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Does intrauterine insemination offer an advantage to cervical cap insemination in a donor insemination program?

To compare pregnancy outcome after IUI versus cervical cap insemination in a donor insemination program. A randomized prospective clinical trial in which patients were alternately inseminated with cryopreserved human semen using either IUI or cervical cap insemination methods. The donor insemination program at Washington University School of Medicine. Forty-two women with either isolated male factor or male factor plus corrected ovulatory dysfunction using clomiphene citrate underwent 141 cycles of donor insemination. Clinical pregnancy rates (PRs) defined as a viable intrauterine gestation>12 weeks or delivered were compared between groups using the chi 2 test. Clinical PRs were significantly higher in the IUI group (16.4%) compared with the cervical cap insemination group (5.9%). The spontaneous abortion rates were similar between the IUI (1.4%) and cervical cap insemination groups (4.4%).

These findings suggest an advantage to IUI over cervical cap insemination in a donor insemination program.

Improving residents' performance on the PRITE: is there a role for peer-assisted learning?

The authors implemented a peer-assisted learning approach to prepare residents for the Psychiatry Resident-In-Training Examination (PRITE), with the goal of increasing test performance. The authors developed a PRITE review curriculum utilizing a peer-assisted learning approach. The residents were randomly assigned to teams and instructed to teach assigned topic(s). The participants' PRITE scores before and after the intervention were compared with the PRITE scores of the previous residents. PGY-2 residents achieved the highest psychiatry percentile increase, and PGY-3 residents achieved the highest psychiatry percentile in the past 7 years. PGY-4 residents' psychiatry percentile decreased, although two residents from the previous year left for a fellowship, and the program accepted one PGY-4 transfer. All of the groups' neurology percentile increased, but were not substantially different from the previous years.

Our preliminary study has shown that implementing a peer-learning strategy to prepare residents for the PRITE is feasible and may lead to promising results.

Does [ Promoter methylation and microsatellite mutation reveal the clonal relationship of multiple urothelial carcinomas with mutator phenotype ]?

The clonality of multiple urothelial carcinomas (UC) is subject to debate and affects treatment. Evidence derived from X-chromosome mosaicism and patterns of molecular alterations supports both a mono- and polyclonal relationship. In contrast to most UC, tumours with the mutator phenotype have frequent mutations in repetitive sequences (MSI) and promoter methylation. The aim of this study was to investigate the clonality of multifocal UC with MSI. We have screened 400 UC for MSI and found it to occur in 1% of bladder and 15% of upper tract UC. Of these, 9 patients, whose tumours had MSI, developed or presented with multiple UC. A total of 32 UC (occurring over 0-6 years, 2-12 TCC per patient), 2 cases of CIS and 9 normal urothelial samples were screened for MSI at 17 loci and aberrant promoter methylation at 7 genes. In 8 of 9 patients, the pattern of microsatellite mutation and promoter methylation suggested that the multiple tumours had a clonal origin. Patterns of aberrant methylation in multiple tumours were more similar than microsatellite mutations, suggesting an earlier carcinogenic timing. MSI and promoter methylation were present in macroscopically normal urothelium from these patients.

Aberrant promoter methylation occurs before microsatellite alteration in UC with mutator phenotype. The majority of recurrent UC with MSI are monoclonal in origin and macroscopically normal urothelium harbours multiple molecular abnormalities. Thus, at the time of apparently successful treatment, there is molecular evidence of residual tumour that subsequently develops into recurrent disease.

Is down-regulated CBS/H2S pathway involved in high-salt-induced hypertension in Dahl rats?

The study was designed to explore the significance of endogenous H2S in the development of high-salt-induced hypertension in rats. High-salt-induced hypertension rat model was made by feeding Dahl rat high-salt diet containing 8% NaCl for 8 weeks with SD rats as control. SBP and aorta structure in rats were observed. Endogenous H2S content and expression of cystathionine β-lyase (CBS), cystathionine γ-lyase and mercaptopyruvate sulfurtransferase in renal tissues were detected. Mechanisms for the impact of high-salt on CBS/H2S in renal tissues were studied, targeting HIF-1α pathway. The effect of H2S on RAS in serum and renal tissue of rats were tested. High-salt reduced endogenous H2S content and inhibited the expression of CBS in renal tissue in salt-sensitive Dahl rats. H2S donor, however, inhibited salt-sensitive hypertension, reversed aortic structural remodeling and inhibited activation of the RAS system in renal tissues in Dahl rats. Expression of HIF-1α was decreased but expression of PHD2 was increased in renal tissue of Dahl rats with high-salt diet, whereas they did not alter in renal tissue of SD rats with high-salt diet. Ex vivo experiment showed that inhibitor of HIF-1α degradation could rescue down-regulated CBS/H2S pathway in renal tissue of Dahl rats with high-salt. In contrast, inhibitor of HIF-1α activity decreased the CBS/H2S pathway in the renal tissue of SD rats treated with high-salt.

Down-regulated CBS/H2S pathway in renal tissues under high-salt insult might be an important pathogenesis of salt-sensitive hypertension.

Do ventral striatum reactivity to reward and recent life stress interact to predict positive affect?

Stressful life events are among the most reliable precipitants of major depressive disorder; yet, not everyone exposed to stress develops depression. It has been hypothesized that robust neural reactivity to reward and associated stable levels of positive affect (PA) may protect against major depressive disorder in the context of environmental adversity. However, little empirical data exist to confirm this postulation. Here, we test the hypothesis that individuals with relatively low ventral striatum (VS) reactivity to reward will show low PA levels in the context of recent life stress, while those with relatively high VS reactivity will be protected against these potentially depressogenic effects. Differential VS reactivity to positive feedback was assessed using blood oxygen level-dependent functional magnetic resonance imaging in a sample of 200 nonpatient young adults. Recent life stress, current depressive symptoms, and PA were assessed via self-report. Linear regression models were used to investigate the moderating effects of VS reactivity on the relationship between recent stress and state PA across participants. Recent life stress interacted with VS reactivity to predict self-reported state PA, such that higher levels of life stress were associated with lower PA for participants with relatively low, but not for those with high, VS reactivity. These effects were independent of age, gender, race/ethnicity, trait PA, and early childhood trauma.

The current results provide empirical evidence for the potentially protective role of robust reward-related neural responsiveness against reductions in PA that may occur in the wake of life stress and possibly vulnerability to depression precipitated by stressful life events.

Is caffeic acid phenyl ester in propolis a strong inhibitor of matrix metalloproteinase-9 and invasion inhibitor : isolation and identification?

Propolis has been used as a folk medicine and has several proven biological activities. Herbal remedies recommended for cancer therapies in Korea. Matrix metalloproteinase (MMP)-9-inhibitory activity of propolis has been assessed. CAPE as an acting compound was isolated and molecular structure was determined. Anti-invasion activity of CAPE was assayed using hepatocarcinoma cells. Propolis ethanol extracts showed a strong inhibitory effect of MMP-9 activity, which is known to be involved in tumor cell invasion and metastasis in a concentration-dependent manner on zymography. Assay guided fractionation led to the isolation of a caffeic acid phenyl ester (CAPE) as the compound responsible for the anti-MMP-9 activity. CAPE was obtained by reversed-phase HPLC, and its structure was elucidated by fast atom bombardment mass spectrometry and tandem mass spectrometry. The purified CAPE inhibited MMP-9 activity with the IC(50) of 1.0-2.0 nmol/l.

CAPE possesses selective antiproliferative activity toward hepatocaricoma cell line Hep3B, but not primary cultured mouse hepatocytes.

Do five common gene variants identify elevated genetic risk for coronary heart disease?

Because multiple genetic variants influence risk for coronary heart disease, we combined multiple variants that had been associated with coronary heart disease in several studies into a genetic risk score and asked whether a high genetic risk score would be significantly associated with coronary heart disease after accounting for traditional risk factors. We considered five variants that were associated with coronary heart disease in two studies and confirmed in the Atherosclerosis Risk in Communities study: rs20455 (KIF6), rs3900940 (MYH15), rs7439293 (PALLD), rs2298566 (SNX19), and rs1010 (VAMP8). We calculated a genetic risk score for each Atherosclerosis Risk in Communities study participant and estimated the hazard ratio for incident coronary heart disease of a high genetic risk score (compared with not-high) in Cox models that adjusted for traditional risk factors during a median of 13 years of follow-up. For white participants with a high genetic risk score (4% of the 9129 whites), compared with those without a high genetic risk score, the hazard ratio for incident coronary heart disease was 1.57 (95% confidence interval 1.21-2.04; P = 0.001). Internal validation using bootstrap samples estimated that a hazard ratio of 1.43 could be expected in external populations.

After adjusting for traditional risk factors, those with a high genetic risk score had a 57% increased risk of incident coronary heart disease in the Atherosclerosis Risk in Communities study.

Does insertion water exchange increase right colon adenoma and hyperplastic polyp detection rates during withdrawal?

Single site studies in male Veterans in the U.S. reported increased detection of presumptive cancer precursors (adenomas, hyperplastic polyps) in the proximal colon (cecum-splenic flexure) by water exchange. Assess the reproducibility of the observation. Analysis of secondary outcomes collected prospectively in 3 similarly designed randomized controlled trials using water exchange, water immersion and insufflation (air or carbon dioxide). detection rates of adenomas and hyperplastic polyps in proximal, transverse and right colon (cecum-ascending). 704 males (173 screening) were evaluated. In the proximal colon, WE showed increased detection of small adenomas (p=0.009) and adenomas plus hyperplastic polyps (p=0.015) (vs insufflation); increased detection of adenomas plus hyperplastic polyps of any size (p=0.045) and of small size (p=0.04) (vs water immersion). In the right colon water exchange increased detection of small adenomas (19% vs 12.1%, p=0.04) (vs insufflation); small adenomas (19% vs 12%, p=0.038), adenomas plus hyperplastic polyps of any size (25% vs 16.7%, p=0.028) and of small size (23.7% vs 14.6%, p=0.012) (vs water immersion). Water exchange significantly improved bowel cleanliness. Sedation had no impact on lesion detection.

Water exchange is a superior insertion technique for detection of adenomas and hyperplastic polyps primarily in the right colon, especially those of small size.

Can universal coverage eliminate health disparities?

Health outcome disparities in racial minorities are well documented. However, it is unknown whether such disparities exist among elderly injured patients. We hypothesized that such disparities might be reduced in the elderly owing to insurance coverage under Medicare. We investigated this issue by comparing the trauma outcomes in young and elderly patients in California. A retrospective analysis of the California Office of Statewide Health Planning and Development hospital discharge database was performed for all publicly available years from 1995 to 2008. Trauma admissions were identified by International Classification of Disease, Ninth Revision, primary diagnosis codes from 800 to 959, with certain exclusions. Multivariate analysis examined the adjusted risk of in-hospital mortality in young (<65 y) and elderly (≥65 y) patients, controlling for age, gender, injury severity as measured by the survival risk ratio, Charlson comorbidity index, insurance status, calendar year, and teaching hospital status. A total of 1,577,323 trauma patients were identified. Among the young patients, the adjusted odds ratio of death relative to non-Hispanic whites for blacks, Hispanics, Asians, and Native Americans/others was 1.2, 1.2, 0.90, and 0.78, respectively. The corresponding adjusted odds ratios of death for elderly patients were 0.78, 0.87, 0.92, and 0.61.

Young black and Hispanic trauma patients had greater mortality risks relative to non-Hispanic white patients. Interestingly, elderly black and Hispanic patients had lower mortality risks compared with non-Hispanic whites.

Does intestinal manipulation during elective aortic aneurysm surgery lead to portal endotoxaemia and mucosal barrier dysfunction?

to investigate the effect of intestinal manipulation on intestinal permeability and endotoxaemia during elective abdominal aortic aneurysm (AAA) surgery. prospective randomised controlled study. fourteen patients undergoing elective infrarenal AAA repair were randomised into either the transperitoneal (n=7) or extraperitoneal approach (n=7). Intestinal permeability was measured preoperatively (PO), and at day 1 (D1) and day 3 (D3) after surgery using the lactulose/mannitol absorption test. Portal and systemic blood samples were taken before clamping, at completion of proximal and distal anastomoses and immediately before abdominal wound closure, for endotoxin measurement using the chromogenic limulus amoebocyte lysate assay. intestinal permeability was significantly increased at D1 (0.107+/-0.04 (mean+/-S.E.M.)) in the transperitoneal group compared to the PO level (0.020+/-0.004, p<0.05) and to the extraperitoneal group at D1 (0.020+/-0.004, p<0.05) which showed no change in comparison with the PO level. No correlation was seen between increased intestinal permeability and aortic clamp time, operation time, amount of blood lost or transfused. However, a significantly higher concentration of portal endotoxin was detected intraoperatively in the transperitoneal group of patients in comparison to the extraperitoneal group (p<0.05). There was a significant positive correlation between portal endotoxaemia and intestinal permeability (r(s)=0.955 p=0.001).

an increase in intestinal permeability and a greater degree of portal endotoxaemia are observed during transperitoneal approach to the aorta. This suggests that intestinal manipulation may impair gut mucosal barrier function and contribute to the systemic inflammatory response seen in AAA surgery.

Is rituximab , Ara-C , dexamethasone and oxaliplatin ( R-ADOx ) effective for treatment of elderly patients with relapsed mantle cell lymphoma?

The management of patients with mantle cell lymphoma (MCL) not eligible for stem cell transplantation in relapse after receiving standard approaches remains challenging, and the search for active and tolerable regimens is still warranted. We have retrospectively analyzed activity of rituximab (375 mg/m(2) i.v. day 1), Ara-C (1,000 mg i.v. total twice daily on day 2) and oxaliplatin (130 mg/m(2) i.v. day 3) (R-ADOx) in 12 patients (median age 69 years) with relapsed MCL. Patients had been heavily pretreated (median 3 prior therapies, range 1-9) and had stage III/IV disease. Nine out of 12 patients responded (75 %, 4 CR, 5 PR). Median progression-free survival was 9.3 months, and overall survival has not been reached. Adverse events greater than grade II included anemia (17 %) and thrombocytopenia (33 %).

R-ADOx is active and well tolerated in heavily pretreated MCL patients.

Is individual perception of recovery related to subsequent sprint performance?

Training recovery is vital for adaptation and performance, and to avoid cumulative fatigue and symptoms associated with overtraining. The use of cold-water immersion (CWI) as a recovery strategy is common; however, the physiological and biochemical rationale behind its use remains unclear. This study aimed to assess the relationship between body temperature responses to water immersion and individual perception of recovery, with subsequent exercise performance. Twelve male rugby players participated in a 3-week cross-over trial where an intense 60 min conditioning session was followed immediately by 15 min of either 14°C CWI, 30°C warm-water immersion (WWI) or passive control (CON) recovery intervention. Postexercise body temperatures and subjective ratings of the recovery intervention were recorded and subsequently related to performance in a 5×40 m repeated sprint protocol undertaken 24 h later. CWI induced large reductions in core body temperature postimmersion (effect size (ES) range 1.05-3.21) and improved subsequent sprint performance compared to WWI (ES 1.04±0.84) and CON (ES 1.44±0.84). Both the degree of temperature decrease at 60 min postimmersion (r=0.6948; p=0.0121) and the subjective rating of the recovery intervention (r=0.5886; p=0.0441) were related to subsequent sprint performance. A very strong linear correlation was observed when these two factors were integrated (r=0.7743; p=0.0031).

A combination of physiological and psychological indices provides an improved indication of subsequent performance and suggests an important role of individual perception in enhancing training recovery.

Do conditioned locomotor stimulant effects of cocaine in rats result from interference with habituation?

Classical conditioning has been proposed to account for the hyperactivity observed in drug-free rats when placed in an environment previously paired with cocaine administration. However, an alternative explanation is that hyperactivity results from an inability of rats to habituate to the environment under the influence of cocaine. In this study, preconditioning exposure to the test environment was increased from one session (standard procedure) to seven (modified procedure) to test the "antihabituation" hypothesis. After preconditioning exposure, six conditioning sessions took place over a 10-day to 13-day period. Paired rats received 10 mg/kg cocaine i.p. prior to activity sessions and saline i.p. upon return to the colony room. Unpaired rats received saline prior to and cocaine after activity sessions. Time-off rats were withheld from the activity boxes, but were subject to all other procedures during conditioning. On the test day, all rats received saline prior to activity sessions. In the standard procedure, paired rats exhibited significantly greater activity than unpaired rats on the test day, consistent with previous reports. In the modified procedure, mean activity (all rats) decreased between the first and last preconditioning sessions. Still, the paired group exhibited greater activity than the unpaired group on the test day, suggesting that a conditioned stimulant effect developed in habituated rats. Activity in the time-off group did not significantly differ from the unpaired group demonstrating the habituation had not dissipated over this time period.

These results support the conclusion that hyperactivity observed on the test day was not a result of antihabituation effects of cocaine.

Does human serum inhibit adhesion and biofilm formation in Candida albicans?

Candida albicans can form biofilms on intravenous catheters; this process plays a key role in the pathogenesis of catheter infections. This study evaluated the effect of human serum (HS) on C. albicans biofilm formation and the expression of adhesion-related genes in vitro. A C. albicans laboratory strain (ATCC90028) and three clinical strains were grown for 24 h in RPMI 1640 supplemented with HS or RPMI 1640 alone (as a control). The growth of biofilm cells of four strains was monitored by a Live Cell Movie Analyzer, and by XTT reduction assay. The expression of the adhesion-related genes BCR1, ALS1, ALS3, HWP1 and ECE1 was analyzed by RT-PCR at three time points (60 min, 90 min, and 24 h). In the adhesion phase, C. albicans cells kept a Brownian movement in RPMI medium containing HS until a large number of germ tubes were formed. In the control group, C. albicans cells quickly adhered to the bottom of the reaction plate. Compared with RPMI 1640, medium supplemented with 3-50% HS caused a significant decrease in biofilm development (all p < 0.001). However, the presence of HS had no significant inhibitory effect on the pre-adhered biofilms (all p > 0.05). Biofilm formation was also inhibited by heat-inactivated and proteinase K pre-treated HS. The presence of 50% HS did not significantly affect the planktonic growth of C. albicans (p > 0.05). At three time points, HS inhibited expression of the ALS1 and ALS3 genes and promoted expression of the HWP1 and ECE1 genes. Significant up-regulation of BCR1 was observed only at the 90-min point.

