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Does oral Administration of Sustained Release Niacin inhibit Platelet Aggregation?

Previous studies have suggested that niacin may have antiplatelet properties, however the effects of niacin on the platelet activity are not well defined. The purpose of this trial was to investigate whether the oral administration of niacin inhibits platelet aggregation. This study was run in three segments measuring the inhibitory effect of niacin: 1) 3 mmol/L niacin in vitro, 2) one hour after 1-gram sustained-release (SR) niacin administration, 3) twelve hours after 2-gram SR niacin administration. Platelet aggregation was measured using the VerifyNow-Aspirin and whole blood impedance aggregometry. Preincubation with niacin resulted in a significant inhibition of platelet aggregation. Significant inhibition of platelet aggregation was found one hour following the oral administration of 1 gram of SR niacin while the oral administration of a 2 gram dose of SR niacin did not produce significant platelet inhibition when platelet aggregation was measured 12 hours after the dose.

Niacin has a small, direct effect on platelet aggregation. Niacin platelet inhibition is transient and may dissipate as it is converted into metabolites. The clinical significance is unknown.

Is oxidative stress increased in critically ill patients according to antioxidant vitamins intake , independent of severity : a cohort study?

Critically ill patients suffer from oxidative stress caused by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Although ROS/RNS are constantly produced under normal circumstances, critical illness can drastically increase their production. These patients have reduced plasma and intracellular levels of antioxidants and free electron scavengers or cofactors, and decreased activity of the enzymatic system involved in ROS detoxification. The pro-oxidant/antioxidant balance is of functional relevance during critical illness because it is involved in the pathogenesis of multiple organ failure. In this study the objective was to evaluate the relation between oxidative stress in critically ill patients and antioxidant vitamin intake and severity of illness. Spectrophotometry was used to measure in plasma the total antioxidant capacity and levels of lipid peroxide, carbonyl group, total protein, bilirubin and uric acid at two time points: at intensive care unit (ICU) admission and on day seven. Daily diet records were kept and compliance with recommended dietary allowance (RDA) of antioxidant vitamins (A, C and E) was assessed. Between admission and day seven in the ICU, significant increases in lipid peroxide and carbonyl group were associated with decreased antioxidant capacity and greater deterioration in Sequential Organ Failure Assessment score. There was significantly greater worsening in oxidative stress parameters in patients who received antioxidant vitamins at below 66% of RDA than in those who received antioxidant vitamins at above 66% of RDA. An antioxidant vitamin intake from 66% to 100% of RDA reduced the risk for worsening oxidative stress by 94% (ods ratio 0.06, 95% confidence interval 0.010 to 0.39), regardless of change in severity of illness (Sequential Organ Failure Assessment score).

The critical condition of patients admitted to the ICU is associated with worsening oxidative stress. Intake of antioxidant vitamins below 66% of RDA and alteration in endogenous levels of substances with antioxidant capacity are related to redox imbalance in critical ill patients. Therefore, intake of antioxidant vitamins should be carefully monitored so that it is as close as possible to RDA.

Are serum levels of soluble interleukin 6 receptor and soluble gp130 elevated in patients with localized scleroderma?

To investigate the clinical relevance of serum soluble interleukin 6 receptor (sIL-6R) and soluble gp130 (sgp130) in localized scleroderma. Serum levels of sIL-6R and sgp130 were examined by ELISA in 45 patients with localized scleroderma. Twenty patients with systemic sclerosis (SSc) and 20 healthy individuals served as controls. Serum levels of both sIL-6R and sgp130 were significantly elevated in patients with localized scleroderma compared with healthy controls. Moreover, serum sgp130 levels in patients with localized scleroderma were significantly higher than in patients with SSc. In patients with localized scleroderma, elevated sIL-6R levels significantly correlated with levels of IgM antihistone antibodies, the presence of rheumatoid factor, the number of linear lesions, and the number of body areas involved. Elevated sgp130 levels were significantly associated with levels of IgG antihistone antibodies, the number of plaque lesions, the total number of lesions, and the number of body areas involved.

These results suggest that elevated serum sIL-6R and sgp 30 may reflect activation of the IL-6 system that may be associated with the development of sclerotic lesions and autoantibody production in localized scleroderma.

Are blood lipids a risk factor for age-related macular degeneration?

To study the levels of lipids in serum, in patients with age-related macular degeneration (AMD), and to establish its pathogenic relevance in the disease. The serums of a total of 40 patients, distributed in a AMD group (25 patients) and a control group (15 patients, with similar ages and without ocular affectation) were studied, correlating the biochemical findings with the clinical examination of these patients. We have observed a mean level of serum total cholesterol statistically superior in AMD patients (control= 200.18+/-18.89 mg/dL; AMD= 227.28+/-5.46 mg/dL; p<0.01). These significant differences are repeated for different lipoproteins (triglycerides, LDL, VLDL and apolipoprotein B), not appearing for the HDL and apolipoprotein A-1. We have not found correlations of these concentrations with the clinical or functional stage of the AMD.

Serum lipids could take part in the pathogenic mechanism of AMD, either by their relation with arteriosclerosis, which would diminish the choroidal flow, or by direct deposit in the Bruch's membrane. However, more longitudinal studies are needed to understand the relation of serum lipids and AMD, and to establish therapeutic approaches on the matter.

Are 2 weeks of daily breastfeeding support insufficient to overcome the influences of formula?

To evaluate the effectiveness of proactive telephone breastfeeding support in low-income, primiparous, primarily Latina women on 1) duration and exclusivity of breastfeeding, 2) satisfaction with feeding, 3) rationale for discontinuing breastfeeding and 4) health care utilization. Randomized controlled trial comparing usual care to 2 weeks of daily telephone calls by nurses by using culturally informed scripted protocols; and qualitative study of focused interviews on a sample of women in the intervention group (n = 40). Breastfeeding duration and exclusivity rates, feeding method satisfaction, and reasons for stopping breastfeeding did not differ significantly between intervention (n = 161) and control (n = 180) groups, with 74% of both breastfeeding at 1 month and 28% and 37%, respectively, at 6 months. Insufficient milk supply was the main reason for stopping in both groups. Intervention infants were less likely to have a sick visit by 1 month (25%) than controls (35%, P = .05). Qualitative interviews revealed that the intervention was informative and helpful, with breastfeeding reported as healthier but harder; formula was a good alternative. Intervention mothers reporting<or =2 supplemental formula feedings on day 4 were more likely than mothers reporting>or =3 supplemental feedings to breastfeed at 1 month (odds ratio 7.7; 95% confidence interval 2.4-24.3).

Two weeks of daily telephone support did not increase breastfeeding duration but was associated with a decrease in sick visits in the first month. Early supplementation and the perception of formula as a good alternative to dealing with the breastfeeding difficulties appeared to be factors in failure of the intervention.

Is redistribution of joint moments associated with changed plantar pressure in diabetic polyneuropathy?

Patients with diabetic polyneuropathy (DPN) are often confronted with ulceration of foot soles. Increased plantar pressure under the forefoot has been identified as a major risk factor for ulceration. This study sets out to test the hypothesis that changes in gait characteristics induced by DPN related muscle weakness are the origin of the elevated plantar pressures. Three groups of subjects participated: people diagnosed with diabetes without polyneuropathy (DC), people diagnosed with diabetic polyneuropathy (DPN) and healthy, age-matched controls (HC). In all subjects isometric strength of plantar and dorsal flexors was assessed. Moreover, joint moments at ankle, knee and hip joints were determined while walking barefoot at a velocity of 1.4 m/s. Simultaneously plantar pressure patterns were measured. Compared to HC-subjects, DPN-participants walked with a significantly increased internal plantar flexor moment at the first half of the stance phase. Also in DPN-subjects the maximal braking and propelling force applied to the floor was decreased. Moreover, in DPN-subjects the ratio of forefoot-to-rear foot plantar pressures was increased. Body-mass normalized strength of dorsal flexors showed a trend to be reduced in people with diabetes, both DC and DPN, compared to HC-subjects. Plantar flexors tended to be less weak in DC compared to HC and in DPN relative to DC.

The results of this study suggest that adverse plantar pressure patterns are associated with redistribution of joint moments, and a consequent reduced capacity to control forward velocity at heel strike.

Is brain cancer an occupational disease of cardiologists?

