 2.28 to 5.69) and T4 (HR, 5.50; 95% CI, 3.42 to 8.86) tumors had significantly worse survival than patients with T1 disease. N1 involvement conferred worse survival in T1 (HR, 3.08; 95% CI, 1.75 to 5.44) and T2 disease (HR, 2.73; 95% CI, 1.84 to 4.07) but not in T3 (HR, 0.99; 95% CI, 0.76 to 1.30) or T4 (HR, 0.98; 95% CI, 0.71 to 1.35) disease. A revised classification showed no overlap in survival across groups.

Progressively more advanced T status is associated with worse SI-NET prognosis. Regional lymph node involvement is a marker of worse survival only among patients with T1 or T2 status. These results suggest that revisions to the current staging classification may be helpful.

Does retirement mean more physical activity?

Evidence on physical activity (PA) and transitions out of full-time employment in middle-to-older age is mainly cross-sectional and focused upon retirement. The purpose was to examine trajectories in PA before and after transitions out of full-time employment. Data were obtained for 5,754 people in full-time employment aged 50-75 from the US Health and Retirement Survey. Logistic regression was used to examine trajectories in twice-weekly participation in light, moderate and vigorous PA among those transitioning to part-time work, semi-retirement, full retirement, or economic inactivity due to disability, in comparison to those remaining in full-time employment. Twice weekly participation in vigorous and light physical activity changed little for those who remained in full-time employment, while moderate physical activity decreased between baseline and follow-up (OR 0.95, 95 % CI 0.91, 0.99). Differences in physical activity according to transitional categories at follow-up were evident. Baseline differences in physical activity across all intensities were greatest among participants transitioning from full-time to part-time employment compared to those who remained in full-time employment throughout the study period (vigorous OR 1.41 95 % CI 1.23, 1.61; moderate OR 1.28 95 % CI 1.12, 1.46; light OR 1.29 95 % CI 1.12, 1.49). Those transitioning to unemployment were already among the least physically active at baseline, irrespective of intensity (albeit, with 95 % CIs spanning unity). Those transitioning to full-time retirement were also among the least active (e.g. vigorous OR 0.71 95 % CI 0.61, 0.81; moderate OR 0.80 95 % CI 0.71, 0.90). Declines in physical activity were reported for those transitioning to economic inactivity due to a disability (vigorous OR 0.29 95 % CI 0.14, 0.64; moderate OR 0.56 95 % CI 0.33, 0.95; light OR 0.34 95 % CI 0.19, 0.63). Physical activity increased regardless of intensity among participants transitioning to semi-retirement (p > 0.05) and full retirement (e.g. vigorous OR 1.28 95 % CI 1.09, 1.51; moderate OR 1.24 95 % CI 1.07, 1.43). Light physical activity increased for those transitioning to unemployment (OR 1.40 95 % CI 1.02, 1.93), though less change was evident in moderate or vigorous physical activity.

The amount and intensity of PA varies by the type of transition out of full-time employment among people in middle-to-older age.

Does physical Activity improve Borderline Ankle-Brachial Index Values in a Cardiovascular Risk Population?

Peripheral arterial disease (PAD) is an underdiagnosed and undertreated disease because it remains asymptomatic for so long. The ankle-brachial index (ABI) is a valid method for detecting PAD in lower extremities. ABI ≤0.90 indicates incident PAD. Recent studies have found that subjects with borderline ABI values (0.91-1.00) have increased mortality rates. The objective of our 7-year follow-up study was to investigate the progression of PAD in borderline ABI subjects, who underwent a multifactorial cardiovascular intervention. A total of 193 subjects with borderline ABI were examined in 2005-2006. None of them had previously diagnosed diabetes, cardiovascular or renal disease or intermittent claudication. They were given conventional treatment for multiple risk factors of cardiovascular diseases (hypertension, hypercholesterolemia, elevated blood glucose, smoking, and overweight). Sixty-four percent of these subjects (n = 123) attended a follow-up visit in 2012. Of the 123 subjects with borderline ABI (mean age 59.0 ± 6.5 years, 62% female) at baseline, 18 (15%, 95% confidence intervals [CI]: 9%-22%) developed incident PAD during the follow-up. The mean ABI was 0.97 ± 0.03 at baseline and 1.01 ± 0.12 at 7-year follow-up visit. The change in mean ABI was +0.04 (95% CI: 0.03-0.07), P < 0.001. ABI improved significantly in 25 (20%) subjects. In multivariate ordered logistic regression analyses high and even moderate leisure-time physical activity (LTPA; odds ratio 6.15; 95% CI: 1.99-19.1) predicted a rise in ABI in comparison to low LTPA.