Human serum reduces biofilm formation by inhibiting the adhesion of C. albicans cells. This response may be associated with the down-regulation of adhesion-related genes ALS1, ALS3 and BCR1. The inhibitory serum component is protease-resistant and heat stable.

Are cigarette smoking and appendectomy risk factors for extraintestinal manifestations in ulcerative colitis?

Two common factors, cigarette smoking and appendectomy, have been found to play a role in ulcerative colitis (UC). Data on their role in the development of extraintestinal manifestations (EIM) are scarce. The relationship between cigarette smoking, appendectomy, and EIM was examined in a prospective study involving 535 (M/F = 319/216) consecutive UC patients followed up for 18 yr. We considered the major EIM: seronegative spondyloarthropathy, pyoderma gangrenosum/erythema nodosum, acute anterior uveitis, and primary sclerosing cholangitis. We excluded patients with a history of EIM or those colectomized before study entry, ex-smokers, and those who started to smoke during the course of UC. In UC patients, seronegative spondyloarthropathy and dermatologic complications were found increased in smokers (p < 0.0001; p = 0.001) or in subjects with appendectomy (p = 0.0003; p = 0.02), while acute anterior uveitis and primary sclerosing cholangitis did not differ. The Kaplan-Meier analysis showed 18-yr rates for EIM of 71% in smokers and 45% in nonsmokers (log-rank test, p = 0.0001), and of 85% in patients with appendectomy and 48% in those without (p = 0.0001). Cox proportional-hazard model showed that cigarette smoking and appendectomy are independent factors promoting EIM. In smokers with appendectomy the adjusted hazard ratio (3.197, 95% CI 1.529-6.684) was higher than in patients with appendectomy alone (2.617, 95% CI 1.542-4.442) or smoking alone (1.947, 95% CI 1.317-2.879).

In UC patients, appendectomy and cigarette smoking are prognostic factors for the development of EIM. The unfavorable effect of cigarette smoking on EIM is additive to that of appendectomy.

Does early developmental assessment of children with major non-cardiac congenital anomalies predict development at the age of 5 years?

the aim of this study was to evaluate cognitive and motor development in children with major congenital anomalies and the predictability of development at age 5 years. a prospective, longitudinal follow-up study was undertaken. The Dutch version of the Bayley Scales of Infant Development - Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) - were administered at the ages of 6, 12, and 24 months. The Revised Amsterdam Children's Intelligence Test - IQ and the Movement Assessment Battery for Children - Total impairment score (TIS) were used at age 5 years. A total of 117 children participated in the study. After excluding 12 children who had a major chromosomal or syndromal abnormality, the analysis was limited to 105 children (50 females, 55 males). Seven groups of congenital anomalies were distinguished: (1) small intestinal anomalies; (2) abdominal wall defects, comprising gastroschisis and omphalocele; (3) oesophageal atresia; (4) congenital diaphragmatic hernia; (5) Hirschsprung disease; (6) anorectal malformations; and (7) miscellaneous diagnoses. Logistic regression analyses served to determine the ability of MDI and PDI to predict IQ and TIS at age 5 years. at age five, 83.7% of 104 children had an IQ of 85 or above and 16.3% an IQ of less than 85. TIS was normal in 71.3% of 87 children, while 17.2% demonstrated a borderline score and 11.5% a definite motor problem. MDI and PDI scores showed equal sensitivity to predict IQ (p=0.004 at 6 and 12mo, p=0.001 at 24mo) and TIS (p<0.001 at 6 and 12mo, p=0.002 at 24mo). MDI and PDI were positively correlated with IQ and TIS; TIS was positively correlated with IQ.

IQ scores at 5 years of age corresponded to Dutch population scores, but TIS scores differed significantly. Early development of children with major congenital anomalies is predictive of development at 5 years, which can guide individualized follow-up for this vulnerable group of children.

Is adolescent alcohol use a risk factor for adult alcohol and drug dependence : evidence from a twin design?

Early alcohol use is associated with abuse and dependence of licit and illicit substances later in life. The role of genetic and environmental factors in this association is not conclusive. In 1992, data on substance use, abuse/dependence and psychiatric disorders were collected from 8169 male twin members of the Vietnam Era Twin Registry. The interview obtained age of onset of regular drinking (one drink/month for 6 or more months). Regression analyses of twin pairs discordant for early alcohol use tested whether the association between early drinking (before age 17) and adult substance use and abuse/dependence remained after controlling for genetic factors, family environment and covariates. Twin models tested for common genetic and/or environmental influences on early drinking and adult alcohol dependence and ever use and abuse/dependence on marijuana and other drugs. Co-twin analyses suggested the association between early regular alcohol use and adult alcohol dependence, marijuana and other drug use, and marijuana and other drug abuse/dependence could not be entirely explained by common genetic and shared family environmental factors. Genetic contributions to early regular drinking were significantly correlated with those on use of marijuana (rA=0.59), use of other drugs (rA=0.64), alcohol dependence (rA=0.54) and abuse/dependence of marijuana and other drugs (rA=0.63 and 0.66). Small but significant unique environmental correlations (rE range 0.11-0.22) indicated that familial factors could not entirely explain the association between early alcohol use and later substance use, abuse and dependence.

Early regular drinking is associated with later alcohol dependence and use, abuse/dependence on drugs. The association is not entirely explained by genetic or shared family environmental factors. This suggests unique environmental factors contribute to transitions from early regular alcohol drinking to use, abuse and dependence on alcohol and other substances.

Is extensive deployment of the stented elephant trunk associated with an increased risk of spinal cord injury?

Thoracic aortic aneurysm repair with the stented elephant trunk technique seems to be associated with an increased risk of spinal cord injury. We investigated whether severe atherosclerosis of the distal landing zone or extensive deployment of the stented elephant trunk is associated with increased risk of spinal cord injury. Twenty-five patients underwent thoracic aortic aneurysm repair with the stented elephant trunk technique. The study population included 19 men and had a mean age of 73 +/- 7 years. All patients underwent a median sternotomy with cardiopulmonary bypass and selective cerebral perfusion. The elephant trunk was fixed with a Z-stent distal to the aneurysm during hypothermic circulatory arrest. Thirteen patients underwent concomitant total aortic arch replacement. Six (24%) patients had spinal cord injury. The presence of severe atherosclerosis at the distal landing zone demonstrated a tendency to increase the incidence of spinal cord injury (36% vs 9%, P = .1218). More distal deployment of the stented elephant trunk was significantly associated with increased risk of spinal cord injury (T8.0 +/- 0.6 vs T6.5 +/- 1.1, P = .0043). Univariate logistic regression analysis identified a history of abdominal aortic aneurysm repair (P = .0296) and the vertebral level of the distal landing zone (P = .0249) as significant independent risk factors for spinal cord injury, and only the latter was significant in multivariate analysis (P = .0396). The combination of a distal landing zone of T7 or greater and a history of abdominal aortic aneurysm repair was the strongest predictor for spinal cord injury (71% vs 6%, P = .0047).

Spinal cord injury after stented elephant trunk deployment might be related to occlusion of the excessive intercostal arteries or thromboembolism. Patients with a history of abdominal aortic aneurysm repair who require extensive deployment of the stented elephant trunk seem to be at a higher risk for spinal cord injury.

Does overexpression of activator of G-protein signaling 3 decrease the proliferation of esophageal squamous cell carcinoma?

Activator of G-protein Signaling 3 (AGS3, also known as GPSM1), is related to cell cycle progression. We investigated the expression of AGS3 in human esophageal squamous cell carcinoma (ESCC) and the therapeutic effect of chemotherapy drugs. Immunohistochemistry and Western blot analysis were performed for AGS3 in 85ESCC samples. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine its prognostic significance. The effect of overexpression of AGS3 on proliferation of esophageal carcinoma TE1 cells was analyzed by serum starvation. AGS3 was down regulated in ESCC as compared with the adjacent normal tissue. Low expression of AGS3 was associated with tumor grade (P=0.002), and AGS3 was negatively correlated with proliferation marker Ki-67 (P<0.01). Univariate analysis showed that AGS3 expression did have a remarkable prediction for poor prognosis (P=0.004), while in vitro, the expression of AGS3 was down regulated with release from serum starvation of TE1 cells.

This study shows that AGS3 is an important regulator of ESCC proliferation.

Obesity and risk factors for the metabolic syndrome among low-income, urban, African American schoolchildren: the rule rather than the exception?

Adult obesity is associated with the metabolic syndrome; however, the prevalence of the metabolic syndrome among young children has not been reported. Clinic-based screening efforts for the metabolic syndrome in low-income neighborhoods, where obesity is prevalent, are limited by minimal health insurance coverage and inadequate access to health care. School-based obesity screening programs may effectively target high-risk populations. The objective was to describe the prevalence of overweight and features of the metabolic syndrome (defined as the presence of>or =3 of the following risk factors: HDL<or = 40 mg/dL, triacylglycerol>or = 110 mg/dL, and blood pressure or waist circumference at or above the 90th percentile) in a pilot, school-based screening program. A cross-sectional study of obesity and the metabolic syndrome was conducted in third- to sixth-grade, low-income, urban, African American children. Lipid and glucose concentrations were measured in fasting capillary finger-stick samples. Age- and sex-specific BMI percentiles were assessed in 385 students, 90 of whom were full participants in this study (participants) and 295 of whom had only height and weight measurements taken (other students). Risk factors of the metabolic syndrome were assessed in the 90 participants (23%). No significant differences in BMI percentiles were found between the participants and the other students. Overall, 44% of the participants had BMIs at or above the 85th percentile, and 59% had an elevated BMI or one metabolic syndrome risk factor. The metabolic syndrome was present in 5.6% of all participants, in 13.8% of participants with BMIs at or above the 95th percentile, and in 0% of participants with BMIs below the 95th percentile.

Most of the African American children attending 2 urban schools in low-income neighborhoods were overweight or had one or more risk factors for the metabolic syndrome. School-based screening programs in high-risk populations may provide an efficient venue for the screening of obesity and related risk factors.

Does smoke inhalation cause a delayed increase in airway blood flow to primarily uninjured lung areas?

Single lung inhalation injury causes tissue damage to the contralateral lung. We therefore examined airway blood flow after smoke inhalation in chronic instrumented sheep to get further information about the underlying pathophysiology. The right lung and lower trachea of 5 animals were smoke-exposed, while their left lung was air-insufflated using a split ventilation technique. Three animals, where both lungs were only air-insufflated, served as controls. Blood flow to the airway was measured using a labeled microsphere technique. All animals were studied for 24 h following smoke inhalation. Then they were sacrificed and their tissues harvested. The airway blood flow to the smoke-exposed lung was elevated 11-fold immediately after inhalation injury. The bronchial blood flow to the air insufflated lung became significantly elevated 24 h post-smoke, although to a lesser extent. The control animals did not show any changes of bronchial blood flow during the observation time.

Damage to one lung can lead to pathophysiologic changes in the contralateral lung. This response appears to be mediated by hematogenous factors.

Vesicoureteral reflux: can the urethra be adequately assessed by using contrast-enhanced voiding US of the bladder?

To prospectively evaluate contrast material-enhanced voiding ultrasonography (US) for assessment of the urethra by using voiding cystourethrography (VCUG) as the reference standard. This study was approved by the ethics committee on human research. Written informed consent was obtained for all patients. A total of 146 pediatric patients suspected of having vesicoureteral reflux underwent US with a galactose-based contrast agent. The bladder was instilled with contrast agent and then filled with saline. US images of the urethra were videotaped before catheterization and during voiding. VCUG was subsequently performed in all patients. In female patients, the probe (a 3.5- or 5-MHz sector array or a 7.5-MHz linear transducer) was positioned longitudinally between the labia. In male patients, the transducer was placed longitudinally on the scrotum and then displaced distally toward the penile urethra. During voiding, attention was focused on the distention of the urethral walls and on the caliber of both the posterior and anterior urethra, which were measured with calipers. Sensitivity and specificity were estimated by using a confidence interval (CI) of 95%. All female patients and 75 male patients showed a normal urethra at both US and VCUG. Posterior urethral valves (PUV) were diagnosed in three patients at voiding US and were confirmed with findings from VCUG. Urethral stenosis was diagnosed in two male patients at voiding US and was confirmed with findings from VCUG. Seven male patients who had undergone surgery for PUV were adequately evaluated with both modalities. Sensitivity of voiding US was 100% (CI 95%: 96.5%, 100%); specificity was 100% (CI 95%: 69.9%, 100%).

Voiding US is a reliable imaging modality for studying the urethra.

MR T1-weighted inversion recovery imaging in detecting brain metastases: could it replace T1-weighted spin-echo imaging?

T1-weighted inversion recovery (T1IR) imaging demonstrates higher brain tissue contrast and is more sensitive to contrast enhancement than T1-weighted spin-echo (T1SE) imaging. However, the effectiveness of the 2 imaging sequences in detecting brain metastases has not been studied. The objective of this report was to determine which sequence should be used for detecting brain metastases by comparing the effectiveness of T1IR imaging with that of T1SE imaging. Thirty-one patients with brain metastases underwent T1SE and T1IR with and without intravenous gadopentetate dimeglumine. T1SE and T1IR images were compared for the number of metastases, degree of contrast enhancement, volume and contrast-to-enhancement ratio (CER) of tumors, and contrast ratio (CR) of tumor to white matter (WM), tumor to gray matter (GM), and tumor to CSF. There were 352 metastases in 31 patients, among which 2 patients with 5 metastases were demonstrated only on postenhanced T1SE images. Pre-enhanced and postenhanced T1SE images detected 162 and 350 lesions, respectively, whereas pre-enhanced and postenhanced T1IR images only discovered 94 and 233 lesions. The degree of tumor contrast enhancement was higher on T1IR images than on T1SE images, whereas no difference in the CER of tumors was found between the 2 sequences. Before enhancement, all of the CRs on T1IR images were higher than on T1SE images. After contrast enhancement, CRs of tumor to WM and tumor to GM were higher on T1SE images than on T1IR images. On the contrary, the CR of tumor to CSF was higher on T1IR images than on T1SE images. Tumor volumes were 5.6 +/- 7.0 cm(3) on postenhanced T1SE images and 5.5 +/- 7.0 cm(3) on postenhanced T1IR images, and no significant difference was found between the 2 groups.

T1SE, but not T1IR, should be used as T1-weighted imaging in detecting brain metastases, because T1SE imaging has a greater sensitivity than T1IR imaging both before and after contrast material administration.

Are crohn 's disease and ulcerative colitis associated with elevated standardized mortality ratios : a meta-analysis?

Evidence regarding all-cause and cause-specific mortality in inflammatory bowel disease (IBD) is conflicting, and debate exists over appropriate study design to examine these important outcomes. We conducted a comprehensive meta-analysis of all-cause and cause-specific mortality in both Crohn's disease (CD) and ulcerative colitis (UC), and additionally examined various effects of study design on this outcome. A systematic search of PubMed and EMBASE was conducted to identify studies examining mortality rates relative to the general population. Pooled summary standardized mortality ratios (SMR) were calculated using random effect models. Overall, 35 original articles fulfilled the inclusion and exclusion criteria, reporting all-cause mortality SMRs varying from 0.44 to 7.14 for UC and 0.71 to 3.20 for CD. The all-cause mortality summary SMR for inception cohort and population cohort UC studies was 1.19 (95% confidence interval, 1.06-1.35). The all-cause mortality summary SMR for inception cohort and population cohort CD studies was 1.38 (95% confidence interval, 1.23-1.55). Mortality from colorectal cancer, pulmonary disease, and nonalcoholic liver disease was increased, whereas mortality from cardiovascular disease was decreased.

Patients with UC and CD have higher rates of death from all causes, colorectal-cancer, pulmonary disease, and nonalcoholic liver disease.

Does timing affect the clinical outcome of adjunctive systemic antibiotic therapy for generalized aggressive periodontitis?

Systemic antibiotics improve the outcome of scaling and root planing (SRP) in patients exhibiting severe periodontitis. This study evaluated the influence of timing of adjunctive systemic antibiotics in the sequence of periodontal therapy. Two cohorts of patients with generalized aggressive periodontitis and treated by SRP, adjunctive antibiotics, and supportive periodontal therapy (SPT) were analyzed retrospectively. Cohort A (17 patients; 36 +/- 5 years of age) received systemic amoxicillin/metronidazole immediately after SRP ("immediate"); cohort B (17 patients; 36 +/- 4 years of age) received the same regimen 3 months after SRP, following SPT, including subgingival reinstrumentation ("late"). Clinical parameters, including probing depth (PD), relative attachment level (RAL), bleeding on probing (BOP), and suppuration, were recorded with a pressure-sensitive electronic probe at baseline and 3 and 6 months after SRP. Significant time*group interactions were found for all clinical parameters except BOP, i.e., timing of antibiotic therapy affected the course of clinical changes over time. Immediate antibiotic therapy produced significantly higher initial changes (0 to 3 months) in PD and RAL. Late antibiotic therapy at 3 months resulted in additional significant improvements in all clinical parameters between 3 and 6 months. In initially deep sites (baseline PD >6 mm), improvements in PD and RAL over 6 months were significantly higher with immediate antibiotic therapy compared to late antibiotic therapy.

Within the limits of a retrospective analysis, these findings indicate that administration of amoxicillin/metronidazole immediately after initial SRP provides more PD reduction and RAL "gain" in initially deep sites than late administration at SPT with reinstrumentation after 3 months.

The levator-urethra gap measurement: a more objective means of determining levator avulsion?

Levator avulsion, a common childbirth-related traumatic abnormality of this muscle, is characterized by a widened gap between the muscle insertion and urethra. This study assessed the use of four-dimensional ultrasound imaging to measure the levator-urethra gap (LUG) in order to identify avulsion. In a retrospective study, we reviewed the records of 118 women seen for clinical assessment and imaging. Axial plane tomographic ultrasound slices were obtained at intervals of 2.5 mm. The distance between the center of the urethra and the levator insertion was measured, blinded to clinical data, and the results were analyzed with reference to the diagnosis on palpation. An interobserver agreement analysis was conducted on 20 randomly selected patients included in the study. A defect had been palpated in 19/116 women (16%) with complete datasets. LUG measurements were significantly higher in women who had been diagnosed with a levator avulsion on palpation (mean +/- SD, 27.6 +/- 6.7 mm vs. 19.7 +/- 3.4 mm; P<0.001). The interobserver intraclass correlation coefficient for LUG measurement was good (0.71; 95% CI, 0.61-0.79). Receiver-operating characteristics analysis suggested a cut-off of 25 mm, with a sensitivity of 63% and a specificity of 94%, for the diagnosis of levator avulsion injury.