To assess the plausibility of radiation as a cause of the statistically unusual event of two cardiologists in Toronto, Ontario who were diagnosed with brain tumours in 1997. Computation of the expected occurrence of brain cancer in Ontario cardiologists and review of the epidemiological literature pertaining to radiation and brain cancer. The occurrence of these two cases is a statistically unusual event--a 'cluster'. There are several plausible explanations for this cluster. First, this may be a chance occurrence, and the tumours may have no causative factors in common. Second, the cause may be radiation exposure. A connection to occupational radiation exposure is biologically plausible, but risk assessment suggests that it is unlikely that this effect would have been observable in the small population of Ontario cardiologists.

Initiation of brain tumours during cardiac fluoroscopic procedures is plausible. Physicians are reminded to practise radiation safety methods during fluoroscopic procedures. The diagnosis of two additional brain tumours in Canadian interventional cardiologists during the past 10 years would confirm the occupational causation theory. The author invites physicians to report knowledge of the diagnosis of brain tumours in Canadian cardiologists to the author or to the editors.

Can different types of retinal emboli be reliably differentiated from one another?

To determine whether ophthalmologists can agree on the qualitative assessment of visible retinal emboli. Inter- and intraobserver agreement study. The retina and vitreous subspecialty session at the 1996 Canadian Ophthalmological Society meeting. A total of 42 observers, of whom 30 were retinal specialists. The observers viewed 17 fundus photographs of 11 patients with embolic acute retinal artery occlusion and classified the visible retinal emboli into one of three groups: cholesterol, calcific or other. Overall, there was slight agreement for the 17 observations (mean kappa = 0.063). The kappa statistic for all cases ranged from slight to fair agreement. Slight interobserver agreement for the six unique photographs was observed (mean kappa = 0.073). Slight intraobserver agreement was found for the three photographs that were shown in different orientations (mean kappa = 0.041) and for the two photographs shown with differing magnification (mean kappa = 0.102).

Overall both intraobserver and interobserver agreement on the qualitative assessment of retinal emboli was poor. With only slight agreement on the classification of emboli, systemic evaluation of acute retinal artery occlusion should not be based on qualitative assessment of retinal emboli.

Do gender and age influence the frequency of Helicobacter pylori infection?

(13)C urea breath test (UBT) is a noninvasive method for detection of Helicobacter pylori (H. pylori) infection. The aim of this study was to determine age and gender differences in patients with positive UBT. During the period 2008-2011, a total of 3,000 patients, who did not receive Hp eradication therapy before our study, underwent UBT in Laboratory of Clinical Hospital Sveti Duh. Data were analyzed according to age and gender. A total of 1,400 patients were positive (47 %), 670 males and 730 females (the male/female ratio for positive UBT was 0.92). The male predominance was found in people born between 1930 and 1939, 1940 and 1949, and 1960 and 1969, respectively. The majority infected are born between from 1940 and 1979, with the highest point from 1950-1969.

Our study results confirm the importance of epidemiologic characteristics of Hp infection in our region.

Are serum fractalkine and interferon-gamma inducible protein-10 concentrations early detection markers for acute renal allograft rejection?

The aims of this study were to determine if characterization of serum concentrations of interferon-gamma inducible protein-10 (IP-10), fractalkine, and their receptors (CXCR3 and CX3CR1) were predictive of acute allograft rejection in kidney transplant recipients. Kidney transplant recipients (n = 52) were enrolled in this study and divide into either the acute rejection (AR, n = 15) or non-acute rejection (NAR, n = 35) groups. Serum samples from recipients were collected 1 day prior to transplantation and on days 1, 3, 5, 7, and 9 post-transplantation. The accuracy of chemokine concentrations for predicting acute rejection episodes was evaluated using receiver operator characteristic (ROC) curves. AR was diagnosed in 15 patients based on histologic changes to renal biopsies. AR patients had significantly higher serum fractalkine, CXCR1, IP-10, and CXCR3 levels compared to levels observed in the NAR group and healthy controls. Fractalkine and IP-10 had the largest area under the ROC curve at 0.86 (95% confidence interval: 0.77-0.96). Following steroid therapy, chemokine levels decreased, which may serve to predict the therapeutic response to steroid therapy.

Measuring serum levels of fractalkine, IP-10, and their receptors (especially the fractalkine/IP-10 combination) may serve as a noninvasive approach for the early diagnosis of renal allograft rejection.

Gastroesophageal reflux disease and obesity: do we need to perform reflux testing in all candidates to bariatric surgery?

Obesity is a strong independent risk factor of gastroesophageal reflux disease (GERD) symptoms and esophageal erosions. However the relationship between obesity and GERD is still a subject of debate. In fact, if in most cases bariatric surgery can diminish reflux by losing a large amount of fat, on the other hand some restrictive procedure can worsen or cause the presence of GERD. Thus, it is unclear if patients candidate to bariatric surgery have to perform pre-operative reflux testing or not.AIM: of the study was to verify the presence of GERD patterns in patients candidate to surgery and the need of pre-operative reflux testing. All patients underwent to a standardized questionnaire for symptoms severity (GERQ), upper endoscopy, high resolution manometry (HRiM) and impedance pH-monitoring (MII-pH). Patients were stratified into: group 1 (negative for both GERQ and endoscopy), group 2 (positive for GERQ and negative for endoscopy), group 3 (positive for both GERQ and endoscopy). A healthy-volunteers group (HV) was assessed. One hundred thirty-nine subjects (obese, 124; HV normal weight, 15) were studied. Group 1 showed comparable mean LES pressure, peristaltic function, bolus transport and presence of hiatal hernia than HV. Group 2 showed a reduction of these parameters, while group 3 showed a statistical significant reduction in LES pressure, peristaltic function, bolus transport and increase in presence of hiatal hernia. At MII-pH, Group 1 showed a not significant increase in reflux patterns; group 2 and 3 showed a significant increase in esophageal acid exposure and in number of refluxes (both acid and weakly acid), with group 3 showing the higher grade of reflux pattern.

Obese subjects with pre-operative presence of GERD symptoms and endoscopical signs could be tested with HRM and MII-pH before undergoing bariatric surgery, especially for restrictive procedures. On the other hand, obese patients without any sign of GERD could not be tested for reflux, showing similar patterns to HV.

Does pretreatment with baicalin attenuate hypoxia and glucose deprivation-induced injury in SH-SY5Y cells?

To explore the neuroprotective effects of baicalin against hypoxia and glucose deprivation-reperfusion (OGD/RO)-induced injury in SH-SY5Y cells. SH-SY5Y cells were divided into a control group, a OGD/RO group, which was subject to OGD/RO induction; and 3 baicalin groups subject to baicalin (1, 5, 25 μmol/L) for 2 h before induction of OGD/RO (low-, medium-, and high-dose baicalin groups). Cell viability was detected by thiazolyl blue tetrazolium bromide (MTT) assay and flow cytometric analysis was used to detect cell apoptosis. Real-time polymerase chain reaction was performed to determine the mRNA expression of caspase-3 gene. Western blot analysis was conducted to determine the expression of nuclear factor (NF)-κB and N-methyl-daspartic acid receptor-1 (NMDAR1). Baicalin could significantly attenuate OGD/RO mediated apoptotic cell death in SH-SY5Y cells; the apoptosis rates in the low-, medium- and high-dose groups were 12.1%, 7.9%, and 5.4%, respectively. Western blot and real-time PCR analysis revealed that significant decrease in caspase-3 expression in the baicalin group compared with the OGD/RO group (P<0.01). Additionally, down-regulation of NF-κB and NMDAR1 was observed in the baicalin group compared with those obtained from the OGD/RO group. Compared with the low-dose baicalin group, remarkable decrease was noted in the medium- and high-dose groups (P<0.01).

Baicalin pre-treatment attenuates brain ischemia reperfusion injury by suppressing cellular apoptosis.

Does anti-CD3 × anti-GD2 bispecific antibody redirect T-cell cytolytic activity to neuroblastoma targets?

The ganglioside GD2 is an attractive target for immunotherapy of neuroectodermal tumors. We tested a unique bispecific antibody anti-CD3 × anti-GD2 (3F8BiAb) for its ability to redirect activated T cells (ATC) to target GD2-positive neuroblastomas. ATC were generated from normal human peripheral blood mononuclear cells (PBMC) by stimulating the PBMC with OKT3 and expanding the T cells in the presence of interleukin 2 (IL-2) for 14 days. ATC were armed with 3F8BiAb (100 ng/10(6)  cells) or Her2BiAb (50 ng/10(6)  cells) prior to use. 3F8 BiAb were tested for its dual-binding specificity to GD2 expressed on cancer cell lines and CD3 expressed on ATC. 3F8BiAb-armed ATC were further tested ex vivo for their cytotoxicity against GD2 positive tumor targets and its ability to induce cytokine response upon binding to targets. GD2 expression in neuroblastoma cells was confirmed by FACS analysis. Specific binding of 3F8BiAb to the tumor targets as well as to ATC was confirmed by FACS analysis. 3F8BiAb-armed ATC exhibited specific killing of GD2 positive neuroblastoma cell lines significantly above unarmed ATC (P < 0.001). GD2BiAb-armed ATC secreted significantly higher levels of Th(1) cytokines and chemokines compared to unarmed ATC (P < 0.001).