Physical activity seems to improve significantly ABI values among men and women with borderline ABI (0.91-1.00).

Automated perimetry and malingerers. Can the Humphrey be outwitted?

Through detailed strategies and sophisticated analysis, the Humphrey automated visual field analyzer attempts to indicate if visual field loss is artefactual. Can these measures be outwitted by malingerers? The author investigated the ease with which motivated individuals (such as are malingerers) could simulate visual field defects consistent with organic neurologic disease on the Humphrey visual field analyzer. Visual field test results were analyzed for characteristic features and compared with visual field tests from patients with documented pituitary tumors. Volunteers, given only broad suggestions as to the visual field they were to simulate, produced consistent, convincing, neurologic-type field defects, according to textbook descriptions of such fields. These plotted fields were only distinguishable from genuine pituitary tumor Humphrey field tests, in that they more convincingly fitted the classic descriptions of visual fields seen with chiasmal compression.

The author concludes that single routine Humphrey visual field tests do not show malingerers. An incidental finding of this study was the extent to which Humphrey visual fields from patients with genuine neurologic disease contain field defects with characteristics different from those of the (kinetic) visual field test appearances described in the textbooks.

Mixed state discrimination: a DSM problem that won׳t go away?

DSM׳s replacement of 'mixed episodes' with 'mixed features' has ironically created a specifier, which potentially lacks specificity because it overlooks two key symptoms: psychomotor agitation and distractibility. Therefore, the present study examined the presence of psychomotor agitation and distractibility across the mood disorder spectrum. Two hundred patients were diagnosed and assigned to one of three groups (depression, bipolar spectrum disorder (BDspectrum) and bipolar disorder) based on clinical evaluation by a psychiatrist. On the basis of MDQ scores, the depression group was then further subdivided into two groups: unipolar depression (UP) and mixed depression (UPmix). These four groups were then compared to examine the relative distribution of psychomotor agitation and distractibility. Participants underwent a clinical evaluation by a psychiatrist and completed a series of questionnaires. Increased distraction, racing thoughts, and increased irritability were the most commonly reported manic symptoms amongst the unipolar depression group. Further, UPmix and BDspectrum had significantly higher psychomotor agitation and distractibility than the other two groups. The present study depended on self-report measures and did not include standardised measures of distractibility and psychomotor agitation. Future research needs to examine pure unipolar patients without any manic symptoms to clarify further how different this group would be from those with mixed features.

The present findings suggest that distractibility and psychomotor agitation may represent the core of mixed states, as they are more common in patients with mixed depression and bipolar spectrum disorder than patients diagnosed with unipolar depression and bipolar I disorder. Future research and clinical implications are discussed.

Citrate induces apoptotic cell death: a promising way to treat gastric carcinoma?

Gastric carcinoma is frequent, particularly in China, and therapy is often inefficient. Because cancer cells are partly or mainly dependent on glycolysis to generate adenosine triphosphate ATP (Warburg effect) and/or to produce precursors (of lipid, nucleotides, etc.) for building new cells, any inhibition of glycolysis may slow down the cell proliferation and/or may kill cells. The antitumor effect of citrate, an anti-glycolytic agent inhibiting phosphofructokinase (PFK) was tested on two human gastric carcinoma cell lines. Cell viability and morphology were assessed after 24-72 h exposure to citrate (5, 10, 220 mM). Apoptosis was assessed by annexin V-FITC/PI staining and Western immunobloting. A 3-day continuous exposure to citrate led to near destruction of the cell population in both cell lines, apoptotic cell death occurred through the mitochondrial pathway in a dose- and time-dependent manner, associated with the reduction of the anti-apoptotic Mcl-1 protein in both lines.