The measurement of LUG is reproducible and strongly associated with levator avulsion trauma diagnosed on vaginal palpation. A cut-off of 25 mm may be used for the diagnosis of levator avulsion injury.

Antibiotic prophylaxis after uncomplicated ureteroscopic stone treatment: is there a difference?

We evaluated the risk of development of a symptomatic urinary tract infection (UTI) based on the antibiotic prophylaxis given to a patient during and after uncomplicated ureteroscopy (URS) for urolithiasis. We retrospectively reviewed the charts of patients who underwent URS, laser lithotripsy, and stent placement for the management of stones from 2004/2005 (group 1) and 2009/2010 (group 2). We excluded all patients with preoperative positive cultures, preoperative antibiotics, urinary diversion, who underwent concomitant percutaneous nephrolithotomy, or had strings attached to the stents. All patients received a first-generation intravenous cephalosporin or fluoroquinolone at the time of initial intervention and had ureteral stents placed intraoperatively. Group 1 received an oral fluoroquinolone for 1 week postoperatively. Group 2 received an oral first-generation cephalosporin antibiotic peri-stent removal only. Antibiotics were appropriately changed according to the local resistance patterns. All stents were removed within 5 to 7 days. Our primary end point was symptomatic UTI. After the exclusion criteria, group 1 had 48 patients, group 2 had 49. There was no statistical difference in the incidence of symptomatic UTI between the two groups; each group had one UTI (2% risk) (P=0.988). There were no cases of readmission, pyelonephritis, UTI, surgical reintervention, or Clostridium difficile. The UTI in group 1 was secondary to Escherichia coli and in group 2, Staphylococcus species; both were managed with oral antibiotics.

The use of oral peri-stent removal antibiotic prophylaxis is sufficient to prevent symptomatic UTIs in patients who have undergone uncomplicated URS for urolithiasis. The judicious use of antibiotics in uncomplicated cases may help lower the incidence of resistant organisms and other complications related to the widespread use of antibiotics.

Do moderate and severe obesity have large differences in health care costs?

To analyze health care use and expenditures associated with varying degrees of obesity for a nationally representative sample of individuals 54 to 69 years old. Data from the Health and Retirement Study, a nationwide biennial longitudinal survey of Americans in their 50s, were used to estimate multivariate regression models of the effect of weight class on health care use and costs. The main outcomes were total health care expenditures, the number of outpatient visits, the probability of any inpatient stay, and the number of inpatient days. The results indicated that there were large differences in obesity-related health care costs by degree of obesity. Overall, a BMI of 35 to 40 was associated with twice the increase in health care expenditures above normal weight (about a 50% increase) than a BMI of 30 to 35 (about a 25% increase); a BMI of over 40 doubled health care costs (approximately 100% higher costs above those of normal weight). There was a difference by gender in how health care use and costs changed with obesity class. The primary effect of increasing weight class on health care use appeared to be through elevated use of outpatient health care services.

Obesity imposes an increasing burden on the health care system, and that burden grows disproportionately large for the most obese segment of the U.S. population. Because the prevalence of severe obesity is increasing much faster than that of moderate obesity, average estimates of obesity effects obscure real consequences for individuals, physician practices, hospitals, and health plans.

Do [ Advanced oxidation protein products induce reactive oxygen species production in endothelial cells ]?

To investigate the effect of advanced oxidation protein products (AOPP) on production of reactive oxygen species (ROS) in endothelial cells. Human umbilical vein endothelial cell line ECV304 were stimulated with AOPP-modified bovine serum albumin (AOPP-BSA) prepared by oxidation of BSA with HOCl in vitro. ROS production in the cells was evaluated by kinetic measurement of dichlorofluoroscein (DCF) fluorescence produced by oxidation of an oxidant-sensitive dye 2,7-dichlorefluorescin (DCFH) using VICTOR 1420 multilabel counter. AOPP-BSA could induce ROS production in ECV304 cells time- and dose-dependently, and the quantity of ROS increased with the oxidation degree of BSA. Pretreatment of cells with a small-molecular-mass glutathione peroxidase mimic ebselen or NADPH oxidase inhibitor apocynin inhibited ROS production by 65% and 29% respectively.

AOPP-BSA induces ROS production in endothelial cells, partially mediated by NADPH oxidase activation.

Does epidural neostigmine produce analgesia but also sedation in women after cesarean delivery?

Intrathecal neostigmine produces analgesia but also nausea, limiting its utility. In contrast, epidural administration of neostigmine has been suggested to produce postoperative analgesia without nausea in nonpregnant patients. The purpose of this study was to examine the dose range for efficacy and side effects of epidural neostigmine in women at cesarean delivery receiving combined spinal-epidural anesthesia. After institutional approval and informed consent, 80 patients for elective cesarean delivery were given combined spinal-epidural anesthesia with 8 mg hyperbaric bupivacaine plus 10 microg fentanyl. Patients were randomized to receive either saline or 75, 150, or 300 microg neostigmine (n = 20 per group) in 10 ml saline after cord clamping. Pain, morphine consumption, and side effects were monitored for 24 h. Global pain assessment for the first 24 h was reduced from 5.4 +/- 0.2 in the saline group to 3.0-3.5 +/- 0.3 in the neostigmine groups, dose independently. Correspondingly, global satisfaction with neostigmine was also improved (P < 0.05). Nausea and morphine consumption were similar among groups. Intraoperative shivering and sedation were increased in the 300-microg neostigmine group only (P < 0.05), and postoperative sedation was increased by neostigmine in a dose-independent fashion (P < 0.05).

Epidural neostigmine produced modest analgesia in women after cesarean delivery. In contrast with previous reports, which focused primarily on nausea, these data suggest that epidural neostigmine can also produce mild sedation for several hours. These data suggest a limited role for single bolus-administration epidural neostigmine for analgesia after cesarean delivery. They also support future study of epidural neostigmine for obstetric analgesia.

Does exercise training increase myocardial perfusion in residual viable myocardium within infarct zone?

To study the effect of exercise training on the myocardial perfusion in the postinfarct myocardium. Twenty-nine patients with stable chronic myocardial infarction were randomly assigned to either a training group (N = 17) or a control group (N = 12). The training group received a 3-month exercise program. Cardiovascular MR was first performed before the training to establish a baseline, and subsequently performed once again upon conclusion of the program. Late gadolinium enhancement was used both to define the infarct and remote zones and to quantify the ratio of the residual viable myocardium (VMR) within the infarct zone. The myocardium was divided into subendocardial and subepicardial layers with equal thickness. The interval change of myocardial perfusion reserve (MPR) was computed for each zone and layer. The association between the exercise-induced perfusion change and VMR was analyzed for layers of the infarct zone. In the training group, the remote zone showed significantly increased MPR. The infarct zone showed no perfusion change in the subendocardial layer, but it demonstrated significantly increased MPR in the subepicardial layer. In the infarct zone, the change in MPR was associated with VMR.

In chronic myocardial infarction, the exercise-induced perfusion change in the infarct zone is proportional to the amount of residual viable myocardium.

Does p95HER-2 predict worse outcome in patients with HER-2-positive breast cancer?

The HER-2 receptor undergoes a proteolytic cleavage generating an NH(2)-terminally truncated fragment, p95HER-2, that is membrane-associated and tyrosine-phosphorylated. We have reported that p95HER-2, but not the full-length receptor, p185HER-2, correlated with the extent of lymph node involvement in patients with breast cancer and its expression was significantly enhanced in nodal metastatic tissue. These facts suggested an important role for p95HER-2 either as a marker or cause of metastasis and poor outcome in breast cancer. In this work, we have studied the prognostic value of p95HER-2 in breast cancer. Primary breast tumor tissues (n = 483) were from surgical resections conducted in hospitals in two different countries: the U.S. (n = 334) and Spain (n = 149). HER-2 protein forms, including p185HER-2 and p95HER-2, were examined in extracts of primary breast tumors by Western blot analysis. The levels of the two forms (high or low) were tested for association with other clinicopathologic factors and for correlation with disease-free survival. The median follow-up was 46 months. A high level of p95HER-2 in primary tumor tissue correlated with reduced 5-year disease-free survival (hazard ratio, 2.55; 95% confidence interval, 2.13-8.01; P < 0.0001). The median time for disease-free survival was 32 versus 139 months in patients with low levels of p95HER-2. In comparison, high levels of the full-length p185HER-2 did not significantly correlate with poor outcome (P > 0.1). Multivariate analysis revealed that high p95HER-2 was an independent predictor of disease-free survival (hazard ratio, 1.59; 95% confidence interval, 1.246-1.990; P = 0.0004).

p95HER-2 expression is an independent prognostic factor in breast cancer and defines a group of patients with HER-2-positive breast cancer with significantly worse outcome.

Are cOX-2 and PPARgamma expression potential markers of recurrence risk in mammary duct carcinoma in-situ?

In women with duct carcinoma in-situ (DCIS) receiving breast conservation therapy (BCT), in-breast recurrences are seen in approximately 10%, but cannot be accurately predicted using clinical and histological criteria. We performed a case-control study to identify protein markers of local recurrence risk in DCIS. Women treated for DCIS with BCT, who later developed in-breast recurrence (cases) were matched by age and year of treatment to women who remained free of recurrence (controls). A total of 69 women were included in the study, 31 cases and 38 controls. Immunohistochemical evaluation of DCIS tissue arrays was performed for estrogen receptor, progesterone receptor, HER-2/neu, cyclin D1, p53, p21, cycloxygenase-2 (COX-2) and peroxisome proliferator activated receptor gamma (PPARgamma). Two markers were significantly different between cases and controls on univariate analysis: strong COX-2 expression was associated with increased risk of recurrence, with 67% vs. 24% positivity in cases and controls p = 0.006; and nuclear expression of PPARgamma was associated with protection from recurrence with 4% vs. 27% positivity in cases and controls, p = 0.024. In a multivariate model which included size, grade, COX-2 and PPARgamma positivity, we found COX-2 positivity to be a strong independent risk factor for recurrence (OR 7.90, 95% CI 1.72-36.23)., whereas size and grade were of borderline significance. PPARgamma expression continued to demonstrate a protective trend, (OR 0.14, 95% CI 0.06-1.84).

Our findings suggest that COX-2 and PPARgamma should be investigated further as biologic markers to predict DCIS recurrence, particularly since they are also potential therapeutic targets.

Does pGC-1α expression in murine AgRP neurons regulate food intake and energy balance?

Food intake and whole-body energy homeostasis are controlled by agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons located in the arcuate nucleus of the hypothalamus. Key energy sensors, such as the AMP-activated protein kinase (AMPK) or sirtuin 1 (SIRT1), are essential in AgRP and POMC cells to ensure proper energy balance. In peripheral tissues, the transcriptional coactivator PGC-1α closely associates with these sensors to regulate cellular metabolism. The role of PGC-1α in the ARC nucleus, however, remains unknown. Using AgRP and POMC neurons specific knockout (KO) mouse models we studied the consequences of PGC-1α deletion on metabolic parameters during fed and fasted states and on ghrelin and leptin responses. We also took advantage of an immortalized AgRP cell line to assess the impact of PGC-1α modulation on fasting induced AgRP expression. PGC-1α is dispensable for POMC functions in both fed and fasted states. In stark contrast, mice carrying a specific deletion of PGC-1α in AgRP neurons display increased adiposity concomitant with significantly lower body temperature and RER values during nighttime. In addition, the absence of PGC-1α in AgRP neurons reduces food intake in the fed and fasted states and alters the response to leptin. Finally, both in vivo and in an immortalized AgRP cell line, PGC-1α modulates AgRP expression induction upon fasting.

Collectively, our results highlight a role for PGC-1α in the regulation of AgRP neuronal functions in the control of food intake and peripheral metabolism.

Does glycine ameliorate lung reperfusion injury after cold preservation in an ex vivo rat lung model?

The role of glycine has not been investigated in lung ischemia-reperfusion injury after cold preservation. Furthermore, the role of apoptosis after reperfusion following cold preservation has not been fully understood. Lewis rats were divided into three groups (n=6 each). In the GLY(-) and GLY(+) groups, isolated lungs were preserved for 15 hr at 4 degrees C after a pulmonary artery (PA) flush using our previously developed preservation solution (ET-K; extracellular-type trehalose containing Kyoto), with or without the addition of glycine (5 mM). In the Fresh group, isolated lungs were reperfused immediately after a PA flush with ET-K. They were reperfused for 60 min with an ex vivo perfusion model. Pulmonary function, oxidative stress, apoptosis, and tumor necrosis factor (TNF)-alpha expression were assessed after reperfusion. Shunt fraction and peak inspiratory pressure after reperfusion in the GLY(-) group were significantly higher than those in the GLY(+) and Fresh groups. Oxidative damage and apoptosis in the alveolar epithelial cells of the GLY(-) group, assessed by immunohistochemical staining and quantification of 8-hydroxy-2'-deoxyguanosine and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling method, were significantly higher than those of the GLY(+) and Fresh groups. There were correlations among shunt fraction, oxidative damage, and apoptosis. There was no expression of TNF-alpha messenger RNA in all groups evaluated by the reverse transcription-polymerase chain reaction.

Glycine attenuates ischemia/reperfusion injury after cold preservation by reducing oxidative damage and suppressing apoptosis independent of TNF-alpha in this model. The suppression of apoptosis might ameliorate lung function after reperfusion.

Does a comprehensive evaluation for aspiration after esophagectomy reduce the incidence of postoperative pneumonia?

This study assesses the effect of using a comprehensive swallowing evaluation before starting oral feedings on aspiration detection and pneumonia occurrence after esophagectomy. The records of all patients undergoing esophagectomy between January 1996 and June 2009 were reviewed. Multivariable logistic regression analysis assessed the effect of preoperative and operative variables on the incidence of aspiration and pneumonia. Separate analyses were performed on patients before (early era, 1996-2002) and after (later era, 2003-2009) a rigorous swallowing evaluation was used routinely before starting oral feedings. During the study period, 799 patients (379 from the early era and 420 from the later era) underwent esophagectomy; 30-day mortality was 3.5% (28 patients). Cervical anastomoses were performed in 76% of patients in the later era compared with 40% of patients in the early era. Overall, 96 (12%) patients had evidence of aspiration postoperatively, and the pneumonia incidence was 14% (113 patients). Age (odds ratio, 1.05 per year; P < .0001) and later era (odds ratio, 1.90; P = .0001) predicted aspiration in all patients in a multivariable model. In the early era, cervical anastomosis and aspiration independently predicted pneumonia. With a comprehensive swallowing evaluation in the later era, the detected incidence of aspiration increased (16% vs 7%, P < .0001), whereas the incidence of pneumonia decreased (11% vs 18%, P = .004) compared with the early era, such that neither anastomotic location nor aspiration predicted pneumonia in the later era.

Esophagectomy is often associated with occult aspiration. A comprehensive swallowing evaluation for aspiration before initiating oral feedings significantly decreases the occurrence of pneumonia.

Is diagnostic peroral video cholangioscopy an accurate diagnostic tool for patients with bile duct lesions?

We evaluated the diagnostic ability of a newly developed peroral video cholangioscopy (PVCS) in patients with pancreaticobiliary disorders. We retrospectively evaluated data from 144 patients with pancreaticobiliary disorders, collected from 5 tertiary referral centers. Endoscopic sphincterotomy (EST) or endoscopic papillary balloon dilation (EPBD) was performed before PVCS. We performed 2 types of PVCS, using a conventional therapeutic duodenoscope. If tissue samples were needed, cholangioscopy-assisted biopsy or fluoroscopy-guided biopsy was performed. PVCS was advanced into the bile duct in all cases after patients received EST (n = 134 cases), EPBD (n = 2), a combination of EST and EPBD (n = 1), or without treatment of the major papilla (n = 7). Biopsy samples were collected successfully from 112 of 120 cases in which endoscopists considered tissue sampling necessary. Endoscopic retrograde cholangiopancreatography (ERCP)/biopsy correctly identified 83 of 96 malignant lesions and 19 of 24 benign lesions (accuracy = 85.0%; sensitivity = 86.5%; specificity = 79.2%; positive predictive value = 94.3%; negative predictive value = 59.4%). Endoscopic retrograde cholangiopancreatography (ERCP)/biopsy plus PVCS correctly identified 95 of 96 malignant lesions and 23 of 24 benign lesions (accuracy = 98.3%; sensitivity = 99.0%; specificity = 95.8%; positive predictive value = 99.0%; negative predictive value = 95.8%). Procedure-related complications included pancreatitis (4 cases, 2.8%) and cholangitis (6 cases, 4.3%).

PVCS is an accurate diagnostic tool for patients with pancreaticobiliary disorders; resolution was well-defined when combined with biopsy analysis. Prospective multicenter clinical trials should evaluate the clinical utility of PVCS in diagnosis of biliary tract diseases.

Are haemorheological alterations in Behçet 's disease related to a tendency for venous thrombosis?

Behçet's disease is associated with an increased risk of thrombosis, although the prothrombotic mechanisms are unclear. Alterations in blood rheology, particularly increased erythrocyte aggregation, might play a role in the development of such thrombotic events. We measured plasma lipids, fibrinogen, haematocrit, erythrocite aggregation, erythrocyte deformability, blood viscosity, plasma viscosity and erythrocyte indexes in patients with a nonactive disease at sampling, and in a well-matched control group. The patient group comprised 42 patients with BD (21 male, 21 female aged 43+/-12 years) and the control group comprised 46 healthy volunteers (23 male, 23 female aged 45+/-13 years). Twelve of the 42 patients with BD had a previous documented history of deep vein thrombosis at least 6 months before entering the study, and the other 30 did not. Compared with controls, patients showed statistically higher fibrinogen concentrations (P=0.001), plasma viscosity (P=0.002), blood viscosity (P=0.006) and erythrocyte aggregation, both at stasis (P=0.001) and at a low shear rate (P=0.002): the other rheological parameters were not statistically significant. No differences were observed in the rheological parameters when patients with and without previous thrombotic episodes were compared.

Although patients with BD show a moderate hyperviscosity syndrome, possibly related to chronic inflammation, this does not seem to play a role in the development of thrombotic events.

Does preoperative dynamic lymphoscintigraphy predict sentinel lymph node metastasis in patients with early breast cancer?