These preclinical findings support the potential of a novel immunotherapeutic approach to target T cells to neuroblastoma.

Does bCG vaccination reduce risk of infection with Mycobacterium tuberculosis as detected by gamma interferon release assay?

To investigate whether BCG vaccination, in addition to a reduction of active tuberculosis, leads to a reduction of Mycobacterium tuberculosis infection during an outbreak of tuberculosis. Pupils (n=199) of a Junior School exposed to a pupil with active pulmonary tuberculosis were screened using a gamma interferon release assay for detection of M. tuberculosis infection (ex vivo ELISPOT assay). Relative risk of M. tuberculosis infection and pulmonary tuberculosis associated with BCG vaccination were calculated and adjusted for exposure risk. Twenty-nine percent of children with previous BCG vaccination had a reactive gamma interferon release assay compared with 47% of unvaccinated children (unadjusted RR 0.61, 95%CI 0.39, 0.96). The protective effect of BCG vaccination persisted following adjustment for other risk factors for infection like ethnicity and proximity to the source case reflected in membership of class and activity groups (corrected relative risk 0.26, 95%CI 0.09, 0.69 and risk reduction of 74%, 95%CI 31%, 91%). A higher proportion of unvaccinated children (11%) were diagnosed with active pulmonary tuberculosis compared with 5% of vaccinated children (RR 0.51 95%CI 0.15, 1.70).

BCG vaccination was associated with a reduction of M. tuberculosis infection diagnosed by gamma interferon release assay testing in school children during a point source outbreak.

Do relationship between substances in seminal plasma and Acrobeads Test results?

To asses the effects of seminal plasma on sperm function. Retrospective case-control study. University hospital. One hundred fourteen infertile men. Acrobeads Test scores (0-4) and measurement of interleukin (IL)-6, soluble IL-6 receptor, epidermal growth factor, insulin-like growth factor-I (IGF-I), transforming growth factor-beta I, superoxide dismutase, calcitonin, and macrophage migration inhibitory factor (MIF) levels in seminal plasma. Kruskal-Wallis test to compare the concentrations of substances as a nonparametric test for differences among Acrobeads Test scores and a multivariable logistic regression model to find independent risk factors associated with abnormal Acrobeads Test results. The Acrobeads Test score was 0 for 7 samples, 1 for 20 samples, 2 for 18 samples, 3 for 28 samples, and 4 for 41 samples. Age, abstinence period, and semen parameters, except for sperm motility and percentage of sperm with abnormal morphology, had no effect on the Acrobeads Test results. Concentrations of IGF-I and MIF were significantly higher in patients with abnormal Acrobeads Test results. Multivariate analysis indicated that MIF and IGF-I were significantly associated with abnormal Acrobeads Test results (scores 0 to 1).

Although further studies are needed, IGF-I and MIF in seminal plasma may have negative effects on sperm function.

Do effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption?

Flavin-containing monooxygenases (FMO) catalyze the metabolism of nucleophilic heteroatom-containing drugs and xenobiotics, including nicotine. Rare mutations in FMO3 are responsible for defective N-oxidation of dietary trimethylamine leading to trimethylaminuria, and common genetic variation in FMO3 has been linked to interindividual variability in metabolic function that may be substrate specific. A genetic model of CYP2A6 function is used as a covariate to reveal functional polymorphism in FMO3 that indirectly influences the ratio of deuterated nicotine metabolized to cotinine following oral administration. The association is tested between FMO3 haplotype and cigarette consumption in a set of nicotine-dependent smokers. FMO3 haplotype, based on all common coding variants in Europeans, significantly predicts nicotine metabolism and accounts for ∼2% of variance in the apparent percent of nicotine metabolized to cotinine. The metabolic ratio is not associated with FMO2 haplotype or an FMO1 expression quantitative trait locus. Cross-validation demonstrates calculated FMO3 haplotype parameters to be robust and significantly improve the predictive nicotine metabolism model over CYP2A6 genotype alone. Functional classes of FMO3 haplotypes, as determined by their influence on nicotine metabolism to cotinine, are also significantly associated with cigarettes per day in nicotine-dependent European Americans (n=1025, P=0.04), and significantly interact (P=0.016) with CYP2A6 genotype to predict cigarettes per day.

These findings suggest that common polymorphisms in FMO3 influence nicotine clearance and that these genetic variants in turn influence cigarette consumption.

Resection or transplantation for early hepatocellular carcinoma in a cirrhotic liver: does size define the best oncological strategy?

Resection and liver transplantation (LT) are the only curative options for hepatocellular carcinoma in cirrhotic patients (HCC-cirr). We tried to define the best primary intention-to-treat strategy in patients undergoing either resection or LT for early single HCC-cirr (≤5 cm). From 1990 to 2010, 198 patients with early HCC-cirr underwent either resection (group R, n = 97) or LT (group T, n = 101) as the primary procedure. Our policy was to prioritize Childs A patients with peripheral lesions for resection rather than LT. Patient and tumor characteristics, and outcomes (recurrence-free survival [RFS] and overall survival [OS]), were studied. A longer diagnosis-to-surgery interval, more Child Pugh B/C patients, and more tumor nodules (on histopathological examination) were found in group T patients. The postoperative mortality (4.1% vs 3.0%, P = 0.72) and rate of major complications (19.1% vs 24.7%, P = 0.35) were similar in groups R and T, respectively, whereas tumor recurrence was higher in group R (62% vs 10% in group T, P<0.0001). The 5-year OS (75% vs 52%, P = 0.0008) and RFS (72% vs 20%, P<0.0001) were better in group T; similarly, more patients were disease free at last follow-up (27% vs 62%, P<0.0001). Resection as the surgical procedure, tumor diameter 3 cm or more on histology, and microvascular tumor invasion were poor prognostic factors for OS and RFS. Including dropout patients from LT list in the analysis, the outcomes in group T were still better (70% and 61% vs 51% and 36% at 5 and 10 years, P = 0.01).

On an intention-to-treat basis, LT is associated with the best survival outcomes in patients with early HCC-cirr. Resection may achieve comparable OS in patients with single HCC-cirr of size smaller than 3 cm; however, the RFS still remains lower than that in patients of group T. This study could serve as a guide for HCC-cirr patients who are candidates for either resection or LT.

Do changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma?

It is not clear whether risk for hepatocellular carcinoma can be accurately determined from long-term changes in serum levels of hepatitis B virus (HBV) DNA or alanine aminotransferase (ALT). We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3160 participants in the REVEAL-HBV study. Development of hepatocellular carcinoma was determined from follow-up examinations and computerized linkage with National Cancer Registry and National Death Certification profiles. Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. During 38,330 person-years of follow-up, 81 participants developed hepatocellular carcinoma (incidence rate, 211.3/100,000 person-years). The risk for hepatocellular carcinoma was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased to <10,000 copies/mL compared with those with baseline levels of HBV DNA<10,000 copies/mL (control group; HR, 2.25; 95% CI, 0.68-7.37). Compared with the control group, the HRs (95% CI) for long-term levels of HBV DNA that persisted at 10,000 to 100,000 copies/mL, decreased to/persisted at 100,000 to 1,000,000 copies/mL, or decreased to/persisted at 1,000,000 to 10,000,000 copies/mL were 3.12 (1.09-8.89), 8.85 (3.85-20.35), and 16.78 (7.33-38.39), respectively. A gradient in ALT level was significantly associated with hepatocellular carcinoma risk: from all low-normal, to ever high-normal, to transient abnormal, to persistent abnormal (Ptrend<.001).

Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for hepatocellular carcinoma. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV.

Does `` Low-dose '' aprotinin modify hemostasis but not proinflammatory cytokine release?