Citrate demonstrates strong cytotoxic activity against two gastric cancer lines, leading to an early diminution of expression of Mcl-1 and to massive apoptotic cell death involving the mitochondrial pathway.

Does prevalence and correlate of elder abuse and neglect in a geriatric psychiatry service?

To determine the prevalence and correlates of 4 types of elder abuse and neglect in a geriatric psychiatry service. We conducted a cross-sectional retrospective chart review of new in- and outpatients seen by the Montreal General Hospital Division of Geriatric Psychiatry in one calendar year. Abuse or neglect was suspected or confirmed in 20 (16%) of 126 patients, comprising financial abuse in 16 (13%), neglect in 7 (6%), emotional abuse in 5 (4%), physical abuse in 3 (2%), and multiple abuse in 7 (6%). On bivariate analysis, patients living with nonspouse family, friends, or other persons were significantly more likely to have suffered abuse than were those living with their spouse or in a supervised setting (OR 10.5; 95%CI, 2.3 to 47.8); widowed, divorced, or separated patients were significantly more likely to have suffered abuse than were married patients (OR 4.7; 95%CI, 1.02 to 22.0). Nonsignificant trends included female sex (OR 4.1; 95%CI, 0.89 to 18.6); alcohol abuse (OR 2.1; 95%CI, 0.71 to 6.2); behaviour problems (OR 1.9; 95%CI, 0.71 to 5.2); and chronic cognitive impairment (OR 1.4; 95%CI, 0.55 to 3.8). Although living situation with nonspouse family, friends, or others and marital status of widowed, divorced, or separated were significantly associated with abuse when examined in separate logistic regression models, both were nonsignificant when examined together, suggesting collinearity. Both were retained in the model because they probably represent different aspects of vulnerability. The final model included living situation with nonspouse family, friends, or others (OR 6.1; 95%CI, 0.75 to 49.5) and widowed, divorced, or separated marital status (OR 2.4; 95%CI, 0.21 to 26.8). Nonsignificant trends included female sex (OR 2.6; 95%CI, 0.45 to 14.4); alcohol abuse (OR 2.2; 95%CI, 0.59 to 7.9); and lowest quartile on the Global Assessment of Functioning (GAF) scale (GAF < 35; OR 2.0; 95%CI, 0.64 to 6.0).

The practical implications of our study are that elder abuse and neglect are common among patients referred to geriatric psychiatry services, that such services should have access to multidisciplinary expertise and resources to deal with abuse, and that certain situations may signal higher risk. In our setting, the situation of living with nonspouse family, friends, or other persons in a nonsupervised setting and a history of family disruption by widowhood, divorce, or separation were significant correlates of abuse. Suggestive but nonsignificant trends of potential importance (OR > or = 2.0) included female sex, alcohol abuse, and lowest quartile of functional status. Study limitations include a cross-sectional retrospective chart review design, a clinically derived sample, a small sample size, and a lack of structured instruments for several variables.

Is multiple endocrine neoplasia type 1 polymorphism D418D associated with sporadic primary hyperparathyroidism?

Sporadic primary hyperparathyroidism (pHPT) occurs separately and in several hereditary disorders including multiple endocrine neoplasia type 1. Irradiation to the neck, female gender, and age are well-identified risk factors that predispose to pHPT. The multiple endocrine neoplasia type 1 gene is the most commonly deranged gene in parathyroid adenomas and contains several polymorphisms including D418D with a prevalence of roughly 50%. We genotyped 162 pHPT patients and control participants to evaluate if the D418D polymorphism is related to development of pHPT. One hundred fourteen of the pHPT patients and control participants were recruited from a health screening and were subjected to measurement of bone mineral density (BMD) at the lumbar spine, femoral neck, and total body. The prevalence of each genotype (ie, MM, Mm, and mm) was for all pHPT patients: 62%, 29%, and 9%; and for all control participants: 32%, 43%, and 25% (P <.0004). For the screening-detected pHPT patients and control participants, the genotype distribution for MM, Mm, and mm was 60%, 30%, and 10%; and 31%, 44%, and 25%, respectively (P =.009). In the screening-recruited control participants, but not in pHPT patients, the MM genotype was also associated with higher total body BMD (P =.01) and BMD at the femoral neck (P =.02), whereas it failed to be significant for BMD at the lumbar spine (P =.08).