Preoperative lymphoscintigraphy is commonly used in sentinel lymph node biopsy (SLNB) for patients with early breast cancer; however, its significance to predict SLN metastasis remains to be determined. Sixty patients were enrolled in a feasibility study of SLNB. Patients with clinically node-negative breast cancer were eligible for this study. Dynamic lymphoscintigraphy was performed before SLNB. All patients underwent SLNB followed by axillary lymph node dissection. A dual mapping procedure using isotope and dye injections was performed. SLNs were identified in 59 of 60 patients (98.3%), with a node-positive rate of 41.7% and a false-negative rate of 1.7%. No SLN was identified in 4 of 60 patients (6.7%) on preoperative lymphoscintigraphy. Interestingly, abnormal accumulation of the radiotracer close to hot spots was observed in 29 of 56 patients (51.8%). Lymph node metastases were detected in 18 of 29 patients (62.0%) with this pattern and 5 of 27 patients (18.5%) without this pattern (P < 0.05). Micrometastases were more frequently detected in node-positive patients without this pattern than in those with this pattern (80 vs. 16.7%). Diagnostic parameters of this pattern to predict SLN metastases, including micrometastases, were 62.1% for sensitivity, 81.5% for specificity, and 71.4% for accuracy.

Abnormal accumulation of the radiotracer close to radioactive spots may indicate SLN metastasis. When dynamic lymphoscintigraphy shows this pattern, surgeons should consider the presence of SLN metastasis and carefully remove additional lymph nodes surrounding radioactive lymph nodes so as not to leave metastatic SLNs behind.

Do symptom overlap between postprandial distress and epigastric pain syndromes of the Rome III dyspepsia classification?

The Rome III criteria for functional dyspepsia recognize two distinct subgroups: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). The aim of this exploratory analysis was to evaluate the Rome III criteria and the validity of the PDS/EPS subgrouping in primary care patients with upper gastrointestinal symptoms. Primary care patients with frequent upper gastrointestinal symptoms included in the Diamond study (NCT00291746) underwent esophageal endoscopy and 24-h pH-metry. Gastroesophageal reflux disease (GERD) was defined as the presence of at least one of the following: reflux esophagitis, pathological esophageal acid exposure, positive symptom association probability (SAP ≥95%) for association of symptoms with acid reflux. Functional dyspepsia was defined by the absence of GERD and peptic ulcer disease on investigation. PDS and/or EPS were diagnosed according to Rome III criteria. In total, 138 patients (41%) had upper gastrointestinal symptoms with normal endoscopy, pH-metry, and SAP results, consistent with the presence of functional dyspepsia. Of these patients, 130 (94%) met criteria for PDS and/or EPS: 13 (10%) had PDS alone, 31 (24%) had EPS alone, and 86 (66%) met criteria for both PDS and EPS.

PDS and EPS overlap in the majority of patients with functional dyspepsia. The value of dividing functional dyspepsia into the subgroups of PDS and EPS is thus questionable. A new approach to classifying functional dyspepsia is needed.

Is waist to stature ratio more strongly associated with cardiovascular risk factors than other simple anthropometric indices?

To determine which is the best anthropometric index among body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR) and waist to stature ratio (WSR) in relation to cardiovascular risk factors. A representative sample of 2895 Hong Kong Chinese aged 25 to 74 years received medical examinations in 1995 and 1996. Anthropometric indices and cardiovascular risk factors in blood were measured, and partial correlation and Receiver Operator Characteristic (ROC) curves were used in analysis. Among 11 cardiovascular risk factors in partial correlation analysis, including ties WSR had the highest r in 6 in men, and 5 in women; followed by WC with 4 in men and 6 in women. In ROC analyses of 21 risk factors and health conditions, the area under curve (AUC) of WSR was the largest for most (13 of 21) factors in men and 10 in women; followed by WHR with 14 in women but only 5 in men. The optimal WSR cutoff value was 0.48 for both men and women.

WSR is the best simple anthropometric index in predicting a wide range of cardiovascular risk factors and related health conditions. A simple message that one's waist circumference should not exceed half the stature is recommended for the public.

Is kE and EE genotypes of ICAM-1 gene K469E polymorphism associated with severe preeclampsia?

Preeclampsia (PE) is one of the most important complications of pregnancy that is associated with significant mortality and morbidity in mother and fetus. Since the etiologic factors in its development are still unclear, we aimed to examine the intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism in preeclamptic and control healthy women. Genetic polymorphism was analyzed in 192 PE and 186 healthy control women. PCR-RFLP method was used to identify K469E polymorphism. The frequency of KK, KE, and EE genotypes of ICAM-1 gene was not different between PE patients and healthy pregnant women. Whereas, the frequency of KE and EE genotypes was significantly higher in severe PE than mild PE women and control group, and the risk of severe PE was 2.4-fold higher in subjects with KE genotype (OR, 2.4 [95% CI, 1 to 5.9]; P = 0.03) and 3.3-fold higher in subjects with EE genotype (OR, 3.3 [95% CI, 1.2 to 9]; P = 0.015) compared to individuals with KK genotype.

We concluded that KE and EE genotypes of K469E polymorphism could increase risk of severe PE.

Do exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice?

'Patient-specific' induced pluripotent stem cells (iPSCs) are attractive because they can generate abundant cells without the risk of immune rejection for cell therapy. Studies have shown that iPSC-derived mesenchymal stem cells (iMSCs) possess powerful proliferation, differentiation, and therapeutic effects. Recently, most studies indicate that stem cells exert their therapeutic effect mainly through a paracrine mechanism other than transdifferentiation, and exosomes have emerged as an important paracrine factor for stem cells to reprogram injured cells. The objective of this study was to evaluate whether exosomes derived from iMSCs (iMSCs-Exo) possess the ability to attenuate limb ischemia and promote angiogenesis after transplantation into limbs of mice with femoral artery excision. Human iPSCs (iPS-S-01, C1P33, and PCKDSF001C1) were used to differentiate into iMSCs in a modified one-step method. iMSCs were characterized by flow cytometry and multipotent differentiation potential analysis. Ultrafiltration combined with a purification method was used to isolate iMSCs-Exo, and transmission electron microscopy and Western blotting were used to identify iMSCs-Exo. After establishment of mouse hind-limb ischemia with excision of femoral artery and iMSCs-Exo injection, blood perfusion was monitored at days 0, 7, 14, and 21; microvessel density in ischemic muscle was also analyzed. In vitro migration, proliferation, and tube formation experiments were used to analyze the ability of pro-angiogenesis in iMSCs-Exo, and quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay were used to identify expression levels of angiogenesis-related molecules in human umbilical vein endothelial cells (HUVECs) after being cultured with iMSCs-Exo. iPSCs were efficiently induced into iMSC- with MSC-positive and -negative surface antigens and osteogenesis, adipogenesis, and chondrogenesis differentiation potential. iMSCs-Exo with a diameter of 57 ± 11 nm and expressed CD63, CD81, and CD9. Intramuscular injection of iMSCs-Exo markedly enhanced microvessel density and blood perfusion in mouse ischemic limbs, consistent with an attenuation of ischemic injury. In addition, iMSCs-Exo could activate angiogenesis-related molecule expression and promote HUVEC migration, proliferation, and tube formation.

Implanted iMSCs-Exo was able to protect limbs from ischemic injury via the promotion of angiogenesis, which indicated that iMSCs-Exo may be a novel therapeutic approach in the treatment of ischemic diseases.

Are higher levels of cardiovascular fitness associated with better executive function and prefrontal oxygenation in younger and older women?

Many studies have suggested that physical exercise training improves cognition and more selectively executive functions. There is a growing interest to clarify the neurophysiological mechanisms that underlie this effect. The aim of the current study was to evaluate the neurophysiological changes in cerebral oxygenation associated with physical fitness level and executive functions. In this study, 22 younger and 36 older women underwent a maximal graded continuous test (i.e., [Formula: see text]O2max ) in order to classify them into a fitness group (higher vs. lower fit). All participants completed neuropsychological paper and pencil testing and a computerized Stroop task (which contained executive and non-executive conditions) in which the change in prefrontal cortex oxygenation was evaluated with near infrared spectroscopy (NIRS). Our findings revealed a Fitness × Condition interaction (p < 0.05) such that higher fit women scored better on measures of executive functions than lower fit women. In comparison to lower fit women, higher fit women had faster reaction times in the Executive condition of the computerized Stroop task. No significant effect was observed in the non-executive condition of the test and no interactions were found with age. In measures of cerebral oxygenation (ΔHbT and ΔHbO2), we found a main effect of fitness on cerebral oxygenation during the Stroop task such that only high fit women demonstrated a significant increase in the right inferior frontal gyrus.

Higher fit individuals who demonstrate better cardiorespiratory functions (as measured by [Formula: see text]O2max ) show faster reaction times and greater cerebral oxygenation in the right inferior frontal gyrus than women with lower fitness levels. The lack of interaction with age, suggests that good cardiorespiratory functions can have a positive impact on cognition, regardless of age.

Does iL-31 regulate differentiation and filaggrin expression in human organotypic skin models?

Atopic dermatitis (AD) is an inflammatory skin disease affecting 10% to 20% of children and 1% to 3% of adults in industrialized countries. Enhanced expression of IL-31 is detected in skin samples of patients with AD, but its physiological relevance is not known. We sought to determine the role of IL-31 in skin differentiation. We used human 3-dimensional organotypic skin models with either primary keratinocytes or HaCaT keratinocytes with inducible IL-31 receptor α to evaluate the effect of IL-31. The consequences were studied by using histology, the expression of markers analyzed by immunofluoresence and quantitative RT-PCR, and gene expression arrays. We observed that IL-31 interferes with keratinocyte differentiation. Gene expression analysis revealed a limited set of genes deregulated in response to IL-31, including IL20 and IL24. In HaCaT keratinocytes with inducible IL-31 receptor α, IL-31 inhibited proliferation upon induction of IL-31 receptor α by inducing cell cycle arrest. As in primary cells, IL-31-treated HaCaT cells elicited a differentiation defect in organotypic skin models, associated with reduced epidermal thickness, disturbed epidermal constitution, altered alignment of the stratum basale, and poor development of the stratum granulosum. The differentiation defect was associated with a profound repression of terminal differentiation markers, including filaggrin, an essential factor for skin barrier formation, and a reduced lipid envelope. The highly induced proinflammatory cytokines IL-20 and IL-24 were responsible for part of the effect on FLG expression and thus for terminal differentiation.

Our study suggests that IL-31 is an important regulator of keratinocyte differentiation and demonstrates a link between the presence of IL-31 in skin, as found in patients with AD, and filaggrin expression.

Are serum IL-18 levels increased in patients with untreated Graves ' ophthalmopathy?

Cytokines play an important role in autoimmune thyroid diseases, and serum levels may reflect the activity of the immune process. This is particularly interesting in Graves' ophthalmopathy, where a reliable serum activity marker is warranted. Interleukin-18 (IL-18) is a potent Th1 cytokine, known to induce interferon (IFN)-gamma and the aim of this study was to evaluate serum IL-18 levels in Graves' ophthalmopathy. Serum IL-18 was measured by ELISA in 52 patients with untreated Graves' ophthalmopathy (who all had been rendered euthyroid with antithyroid drugs), 52 healthy controls matched for sex, age, and smoking habits, and 15 euthyroid patients who had been treated for Graves' hyperthyroidism and ophthalmopathy in the past. Serum IL-18 (median values in pg/ml with range) levels did not differ between the untreated Graves' ophthalmopathy patients-226 (61-704) pg/ml, matched healthy controls-194 (17-802) pg/ml, and Graves' ophthalmopathy patients treated in the past-146 (0-608) pg/ml. No correlation was observed between serum IL-18 levels and thyroid function or antithyroid antibodies. There was no correlation between serum IL-18 levels and smoking habits.

We conclude that Graves' ophthalmopathy does not affect serum IL-18.

Does knockdown of MADD and c-FLIP overcome resistance to TRAIL-induced apoptosis in ovarian cancer cells?

The clinical utility of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the treatment of established human malignancies is limited by the development of resistance to TRAIL. We hypothesized that knockdown of map-kinase activating death domain containing protein (MADD), a TRAIL-resistance factor, may overcome TRAIL resistance in ovarian cancer cells. MADD expression in resected ovarian cancer specimens and cell lines was quantified with the use of polymerase chain reaction. Sensitivity of ovarian cancer cell lines to TRAIL, with or without MADD knockdown, was assessed. MADD is expressed at relatively higher levels in human malignant ovarian cancer tissues and cell lines, compared with normal ovarian tissues. The cell lines OVCA429 and OVCAR3 were susceptible, and cell lines CAOV-3 and SKOV-3 were resistant to TRAIL. MADD knockdown in CAOV-3 cells, but not in SKOV-3 cells, conferred TRAIL sensitivity. Knockdown of cellular Fas-associated death domain-like interleukin-1 beta-converting enzyme-inhibitory protein (c-FLIP) in SKOV-3 cells increased spontaneous and TRAIL-induced apoptosis, which was further increased on MADD knockdown.

MADD/c-FLIP(L) knockdown can render TRAIL-resistant ovarian cancer cells susceptible to TRAIL.

Does dobutamine stress test unmask cardiac sympathetic denervation in Parkinson 's disease?

Cardiac uptake of [(123)I]metaiodobenzyl guanidine (MIBG) is reduced in patients with Parkinson's disease (PD). However, the cardiac sympathetic abnormality associated with this reduction is unclear. To unmask this abnormality in PD patients we examined the functional consequences of cardiac beta-receptor activation. Cardiovascular responses to stepwise administration of the beta1-receptor agonist, dobutamine (DOB), were assessed in 25 PD patients and 12 age-matched controls. Changes in blood pressure were compared to determine the optimal dose at which to detect denervation supersensitivity, and cardiac contractility was measured by DOB echocardiography, based on peak aortic flow velocity. The relations of these cardiovascular responses to the ratio of MIBG uptake into the heart vs. that into the mediastinum (H/M ratio) were analyzed. At 4 microg/kg/min DOB, systolic blood pressure increased more in PD patients than in controls (PD, 17.5+/-12.3 mm Hg; control, 7.2+/-6.2 mm Hg, p<0.01), suggesting the presence of denervation supersensitivity. At this DOB dose cardiac contractility also increased more in PD than in controls (PD, 39.0+/-15.7%; control, 23.5+/-5.2%, p<0.005) and this hyperdynamic response was significantly correlated with reduced H/M ratios (early: r=-0.63, p<0.01, delayed: r=-0.66, p<0.01).

Low-dose DOB unmasks cardiac sympathetic denervation in PD patients, and decreased MIBG uptake indicates the presence of denervation supersensitivity within the heart, resulting in hyperdynamic cardiac contractility in response to a beta 1-stress condition.

Does malvidin protect WI-38 Human Fibroblast Cells Against Stress-induced Premature Senescence?

Malvidin is one of the most abundant components in red wines and black rice. The effects of malvidin on aging and lifespan under oxidative stress have not been fully understood. This study focused on the anti-aging effect of malvidin on stress-induced premature senescence (SIPS) in WI-38 human lung-derived diploid fibroblasts. In order to determine the viability of WI-38 cells, MTT assay was conducted, and malondialdehyde level was determined using thiobarbituric acid-reactive substance assay. Protein expression of inflammation-related factors was also evaluated by Western blot analysis. Acute and chronic oxidative stress via hydrogen peroxide (H2O2) treatment led to SIPS in WI-38 cells, which showed decreased cell viability, increased lipid peroxidation, and a shortened lifespan in comparison with non-H2O2-treated WI-38 cells. However, malvidin treatment significantly attenuated H2O2-induced oxidative stress by inhibiting lipid peroxidation and increasing cell viability. Furthermore, the lifespan of WI-38 cells was prolonged by malvidin treatment. In addition, malvidin downregulated the expression of oxidative stress-related proteins, including NF-κB, COX-2, and inducible nitric oxide synthase. Furthermore, protein expression levels of p53, p21, and Bax were also regulated by malvidin treatment in WI-38 cells undergoing SIPS.

Malvidin may potentially inhibit the aging process by controlling oxidative stress.

Are changes in serum lipids , independent of weight , associated with changes in symptoms during long-term clozapine treatment?

Investigators have reported that weight gain attributed to clozapine is associated with its clinical response. However, weight gain is a nonspecific physiological variable that, in itself, does not explain the mechanism underlying this relation. Alternatively, other biological variables that are often associated with weight gain, such as serum lipids, may assist in explaining this observation. The primary objective of this study was to determine whether an increase in serum lipids is associated with improvement in schizophrenia symptoms during steady state treatment with clozapine. The data for this study represent a subset of data from a randomized, double-blinded trial that evaluated subjects with schizophrenia who demonstrated a poor treatment response to clozapine. While continuing their clozapine therapy, subjects were randomly assigned to receive either risperidone 3 mg daily or placebo for 8 weeks. This course of treatment was followed by an optional (open-label) 18 weeks of augmentation with risperidone. In the present study, we included all subjects from the previously reported trial who had fasting lipid analyses and Positive and Negative Syndrome Scale (PANSS) scores from days 7 and 63 (n = 55). For the primary analyses, we used multiple regression to examine the association between serum lipid concentrations and PANSS scores, after controlling for weight. The analyses showed that the change in serum lipid concentration predicted change in symptoms over that of change in weight. Specifically, an increase in serum triglyceride concentration was associated with a decrease in the total PANSS score (p = 0.037). In addition, an increase in either serum total cholesterol concentration (p = 0.007), serum triglyceride concentration (p = 0.017) or their combined effect (p = 0.010) was associated with a decrease in PANSS negative subscale scores.

Elevation of serum lipids is associated with an improvement in schizophrenia symptoms in subjects treated with clozapine. Although the mechanism is unclear, serum lipids may play a role in influencing clozapine's therapeutic activity.

Does the Omega-3 Polyunsaturated Fatty Acid Docosahexaenoic Acid ( DHA ) reverse Corticosterone-Induced Changes in Cortical Neurons?