Cytokines are implicated in the pathogenesis of the "whole-body inflammatory response" that may complicate the period after cardiopulmonary bypass (CPB). Low-Dose aprotinin in the pump during CPB has been shown to improve postoperative hemostasis and platelet preservation. We tested the hypothesis that low-dose aprotinin influences the inflammatory reaction (in terms of cytokine release) after CPB. In a prospective, randomized study, 36 patients undergoing elective coronary artery bypass grafting were investigated. Nineteen patients received low-dose aprotinin (2 x 10(6) KIU (280 mg] in the pump), and a control group of 19 did not. Complement activation, cytokine production, leukocyte elastase release. D-dimer level, full blood count, postoperative blood loss, and transfusion requirements were analyzed before, during, and after after CPB. Interleukin-1 beta was not detected in either group, whereas traces of tumor necrosis factor-alpha were infrequently observed. Plasma elastase, interleukin-6, interleukin-8, and neutrophil count increased (p < 0.001) during and after CPB compared with the baseline levels, reaching a peak at 2 hours after protamine administration in both groups before returning toward baseline at 24 hours. Proinflammatory cytokine markers did not differ significantly (p > 0.1) between the groups throughout the study period. The C5b-9 level increased (p < 0.001) in both groups perioperatively, reaching its peak 15 minutes after protamine. Twenty-four-hour postoperative blood loss was significantly (p < 0.001) reduced in the aprotinin group in association with markedly reduced D-dimer levels (p < 0.001). Patients in the aprotinin group also received significantly less banked blood postoperatively than the control group (p < 0.01).

Low-dose aprotinin fails to modify proinflammatory cytokine release, yet confers hemostatic improvement through reduced fibrinolysis in patients undergoing routine coronary artery bypass grafting.

Albuterol Overuse: A Marker of Psychological Distress?

Albuterol overuse, 3 or more canisters per year, is associated with poor asthma control and frequent exacerbations. To describe albuterol use on symptom and symptom-free days and identify predictors of albuterol overuse and controller medication underuse. Secondary analyses of data from adults with mild asthma from the Trial of Asthma Patient Education were carried out. Based on albuterol use of 80% or more on symptom days and less than 20% on symptom-free days, participants were characterized as expected users, overusers, or underusers of albuterol. Good controller medication adherence was defined as 80% or more of prescribed doses. Data included demographic characteristics, diary data, spirometry, and scores from standardized questionnaires. Bivariate associations were examined between categorization of medication use and measured characteristics. Of the 416 participants, 212 (51%) were expected users, 114 (27%) were overusers, and 90 (22%) were underusers of albuterol. No differences were observed among the user groups by demographic characteristics or lung function. Expected users demonstrated the highest asthma-related knowledge, attitudes, and efficacy. Overusers reported the greatest symptom burden, worst asthma control, and highest frequency of symptom days. Overusers also had the highest burden of depression symptoms. More frequent symptom days accounted for 15% of overuse, greater use on symptom days accounted for 31%, and greater use on symptom free days accounted for 54% of overuse. Mean controller adherence was high across all groups, and there were no differences between the groups.

Although overusers experienced more frequent symptom days and used more albuterol on those days, most overuse was attributable to unexpected use on symptom-free days. High levels of comorbid depression were observed, particularly among overusers and among those nonadherent to controller medication.

Is rheumatoid arthritis joint progression in sustained remission determined by disease activity levels preceding the period of radiographic assessment?

Joint damage is related to disease activity in rheumatoid arthritis (RA), but the degree of its progression and the temporal associations between disease activity and joint damage are unclear. The aim of this study was to evaluate whether there is a latency in the effect of disease activity on radiographic progression in patients with RA. Data were obtained from the PREMIER trial, a 2-year randomized, controlled clinical trial of adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in early RA. Radiographic progression of joint damage was calculated using the modified total Sharp score in a subset of patients whose disease was in remission (Simplified Disease Activity Index<or=3.3) in the second year of the trial. The progression of damage in the second year was compared between groups of patients whose disease was already in remission for an additional period of 3, 6, or 9 months during the first year. Analysis of variance was used to test for a linear trend. Among 794 patients with early RA, 119 (15%) achieved sustained remission during the second year, with no difference in radiographic progression across the 3 treatment groups. Radiographic progression in the second year was significantly different between patients with 3, 6, or 9 additional months of remission during year 1 (mean change in the modified Sharp score 1.19 in those with 3 additional months of remission versus 0.20 in those with 6 additional months of remission and -0.32 in those with 9 additional months of remission; P<0.05). The results were supported by similar findings in a series of sensitivity analyses.

These data indicate that the level of disease activity as well as the duration of remission affect subsequent progression of radiographic damage in RA. This latency between disease activity and its effects on radiographic progression should be considered when evaluating radiographic outcomes in trials of RA.

Does endovascular approach to abdominal aortic aneurysms limit the postoperative systemic immune response?

endovascular repair of abdominal aortic aneurysms (E-AAA) has in recent years developed as an alternative to the conventional open repair (C-AAA). Adverse outcomes following the open approach may relate to immune cell activation and the systemic inflammatory response syndrome (SIRS) and organ failure but the benefits in this respect of the endovascular approach are unclear. This study evaluated this question and focused on T-cell activation and function. prospective clinical study. twenty patients undergoing abdominal aortic aneurysm repair (12 C-AAA and 8 E-AAA). peripheral T-cell expression of surface markers CD69, CD62L and CD25 in vivo and Interleukin 2 (IL-2) and Interleukin-10 (IL-10) responses to the superantigen staphylococcal enterotoxin B (SEB) in vitro were measured preoperatively, 24 h and 1 week postoperatively. there was no significant increase (p=0.23) in the incidence of SIRS in the open compared with the endovascular group. Enhanced T cell activation occurred following C-AAA and this was associated with significantly greater IL-2 production in response to SEB, with no change in IL-10 production.

E-AAA attenuates proinflammatory T-cell changes compared with C-AAA repair. A reduction in T-cell activation and impaired responsiveness to superantigen suggests that the immunological sequelae of the endovascular approach to aneurysm repair is more favourable than after the open approach with potentially less risk of adverse outcomes. Proof of this thesis will require a larger prospective study.

Is preference for a cocaine-associated environment attenuated by augmented accumbal serotonin in cocaine withdrawn rats?

Recent studies have found decreased serotonin (5-HT) transmission within the nucleus accumbens following withdrawal from chronic cocaine. We sought to investigate whether increasing brain 5-HT levels would decrease behavioral responses that occur following cocaine withdrawal, namely increased preference for a cocaine environment and anxiety. The conditioned place preference and the defensive burying paradigms were used to measure the behavioral responses that occur 1 week following cocaine withdrawal. We show that pharmacological agents that increase 5-HT transmission (sertraline or 5-hydoxytryptophan, 5-HTP) abolish the preference of subchronically cocaine-treated, abstinent rats for a cocaine-associated environment. Similar results were seen when sertraline was microinjected into the nucleus accumbens. Conversely, rats acutely conditioned with cocaine showed an increased preference for a cocaine-associated environment when pretreated with these drugs. Sertraline also decreased the heightened anxiety-like behaviors found in subchronically treated cocaine rats.

These results indicate that drugs that augment 5-HT function may reduce the desire for cocaine following cocaine withdrawal, and thus facilitate cocaine abstinence in dependent subjects.

Does routine aspiration thrombectomy improve the diagnosis and management of embolic myocardial infarction?

Assess the effect of aspiration thrombectomy on diagnosis and management of embolic acute myocardial infarction. Discrimination of embolic acute myocardial infarction from atherosclerotic plaque rupture/erosion prompts oral anticoagulation treatment of source of embolus, as well as avoiding unnecessary stenting and dual antiplatelet therapy. However, detection is difficult without aspiration. We compared rates of diagnosis of embolic infarction for 2.5 years prior to (pre-RAT) and 2.5 years post routine aspiration thrombectomy (post-RAT). Baseline demographics, outcomes, and treatment strategies were also compared between the embolic infarction and atherosclerotic infarction. Diagnosed embolic infarction rose from 1.2% in the pre-RAT era to 2.8% in the post-RAT period (P < 0.05). In addition, more successful removal of thrombus by aspiration led to less stenting (20% vs. 55% P < 0.05) in the post-RAT period thus avoiding the hazards of "triple therapy." Embolic infarction was more frequently associated with atrial fibrillation (55% vs. 8%), had higher mortality (17% vs. 4%), and had higher rates of embolic stroke (13% vs. 0.3%) when compared with atherosclerotic MI (all P < 0.05).