We report that the MM genotype was overrepresented in pHPT patients compared with control participants, suggesting a novel marker for pHPT. Furthermore, the MM genotype was associated with higher BMD at the femoral neck and in the total body in the screening-recruited control participants.

Does [ Recombinant human epithelial growth factor accelerate healing of cervical erosion ]?

To observe the effect of recombinant human epithelial growth factor (rhEGF) in promoting the healing of cervical erosion. Forty-eight patients with cervical erosion were treated with rhEGF and 30 with 500 kHz high-frequency electromagnetic wave, and the effects of the therapies were compared in terms of healing of the cervical wound, healing time, volume of vaginal discharge and bleeding and the lasting time. In comparison with radiofrequency therapy, the healing of the lesion took significantly shorter time with rhEGF therapy, which also resulted in less vaginal discharge that lasted for shorter time without causing vaginal bleeding.

rhEGF can obviously accelerate the healing of cervical erosion.

Are You Missing an Entropion?

Entropion is the inward turning of the eyelid. The most common type of entropion is involutional, a combination of eyelid laxity, lower eyelid retractor weakness, and orbicularis oculi override. Unfortunately, the condition can be intermittent and remain undiagnosed, leading to ocular surface damage. In suspected cases, clinicians can use provocation techniques to elicit the condition. These include the forced closure of the eyelids, the tetracaine provocation test, and the test of induced entropion (TIE). The authors present an alternative diagnostic test: the TIE-2. The TIE-2 test is performed by asking the patient to look down while the examiner holds the upper eyelid open and high to prevent downward movement. The patient is then asked to close their eyelids as tightly as possible. An entropion will then be induced. To illustrate the technique, the authors present 2 patients seen in the oculoplastics clinic with symptoms and signs suggestive of intermittent entropion, in whom conventional provocation tests were unsuccessful. In both cases, conventional methods did not provoke an entropion. However, the TIE-2 test successfully induced an entropion, leading to the correct diagnosis and appropriate management.

When there is suspicion of intermittent entropion that is not revealed with existing provocation tests, the TIE-2 is a simple and useful diagnostic tool.

Does platelet size correlate with function in patients undergoing cardiac surgery?

Platelet dysfunction secondary to cardiopulmonary bypass (CPB) is one of the major reasons for nonsurgical post-operative bleeding in cardiac surgery. Whether platelet size is an indicator for platelet function was investigated in patients undergoing coronary artery bypass grafting. Prospective study. Intra-operative, cardiac surgery operations. 80 consecutive patients undergoing coronary artery bypass grafting. Excluding criteria were pre-operative coagulation disorders and medication with anticoagulants within the last 10 days before the operation day. Platelet function was assessed by aggregometry using a turbidimetric method (inductors: ADP 2.0 mumol/l, collagen 4 micrograms/l, epinephrine 25 mumol/l). Mean platelet volume (MPV) was measured by an electrical conductivity method. Measurements were carried out before, during, and after CPB until the 1st post-operative day on intensive care unit (ICU). Platelet size decreased significantly during CPB (max. -25% after weaning from bypass) and returned to baseline values on the 1st post-operative day. Platelet count (ranging from 93 - 304 x 10(9)/l) did not correlate significantly with MPV or aggregation variables. Maximum aggregation and maximum gradient of aggregation induced by ADP and collagen were significantly decreased by CPB with the most pronounced reduction at the end of CPB (ranging from -25% to -45%). Analyses of co-variance revealed a significant correlation between changes in MPV and changes in aggregation variables (ADP, collagen).

Platelet volume is easy to measure even in the operation room or in ICU and may indicate abnormalities in platelet function in the post-bypass period of cardiac surgery patients.

Do bone marrow micrometastases correlate with sentinel lymph node metastases in breast cancer patients?