Chronic exposure to the glucocorticoid hormone corticosterone exerts cellular stress-induced toxic effects that have been associated with neurodegenerative and psychiatric disorders. Docosahexaenoic acid is a polyunsaturated fatty acid that has been shown to be of benefit in stress-related disorders, putatively through protective action in neurons. We investigated the protective effect of docosahexaenoic acid against glucocorticoid hormone corticosterone-induced cellular changes in cortical cell cultures containing both astrocytes and neurons. We found that glucocorticoid hormone corticosterone (100, 150, 200 μM) at different time points (48 and 72 hours) induced a dose- and time-dependent reduction in cellular viability as assessed by methyl thiazolyl tetrazolium. Moreover, glucocorticoid hormone corticosterone (200 μM, 72 hours) decreased the percentage composition of neurons while increasing the percentage of astrocytes as assessed by βIII-tubulin and glial fibrillary acidic protein immunostaining, respectively. In contrast, docosahexaenoic acid treatment (6 μM) increased docosahexaenoic acid content and attenuated glucocorticoid hormone corticosterone (200 μM)-induced cell death (72 hours) in cortical cultures. This translates into a capacity for docosahexaenoic acid to prevent neuronal death as well as astrocyte overgrowth following chronic exposure to glucocorticoid hormone corticosterone. Furthermore, docosahexaenoic acid (6 μM) reversed glucocorticoid hormone corticosterone-induced neuronal apoptosis as assessed by terminal deoxynucleotidyl transferase-mediated nick-end labeling and attenuated glucocorticoid hormone corticosterone-induced reductions in brain derived neurotrophic factor mRNA expression in these cultures. Finally, docosahexaenoic acid inhibited glucocorticoid hormone corticosterone-induced downregulation of glucocorticoid receptor expression on βIII- tubulin-positive neurons.

This work supports the view that docosahexaenoic acid may be beneficial in ameliorating stress-related cellular changes in the brain and may be of value in psychiatric disorders.

Is visual Assessment of Chest CT Images Independently Useful for Genetic Association Analysis in Studies of Chronic Obstructive Pulmonary Disease?

Automated analysis of computed tomographic (CT) lung images for epidemiologic nand genetic association studies is increasingly common, but little is known about the utility of visual versus semi-automated emphysema and airway assessments for genetic association studies. Assess the relative utility of visual versus semi-automated emphysema and airway assessments for genetic association studies. A standardized inspection protocol was used to visually assess chest CTs for 1540 non-Hispanic white subjects within the COPDGene Study for the presence and severity of radiographic features representing airway wall thickness and emphysema. A genome-wide association study (GWAS) was performed, and two sets of candidate SNPs with a higher prior likelihood of association were specified a priori for separate analysis. For each visual CT exam feature, a corresponding semi-automated CT feature(s) was identified for comparison in the same subjects. GWAS for visual features of chest CT scans identified a genome-wide significant association with visual emphysema at the 15q25 locus (p=6.3e-9). In the a priori specified set of 19 previously identified GWAS loci, seven and eight loci were associated with airway measures or emphysema measures, respectively. In the a priori specified candidate gene set, 13 out of 196 candidate genes harbored a nearby SNP significantly associated with an emphysema phenotype. Visual CT exam associations were robust to adjustment for semi-automated correlates in many cases.

Standardized visual assessments of emphysema and airway disease are significantly associated with genetic loci previously associated with COPD susceptibility or semiautomated CT exam phenotypes in GWAS. Visual CT measures of emphysema and airways disease offer independent information for genetic association studies in relation to standard semi-automated measures.

Outcomes of patients with healthcare-associated pneumonia: worse disease or sicker patients?

Healthcare-associated pneumonia (HCAP) is an entity distinct from community-acquired pneumonia (CAP). HCAP has a higher case-fatality rate, due either to HCAP organisms or to the health status of HCAP patients. The contribution of HCAP criteria to case-fatality rate is unknown. We conducted a retrospective review of adult patients admitted with a diagnosis of pneumonia from July 2007 through November 2011 to 491 US hospitals. HCAP was defined as having at least 1 of the following: prior hospitalization within 90 days, hemodialysis, admission from a skilled nursing facility, or immune suppression. We compared characteristics of patients with CAP and patients with HCAP and explored the contribution of HCAP criteria to case-fatality rate in a hierarchical generalized linear model. Of 436,483 patients hospitalized with pneumonia, 149,963 (34.4%) had HCAP. Compared to CAP patients, HCAP patients were older, had more comorbidities, and were more likely to require intensive care unit (ICU) care. In-hospital case-fatality rate was higher among patients with HCAP, compared to those with CAP (11.1% vs 5.1%, P<.001). After adjustment for demographics, comorbidities, presence of other infections, early ICU admission, chronic and acute medications, early tests and therapies, and length of stay, HCAP remained associated with increased case-fatality rate (odds ratio [OR], 1.35 [95% confidence interval (CI), 1.32-1.39]); odds of death increased for each additional HCAP criterion (OR [95% CI]: 1 criterion, 1.27 [1.23-1.31], 2 criteria, 1.55 [1.49-1.62], and 3 or more criteria, 1.88 [1.72-2.06]).

After adjustment for differences in patient characteristics, HCAP was associated with greater case-fatality rate than CAP. This difference may be due to HCAP organisms or to HCAP criteria themselves.

Are a Formin Homology protein and a profilin required for cytokinesis and Arp2/3-independent assembly of cortical microfilaments in C. elegans?

F-actin is enriched at the cortex of embryonic cells in the nematode Caenorhabditis elegans and is required for multiple processes that include the establishment of an anterior-posterior (A-P) axis and cytokinesis. However, the mechanisms that regulate cortical microfilament (MF) assembly remain poorly understood. We show here that a profilin called PFN-1 accumulates at the cortex independent of the actin cytoskeleton and is required for the assembly or maintenance of cortical MFs and myosin. Reducing PFN-1 levels by RNAi results in cytokinesis and A-P polarity defects. PFN-1 binds to the Formin Homology (FH) protein CYK-1, which also is required for cortical MFs. In contrast to PFN-1 and CYK-1, the Arp2/3 complex appears to be dispensable for the assembly of cortical MFs, for A-P polarity, and for cytokinesis. Instead, the Arp2/3 complex is required for cell migrations that occur during gastrulation and may also be involved in cellular rearrangements required for epidermal enclosure prior to elongation of ovoid embryos into vermiform larvae.

We conclude that the FH protein CYK-1 and the profilin PFN-1 mediate the Arp2/3-independent assembly of MFs and are required for cytokinesis in the early embryo. These data suggest that CYK-1 and PFN-1 may nucleate MFs, as has recently been shown for an FH protein and a profilin in yeast.

Does heat shock protein suppress the senescent lung cytokine response to acute endotoxemia?

Previous reports demonstrate that heat shock protein (HSP) can alter the pulmonary inflammatory cascade. We wished to determine if this mechanism is active in the senescent mouse. A dose-response and time-response curve for sodium arsenite (SA) induction of HSP was constructed. Eight 25-month-old B6C3F1 mice were given either 1, 2, 4, or 6 mg/kg SA. At 4 hours, the lungs were harvested and assayed for HSP by Western blot. Next, 8 mice were given 4 mg/kg SA and the lungs harvested at either 1, 2, 4, or 6 hours after injection and assayed for HSP. Next, 12 mice were prepared: Half received 4 mg/kg SA and 4 hours later, all received 0.5 mg/kg lipopolysaccharide (LPS). After 4 hours, lungs were harvested and Interleukin-1beta mRNA was assayed by Northern blot and semi-quantified by densitometry. The optimum SA dose was determined to be 4 mg/kg. The maximum HSP production was at 4 hours. Mice receiving LPS only showed a marked increase (3-fold) in IL-1 message compared with the mice pretreated with SA.

These data suggest that in the senescent as in the mature mouse lung, HSP downregulates the inflammatory cascade in response to LPS.

Is the pancreas affected in patients with septic shock?

Hyperamylasemia can be observed anecdotally during the course of severe sepsis or septic shock. This study aimed to investigate the possibility of pancreatic involvement in patients with septic shock using serum pancreatic enzyme determinations and imaging techniques in 21 consecutive patients with septic shock and 21 healthy subjects as controls. The serum activity of pancreatic amylase and lipase was assayed initially in all subjects and 24 and 48 hours after the initial observation in the 21 patients with septic shock. All patients also underwent radiological examination to detect pancreatic abnormalities. The serum activity of pancreatic amylase was significantly higher in the 21 patients with septic shock than in the 21 control subjects during the study period, while the serum activity of lipase was similar to that of the control subjects. Amylase and lipase serum activity did not significantly changed throughout the study period in the 21 patients with septic shock. None of the patients with pancreatic hyperenzymemia had clinical signs or morphological alterations compatible with acute pancreatitis.

The presence of pancreatic hyperenzymemia in septic shock patients is not a biochemical manifestation of acute pancreatic damage, and the management of these patients should be dependent on the clinical situation and not merely the biochemical results.

Does exposure to gold nanoparticles produce cardiac tissue damage that depends on the size and duration of exposure?

Current research focuses on cancer therapy, diagnostics and imaging, although many challenges still need to be solved. However, for the application of gold nanoparticles (GNPs) in therapy and diagnostics it is necessary to know the bioaccumulation and local or systemic toxicity associated to them. The aim of the present study was to investigate the effects of intraperitoneal administration of GNPs on the histological alterations of the heart tissue of rats in an attempt to cover and understand the toxicity and the potential role of GNPs in the therapeutic and diagnostic applications. Animals were randomly divided into 3 GNPs-treated rats groups and one control group (CG). The 10, 20 and 50 nm GNPs were administered intraperitonealy at the rate of 3 or 7 days as follows: Group 1: received infusion of 100 μl GNPs of size 10 nm for 3 or 7 days; Group 2: received infusion of 100 μl GNPs of size 20 nm for 3 or 7 days; Group 3: received infusion of 100 μl GNPs of size 50 nm for 3 or 7 days. received no GNPs. In comparison with the respective control rats, GNPs-treated rat received 100 μl of 10 and 20 nm particles for 3 days or 7 days demonstrating congested heart muscle with prominent dilated blood vessels, scattered and extravasations of red blood cells, focus of muscle hyalinosis, disturbed muscle fascicles, dense prominent focus of inflammatory cells infiltrate by small lymphocytes and few plasma cells while GNPs-treated rat received 100 μl of 50 nm particles for 3 or 7 days demonstrating benign normal looking heart muscle with normal muscle direction and fascicles, and very few scattered small lymphocytes.

The histological alterations induced by intraperitoneal administration of GNPs were size-dependent with smaller ones induced more affects and related with time exposure of GNPs. This study suggests that interaction of GNPs with proteins and various cell types might be evaluated as part of the toxicological assessment in addition to further experiments related to tissues antioxidant enzymes, oxidative parameters, lipid peroxidation, production of free radicals and/or ROS and cytokine, histomorphologcal and ultrastrucural will be performed to cover and understand the toxicity and the potential use of GNPs as therapeutic and diagnostic tool.

Does altered neutrophil count at diagnosis of invasive meningococcal infection in children?

Invasive meningococcal infections can be devastating. Substantial endotoxemia releases mature and immature neutrophils. Endothelial margination of mature neutrophils may increase the immature-to-total neutrophil ratio (ITR). These changes have not been previously well-described in invasive meningococcal disease. Using 2001 to 2011 data from the US Multicenter Meningococcal Surveillance Study, the diagnostic sensitivity and clinical correlates of white blood cell count, absolute neutrophil count (ANC), immature neutrophil count (INC) and ITR were evaluated alone and in combination at the time of diagnosis of invasive meningococcal disease. Two hundred sixteen patients were evaluated: meningococcemia (65), meningitis (145) and other foci (6). ANC ≤1000/mm(3) or ≥10,000/mm(3) was present in 137 (63%), INC ≥500/mm(3) in 170 (79%) and ITR ≥0.20 in 139 (64%). One or more of these 3 criteria were met in 204 of the 216 (94%). Results were similar for meningococcemia and meningitis subgroups. All 13 cases with mildest disease met 1 or more of the 3 criteria. Eight children presented with ANCs <1000/mm(3): 3 of them died and a fourth required partial amputation in all 4 limbs.

Invasive meningococcal disease is characterized by striking abnormalities in ANC, INC and/or ITR. Neutropenia was associated with a poor prognosis. Notably, without INCs, 37% of cases would have been missed. Automated methods not measuring immature white blood cells should be avoided when assessing febrile children. Serious infection should be considered when counts meet any of the 3 criteria.

Do enucleation and limited pancreatic resection provide long-term cure for insulinoma in multiple endocrine neoplasia type 1?

To assess the characteristics and long-term outcome after surgery in patients with multiple endocrine neoplasia type 1 (MEN1)-associated insulinoma. Retrospective analysis of prospectively collected data of MEN1 patients with organic hyperinsulinism at a tertiary referral center. Thirteen (17%) of 74 patients with MEN1 had organic hyperinsulinism. The median age at diagnosis was 27 (range 9-48) years. In 7 patients insulinoma was the first manifestation of the syndrome. All patients had at least one pancreatic neuroendocrine neoplasm (pNEN) upon imaging, including CT, MRI or endoscopic ultrasonography. Seven patients had solitary lesions upon imaging, 4 patients had one dominant tumor with coexisting multiple small pNENs, and 2 patients had multiple lesions without dominance. Eight patients had limited resections (1 segmental resection, 7 enucleations), 4 subtotal distal pancreatectomies, and 1 patient a partial duodenopancreatectomy. There was no postoperative mortality. Six patients experienced complications, including pancreatic fistula in 5 patients. Pathological examination revealed median three (range 1-14) macro-pNENs sized between 6 and 40 mm, and a total of 14 potentially benign insulinomas were detected in the 13 patients. After median follow-up of 156 months, only 1 patient developed recurrent hyperinsulinism after initial enucleation. Twelve patients developed new pNENs in the pancreatic remnant and 4 patients underwent reoperations (3 for metastatic ZES, 1 for recurrent hyperinsulinism). One of 5 patients with an initial extended pancreatic resection developed insulin-dependent diabetes mellitus.

Enucleation and limited resection provide long-term cure for MEN1 insulinoma in patients with solitary or dominant tumors. Subtotal distal pancreatectomy should thus be preserved for patients with multiple pNENs without dominance given the risk of exocrine and endocrine pancreas insufficiency in the mostly young patients.

Are four-dimensional magnetic resonance imaging-derived ascending aortic flow eccentricity and flow compression linked to aneurysm morphology†?

The impact of specific blood flow patterns within ascending aortic and/or aortic root aneurysms on aortic morphology is unknown. We investigated the interrelation of ascending aortic flow compression/peripheralization and aneurysm morphology with respect to sinotubuar junction (STJ) definition. Thirty-one patients (aortic root/ascending aortic aneurysm >45 mm) underwent flow-sensitive 4D magnetic resonance thoracic aortic flow measurement at 3 Tesla (Siemens, Germany) at two different institutions (Freiburg, Germany, and San Francisco, CA, USA). Time-resolved image data post-processing and visualization of mid-systolic, mid-ascending aortic flow were performed using local vector fields. The Flow Compression Index (FCI) was calculated individually as a fraction of the area of high-velocity mid-systolic flow over the complete cross-sectional ascending aortic area. According to aortic aneurysm morphology, patients were grouped as (i) small root, eccentric ascending aortic aneurysm (STJ definition) and (ii) enlarged aortic root, non-eccentric ascending aortic aneurysm with diffuse root and tubular enlargement. The mean FCI over all patients was 0.47 ± 0.5 (0.37-0.99). High levels of flow compression/peripheralization (FCI <0.6) were linked to eccentric aneurysm morphology (Group A, n = 11), while low levels or absence of aortic flow compression/peripheralization (FCI >0.8) occurred more often in Group B (n = 20). The FCI was 0.48 ± 0.05 in Group A and 0.78 ± 0.14 in Group B (P < 0.001). Distribution of bicuspid aortic valve (P = 0.6) and type of valve dysfunction (P = 0.22 for aortic stenosis) was not found to be different between groups.

Irrespective of aortic valve morphology and function, ascending aortic blood flow patterns are linked to distinct patterns of ascending aortic aneurysm morphology. Implementation of quantitative local blood flow analyses might help to improve aneurysm risk stratification in the future.

Does constraint-induced movement therapy result in increased motor map area in subjects 3 to 9 months after stroke?

Constraint-induced movement therapy (CIMT) has received considerable attention as an intervention to enhance motor recovery and cortical reorganization after stroke. The present study represents the first multi-center effort to measure cortical reorganization induced by CIMT in subjects who are in the subacute stage of recovery. A total of 30 stroke subjects in the subacute phase (>3 and <9 months poststroke) were recruited and randomized into experimental (receiving CIMT immediately after baseline evaluation) and control (receiving CIMT after 4 months) groups. Each subject was evaluated using transcranial magnetic stimulation (TMS) at baseline, 2 weeks after baseline, and at 4-month follow-up (ie, after CIMT in the experimental groups and before CIMT in the control groups). The primary clinical outcome measure was the Wolf Motor Function Test. Both experimental and control groups demonstrated improved hand motor function 2 weeks after baseline. The experimental group showed significantly greater improvement in grip force after the intervention and at follow-up (P = .049). After adjusting for the baseline measures, the experimental group had an increase in the TMS motor map area compared with the control group over a 4-month period; this increase was of borderline significance (P = .053).

Among subjects who had a stroke within the previous 3 to 9 months, CIMT produced statistically significant and clinically relevant improvements in arm motor function that persisted for at least 4 months. The corresponding enlargement of TMS motor maps, similar to that found in earlier studies of chronic stroke subjects, appears to play an important role in CIMT-dependent plasticity.

Does cOOH-terminal truncated HBV X protein play key role in hepatocarcinogenesis?

X protein (HBx), a product of hepatitis B virus, has been closely associated with the development of hepatocellular carcinoma (HCC). Based on observations that the COOH-terminal truncated HBx was frequently detected in HCC, the aim of this study is to evaluate the function of COOH-terminal truncated HBx in hepatocarcinogenesis. Expression pattern of HBx was analyzed by immunohistochemistry on tissue microarray containing 194 pairs of HCCs and their matched nontumor liver tissues. MIHA and HepG2 cells transfected with full-length (X2) and COOH-terminal truncated HBx (X1) were tested for their ability to grow in soft agar and form tumors in vivo. Proliferation and apoptosis were assessed using 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt and terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling assays, respectively. To gain additional insight, the expression profile of HepG2-X2 and HepG2-X1 were compared using cDNA microarray. COOH-terminal truncated HBx was frequently detected in HCCs (79.3%, n = 111), and our in vitro and in vivo studies showed that the truncated rather than the full-length HBx could effectively transform immortalized liver cell line MIHA. Interestingly, expression profiling revealed differential expression of key genes implicated in the control of cell cycle and apoptosis.