Routine aspiration thrombectomy more readily identifies embolic infarction allowing more specific therapy and avoidance of stenting and triple anticoagulant therapy.

Do dictyostelium cells bind a secreted autocrine factor that represses cell proliferation?

Dictyostelium cells secrete the proteins AprA and CfaD. Cells lacking either AprA or CfaD proliferate faster than wild type, while AprA or CfaD overexpressor cells proliferate slowly, indicating that AprA and CfaD are autocrine factors that repress proliferation. CfaD interacts with AprA and requires the presence of AprA to slow proliferation. To determine if CfaD is necessary for the ability of AprA to slow proliferation, whether AprA binds to cells, and if so whether the binding requires the presence of CfaD, we examined the binding and effect on proliferation of recombinant AprA. We find that the extracellular accumulation of AprA increases with cell density and reaches a concentration of 0.3 microg/ml near a stationary cell density. When added to wild-type or aprA- cells, recombinant AprA (rAprA) significantly slows proliferation at 0.1 microg/ml and higher concentrations. From 4 to 64 microg/ml, the effect of rAprA is at a plateau, slowing but not stopping proliferation. The proliferation-inhibiting activity of rAprA is roughly the same as that of native AprA in conditioned growth medium. Proliferating aprA- cells show saturable binding of rAprA to 92,000 +/- 11,000 cell-surface receptors with a KD of 0.03 +/- 0.02 microg/ml. There appears to be one class of binding site, and no apparent cooperativity. Native AprA inhibits the binding of rAprA to aprA- cells with a Ki of 0.03 mug/ml, suggesting that the binding kinetics of rAprA are similar to those of native AprA. The proliferation of cells lacking CrlA, a cAMP receptor-like protein, or cells lacking CfaD are not affected by rAprA. Surprisingly, both cell types still bind rAprA.

Together, the data suggest that AprA functions as an autocrine proliferation-inhibiting factor by binding to cell surface receptors. Although AprA requires CfaD for activity, it does not require CfaD to bind to cells, suggesting the possibility that cells have an AprA receptor and a CfaD receptor, and activation of both receptors is required to slow proliferation. We previously found that crlA- cells are sensitive to CfaD. Combined with the results presented here, this suggests that CrlA is not the AprA or CfaD receptor, and may be the receptor for an unknown third factor that is required for AprA and CfaD activity.

Is minimally invasive video-assisted parathyroidectomy a safe procedure to treat primary hyperparathyroidism?

Cervical exploration to identify the four parathyroid glands was considered to be the gold standard for management of primary hyperparathyroidism. In recent years, advances in preoperative localizing techniques have led to the use of more targeted, minimally invasive procedures to remove parathyroid glands. We present our series of patients who underwent Minimally Invasive Video-Assisted Parathyroidectomy (MIVAP) procedures and our results in treating primary hyperparathyroidism. Patients who underwent video-assisted parathyroidectomy were identified from a prospectively maintained database. Clinico-pathological data including indications for surgery, complications, conversion to open procedure and success of surgery were obtained from clinical notes. A total of 56 patients underwent MIVAP between 2002 and 2010 at a district general hospital setup. The clinical indication was diagnosed primary hyperparathyroidism. Preoperative localization was attempted in all patients by sestamibi and high resolution ultrasound scans. The median age of patients was 65 years (32-82) and the median operating time was 78 min (20-168). Conversion to open procedure was done in 8/56 (14%) cases. The reason for conversion was failed exploration in 5 patients, inability to retrieve a very large friable adenoma in one patient, lipo-adenoma in one patient and very small parathyroid adenoma in one patient. Postoperative complications happened in one patient (2%) who developed postoperative sepsis resulting in temporary recurrent laryngeal nerve (RLN) palsy. All but 5 patients became normo-calcaemic following surgery.

MIVAP is a safe and effective procedure for treating patients with primary hyperparathyroidism. It also allows classical 4 gland exploration, whenever necessary.

Is the 712A/G polymorphism of Brain-derived neurotrophic factor associated with Parkinson 's disease but not Major Depressive Disorder in a Chinese Han population?

Overlaps in clinical, pathological and molecular characteristics of Parkinson's disease (PD) and Major Depressive Disorder (MD-D) have promoted association studies in search of common genetic risk factors that may predispose or modify this spectrum of disorders. Experimental and clinical data suggest that genetic variations in Brain-derived neurotrophic factor (BDNF) gene may increase the risk for PD and MD-D. Two hundred and sixty-six PD, 83 MD-D and 400 controls were recruited for this study, assessed using a battery of neuropsychological tests, and genotyped for 11757C/G, 712A/G, 196A/G, and 270C/T in BDNF gene. 712A/G was associated with 2.50-fold time risk of PD. By combining genotypes AG/AA with 712 GG genotype as reference (OR=1) in stratification analysis, AG/AA genotypes were associated with PD (OR=2.94, 95% CI=1.88-4.61). Accordingly, the A allele was significantly overrepresented in PD compared with the G allele (OR=3.16, 95% CI=2.08-4.81). This distribution in females and males were similar.

Our results suggested a novel association between BDNF 712A/G AG/AA genotypes and PD in a Chinese Han population.

Is high plasmatic angiotensin-converting enzyme ( ACE ) activity correlated with training-induced left ventricular growth in ACE congenic rats?

The aim of this study was to determine the influence of angiotensin-converting enzyme (ACE) genotype on left ventricular growth after endurance training, in ACE congenic rats with plasma ACE activity twice as high as the donor strain (LOU), thus mimicking the ACE I/D polymorphism observed in humans. LOU and congenic rats (n = 12) were submitted to an endurance training on a treadmill for 7 weeks, while similar LOU and congenic rats (n = 10) constituted the control groups. Blood pressure, skeletal muscle citrate synthase activity, plasma and left ventricular ACE activity were assessed, and echocardiography was performed before and after the training. Angiotensin-converting enzyme plasmatic activity of congenic rats (188.2 +/- 26.6 in controls and 187.1 +/- 22.6 IU in trained rats respectively) was twofold that of the LOU strain (91.9 +/- 23.3 in controls, and 88.3 +/- 18.1 IU in trained rats respectively). After training, congenic and LOU rats showed a similar significant increase in citrate synthase activity (P < 0.05), and in the left ventricular mass/body mass ratio x 10(3): 3.7 +/- 0.3 and 3.6 +/- 0.6 in the trained congenic and LOU groups, respectively, vs. 3.0 +/- 0.1 and 2.9 +/- 0.2 in the control congenic and LOU groups respectively (P < 0.05). There was no significant correlation between ACE plasma activity and left ventricular mass in trained or untrained congenic rats.

We conclude that training-induced left ventricular growth is not associated with plasma ACE activity in congenic rats.

Is serum eotaxin-1 increased in extremely-low-birth-weight infants with bronchopulmonary dysplasia or death?

Early systemic inflammation in extremely-low-birth-weight (ELBW) infants is associated with an increased risk of bronchopulmonary dysplasia (BPD). Our objective was to identify circulating biomarkers and develop prediction models for BPD/death soon after birth. Blood samples from postnatal day 1 were analyzed for C-reactive protein (CRP) by enzyme-linked immunosorbent assay and for 39 cytokines/chemokines by a multiplex assay in 152 ELBW infants. The primary outcome was physiologic BPD or death by 36 wk. CRP, cytokines, and clinical variables available at ≤24 h were used for forward stepwise regression and Classification and Regression Tree (CART) analysis to identify predictors of BPD/death. Overall, 24% developed BPD and 35% died or developed BPD. Regression analysis identified birth weight and eotaxin (CCL11) as the two most significant variables. CART identified FiO2 at 24 h (11% BPD/death if FiO2 ≤28%, 49% if >28%) and eotaxin in infants with FiO2 > 28% (29% BPD/death if eotaxin was ≤84 pg/ml; 65% if >84) as variables most associated with outcome.

Eotaxin measured on the day of birth is useful for identifying ELBW infants at risk of BPD/death. Further investigation is required to determine if eotaxin is involved in lung injury and pathogenesis of BPD.

Does intratracheal administration of sildenafil and surfactant alleviate the pulmonary hypertension in newborn piglets?