Sentinel lymph node biopsies (SLNB) are used to detect axillary metastases as an important prognostic indicator for breast cancer patients. Bone marrow micrometastases (BMM) have also been shown to predict prognosis. This study examines whether SLNB and BMM are associated. A retrospective analysis was performed on 124 stages I to III breast cancer patients treated with mastectomy or lumpectomy, SLNB, and bone marrow aspiration between 1997 and 2003. SLNB were examined for the presence of metastases by hematoxylin and eosin (H&E) stains and also by immunohistochemistry (IHC) for lymph nodes negative by H&E. The kappa statistic was used to evaluate the association (agreement) between SLNB and BMM. In this study population, 36 patients (29%) had micrometastases detected in their bone marrow, and 51 patients (41%) had positive sentinel lymph nodes. Of the patients with positive BMM (n = 36), 53% (19 of 36) had positive SLNB (14 of 19 by H&E and 5 of 19 by IHC). In patients with negative BMM (n = 88), 36% (32 of 88) had a positive SLNB (27 of 32 by H&E and 5 of 32 by IHC). The kappa statistic and associated 95% confidence interval indicated poor agreement between SLNB and BMM (kappa = 0.15; 95% CI = -0.03, 0.32).

There was poor agreement between axillary metastases and micrometastases detected in the bone marrow. This study suggests that BMM and axillary metastases are not concordant findings in most patients.

Presumed consent for organ donation: is Romania prepared for it?

In November 2007, a legislative initiative regarding the presumed consent for organ donation was proposed for parliamentary debate in Romania and was followed by public debate. The study aimed to asses public opinions expressed in the Romanian media. An Internet search was made. The pro and con reasons, the affiliation of parts involved in the debate and suggested future direction of action were identified. The Internet search had 8572 results. The parts involved in the pro and con debate consisted of governmental structures, physicians, ethicists, politicians, media, religious authorities, nongovernmental associations, and lay persons. The main pros were the low rate of organ donation and the long waiting lists, enhancement of organ procurement, avoidance of wasting valuable organs, avoiding responsibility, and the stress imposed to the family in giving the donation consent, humanitarian purposes (saving lives), going along with the scientific progress, and less bureaucracy. The main cons were an unethical issue, violation of human rights, denial of brain death, unethical advantage of public ignorance, unethical use of underprivileged people, little results in terms of organ procurement, but huge negative effects on public opinion, public mistrust in transplant programs and impossibility of refusal identification due to particularities of the Romanian medical system.

The con opinions prevailed. For the moment, Romania seems to be unprepared to accept presumed consent. A future change in public perception regarding organ transplantation may modify the terms of a public debate.

Is omentum better site than kidney capsule for growth , differentiation , and vascularization of immature porcine β-cell implants in immunodeficient rats?

Rapid revascularization of islet cell implants is important for engraftment and subsequent survival and function. Development of an adequate vascular network is expected to allow adaptive growth of the β-cell mass. The present study compares omentum and kidney capsule as sites for growth and differentiation of immature β-cell grafts. Perinatal porcine islet cell grafts were implanted in omentum or under kidney capsule of nondiabetic nude rats. Implants were compared over 10 weeks for their respective growth, cellular composition, number and size of β cells, their proliferative activity, and implant blood vessel density. In both sites, the β-cell volume increased fourfold between weeks 1 and 10 reflecting a rise in β-cell number. In the omental implants, however, the cellular insulin reserves and the percent of proliferating cells were twofold higher than in kidney implants. In parallel, the blood vessel density in omental implants increased twofold, reaching a density comparable with islets in adult pig pancreas. A positive correlation was found between the percent bromodeoxyuridine-positive β cells and the vessel density.

Growth of the β-cell volume proceeds similarly in the omentum and under the kidney capsule. However, the omentum leads to higher insulin reserves and an increased pool of proliferating cells, which might be related to a more extended vascular network. Our observations support the omentum as an alternative site for immature porcine islet cells, with beneficial effects on proliferation and implant revascularization.

Does cardiac MRI improve identification of etiology of acute ischemic stroke?