These findings strongly suggest that the COOH-terminal truncated HBx plays a critical role in the HCC carcinogenesis via the activation of cell proliferation.

Is intravenous contrast necessary for detection of clinically significant extracolonic findings in patients undergoing CT colonography?

To determine whether intravenous contrast (IVC) is necessary for detection of extracolonic findings (ECFs) in patients undergoing CT colonography (CTC). We performed a retrospective review of CT findings in 179 cases of CTC studies performed over 18 months where both pre-contrast (NECT) and post-contrast (CECT) scans were performed in the prone and supine positions, respectively, in the same patients. All ECFs were recorded on a per patient basis and graded according to the colonography reporting and data system classification. There was no significant change in E grade for the cohort (p = 0.171) between the NECT and CECT scans. On the CECT scans, additional findings were detected in 49.1% of patients. Overall, there were 27/179 (15.1%) patients graded E3 and 18/179 (10.1%) patients graded E4 on the CECT study. Compared with the NECT study, there was a decrease of 12.9% of patients graded E3 and no change in the number of patients graded E4.

With IVC administration, additional ECFs are detected in nearly half of all patients. However, there was no increase in the number of patients with clinically significant lesions. The risk-benefit ratio of routine IVC administration for CTC in symptomatic patients thus requires further evaluation.

Are iL13RA2 gene polymorphisms associated with systemic sclerosis?

To investigate the influence of genetic variability on the phenotypic expression of systemic sclerosis (SSc), by testing possible associations between single nucleotide polymorphisms (SNP) in IL13RA1 and IL13RA2 genes and SSc in a Caucasian population. As IL13RA1 and IL13RA2 are located on the X chromosome and SSc occurs far more frequently in women than in men, only women were genotyped. The study group comprised 97 women with SSc, 36 with diffuse (dcSSc) and 61 with limited (lcSSc) cutaneous forms of disease, and 109 healthy controls. Patients and controls were Caucasian. We investigated 4 SNP in IL13RA1 and 3 in IL13RA2 by polymerase chain reaction amplifications and enzymatic digestion or primer extension reactions and denaturing high-performance liquid chromatography. We detected an association between IL13RA2 rs638376 and patients with SSc [p = 0.004, odds ratio (OR) = 1.85, confidence interval (CI) 1.22-2.74, p corr = 0.02], as well as with dcSSc in that subgroup of patients (p = 0.01, OR 2.22, 95% CI 1.27-3.89, p corr = 0.05). The IL13RA2 rs638376G allele frequency was higher in patients with SSc (51.6%) than in controls (36.4%, p = 0.003, OR 1.86, 95% CI 1.24-2.79, p corr = 0.015) and in the subgroup with dcSSc (57.6%) than in controls (36.4%, p = 0.003, OR 2.37, 95% CI 1.35-4.15, p corr = 0.015). One other IL13RA2 SNP was only associated with the dcSSc subgroup: the IL13RA2 rs5946040G allele was more common in patients with dcSSc (33.8%) than in controls (17%, p = 0.004, OR 2.5, 95% CI 1.36-4.60, p corr = 0.02).

Our data suggest that IL13RA2 gene polymorphisms may be involved in susceptibility to SSc. Further studies are under way to show that they contribute to disease.

Head trauma in children younger than 2 years: are there predictors for complications?

To determine the incidence of skull fracture (SF) and intracranial injury (ICA) among children younger than 2 years evaluated in a pediatric emergency department for head trauma; whether historical features and/or physical findings are predictive of injury type; and whether clinical criteria could allow a selective approach to radiographic imaging. Retrospective medical record review. Tertiary pediatric emergency department. Case series of 278 children aged younger than 24 months evaluated for head injury. Presence of SF and/or ICA. Diagnoses at discharge included 227 minor head injuries, 39 isolated SF, 9 ICA with SF, and 3 isolated ICA. Children younger than 12 months had the highest incidence of SF/ICA (29%) vs 4% for children aged 13 to 24 months (P<.001). Seven percent of complications from SF/ICA resulted from falls 3 ft (0.9 m) or less [corrected]. Incidence of behavioral change, loss of consciousness, emesis, and seizures did not differ significantly between those with minor head injuries and those with SF/ICA. Scalp abnormalities were more common in children with SF/ICA (P<.001). Sixty-two percent of children with isolated SF and 58% of children with ICA had no history of loss of consciousness, emesis, seizure, or behavioral change. Ninety-two percent of children with isolated SF and 75% of children with ICA had normal levels of consciousness and nonfocal neurologic examinations at diagnosis. Among children who fell 3 ft or less (0.9 m) [corrected] and had no loss of consciousness, emesis, seizure, behavioral change, or scalp abnormality, none of 31 (95% confidence interval [CI], 0-0.10) children younger than 24 months and none of 20 (95% CI, 0-0.15) children younger than 12 months had SF/ICA.

Both SF and ICA are common in children younger than 2 years evaluated for head trauma. Children younger than 12 months are at highest risk. Injuries resulted from relatively minor falls and occurred in alert, neurologically normal children. Clinical signs and symptoms were insensitive predictors of SF/ICA; however, a grouping of features (fall<or = 3 ft [0.9 m], no history of neurologic symptoms, and normal scalp physical examination results) identified a subset of children at low risk for complications.

Do endogenous and exogenous nitric oxide protect against intracoronary thrombosis and reocclusion after thrombolysis?

Nitric oxide (NO), an endothelium-derived relaxing factor, plays an important role in regulating platelet activation. We evaluated the effect of NO in a canine model of intracoronary thrombosis, thrombolysis, and reocclusion. Before thrombosis was induced, 34 anesthetized dogs were treated with a continuous intracoronary infusion of saline (n = 8); NG-nitro-L-arginine (L-NNA, n = 8), an inhibitor of NO synthetase; L-arginine (n = 7), the precursor for NO; or sodium nitroprusside (SNP, n = 11), an NO donor. Ten minutes after the infusion was begun, an electric current of 150 microA was applied to the endothelium of coronary arteries to induce thrombosis. Occlusive thrombi developed in all dogs in the saline group (38 +/- 4 minutes) and the L-NNA group (30 +/- 6 minutes), in 6 of 7 dogs in the L-arginine group (81 +/- 18 minutes), and in 6 of 11 dogs in the SNP group (102 +/- 21 minutes) (P < .01). The time to thrombus was prolonged by L-arginine (P < .05) and SNP (P < .01). After 3 hours of thrombus formation in coronary arteries, tissue plasminogen activator and heparin were administered intravenously. Thrombi were lysed in 4 (of 8) dogs in the saline group (71 +/- 8 minutes), in 4 (of 8) dogs in the L-NNA group (72 +/- 8 minutes), in 4 (of 6) dogs in the L-arginine group (50 +/- 14 minutes), and in 4 (of 6) dogs in the SNP group (49 +/- 11 minutes) (P > .05). After thrombolysis, coronary artery reocclusion developed in all reperfused dogs in the saline group (30 +/- 8 minutes) and in the L-NNA group (48 +/- 12 minutes), in 3 (of 4) reperfused dogs in the L-arginine group (123 +/- 26 minutes), and in 3 (of 4) reperfused dogs in the SNP group (128 +/- 19 minutes) (P < .01). The ex vivo platelet aggregation induced by collagen was inhibited after in vivo treatment with L-arginine or SNP.

Increasing NO production or giving an NO donor may inhibit platelet aggregation and delay intracoronary thrombus formation and reocclusion after thrombolysis.

Do alpha1,3-Galactosyltransferase gene-knockout miniature swine produce natural cytotoxic anti-Gal antibodies?

The expression of galactose alpha 1,3 galactose (Gal) in pigs has proved a barrier to xenotransplantation. Miniature swine lacking Gal (Gal pigs) have been produced by nuclear transfer/embryo transfer. The tissues of five Gal pigs of SLA dd haplotype (SLA) were tested for the presence of Gal epitopes by staining with the Griffonia simplicifolia IB4 lectin. Their sera were tested by flow cytometry for binding of IgM and IgG to peripheral blood mononuclear cells (PBMC) from wild-type (Gal) SLA-matched pigs; serum cytotoxicity was also assessed. The cellular responses of PBMC from Gal swine toward Gal SLA-matched PBMC were tested by mixed leukocyte reaction and cell-mediated lympholysis assays. None of the tissues tested showed Gal expression. Sera from all five Gal pigs manifested IgM binding to Gal pig PBMC, and sera from three showed IgG binding. In all five cases, cytotoxicity to Gal cells could be demonstrated, which was lost after treatment of the sera with dithiothreitol, indicating IgM antibody-mediated cytotoxicity. PBMC from Gal swine had no proliferative or cytolytic T-cell response toward Gal SLA-matched PBMC.

Gal pigs do not express Gal epitopes and develop anti-Gal antibodies that are cytotoxic to Gal pig cells. The absence of an in vitro cellular immune response between Gal and Gal pigs is related to their identical SLA haplotype and indicates the absence of immunogenicity of Gal in T-cell responses. The model of Gal organ transplantation into a Gal SLA-matched recipient would be a valuable large animal model in the study of accommodation or B-cell tolerance.

Does drug lead agents from methanol extract of Nigerian bee ( Apis mellifera ) propolis?

Propolis is a bee (Apis mellifera) product of plant origin with varied chemical composition depending on the ecology of the botanical origin. It has been reported in literature to possess various therapeutic effects both traditionally, clinical trial, and animal study. In the present study bioactive principle in methanol extract of Nigerian bee (A. mellifera) propolis was determined by gas chromatography-mass spectrometry (GC/MS) study. The methanol extract of Nigerian bee (A. mellifera) propolis was characterized for its chemical composition by preliminary phytochemicals screening and GC/MS analysis using standard procedures and methods. Phytochemical screening revealed the presence of flavonoids, saponins, alkaloids, tannins, cardiac glycosides, anthraquinones phlobatannins, and steroids while GC/MS chromatogram revealed nineteen peaks representing 60 different chemical compounds. The first compounds identified with less retention time (RT) (13.33s) were methyl tetradecanoate, tridecanoic acid, methyl ester, decanoic acid, methyl ester while squalene, all-trans-squalene, 2,6,10-dodecatrien-1-ol, 3,7,11-trimethyl-, (E,E)- and farnesol isomer a took longest RT (23.647s) to identify. Methyl 14-methylpentadecanoate, hexadecanoic acid methyl ester, methyl isoheptadecanoate, and methyl tridecanoate were the most concentrated constituent as revealed by there peak height (26.01%) while eicosanoic acid was the least concentrated (peak height 0.81%) constituent of Nigerian bee propolis.

The presence of these chemical principles is an indication that methanol extract of Nigeria bee propolis, if properly screened could yield a drug of pharmaceutical importance.

Personnel-itis: a myth or a pathology?

To evaluate whether medical personnel differ from the general population in obstetrical and perinatal outcomes. The participants comprised 46 physicians and 116 nurses employed at one medical center who gave birth in its maternity hospital. General medical and obstetrical data on their latest ("index") pregnancy and delivery were extracted from real-time computerized patient files. The control group included 162 women who gave birth during the same period in the same hospital. The study group had significantly more deliveries, cesarean sections, and terminations of pregnancy prior to the index pregnancy. The medical personnel conceived significantly more often with assisted reproductive technologies (ART) (18.8% vs. 8% for controls, P<0.05), and had significantly more obstetrical complications, i.e., premature contractions, gestational diabetes mellitus, preeclamptic toxemia, and 2nd/3rd trimester bleeding or chorioamnionitis (42.5% vs. 29% for controls, P<0.05). The rate of vaginal birth after cesarean delivery (VBAC) was lower in the study group (22.2% vs. 33.3% for controls, P=0.03). There was no difference in gestational age at delivery, birth weight, or adverse neonatal outcome.

Medical personnel utilized ART more frequently and had more pregnancy complications as well as a lower incidence of VBAC than non-personnel. Neonatal outcomes were similar for both groups.

Are mechano-stimulated modifications in the chloroplast antioxidant system and proteome changes associated with cold response in wheat?

Mechanical wounding can cause morphological and developmental changes in plants, which may affect the responses to abiotic stresses. However, the mechano-stimulation triggered regulation network remains elusive. Here, the mechano-stimulation was applied at two different times during the growth period of wheat before exposing the plants to cold stress (5.6 °C lower temperature than the ambient temperature, viz., 5.0 °C) at the jointing stage. Results showed that mechano-stimulation at the Zadoks growth stage 26 activated the antioxidant system, and substantially, maintained the homeostasis of reactive oxygen species. In turn, the stimulation improved the electron transport and photosynthetic rate of wheat plants exposed to cold stress at the jointing stage. Proteomic and transcriptional analyses revealed that the oxidative stress defense, ATP synthesis, and photosynthesis-related proteins and genes were similarly modulated by mechano-stimulation and the cold stress.

It was concluded that mechano-stimulated modifications of the chloroplast antioxidant system and proteome changes are related to cold tolerance in wheat. The findings might provide deeper insights into roles of reactive oxygen species in mechano-stimulated cold tolerance of photosynthetic apparatus, and be helpful to explore novel approaches to mitigate the impacts of low temperature occurring at critical developmental stages.

Do glucocorticoids increase CD4CD25 cell percentage and Foxp3 expression in patients with multiple sclerosis?

To determine whether percentages of CD4(+)CD25(high) T cells (a group of regulatory T cells, Treg) differ in patients with multiple sclerosis (MS) in relapse vs remission after glucocorticoid treatment and whether treatment for relapses changes Treg population and the expression of Foxp3, a key Treg-associated molecule. Peripheral blood mononuclear cells (PBMC) were obtained from 20 patients with MS during relapse, just before and 2 days after starting steroid treatment (i.v. methylprednisolone 1 g/day for 3 days) and then 6 weeks after treatment. CD4(+)CD25(hi) cells were analysed by using flow cytometry. Cytokines were measured by using an ELISA and Foxp3, CD3 and CD25 expression by using quantitative real-time PCR. The percentage of CD4(+)CD25(hi) cells, plasma IL-10 and Foxp3/CD3 ratio increased 48 h after methylprednisolone initiation and returned to baseline values by 6 weeks post-treatment.

Results suggest that glucocorticoids increase Treg cell functional molecules and percentages. This may be a mechanism whereby steroids expedite recovery from MS relapses.

Does time-frequency mapping of the rhythmic limb movements distinguish convulsive epileptic from psychogenic nonepileptic seizures?

A definite diagnosis of psychogenic nonepileptic seizures (PNES) usually requires in-patient video-electroencephalography (EEG) monitoring. Previous research has shown that convulsive psychogenic nonepileptic seizures (PNES) demonstrate a characteristic pattern of rhythmic movement artifact on the EEG. Herein we sought to examine the potential for time-frequency mapping of data from a movement-recording device (accelerometer) worn on the wrist as a diagnostic tool to differentiate between convulsive epileptic seizures and PNES. Time-frequency mapping was performed on accelerometer traces obtained during 56 convulsive seizure-like events from 35 patients recorded during in-patient video-EEG monitoring. Twenty-six patients had PNES, eight had epileptic seizures, and one had both seizure types. The time-frequency maps were derived from fast Fourier transformations to determine the dominant frequency for sequential 2.56-s blocks for the course of each event. The coefficient of variation (CoV) of limb movement frequency for the PNES events was less than for the epileptic seizure events (median, 17.18% vs. 52.23%; p < 0.001). A blinded review of the time-frequency maps by an epileptologist was accurate in differentiating between the event types, that is, 38 (92.7%) of 41 and 6 (75%) of 8 nonepileptic and epileptic seizures, respectively, were diagnosed correctly, with seven events classified as "nondiagnostic." Using a CoV cutoff score of 32% resulted in similar classification accuracy, with 42 (93%) of 45 PNES and 10 (91%) of 11 epileptic seizure events correctly diagnosed.

Time-frequency analysis of data from a wristband movement monitor could be utilized as a diagnostic tool to differentiate between epileptic and nonepileptic convulsive seizure-like events.

Do [ Self-care behavior and patients ' knowledge about self-care predict rehospitalization among older adults with heart failure ]?

This study examined the association of self-care behavior and patients' knowledge about self-care with rehospitalization among older adults with heart failure (HF). Case-control comparison (116 cases and 209 controls) nested in a prospective cohort of patients aged 65 years and older admitted for HF at 4 Spanish hospitals. Cases were patients experiencing a first emergency rehospitalization in the 6 months following the index hospital admission. Controls were patients who did not undergo a rehospitalization during such time-period. The number of self-care behaviors was inversely associated with the frequency of readmission (p for linear trend: 0.006). Compared with patients showing the appropriate self-care behavior, hospital readmission was more frequent among those who did no go for a walk daily or did not engage in any daily physical activity (hazard ratio [HR] 1.55; 95% confidence limits [CL] 1.04-2.29), and among those who did not keep their medical appointments (HR 1.82; 95% CL 1.10-3.02). Hospital readmission was also more frequent among patients who: failed to take their medication at the scheduled time (HR 2.07; 95% CL 1.15-3.72); stopped taking their medication when it disagreed with them (HR 1.76; 95% CL 1.08-2.85); and failed to adhere to their drug treatment (HR 1.96; 95% CL 1.29-2.98). Furthermore, the fewer the number of behaviors which patients knew to be required for self-care, the greater the frequency of rehospitalization (p for linear trend:0.029).

A lower degree of self-care and of patients' knowledge about self-care predicted a higher risk of hospital readmission.

Are femoral localization and higher ultrafiltration rate but not concentration of heparin used for canal locking of hemodialysis catheter negative predictors for its malfunction?

Non-tunneled, temporal hemodialysis (HD) catheters are commonly used as short-term vascular access for the HD procedure. One of their late complications is thrombotic occlusion of the catheter ensuing in their malfunction. A heparin lock is conventionally used for maintaining the patency of the catheter. The aim of the study was to evaluate the influence of heparin concentration used for locking the catheter canals (5,000 vs. 2,500 IU/ml) and some other clinical and laboratory variables at the time of temporal HD catheter functioning. Catheter malfunction was defined as the inability to attain and maintain a blood flow of at least 150 ml/min. 174 consecutive HD catheters inserted into jugular or femoral veins (114 patients) were followed up and remained in use for a total of 3,284 days. Catheter thrombosis occurred in 53 cases (30.5%) during the study period, giving an overall rate of 16 episodes per 1,000 catheter-days at risk. In univariate Cox proportional hazard analysis, predictors of catheter dysfunction were: femoral localization (HR 4.92, 95% CI 4.30-5.50), acute renal failure (HR 1.75, 95% CI 1.18-2.32), higher mean ultrafiltration (UF) (HR 1.31, 95% CI 0.99-1.63) and higher concentration of hemoglobin (HR 1.15, 95% CI 0.99-1.33). The concentration of heparin used for canal locking did not influence the time of catheter functioning (HR 1.1, p = 0.7). In multivariate Cox proportional hazard analysis (chi2 = 38.5, d.f. = 4, p < 0.0001) the remaining statistically independent predictors of catheter malfunction were: femoral localization (HR 5.94, 95% CI 5.27-6.61, p < 0.0001) and higher UF (HR 1.60, 95% CI 1.24-1.94, p < 0.01).