To study systemic and pulmonary effects of low-dose sildenafil with surfactant in newborn piglets with pulmonary hypertension (PHT) induced by thromboxane A(2) analog (U46619). Piglets (1-3 days, 1.7-2.5 kg) were mechanically ventilated and prepared for the continuous measurement of mean systemic and pulmonary arterial pressures (MAP and PAP, respectively), heart rate and pulmonary artery flow (as cardiac output). Following stabilization, PHT was induced by intravenous U46619 infusion (0.2-0.8 microg/kg/min) for 120 min. Piglets were randomized for intratracheal administration of surfactant (BLES, 4 ml/kg) with saline (n=6) or sildenafil (0.05 mg/kg, n=6) given after 60 min of U46619 treatment. Temporal changes of hemodynamic measurements were analyzed by two-way ANOVA. There was progressive PHT induced by U46619 (161% of baseline), with increased PAP and pulmonary vascular resistance and decreased cardiac output. Surfactant and sildenafil combined improved PAP along with reduced pulmonary vascular resistance. Cardiac output was higher with surfactant and sildenafil combined than surfactant alone. No significant changes in heart rate, stroke volume, MAP and systemic vascular resistance were observed. Ratio of PAP:MAP was lowered with surfactant and sildenafil combined. Systemic oxygen consumption was not different between groups but the oxygen extraction ratio was higher than baseline in surfactant alone (P<0.05).

Adding low-dose sildenafil to surfactant is effective in alleviating the progressive PHT developed in newborn piglets induced by thromboxane A(2). Intratracheal sildenafil may be a useful therapeutic adjunct to critically ill neonates with PHT.

New tobacco products: do smokers like them?

There is little information about smokers who tried potentially reduced exposure products (PREPs) (Eclipse, Omni, Advance Lights, Accord, or Ariva), why they tried them, if they liked these products, and if they will continue to use them. The objectives of this qualitative study were to understand: (1) how smokers who tried PREPs learned about them, (2) reasons for first trying PREPs, (3) which PREP(s) they tried, (4) what they thought of the product at first trial, (5) reasons for continuing or discontinuing use, and (6) whether they would recommend PREPs to others. In October 2002, 16 focus group sessions were conducted with current cigarette smokers aged 30-50 years: eight groups in Chattanooga, Tennessee, and eight in Dallas, Texas. Specific focus groups were composed of white men, white women, African American men, African American women, Hispanic men, or Hispanic women. The majority of the participants learned about PREPs through advertising or promotion, family, friends, and co-workers; major reasons given for first trying PREPs were that the products were free or inexpensive, they wanted to stop smoking, they believed the product claims of fewer health risks, or they were curious; most of them tried Eclipse probably because the focus groups were conducted in the same cities where Eclipse was introduced; most participants did not like PREPs; most discontinued the use of PREPS, some who continued to use them did so infrequently and also kept smoking their regular brands of cigarettes; and most would not recommend PREPs, although a few might recommend them to specific groups (for example, new smokers, the young, women, curious or health conscious people).

Although most established smokers did not like the PREPs they tried and will not recommend them to anyone, a minority of established smokers believe that there may be a market for these products.

Perfluorooctanoic acid and ammonium perfluorooctanoate: volatile surfactants for proteome analysis?

Fluorinated surfactants are being explored as mass spectrometry (MS)-friendly alternatives to sodium dodecyl sulfate (SDS) for proteome analysis. Previous work demonstrates perfluorooctanoic acid (PFOA) to be compatible with electrospray ionization (ESI)-MS. The high volatility of PFOA provides an intrinsic approach to potentially eliminate the surfactant during ESI, or alternatively through solvent evaporation prior to MS. The ammonium salt of PFOA, ammonium perfluorooctanoate (APFO), is likely favored for proteome experiments; the MS and liquid chromatography (LC)/MS tolerance of APFO has not been established for proteome applications. Standard proteins and peptides, as well as a yeast proteome mixture, were individually spiked with surfactants (APFO, PFOA, SDS), and subjected to direct infusion ESI-MS, LC/MS/MS and LC/UV. The level of fluorinated surfactant remaining after solvent evaporation under varying conditions (time, pH, salt and protein content) was quantified and compared to the threshold tolerance level of the surfactant in an MS experiment (determined herein). Whereas PFOA is found ineffective at assisting protein solubilization, APFO is as effective as SDS for resolubilization of acetone-precipitated yeast proteins (~100% recovery). Unfortunately, the LC and MS threshold tolerance of APFO is only minimally greater than SDS (~2-fold higher concentration to cause 50% suppression). Nonetheless, the benefits of APFO in a proteome experiment are realized following a one-step evaporation protocol for removal of the surfactant in acidified solvent.

APFO is considered a favoured alternative to SDS for proteome solubilization. Strictly speaking, APFO is not an 'MS-friendly' surfactant for proteome characterization; the detergent not only suppresses ESI signals at high concentration, but also perturbs reversed phase separation. However, the simplicity of APFO removal ahead of LC/MS justifies its use over the conventional SDS.

Is nasal patency related to dust exposure in woodworkers?

A cross sectional study of 54 furniture factories and three control factories was conducted to investigate the relation between subjective and objective nasal obstruction and exposure to wood dust. Acoustic rhinometry was performed on 161 woodworkers and 19 controls. For each person, four measuring rounds were performed: before work, after 4 hours of work, and after 7 hours of work before and after decongestion. Before the first and third measuring round, each person rated the current feeling of nasal obstruction in the left and right nostril separately, using a visual analogue scale. Personal passive dust measurements were performed on 140 woodworkers. The mean (SD) of equivalent inhalable dust was relatively low, 1.17 (0.62) mg/m(3), range 0.17-3.44 mg/m(3). The exposure was divided into four levels: controls, low exposure, medium exposure, and high exposure. For the two highest concentrations of exposure, a significant increase in congestion--decreased nasal cavity volume and cross sectional areas--was found after 4 and 7 hours of work, compared with before work. Multivariate linear regression analysis showed positive correlations between concentration of dust and change in mucosal swelling. A significant increase in self rated nasal obstruction was found after work compared with before work for the two highest exposure groups. No correlation between objective nasal variables and self rated nasal obstruction was found.

Exposure to wood dust was related in a dose dependent manner to acute nasal obstruction measured by acoustic rhinometry and self reported obstruction, but no correlation was found between measured and self reported obstruction.

Is cell proliferation assessed by Ki-67 immunoreactivity on formalin fixed tissues a predictive factor for survival in prostate cancer?

Proliferation rate may be an important determinant of tumor progression. To evaluate the predictive value of proliferation, immunoreactivity for the proliferation associated antigen Ki-67 was related to survival in a series of patients with prostate cancer. Formalin fixed tissue, obtained by transurethral resection from 125 previously untreated prostate tumors, was examined with an immunohistochemical method for Ki-67. Ki-67 index was defined as the percentage of immunoreactive cells in a tumor. Patients were followed with surveillance after transurethral resection. The cause of death was determined by examination of patient records 11 to 19 years postoperatively (mean followup 71 months). At evaluation 17 patients (14%) were still at risk and 55 (44%) had died of prostate cancer. Mean Ki-67 index was 2.1. Ki-67 index correlated with grade (p < 0.0005) and weakly with stage (p = 0.019). Mean survival of patients with a Ki-67 index of more than 3 was less than half that of patients with a Ki-67 index of less than 3 (53 versus 132 months, p < 0.00005). The difference in survival remained in an analysis of the intermediately differentiated tumors (61 versus 126 months, p = 0.0032). In a Cox multiple regression analysis for cancer specific survival, including Ki-67 index, grade, stage, metastasis and age, Ki-67 index remained an independent predictive factor.

Our study indicates that proliferation rate, assessed by Ki-67 immunoreactivity in formalin fixed tissues, is a predictive marker for outcome in prostate cancer.

Inpatient hospitalization of oncology patients: are we missing an opportunity for end-of-life care?

Despite advances in the care of patients with cancer over the last 10 years, cancer remains the second leading cause of death in the United States. Many patients receive aggressive, in-hospital end-of-life care at high cost. There are few data on outcomes after unplanned hospitalization of patients with metastatic cancer. In 2000 and 2010, data were collected on admissions, interventions, and survival for patients admitted to an academic inpatient medical oncology service. The 2000 survey included 191 admissions of 151 unique patients. The 2010 survey assessed 149 admissions of 119 patients. Lung, GI, and breast cancers were the most common cancer diagnoses. In the 2010 assessment, pain was the most common chief complaint, accounting for 28%. Although symptoms were the dominant reason for admission in 2010, procedures and imaging were common in both surveys. The median survival of patients after discharge was 4.7 months in 2000 and 3.4 months in 2010. Despite poor survival in this patient population, hospice was recommended in only 23% and 24% of patients in 2000 and 2010, respectively. Seventy percent of patients were discharged home without additional services.