An accurate subtype classification of acute ischemic stroke is important in clinical practice as it can greatly influence patient care in terms of acute management and devising secondary stroke prevention strategies. Approximately, one third of ischemic strokes are cryptogenic despite a comprehensive workup. Diagnostic workup for detecting cardioaortic sources of cerebral embolism commonly includes transthoracic echocardiography (TTE). However, TTE has a limited diagnostic power to detect some of the cardioaortic abnormalities and additional imaging modalities are often needed to accurately assess such abnormalities. We evaluated the feasibility of cardiovascular magnetic resonance (CMR) imaging to detect the cardioaortic sources of ischemic stroke. A total of 106 patients were included, of which 85 had an ischemic stroke and 21 had a transient ischemic attack (TIA). Routine diagnostic workup (RDW) included brain diffusion-weighted image MRI, telemetry, magnetic resonance angiography/CT angiography of head and neck, carotid duplex ultrasonography, laboratory studies and TTE. Patients additionally underwent CMR. Subtype assignment was performed in accordance with the Stop Stroke Study of the Trial of Org 10172 in Acute Stroke Treatment classification system by a stroke neurologist after reviewing the admission notes and diagnostic test results. A second subtype classification was assigned with an additional criterion defined based on delayed enhancement (DE)-CMR findings. Additionally, the presence of non-coronary artery disease (CAD) scarring was assessed in ischemic stroke patients and compared with the TIA patients as the control group. RDW detected cardioaortic embolism (CAE) stroke in 32 (37.6%) patients and cryptogenic stroke in 23 patients (27.1%). Addition of CMR resulted in a 26.1% reduction in the rate of cryptogenic strokes (6 patients). Furthermore, DE-CMR findings allowed for reclassification of three additional cryptogenic subtypes, resulting in a 39.1% reduction of cryptogenic stroke rate. Non-CAD scarring was detected in 13 (15.3%) stroke patients as opposed to only 1 (4.8%) TIA patient.

CMR is a valuable tool for the detection of CAE sources in patients with cryptogenic ischemic stroke and provides clinicians with a unique set of information that may substantially change the long-term management of these patients. DE-CMR also detects non-CAD scarring, which may indicate a predisposition to ischemic stroke. Further studies with larger samples and long-term follow-up are needed to further evaluate the clinical significance of our findings.

Are serum concentrations of fibroblast growth factor 21 elevated in patients with congenital or acquired lipodystrophy?

Patients with lipodystrophy (LD) suffer from loss of subcutaneous adipose tissue accompanied by dysregulation of several adipocyte-secreted factors. However, regulation of adipocyte-expressed fibroblast growth factor (FGF) 21 which acts in an insulin-mimetic, lipid-lowering, and anti-atherogenic manner has not been investigated in non-human immunodeficiency virus (HIV) LD. Circulating serum FGF21 levels were quantified in 37 patients with non-HIV LD and 37 controls matched for age, gender, and body mass index. Moreover, FGF21 plasma levels and mRNA expression were measured in LD mice and control animals. Additionally, serum FGF21 levels were assessed in 10 LD patients before and during metreleptin therapy. Median FGF21 serum concentrations were significantly higher in LD patients (381.2ng/l) as compared to the control group (231.2ng/l; p=0.023). There was an independent and positive association between circulating FGF21 and serum triglycerides (TG), as well as fibrate treatment, in multiple linear regression analysis. LD mice showed significantly upregulated FGF21 plasma levels (4.5-fold), as well as mRNA expression in various adipose tissue depots and liver as compared to controls (p<0.05). Metreleptin treatment did not significantly alter circulating FGF21 levels in human subjects.

Serum concentrations of FGF21 are elevated in patients with non-HIV LD with adipose tissue and liver being potential sources of increased production. TG and fibrate treatment are independent positive predictors of circulating FGF21.

Are tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability activated and cytotoxic?