A lower concentration of heparin (2,500 IU/ml) prevents catheter thrombosis as effectively as a standard one (5,000 IU/ml). Femoral localization of HD catheters and higher UF during the HD procedure are the factors predisposing for catheter malfunction.

Does inducible NOS have a protective role against hypoxia/reoxygenation injury in rat heart?

The present study analyzes the role of the nitric oxide (NO) derived from inducible NO synthase (iNOS) under cardiac hypoxia/reoxygenation situations. For this, we have designed a follow-up study of different parameters of cell and tissue damage in the heart of Wistar rats submitted for 30 min to acute hypobaric hypoxia, with or without prior treatment with the selective iNOS inhibitor N-(3-(aminomethyl)benzyl) acetamidine or 1400W (10 mg/kg). The rats were studied at 0 h, 12 h, and 5 days of reoxygenation, analyzing NO production (NOx), lipid peroxidation, apoptosis, and protein nitration expression and location. This is the first time-course study which analyzes the effects of the iNOS inhibition by 1400W during hypoxia/reoxygenation in the adult rat heart. The results show that when 1400W was administered before the hypoxic episode, NOx levels fell, while both the lipid peroxidation level and the percentage of apoptotic cells rose throughout the reoxygenation period. Levels of nitrated proteins expression fell only at 12 h post-hypoxia.

The inhibition of iNOS raises the peroxidative and apoptotic level in the hypoxic heart indicating that this isoform may have a protective effect on this organ against hypoxia/reoxygenation injuries, and challenging the conventional wisdom that iNOS is deleterious under these conditions. These findings could help in the design of new treatments based on NO pharmacology against hypoxia/reoxygenation dysfunctions.

Is proinflammatory profile of in vitro monocytes in the ageing affected by lymphocytes presence?

Aging is associated with complex and constant remodeling of the immune function, resulting in an increasing susceptibility to infection and others diseases. The infections caused by Gram-negative microorganisms, present in nursing homes and hospitals, constitute one of the most common infections in the elderly, and are mainly combated by innate immune cells. Although the functions of innate immunity seem more preserved during aging than of adaptive immune mechanisms, two systems operate in an integrated way in the body, so that injury in one part of the immune system inevitably affects the other as they are part of a defensive network. The aim of this study was to investigate the in vitro production of proinflammatory (TNF-α, IL-6, IL-1β, CXCL-8 and MCP-1) and anti-inflammatory (TGF-β and IL-10) cytokines by monocytes, stimulated or not (basal) with lipopolysaccharide, from healthy young and elderly subjects. By means of PBMCs, we also studied if cytokine profile is altered in these different patient groups, in the presence of lymphocytes, under the same experimental conditions. The monocytes from elderly presented higher basal production of TNF-α, MCP-1 and lower of TGF-β than young monocytes. PBMC showed similar cytokines production, irrespective age or stimulation presence. In the presence of lymphocytes, the spontaneous production of IL-10 was higher and of TGF-β was lower than monocytes, regardless of age. After LPS-stimulation, the presence of lymphocytes resulted in increased IL-6, IL-1β, MCP-1 and IL-10 and decreased CXCL-8 and TGF-β in comparison to pure culture of monocytes from young patients. With age, the same differences were observed, except for CXCL-8 and TGF-β which production was the same between monocytes and PBMC stimulated with LPS.

These findings reinforce the systemic state of inflamm-aging frequently reported in elderly and considered a factor of susceptibility to numerous diseases. Still, the cytokine production from just monocytes of the elderly showed alterations, while in the lymphocyte presence not, suggesting an immunomodulator role of lymphocytes on monocytes. In addition, the differences between the production patterns by LPS-stimulated PBMC between young and elderly volunteers can be related with an imbalance in response against Gram-negative bacteria in throughout life.

Are muscle wasting and impaired myogenesis in tumor bearing mice prevented by ERK inhibition?

The onset of cachexia is a frequent feature in cancer patients. Prominent characteristic of this syndrome is the loss of body and muscle weight, this latter being mainly supported by increased protein breakdown rates. While the signaling pathways dependent on IGF-1 or myostatin were causally involved in muscle atrophy, the role of the Mitogen-Activated-Protein-Kinases is still largely debated. The present study investigated this point on mice bearing the C26 colon adenocarcinoma. C26-bearing mice display a marked loss of body weight and muscle mass, this latter associated with increased phosphorylated (p)-ERK. Administration of the ERK inhibitor PD98059 to tumor bearers attenuates muscle depletion and weakness, while restoring normal atrogin-1 expression. In C26 hosts, muscle wasting is also associated with increased Pax7 expression and reduced myogenin levels. Such pattern, suggestive of impaired myogenesis, is reversed by PD98059. Increased p-ERK and reduced myosin heavy chain content can be observed in TNFα-treated C2C12 myotubes, while decreased myogenin and MyoD levels occur in differentiating myoblasts exposed to the cytokine. All these changes are prevented by PD98059.

These results demonstrate that ERK is involved in the pathogenesis of muscle wasting in cancer cachexia and could thus be proposed as a therapeutic target.

Does nMR identify atherogenic lipoprotein abnormalities in early diabetic nephropathy that are unrecognized by conventional analysis?

Lipoprotein abnormalities are likely contributors to the high risk of cardiovascular disease in the chronic kidney disease (CKD) population, although information is limited. Specifically, little is known about lipoprotein abnormalities during the early stages of diabetic kidney disease. The aim of this study was to investigate the relationship between lipoproteins and early manifestations of CKD in the 517 Type 2 diabetes mellitus (T2DM) patients who participated in the Insulin Resistance Atherosclerosis Study (IRAS). Lipoprotein abnormalities were measured by conventional lipid analysis, nuclear magnetic resonance (NMR) spectroscopy, gel gradient electrophoresis (GE), immunoprecipitation (IP), and ELISA. We grouped the cases into albumin to creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) quartiles. In the conventional lipid analysis, triglycerides (TG) correlated directly with ACR and inversely with eGFR quartiles (p = 0.01), while LDL, HDL cholesterol did not correlate with change in ACR or eGFR. ACR was directly associated with apoB, total VLDL, medium VLDL, IDL and small LDL particle concentrations (p < or = 0.03), and inversely with large LDL particles (p = 0.01) and LDL size (p = 0.008). Estimated GFR quartiles were inversely associated with total VLDL, small VLDL, IDL, and medium HDL particles (p < or = 0.01).

In subjects with T2DM, mild albuminuria and reduction in eGFR were associated with numerous atherogenic lipoprotein abnormalities that were detected by the combination of NMR spectroscopy, gel gradient electrophoresis, immunoprecipitation and ELISA but not by the standard clinical lipid analysis.

Is usage of hypnotics associated with mortality?

To investigate the influence of hypnotic usage on all-cause and cause-specific mortality in a middle-aged population. A cohort of 1750 men and 1773 women aged 30-65 years who responded to a postal questionnaire in 1983. The questionnaire included questions about hypnotic usage, sleep duration, sleep complaints, medical conditions, depression, demographic and life style variables. Mortality data for the period 1983-2003 were collected. Regular hypnotic usage was reported by 1.7% of men and 2.2% of women, and was associated with short sleep, sleeping difficulties, several health problems and depression. During the 20-year follow-up period 379 men (21.5%) and 278 women (15.5%) died. After adjustment for potential risk factors in multivariate analyses regular hypnotic usage was associated with significantly increased risk of all-cause mortality in men (Hazard ratios [HR], 4.54; 95% confidence interval [CI], 2.47-8.37) and in women 2.03 (95% CI, 1.07-3.86). With regard to cause-specific mortality, regular hypnotic usage in men was a risk factor for coronary artery disease death, cancer death, suicide and death from "all remaining causes." In women it was a risk factor for suicide.

Our results show an increased risk of all-cause mortality and cause-specific mortality in regular users of hypnotics.

Does angiotensin AT2 receptor stimulation cause neuroprotection in a conscious rat model of stroke?

The angiotensin II type 2 receptor (AT(2)R) is implicated to be neuroprotective in stroke, although this premise has not been directly tested. Therefore, we have examined the neuroprotective effect of AT(2)R stimulation after intracerebroventricular administration of AT(2)R agonist CGP42112 in a conscious rat model of stroke. Spontaneously hypertensive rats were treated with either CGP42112 (0.1 to 10 ng/kg/min intracerebroventricularly) alone or in combination with the AT(2)R antagonist PD123319 (36 ng/kg/min intracerebroventricularly) beginning 5 days before stroke induction. A focal reperfusion model of stroke was induced in conscious spontaneously hypertensive rats by administering endothelin-1 to the middle cerebral artery through a surgically implanted cannula. Behavioral tests were used to assess the severity of neurological deficit as a result of the ischemic event. Cortical and striatal infarct volumes were measured 72 hours poststroke. Blood pressure was unaffected by treatments. CGP42112 dose-dependently reduced cortical infarct volume poststroke, and PD123319 abolished the neuroprotective effect of CGP42112. PD123319 had no effect on infarct volume alone. These results were consistent with the behavioral findings, indicating that CGP42112 reduced motor deficit on the ledged beam test at 72 hours poststroke and immunohistochemical analyses showing that CGP42112 increased neuronal survival and minimized the loss of AT(2)R expression in the infarcted region.

Based on infarct, behavioral, and immunohistochemical data, these results indicate that centrally administered CGP42112 exhibits a neuroprotective effect, which was independent of blood pressure. Thus, for the first time, we have shown that central AT(2)R stimulation is neuroprotective in a conscious rat model of stroke.

Is uroplakin a reliable immunohistochemical marker for malignant mesothelioma of the pleura?

To analyze the immunohistochemical expression of uroplakin (URO) in pleural malignant mesothelioma (PMM). We analyzed URO expression in PMM using similar immunohistochemical techniques at 2 separate institutions. At an antibody dilution of 1:10, 0/5 PMMs were immunoreactive for URO. At 1:8, diffuse weak cytoplasmic staining was seen in all 38 PMMs tested, but no membrane staining was observed. Adjacent nontumor tissue and positive control tissue showed cytoplasmic staining of equivalent intensity. Similar staining results were observed in 27 PMMs at a 1:5 dilution.

At an antibody dilution for which positive and negative control tissues stain appropriately, PMM does not stain for URO. At higher antibody concentrations, PMM exhibits nonspecific cytoplasmic staining. We assert that URO is not a useful immunohistochemical marker for the detection of PMM. Further studies addressing whether URO is overexpressed at the mRNA level in PMM are warranted.

Does bone age correspond with chronological age at type 1 diabetes onset in youth?

To our knowledge, only two controversial articles have reported the study of bone age at diagnosis in diabetic children. The aim of this study was to compare chronological age with bone age and to evaluate the impact of A1C on bone age in children at diagnosis of type 1 diabetes. In 496 diabetic children, height was measured at diagnosis and height SD score was calculated using the British 1990 growth reference. Bone age was determined according to the Greulich and Pyle method, and A1C levels were measured. Participants' height was normal for age and sex. No significant differences were found between chronological age and bone age, and there was no correlation between Delta (bone age - chronological age) and A1C.

This study showed that height and bone maturation among diabetic children are normal for age and sex and independent of A1C at diagnosis of type 1 diabetes.

Do peripheral blood-derived endothelial progenitor cells enhance vertical bone formation?

This study presents a novel cell-based approach for extra-cortical bone regeneration. To enhance vertical bone formation by combining guided bone regeneration and transplantation of peripheral blood-derived endothelial progenitor cells (EPCs) in a rat calvaria model. EPCs were isolated from peripheral blood of inbred rats. Gold domes (7 mm radius, 5 mm height) were filled with β-tricalcium phosphate (βTCP) mixed with 5 × 10(5) EPC. Domes filled with βTCP served as control (CNT). Rats were sacrificed after 3 months. Vertical bone augmentation was analyzed using histology, histomorphometry, and microcomputed tomography (μCT). In all rats, hard tissue filled the space under the dome. Histomorphometric analysis revealed that EPC transplantations doubled vertical bone height (EPC 4.04 ± 0.22 mm vs CNT 2.29 ± 0.22 mm, p ≤ .001). EPC also caused ∼50% increase in bone area fraction (EPC 47.3 ± 3.1% vs CNT 31.1 ± 2.7%, p ≤ .003). μCT results also showed that bone volume fraction (BV/TV) was higher in EPC group (p = .0169). In both groups, BV/TV declined from the bottom to the top of the samples. No differences in tissue mineral density were found between EPC and CNT groups.

EPC transplantation significantly improved bone formation especially in the areas that are remote from the original bone.

Are qRS duration and QRS fractionation on surface electrocardiogram markers of right ventricular dysfunction and atrialization in patients with Ebstein anomaly?

Ebstein anomaly is a rare and heterogeneous congenital heart defect affecting the tricuspid valve and right ventricular (RV) myocardium. Few studies have analysed the electrocardiographic features of Ebstein anomaly and none has addressed correlations with disease severity. Patients with Ebstein anomaly who had undergone electrocardiography and cardiac magnetic resonance (CMR) within 6 weeks between 2001 and 2009 were included. Exclusion criteria were: associated congenital cardiac defect, previous RV myoplasty and/or reduction surgery, class I anti-arrhythmic drug therapy, and paced/pre-excited QRS. Standard electrocardiogram (ECG) findings were correlated with CMR-based RV measures and clinical profile. The mean age of the 63 study patients was 22 ± 13 years. An RV conduction delay (rsR' pattern in right precordial leads) was present in 45 patients (71%). The QRS duration correlated with anatomic RV diastolic volume (r = +0.56, P < 0.0001) and inversely with RV ejection fraction (EF; r = -0.62, P < 0.0001). The presence of QRS fractionation predicted greater atrialized RV volume (80 ± 31 vs. 45 ± 37 mL/m(2), P < 0.001). Normal QRS duration was associated with smaller anatomic RV diastolic volume (150 ± 57 vs. 256 ± 100 mL/m(2); P < 0.0001), higher RV EF (48 ± 6 vs. 34 ± 14%; P < 0.0001), higher oxygen consumption (VO(2)) at cardiopulmonary exercise (25.8 vs. 21.8 mL/kg/min, P = 0.05) and lower incidence of oxygen desaturation with exercise (25 vs. 65%, P = 0.02).

Delayed and prolonged depolarization of the RV is common in patients with Ebstein anomaly. The QRS duration is a marker of RV enlargement and dysfunction. QRS fractionation is associated with a greater atrialized RV volume. A preserved surface ECG identifies a subset of patients with Ebstein anomaly with mild morphological and functional abnormalities and better clinical profile.

Does nFAT2 inhibitor ameliorate diabetic nephropathy and podocyte injury in db/db mice?

Podocyte injury plays a key role in the development of diabetic nephropathy (DN). We have recently shown that 11R-VIVIT, an inhibitor of cell-permeable nuclear factor of activated T-cells (NFAT), attenuates podocyte apoptosis induced by high glucose in vitro. However, it is not known whether 11R-VIVIT has a protective effect on DN, especially podocyte injury, under in vivo diabetic conditions. Hence, we examined the renoprotective effects of 11R-VIVIT in diabetic db/db mice and the possible mechanisms underlying its protective effects on podocyte injury in vivo and in vitro. Type 2 diabetic db/db mice received i.p. injections of 11R-VIVIT (1 mg·kg(-1)) three times a week and were killed after 8 weeks. Immortalized mouse podocytes were cultured under different experimental conditions. 11R-VIVIT treatment markedly attenuated the albuminuria in diabetic db/db mice and also alleviated mesangial matrix expansion and podocyte injury. However, body weight, food and water intake, and glucose levels were unaffected. It also attenuated the increased NFAT2 activation and enhanced urokinase-type plasminogen activator receptor (uPA receptor) expression in glomerulor podocytes. In cultured podocytes, the increased nuclear accumulation of NFAT2 and uPA receptor expression induced by high glucose treatment was prevented by 11R-VIVIT or NFAT2-knockdown; this was accompanied by improvements in the filtration barrier function of the podocyte monolayer.

The NFAT inhibitor 11R-VIVIT might be a useful therapeutic strategy for protecting podocytes and treating DN. The calcinerin/NFAT2/uPA receptor signalling pathway should be exploited as a therapeutic target for protecting podocytes from injury in DN.

Does cell death and quantitative reduction of rest of Malassez according to age?

Rests of Malassez are clusters of epithelial cells that remain in the periodontal ligament throughout life. However, it has been reported that the number of these structures decreases with age, and some epithelial cells undergo apoptosis in rests of Malassez of young and adult rats. Therefore, the purpose of the present study was to investigate the incidence of epithelial cell death and the quantitative changes in the rests of Malassez in rat molars of different ages. Fragments containing the upper molars of rats aged 29, 45 and 120 d were fixed, decalcified and embedded for analysis by light microscopy. In the sections stained by hematoxylin and eosin, the number of rests of Malassez and the number of nuclei of these epithelial structures were obtained. Moreover, the nuclei exhibiting typical features of cell death were also counted in each rest of Malassez. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method for detection of cell death was also carried out. In all groups examined, some rests of Malassez exhibited epithelial cell nuclei with typical features of apoptosis and some of them were also TUNEL positive. From 29 to 120 d of age in rats, the quantitative analysis showed a significant decrease in the total number of rests of Malassez in the cervical, middle and furcation regions of the periodontal ligament. Moreover, a significant decrease of epithelial cell nuclei was concomitant to an increase in the frequency of cell death in the oldest rats.

These results suggest that epithelial cell death by apoptosis may be, at least in part, responsible for the reduction in the number of rests of Malassez according to age.

Fluctuating prostate-specific antigen levels in patients with initial negative biopsy: should we be reassured?