On the basis of our data, an unscheduled hospitalization for a patient with advanced cancer strongly predicts a median survival of fewer than 6 months. We believe that hospital admission represents an opportunity to commence and/or consolidate appropriate palliative care services and end-of-life care.

Is peak stimulated insulin secretion associated with specific changes in gene expression profiles in sporadic insulinomas?

The molecular pathways that are responsible for pathologic insulin secretion by insulinomas have not been characterized. We studied gene expression profiles from insulinomas and determined associations between these changes and preoperative peak serum insulin levels. Ten patients with insulinomas underwent calcium-stimulated arteriography and surgical resection. Tumor RNA was isolated; corresponding complementary DNA was hybridized to 10K human complementary DNA arrays. Pooled human islet cell complementary DNA served as the control. Cluster analysis of gene expression and analysis of expression ratios was performed. Nineteen genes were up-regulated at least 3-fold in insulinomas compared with controls, which included the genes for islet amyloid polypeptide and proprotein convertase type 2. Cluster analysis revealed 2 groups of patients with insulinoma and with distinct patterns of gene expression. Mean peak serum insulin values between groups were 196 and 1100 (U/mL (P<.05), which demonstrates a significant difference in insulin response to calcium stimulation between these 2 groups.

We show that genes that are relevant to the pathogenesis of hyperinsulinemia are expressed preferentially in insulinomas. In addition, patients with a distinct and common pattern of gene expression had significantly higher stimulated insulin secretion levels. The study of these genes may help to identify the biochemical pathways that are responsible for pathologic insulin secretion.

Do subjects with seasonal allergic rhinitis and nonrhinitic subjects react differentially to nasal provocation with chlorine gas?

Nasal irritation and associated symptoms (nasal congestion, rhinorrhea, and sinus headache) are important elements of the response to indoor and outdoor air pollution. Marked interindividual variability in such symptoms has been suggested clinically and epidemiologically, but little experimental data exist on this issue. We sought to test the hypothesis that subjects with seasonal allergic rhinitis (SAR) exhibit a more marked physiologic response (congestion) after nasal irritant provocation than do nonrhinitic subjects. We studied eight subjects with SAR and eight nonrhinitic subjects; subjects with SAR were studied out of season. In a single-blind crossover study, subjects had their nasal airway resistance (NAR) measured in triplicate before, immediately after, and 15 minutes after a 15-minute exposure to either filtered air or 0.5 ppm chlorine in filtered air, administered through a nasal mask in a climate-controlled chamber. Log-transformed NAR values were analyzed in a repeated-measures analysis of variance model, with confirmatory testing using paired t tests. The net (chlorine minus air day) percent change in NAR from baseline (before exposure) to immediately after exposure was +24% in the SAR group and +3% in the nonrhinitic group (p < 0.05). The corresponding net changes from baseline to 15 minutes after exposure were +21% in the SAR group and -1% in the nonrhinitic group (p < 0.05).

The observed augmented nasal congestive response of subjects with SAR versus nonrhinitic subjects to a controlled low-level chemical irritant provocation is consistent with epidemiologic surveys showing a higher prevalence of nasal symptoms among subjects with SAR than nonrhinitic subjects in environments involving irritant air pollutants.

Does nitric oxide-dependent suppression of thioredoxin-interacting protein expression enhance thioredoxin activity?

Cellular redox balance is regulated by enzymatic and nonenzymatic systems and freely diffusible nitric oxide (NO) promotes antioxidative mechanisms. We show the NO-dependent transcriptional regulation of the antioxidative thioredoxin system. Incubation of rat pulmonary artery smooth muscle cells (RPaSMC) with the NO donor compound S-nitroso-glutathione (GSNO, 100 micromol/L) suppressed thioredoxin-interacting protein (Txnip), an inhibitor of thioredoxin function, by 71+/-18% and enhanced thioredoxin reductase 2.7+/-0.2 fold (n=6; both P<0.001 versus control). GSNO increased thioredoxin activity (1.9+/-0.5-fold after 4 hours; P<0.05 versus control). Promoter deletion analysis revealed that NO suppression of Txnip transcription is mediated by cis-regulatory elements between -1777 and -1127 bp upstream of the start codon. Hyperglycemia induced Txnip promoter activity (3.9+/-0.2-fold; P<0.001) and abolished NO effects (-37.4+/-1.0% at 5.6 mmol/L glucose versus 12.4+/-2.1% at 22.4 mmol/L glucose; P<0.05). Immunoprecipitation experiments demonstrated that GSNO stimulation and mutation of thioredoxin at Cys69, a site of nitrosylation, had no effect on the Txnip/thioredoxin interaction.

NO can regulate cellular redox state by changing expression of Txnip and thioredoxin reductase. This represents a novel antioxidative mechanism of NO independent of posttranslational protein S-nitrosylation of thioredoxin.

Do pulsed lasers produce an effective photodynamic therapy response?

Photodynamic therapy (PDT) in dermatology is traditionally performed with topical aminolevulinic acid (ALA) and continuous-wave (CW) illumination with blue or red light. Recently, several authors have reported success with laser and other pulsed-light sources for PDT. While the clinical benefits on sun-exposed skin are apparent, no study has demonstrated that the pulsed light sources are responsible for the observed response. A placebo-controlled study of two pulsed light sources previously reported for PDT: the pulsed dye laser (PDL) or broadband flashlamp filtered intense pulsed light (IPL). Sun-hidden skin was prepared with microdermabrasion and acetone scrub followed by ALA under occlusion. Laser or IPL was delivered under conditions previously reported to produce a clinical response. Control areas were exposed to standardized CW blue light or to no light. A second control area was prepared and received light and the ALA vehicle. IPL and PDL demonstrated a faint dose-response effect on PDT activation, but were less potent than a smaller fluence of CW blue light. Ambient light activated ALA-treated skin.

Both IPL and PDL are capable of activation of PDT but produce dramatically less PDT reaction than the standard CW blue-light broadband source. Physicians desiring a robust PDT response might select CW sources over pulsed sources. Ambient light may activate a PDT reaction.

Is fucoidan-dependent increased membrane components in HepG2 cells : effect of fucoidan due to gene expression?

The precise mechanism of the therapeutic effects of fucoidan (sulphated polyfucose) on cultured hepatocarcinoma HepG2 cells is as yet unclear. Protein components between fucoidan-treated and non-treated HepG2 cells were compared through a quantitative micro-sequencing method. A dramatic and immediate increment of the membrane compartment and a decrement of RNA virus by fucoidan, as an effect of the Ishi-Mozuku (an edible brown seaweed Mozuku of Japan), are demonstrated. The ratio of membrane glycoproteins to total cellular proteins increases from 28.9% to 43.2% (1.5-fold), and the positive-sense single-stranded RNA viral proteins among the total cellular proteins decrease from 5.3% to 0.29% (18-fold), respectively, in response to 0.102 mg/ml fucoidan in HepG2 cells over three days' period.

Fucoidan seems to retard the growth of HepG2 cells through membrane glycoprotein metabolism. Therefore, fucoidan could be expected to have a therapeutic effect on hepatocellular carcinoma.

Does colonic fermentation of indigestible carbohydrates contribute to the second-meal effect?

Low postprandial blood glucose is associated with low risk of metabolic diseases. A meal's ability to diminish the glucose response to carbohydrates eaten during the following meal is known as the "second-meal effect" (SME). The reduced glycemia elicited by low-glycemic-index (LGI) foods consumed during the first meal has been suggested as the main mechanism for SME. However, LGI foods often increase colonic fermentation because of the presence of fiber and resistant starch. The objective was to study the SME of greater fermentation of high-glycemic-index (HGI) and LGI carbohydrates eaten during a previous meal. Ten healthy volunteers ate 3 breakfast test meals consisting of sponge cakes made with rapidly digestible, nonfermentable amylopectin starch plus cellulose (HGI meal), amylopectin starch plus the fermentable disaccharide lactulose (HGI-Lac meal), or slowly digestible, partly fermentable amylose starch plus cellulose (LGI meal). Five hours later, subjects were fed the same standard lunch containing 93 g available carbohydrates. Blood was collected for measurement of glucose, insulin, and nonesterified fatty acids (NEFAs). Breath hydrogen was measured as a marker of colonic fermentation. Postlunch gastric emptying was measured by using ultrasonography. Both the HGI-Lac and LGI meals improved glucose tolerance at lunch. In the case of the HGI-Lac meal, this effect was concomitant with low NEFA concentrations and delayed gastric emptying.