Patients with colorectal cancer that display high-level microsatellite instability (MSI-H) appear to have a better prognosis. This may be explained by the pronounced T cell infiltrate seen in MSI-H tumours that is related to a specific antigen-driven immune response. The nature of tumour-infiltrating lymphocytes in colorectal cancers was investigated using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. Quantitative fluorescent hydrolysis probe-based reverse transcriptase-PCR assays were used to detect levels of mRNA specifying T cell markers in fresh frozen colorectal tissue from MSI-H tumours and those with little or no microsatellite instability (microsatellite stable (MSS) tumours). In addition, immunohistochemistry was performed on paraffin-embedded sections to compare expression of the same T cell markers and the activation markers granzyme B and interleukin 2 receptor alpha-subunit (IL-2Ralpha) in MSI-H and MSS tumours. MSI-H tumours contained higher ratios of CD8/CD3 mRNA copy numbers than MSS tumours (P = 0.016), confirming the cytotoxic nature of lymphocyte infiltrates in this subset of colorectal cancers. Furthermore, immunohistochemistry confirmed that MSI-H tumours contained more infiltrating lymphocytes than MSS tumours, as shown by increased expression of CD3 (P = 0.003) and CD8 (P = 0.008). Consistent with other studies, the lymphocytes in MSI-H tumours were activated as indicated by significantly higher granzyme B counts (P = 0.020) and a significantly higher level of expression of IL-2Ralpha (P = 0.017).

The results support the hypothesis that MSI-H colorectal cancers may be more immunogenic than MSS tumours.

Low uptake of prenatal screening for Down syndrome in minority ethnic groups and socially deprived groups: a reflection of women's attitudes or a failure to facilitate informed choices?

It is not known if lower uptake of prenatal screening for Down syndrome in women from minority ethnic groups and socioeconomically disadvantaged women reflects more negative attitudes towards undergoing the test or women not acting in line with their attitudes i.e. not making an informed choice. Uptake of prenatal screening, attitudes towards undergoing the test, uptake-attitude consistency, and informed choice were assessed in a prospective study of 1499 pregnant women attending two UK hospitals. Uptake was higher in white and socioeconomically advantaged women than in other women. There were no differences in attitudes towards undergoing the test; all women expressed relatively positive attitudes. Uptake-attitude consistency was higher in white and socioeconomically advantaged women than others, particularly in those with positive attitudes towards undergoing the test (76% white women with positive attitudes had the test compared with 45% South Asian women [difference 31%, 95% confidence interval (95% CI) 18-43] and 78% socioeconomically advantaged women compared with 63% more disadvantaged women (difference 15%, 95% CI 7-24)). Controlling for demographic variables, South Asian and socioeconomically disadvantaged women with positive attitudes were less likely to make an informed choice than other women [odds ratio (OR) 0.22, 95% CI 0.10-0.45 and OR 0.62, 95% CI 0.41-0.93, respectively].

Lower uptake of screening for Down syndrome in women from minority ethnic groups and socioeconomically disadvantaged women does not reflect more negative attitudes towards screening but rather lower rates of informed choice, as assessed in this study. Healthcare systems appear to facilitate informed choices in the context of prenatal screening for Down syndrome screening less well for women from minority ethnic groups and those who are socioeconomically disadvantaged than for other women.

Do cognitive patterns of brain magnetic activity correlate with hippocampal atrophy in Alzheimer's disease?

Many reports support the clinical validity of volumetric MRI measurements in Alzheimer's disease. To integrate functional brain imaging data derived from magnetoencephalography (MEG) and volumetric data in patients with Alzheimer's disease and in age matched controls. MEG data were obtained in the context of a probe-letter memory task. Volumetric measurements were obtained for lateral and mesial temporal lobe regions. As expected, Alzheimer's disease patients showed greater hippocampal atrophy than controls bilaterally. MEG derived indices of the degree of activation in left parietal and temporal lobe areas, occurring after 400 ms from stimulus onset, correlated significantly with the relative volume of lateral and mesial temporal regions. In addition, the size of the right hippocampus accounted for a significant portion of the variance in cognitive scores independently of brain activity measures.

These data support the view that there is a relation between hippocampal atrophy and the degree of neurophysiological activity in the left temporal lobe.

Does a kidney-sharing alliance have to sacrifice cold ischemic time for better HLA matching?