To evaluate whether the risk of having a positive repeat prostate biopsy is lower in patients with fluctuating prostate-specific antigen (PSA) levels than in patients with a steady or steadily increasing PSA level. Files were extracted from the 2000-2003 databases of two teaching hospitals; 191 patients who had a first negative biopsy followed by one or more sets of biopsies and at least two PSA measurements were included. A 'fluctuating PSA level' in a patient was defined as a PSA series including at least one PSA value lower than the one immediately preceding it. The median PSA level at the first biopsy was 7 ng/mL, while that for the second, third and fourth biopsies were 8.0, 8.0 and 8.7 ng/mL, respectively. The median time between the first and second, and the second and third PSA tests was 290 and 317 days, respectively. Prostate cancer was eventually detected in 53 men (27.7%) in whom 39 it was at the first repeat biopsy. Among the 79 patients with a fluctuating PSA level, 17 (22%) had prostate cancer, vs 36 (32%) among the 112 with a 'steady' PSA level; the difference was not significant (P=0.14). When considering the 53 patients diagnosed with prostate cancer, the 17 with a fluctuating PSA level and the 36 others had no significant difference in age, T stage, first PSA level and Gleason score.

In the present study, by contrast with the common and unfounded view, the risk of having a positive repeat prostate biopsy was no lower in men with a fluctuating PSA level than in those with a steady or steadily increasing PSA level. The practical and economical implications warrant further studies to confirm these findings.

Does increased coupling of caveolin-1 and estrogen receptor α contribute to the fragile X syndrome?

Fragile X syndrome (FXS) is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the FMR1 gene. Interaction between estrogen receptor (ER) and lipid raft caveolae is critical for the estrogen signaling. Here, we tested the hypothesis that impaired ER-caveolae coupling contributes to the mental retardation of FXS. Fmr1 knockout (KO) mouse was used as the model of FXS. Multiple techniques were performed including primary neuronal culture, short hairpin RNA (shRNA) interference, Western blot, electrophysiological recording, RNA-binding protein immunoprecipitation, reverse transcriptase polymerase chain reaction, and behavioral tests. In this study, we report that GluA1 surface expression and phosphorylation induced by 17β-estradiol (E2) were impaired in the Fmr1 KO neurons. The E2-mediated facilitation of long-term potentiation and fear memory was impaired in the anterior cingulate cortex of Fmr1 KO mice. The increased coupling of caveolin-1 (CAV1) and the membrane estrogen receptor ERα under basal conditions contributed to the impairment of ER signaling in Fmr1 KO neurons. FMRP (fragile X mental retardation protein) interacted with CAV1 mRNA, and knockdown of CAV1 with shRNA rescued the synaptic GluA1 delivery, plasticity, and memory in Fmr1 KO mice.

This is the first demonstration that the coupling between ERα and lipid raft CAV1 is critical for membrane ER signaling in synaptic plasticity. Therefore, increased coupling of CAV1 and ERα may elucidate a critical abnormal mechanism of FXS.

Is systolic blood pressure variability an important predictor of cardiovascular outcomes in elderly hypertensive patients?

In hypertensive persons aged 60 years or below, visit-to-visit SBP variability is directly associated with cardiovascular events, especially stroke. It is unclear whether such a relationship exists for older persons. We investigated whether there is a relationship between visit-to-visit SBP variability and cardiovascular events in an elderly population, and identified the factors associated with increased SBP variability. Information from 49771 visits of 5880 patients aged at least 65 years being treated for hypertension in the Second Australian National Blood Pressure study was used. Patients were followed for 4.1 (median) years and had eight (median) doctor visits during the study. SBP variability was defined as within-individual SD of SBP across study follow-up visits. Increased visit-to-visit SBP variability was found to be a strong predictor for future cardiovascular events in this elderly population. The hazard ratio (95% confidence interval) for any first fatal/nonfatal cardiovascular event for highest decile compared with lowest decile of SBP variability was 2.18 (1.52-3.13) after adjusting for sex, age, treatment including other baseline variables, and average on-treatment SBP. A similar effect was observed for stroke (hazard ratio 2.78, 1.28-6.05), myocardial infarction (hazard ratio 4.11, 1.87-9.06), and heart failure (hazard ratio 4.79, 1.82-12.62). Highest SBP variability was also a predictor of post-trial fatal cardiovascular events. Increased visit-to-visit SBP variability was related to age, pulse pressure, changing physicians, smoking, treatment allocation, and the use of multiple BP-lowering drugs.

These findings suggest that reducing visit-to-visit SBP variability might be an important objective in addition to conventional blood pressure-lowering in elderly hypertensive patients.

Is restriction in hip internal rotation associated with an increased risk of ACL injury?

Evidence suggests that femoroacetabular impingement (FAI) in athletes may increase the risk of anterior cruciate ligament (ACL) injury. This study correlates ACL injury with hip range of motion in a consecutive series of elite, contact athletes and tests the hypothesis that a restriction in the available hip axial rotation in a dynamic in silico model of a simulated pivot landing would increase ACL strain and the risk of ACL rupture. Three hundred and twenty-four football athletes attending the 2012 NFL National Invitational Camp were examined. Hip range of internal rotation was measured and correlated with a history of ACL injury and surgical repair. An in silico biomechanical model was used to study the effect of FAI on the peak relative ACL strain developed during a simulated pivot landing. The in vivo results demonstrated that a reduction in internal rotation of the left hip was associated with a statistically significant increased odds of ACL injury in the ipsilateral or contralateral knee (OR 0.95, p = 0.0001 and p < 0.0001, respectively). A post-estimation calculation of odds ratio for ACL injury based on deficiency in hip internal rotation demonstrated that a 30-degree reduction in left hip internal rotation was associated with 4.06 and 5.29 times greater odds of ACL injury in the ipsilateral and contralateral limbs, respectively. The in silico model demonstrated that FAI systematically increased the peak ACL strain predicted during the pivot landing.

FAI may be associated with ACL injury because of the increased resistance to femoral internal axial rotation during a dynamic maneuver such as a pivot landing. This insight may lead to better interventions to prevent ACL injury and improved understanding of ACL reconstruction failure.

Do the manipulations in pediatric inguinal hernia operations affect the vascularization of testes?

The aim of this study is to evaluate the effect of manipulations performed in inguinal hernia operations on testicular perfusion, in pediatric age group using Doppler ultrasonography (DUS). In this prospective clinical trial, 51 boys who underwent elective inguinal hernia repair were examined before the operation and in early-late postoperative periods. Blood flow indices of centripetal and capsular arteries including peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistivity index (RI) were examined by DUS. There was a statistically significant increase in early postoperative PSV and RI values compared with preoperative findings. These values turned to normal in late postoperative period. The increase in early and decrease in late postoperative EDV values were not statistically significant compared to preoperative findings.

The surgical manipulations performed in inguinal hernia operations in children cause transient changes in testes vascularization in early postoperative period but turns to normal late postoperatively.

Is sagittal abdominal diameter a strong anthropometric measure of visceral adipose tissue in the Asian general population?

Finding the anthropometric measure of visceral obesity is essential to clinical practice, because it predicts cardiovascular and metabolic risks. Sagittal abdominal diameter (SAD) has been proposed as an estimate of visceral adipose tissue (VAT). The aim of the present study was to evaluate the usefulness of SAD in predicting visceral obesity by comparing SAD to other anthropometric measures. Estimation of subcutaneous and visceral adipose tissue and measurement of SAD and transverse abdominal diameter using computed tomography at the umbilical level were obtained in 5,257 men and women who were enrolled in a health checkup program in Korea. To compare SAD to other anthropometric measures, linear regression analyses were used to determine correlations between anthropometrics and visceral obesity. SAD showed a stronger correlation to VAT than waist circumference, BMI, and transverse abdominal diameter in the both sexes (men: r = 0.804, women: r = 0.724). Waist circumference showed generally stronger associations to subcutaneous adipose tissue (SAT) than to VAT (men: r = 0.789 vs. 0.705, women: r = 0.820 vs. 0.636). Even after subdividing according to age or BMI in both sexes and analyzing multiple regressions, SAD showed the strongest correlation to VAT.

SAD showed the strongest correlation to VAT irrespective of age, sex, and the degree of obesity compared with other anthropometric measures, whereas waist circumference may have a stronger correlation to SAT than to VAT. The clinical use of SAD has advantages over other anthropometric measures in predicting VAT.

Are polymorphisms of estrogen metabolism-related genes ESR1 , UGT2B17 , and UGT1A1 associated with osteoporosis in surgically menopausal Japanese women?

Bilateral salpingo-oophorectomy (BSO) is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve their quality of life. This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical) menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 (ESR1) and UDP-glucuronosyl transferase (UGT) genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated. No significant association was found between osteoporosis and polymorphisms in ESR1, UGT2B17, or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations.

These results suggest that the ESR1, UGT2B17, and UGT1A1 polymorphisms are not genetic factors affecting osteoporosis in postmenopausal Japanese women.

Are myocardial scars determined by delayed-enhancement magnetic resonance imaging and positron emission tomography common in right ventricles with systemic function in long-term follow up?

To test the hypothesis that myocardial scars are common in patients with systemic right ventricles. 27 consecutive patients with systemic right ventricle were studied with delayed-enhancement magnetic resonance imaging and positron emission tomography. Of the 27 patients, 18 had had an atrial switch operation a mean of 21.8 (SD 4.5) years previously and were 23.4 (SD 5.3) years old. Nine patients without previous heart surgery had congenitally corrected transposition of the great arteries and were 35.3 (SD 15.6) years old. Only one patient had a subendocardial scar identified by delayed-enhancement magnetic resonance imaging. Positron emission tomography identified no myocardial scars.

This study shows that the hypothesis that myocardial scars are common in patients with systemic right ventricles is not correct.

Does word Memory Test predict Recovery in Claimants With Work-Related Head Injury?

To investigate the predictive validity of the Word Memory Test (WMT), a verbal memory neuropsychological test developed as a performance validity measure to assess memory, effort, and performance consistency. Cohort study with 1-year follow-up. Workers' compensation rehabilitation facility. Participants included workers' compensation claimants with work-related head injury (N=188; mean age, 44y; 161 men [85.6%]). Not applicable. Outcome measures for determining predictive validity included days to suspension of wage replacement benefits during the 1-year follow-up and work status at discharge in claimants undergoing rehabilitation. Analysis included multivariable Cox and logistic regression. Better WMT performance was significantly but weakly correlated with younger age (r=-.30), documented brain abnormality (r=.28), and loss of consciousness at the time of injury (r=.25). Claimants with documented brain abnormalities on diagnostic imaging scans performed better (∼9%) on the WMT than those without brain abnormalities. The WMT predicted days receiving benefits (adjusted hazard ratio, 1.13; 95% confidence interval, 1.04-1.24) and work status outcome at program discharge (adjusted odds ratio, 1.62; 95% confidence interval, 1.13-2.34).

Our results provide evidence for the predictive validity of the WMT in workers' compensation claimants. Younger claimants and those with more severe brain injuries performed better on the WMT. It may be that financial incentives or other factors related to the compensation claim affected the performance.

Do cognitively impaired stroke patients do benefit from admission to an acute rehabilitation unit?

To determine whether cognitively impaired stroke patients benefit (defined as having an improved level of functional independence and capable of being discharged home) from admission to an acute rehabilitation unit. Retrospective analysis of data from a historical cohort of patients with acute stroke within the last 4 weeks or less. Acute stroke rehabilitation unit. The study sample was divided into 4 distinct groups based on admission Mini-Mental State Examination (MMSE) scores: cognitively intact (MMSE score range, > or =25 points), mild cognitive impairment (MMSE score range, 21-24), moderate cognitive impairment (MMSE score range, 10-20), and severe cognitive impairment (MMSE score range, < or =9 points). Not applicable. Primary outcome measures were: change in total FIM instrument score, cognitive FIM subscore, length of stay (LOS), FIM efficiency, and discharge disposition (home vs not-to-home). Based on the MMSE cut scores, there were 233 cognitively intact patients and 435 cognitively impaired (mild, n=139; moderate, n=165; severe, n=131) patients. The cognitively intact and the 3 cognitively impaired groups were similar in age, sex, and ethnicity. The data show that the 3 cognitively impaired groups of patients had delayed onset to acute rehabilitation admission and greater stroke severity and disability. The change in FIM total score and FIM efficiency was similar between the cognitively intact and the 3 cognitively impaired groups (P=.058). There were, however, statistically significant changes in the FIM cognitive subscore favoring the cognitively impaired groups (P<.001). Similarly, patients in the cognitively intact group had a shorter LOS (P<.001) and more home discharges (P<.001).

Our results suggest that despite severe neurologic impairment(s) and disability, cognitively impaired stroke patients make significant functional gains while undergoing rehabilitation and many can be discharged home. Based on these results, stroke patients with cognitive impairments benefit from rehabilitation and should be given the same access to acute rehabilitation services as stroke patients who are cognitively intact.

Is motor neuron regeneration through end-to-side repairs a function of donor nerve axotomy?

Over the past decade, a growing body of literature has emerged supporting the use of end-to-side (terminolateral) neurorrhaphy for the treatment of selected peripheral nerve injuries. It remains unclear, however, whether injury to the donor nerve is necessary to achieve significant regeneration through such repairs. End-to-side repair was studied in a rodent model in which the terminal limb of a transected peroneal nerve was sutured to the lateral aspect of the tibial nerve. Twenty-eight Lewis rats were randomized to four groups of seven animals each corresponding to incrementally greater donor nerve injuries as follows: group 1, conventional end-to-side neurorrhaphy; group 2, end-to-side neurorrhaphy with proximal crush injury; group 3, end-to-side neurorrhaphy with neurotomy; and group 4, end-to-end repair of transected peroneal nerve (positive control). At 12 weeks, retrograde labeling of cell bodies of the ventral horn demonstrated significant differences between experimental groups, with mean counts in group 4 (1237 +/- 171) > group 3 (522 +/- 204) > group 2 (210 +/- 132) > or = group 1 (126 +/- 146). This association between nerve injury and motor neuron counts was closely mirrored in quantitative assessments of peripheral nerve regeneration and normalized wet muscle masses.

These data support the hypothesis that donor nerve injury is a prerequisite for significant motor neuronal regeneration across end-to-side repairs. Motor neuron regeneration through end-to-side repairs is optimized by deliberate transection of donor nerve axons.

Is loop diuretic use at discharge associated with adverse outcomes in hospitalized patients with heart failure : a report from the Japanese cardiac registry of heart failure in cardiology ( JCARE-CARD )?

Loop diuretics are commonly used in patients with heart failure (HF) to remove retained fluid and improve symptoms. However, they may potentially worsen outcomes in HF. It remains unknown whether the use of loop diuretics is associated with adverse HF outcomes in routine clinical practice. We thus determined the effects of loop diuretic use at discharge on long-term mortality and rehospitalization among patients hospitalized with HF. The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied the characteristics and treatments of a broad sample of patients hospitalized with worsening HF and followed for 2.1 years. Among a total of 2,549 HF patients, loop diuretics were used by 2,015 patients (79%), but not 534 patients (21%). The mean age was 70.7 years and 60% were male. Etiology was ischemic in 32% and mean left ventricular ejection fraction was 42%. After adjustment for covariates, discharge use of loop diuretics was associated with significant adverse risks of cardiac death (adjusted hazard ratio [HR] 2.348, 95% confidence interval [CI] 1.246-4.423, P=0.008) and rehospitalization (adjusted HR 1.427, 95% CI 1.040-1.959, P=0.027).

Among patients hospitalized with worsening HF, loop diuretic use at discharge was associated with long-term adverse outcomes, which suggests that routine chronic use of loop diuretics may be harmful for patients with HF.

Does rectal cancer surgery in older people increase postoperative complications -- a retrospective analysis?

Rectal cancer surgery in the older population remains a highly controversial topic. The present study was designed to assess whether older patients had an increased risk for postoperative complications after rectal resection for malignancies. Consecutive patients (n=627), who underwent rectal cancer resection at a single institution, were included in the study and analyzed retrospectively. Short-term complications were compared between patients≥80 years (n=55) and <80 years (n=572). Additionally, predictive factors for postoperative complications were analyzed. The older aged group showed a significantly higher rate of co-morbidities compared to controls, in terms of cardiovascular and pulmonary diseases (P=0.002, P=0.006). In older patients, a Hartmann's procedure and transanal endoscopic microsurgery (TEM) were performed most frequently (P<0.0001).The overall complication rate was 39% (n=244) (medical: n=59 (9%), surgical: n=185 (30%)), including 24 (44%) complications in the older aged group (medical: n=6 (11%), surgical: n=18 (33%)). Notably, the incidence of surgical and medical complications showed no significant difference between patients and controls (P=0.58, P=0.69).Neurological and cardiovascular disorders were associated with an increased risk for a eventful postoperative course in the older aged group (P=0.03, P=0.04).

Rectal cancer resection can be performed safely in selected older patients. Age itself should not be considered as a risk factor for postoperative complications.

Does consumption of broccoli sprouts during late gestation and lactation confer protection against developmental delay induced by maternal inflammation?

The presence of a fetal inflammatory response is linked to cerebral palsy. Unfortunately no preventive therapies are available. In this study, we determined whether dietary supplementation with broccoli sprouts (BrSp), a phase-II enzyme inducer, would be effective in preventing the behavioural and pathologic manifestations in a rodent model of inflammation during late pregnancy. Pregnant Long-Evans rats were administered i.p. Injections of saline (100μl) or lipopolysaccharide (LPS, 200μg/kg), every 12h on embryonic day (E) 19 and 20. In the treatment groups, dams were supplemented with 200mg/day of dried BrSp from E14 until postnatal day 21. Pups underwent a series of neurodevelopmental reflex tests from postnatal day 3-21 followed by neuropathological analyses. Pups born from the LPS group were significantly growth restricted (p<0.001) and delayed in hindlimb placing (p<0.05), cliff avoidance (p<0.05), and gait (p<0.001) compared to controls. In the open field behaviour analyses, LPS pups had an increase in grooming behaviour (p<0.05) and a decreased amount of time spent in the center of the box compared to controls. Dietary supplementation with BrSp to offspring exposed to LPS had increased birth weights (p<0.001), were no longer delayed in acquiring hindlimb placing, cliff avoidance, gait, and posture, and groomed less compared to LPS alone pups (p<0.01). Histological analyses revealed that LPS pups had reduced myelin basic protein compared to controls.

Our data suggest that BrSp dietary supplementation during pregnancy may be effective in preventing growth restriction and neurodevelopmental delays.