The Scotland-Northern Ireland Kidney Allocation Alliance was created in August 1998. The purpose was to optimize the transplant service through increased regional exchange, higher quality matched kidneys, and better organ distribution. An analysis was performed on prospectively collected data regarding retrieval and transplant activity. The degree of HLA matching, the cold ischemic time (CIT), the balance of exchange, and graft survival were analyzed for a 2-year period after the introduction of the new alliance and compared with the last year before alliance. There was a 17.7% increase in the number of transplants performed. In the 2-year period, 78% of kidneys were exported from the retrieving center compared with 55% in the prealliance year, (P<0.05, chi2). The proportion of 000 mismatched transplants and other favorable matches increased from 9.5 to 21% and from 52.5 to 61%, respectively. There was no significant difference between the CIT for the three study periods, nor between the CIT for locally used kidneys versus those exchanged within the Alliance (P>0.05, Student's t test). The largest center was a net importer of kidneys, whereas small and medium-sized centers balanced their exchange within the 2-year period. The 1-year transplant survival rate improved from 81.5% in the prealliance year to 88.4% at the end of the second year.

The introduction of a regional kidney allocation alliance has improved the degree of HLA matching and increased the exchange of organs, without a significant increase in the CIT and any detrimental effect on graft survival.

Does activation of GPR40 attenuate chronic inflammation induced impact on pancreatic β-cells health and function?

Chronic inflammation-mediated β-cell apoptosis is known to decrease β-cell mass in diabetes leading to reduced insulin secretion. Exposure to pro-inflammatory cytokines can stimulate apoptosis in pancreatic β-cells. The G protein coupled receptor 40 (GPR40) is implicated for glucose induced insulin secretion. We hypothesized that GPR40 activation can protect β-cells from inflammation-induced apoptosis and restore glucose stimulated insulin secretion. By exposing NIT1 insulinoma cells and rat islets to a cocktail of pro-inflammatory cytokines (TNFα and IL1β), we mimicked inflammatory signaling as seen by JNK and NFκB activation and increased mRNA levels of TNFα, IL1β and NOS2a. These changes were reversed by pharmacological activation of GPR40 by a specific, small molecule, CNX-011-67. Further, GPR40 activation reduced inflammation-mediated oxidative and endoplasmic reticulum (ER) stresses. Importantly, GPR40 activation decreased inflammation-induced apoptosis as measured by key markers. These impacts of GPR40 were mediated through activation of PLC, CaMKII, calcineurin and cAMP. Cell survival was also enhanced by GPR40 activation as seen from the increased phosphorylation of Akt/PKB and enhanced expression of BCL2 and PDX1 genes. Interestingly, GPR40 activation restored both, inflammation-mediated inhibition on insulin secretion and intracellular insulin content.

In this study, we provide evidences that CNX-011-67, a GPR40 agonist, reduces inflammatory signaling and apoptosis in pancreatic β-cells while promoting insulin secretion and synthesis. Activation of GPR40 leads to attenuation of β-cell dysfunction caused by chronic inflammation and thus could be of immense clinical value to improve insulin secretion and β-cell survival.

Does urokinase plasminogen activator stimulate vascular smooth muscle cell proliferation via redox-dependent pathways?

We showed previously that increased urokinase plasminogen activator (uPA) expression contributes to vascular smooth muscle cell (VSMC) proliferation and neointima formation after injury. Proliferation of cultured rat aortic VSMCs induced by uPA was inhibited by the antioxidant ebselen. Because increases in VSMC reactive oxygen species (ROS) contribute to VSMC proliferation, we hypothesized that uPA increases ROS generation by regulating expression or activity of cellular oxidases. uPA stimulated ROS production to levels equivalent to angiotensin II as measured by electron spin resonance and fluorescent redox indicators (dichlorofluorescein diacetate, lucigenin, and hydroethidine). The increase in ROS was biphasic, with the first peak at 30 minutes and the second peak at 4 hours. uPA increased expression of the NAD(P)H oxidases Nox1 and Nox4 as measured by RT-PCR and Western blot analysis. Knockdown of Nox1 and Nox4 expression with small interfering RNA showed that both isoforms (Nox1>Nox4) contributed significantly to uPA-stimulated ROS production and VSMC proliferation. Transfection of VSMCs with uPA cDNA to increase endogenous uPA expression enhanced ROS production dramatically, suggesting that autocrine uPA production may be an important mechanism for uPA-mediated VSMC events.

These data show that uPA is an autocrine VSMC growth factor that increases ROS generated by both Nox1 and Nox4 oxidases.