Fermentable carbohydrates, independent of their effect on a food's glycemic index, have the potential to regulate postprandial responses to a second meal by reducing NEFA competition for glucose disposal and, to a minor extent, by affecting intestinal motility.

Is alkaline phosphatase normalization associated with better prognosis in primary sclerosing cholangitis?

Primary sclerosing cholangitis results in elevated but fluctuating serum alkaline phosphatase levels that occasionally return to normal. To investigate the frequency of normalization of alkaline phosphatase in newly diagnosed primary sclerosing cholangitis patients and the subsequent clinical outcomes. Records of newly diagnosed primary sclerosing cholangitis patients were examined retrospectively for laboratory values and clinical end points (cholangiocarcinoma, liver transplantation and death) within 10 years of diagnosis. Data from a recent prospective ursodeoxycholic acid treatment trial were also studied. Eighty-seven patients met the inclusion criteria. Normalization of alkaline phosphatase was seen in 35 (40%) patients. Five (14%) patients with normalization reached an end point whereas 17 (33%) of the patients with persistent elevation reached an end point (P = 0.02). Ursodeoxycholic acid was used similarly by both groups. When the investigative criteria were applied to a prospective trial, there was again a significant relationship between normalization of alkaline phosphatase and survival in patients receiving ursodeoxycholic acid (P < 0.01) and the placebo group (P = 0.02).

Serum alkaline phosphatase was found to normalize in a high proportion of newly diagnosed primary sclerosing cholangitis patients. This was significantly associated with a better prognosis in a retrospective cohort and when data from a prospective treatment trial was evaluated.

Does phylogeny of diving beetles reveal a coevolutionary arms race between the sexes?

Darwin illustrated his sexual selection theory with male and female morphology of diving beetles, but maintained a cooperative view of their interaction. Present theory suggests that instead sexual conflict should be a widespread evolutionary force driving both intersexual coevolutionary arms races and speciation. We combined Bayesian phylogenetics, complete taxon sampling and a multi-gene approach to test the arms race scenario on a robust diving beetle phylogeny. As predicted, suction cups in males and modified dorsal surfaces in females showed a pronounced coevolutionary pattern. The female dorsal modifications impair the attachment ability of male suction cups, but each antagonistic novelty in females corresponds to counter-differentiation of suction cups in males.

A recently diverged sibling species pair in Japan is possibly one consequence of this arms race and we suggest that future studies on hypoxia might reveal the key to the extraordinary selection for female counter-adaptations in diving beetles.

Do ambulance crews with one advanced paramedic skills officer have longer scene times than crews with two?

In 1999, the Metropolitan Ambulance Service (MAS), Melbourne, Australia began implementing The Emergency Operations Plan (1998). One of the initiatives of the plan was the addition of crews with one advanced paramedic skills (APS) officer and one non-APS officer (mixed crews). All previous APS crews contained two APS officers working together. There was concern that mixed crews would have longer scene times than all-APS crews. This study aims to compare scene times at time critical cases for mixed crews and all-APS crews. Prospective, non-randomised comparison of scene times for time critical cases for three mixed crew units and three all-APS units for the months of August to October 1999. The crew types were also compared by explicit retrospective audit for rates of APS procedures attempted and APS procedure failure rates. Data were analysed using SPSS, t test, and chi(2) test where appropriate. There were 1700 time critical cases in the study period of which 1537 had valid data for the calculation of scene times. A total of 714 cases were attended by mixed crews and 823 cases by all-APS crews. The mean scene time for mixed crews was 15.54 minutes compared with 16.92 minutes for all-APS crews. This difference is statistically significant (p=0.002). All-APS crews performed a slightly higher number of APS procedures (0.90/time critical case versus 0.76/time critical case; p=0.001). There was no significant difference in procedure failure rates.

Mixed crews demonstrated shorter scene times than all-APS crews, although this is unlikely to be clinically significant. The concern that mixed crews would have longer scene time was not substantiated and should not be considered as a barrier to the development of mixed crew staffing models.

Does remote ischemic perconditioning attenuate acute inflammation of experimental musculocutaneous flaps following ischemia-reperfusion injury?

In free flap reconstruction and replantation surgery, prolonged ischemia time may lead to flap or replantation failure. The aim of the study was to investigate the effects of hypothermic flap ischemia or remote ischemic perconditioning (RIPER) during normothermic ischemia on acute inflammation of musculocutaneous flaps subjected to ischemia-reperfusion injury. In 24 pigs, a musculocutaneous latissimus dorsi flap was dissected and subjected to 4 hours of arterial ischemia and 7 hours of reperfusion. The animals were allocated into two experimental groups: hypothermic flap ischemia at 4°C (n = 8) or normothermic flap ischemia with RIPER (n = 8), and one control group with normothermic flap ischemia (n = 8). The hypothermic ischemic flaps were cooled in a basin with fresh water and ice. RIPER was initiated 1 hour before reperfusion, by inducing three 10 min cycles of hind limb ischemia with a tourniquet, each separated by 10 min of reperfusion. Acute inflammation was described by inflammatory cytokine secretion (IL-1β, IL-6, IL-10, IL-12p40, and TNF-α) from the flap during reperfusion, and by quantitative determination of macrophages in flap biopsies of dermis, subcutaneous tissue, and skeletal muscle following reperfusion. No significant differences were found between normothermic and hypothermic flap ischemia in inflammatory cytokine secretion. However, the IL-6 secretion was significantly reduced in the RIPER group compared with the control group at 5 hours of reperfusion (P = 0.036), and in the RIPER group compared with the hypothermic ischemia group at 3 (P = 0 0.0063), 5 (P = 0.0026), and 7 hours of reperfusion (P = 0.028). The IL-12p40 secretion was significantly reduced in the RIPER group compared with the control group (P = 0.0054) as well as the hypothermic ischemia group (P = 0.028) at 5 hours of reperfusion. No significant difference was found among groups in macrophage infiltration.

RIPER reduced IL-6 and IL-12p40 secretion during reperfusion of porcine musculocutaneous flaps, when compared with hypothermic ischemic flaps and normothermic ischemic flaps without RIPER. © 2016 Wiley Periodicals, Inc. Microsurgery, 2016.

Does androgen substitution with testosterone undecanoate in survivors of bilateral testicular cancer require individually-adjusted injection intervals?

• To explore the efficacy and safety of testosterone undecanoate (TU) (Nebido®; Bayer Schering Pharma AG, Berlin, Germany) in patients with bilateral germ cell testicular cancer (GCTC) who have switched androgen substitution from testosterone enanthate (Primoteston Depot®, Bayer Schering Pharma AG). • In total, 47 bilaterally orchidectomized GCTC patients were included in a prospective study to monitor serum gonadal hormones, biochemical safety and symptoms of hypogonadism based on the Aging Males' Symptoms scale during TU treatment for a 28-week period. • During treatment, serum levels of total (TT) and calculated free testosterone (CFT) increased with simultaneously decreasing levels of FSH and LH. However, considerable variations in median levels of TT and CFT were observed during the study. The highest levels of TT and CFT were observed 1-2 weeks after each injection and the lowest immediately before the second injection. • Insufficient levels of TT (< 8 nmol/L) were observed in 10 patients, with nine of these during the second half of the first treatment cycle. Supernormal levels of TT (> 35 nmol/L) were measured in 28 patients of which 26 occurred at least once during the first 3 weeks of each treatment cycle. • A follow-up review at median 39 months after study start showed a median steady-state injection interval of 10 weeks, with an individual variability of 6-14 weeks. Symptoms according to the Aging Males' Symptoms scale remained unchanged. No severe toxicity was encountered. Only one patient experienced transient elevation of serum alanine transaminase and aspartate transaminase with maximal Common Toxicity Criteria, grade 2.

• TU is safe and highly efficient for the treatment of anorchid GCTC survivors. • Androgen substitution with TU in bilateral GCTC survivors requires individually-adjusted injection intervals. In most cases, 10-week intervals appear to be sufficient.

Does skeletal Muscle Erythropoietin Expression be Responsive to Hypoxia and Exercise?

Erythropoietin is responsible for regulating the growth and development of red blood cells. Reports conflict on whether skeletal muscle is able to produce erythropoietin and release it into circulation and if exercise affects this. We set out to determine how erythropoietin is regulated in skeletal muscle and to determine whether skeletal muscle-derived erythropoietin can stimulate erythropoiesis. Using an in vitro approach, we exposed proliferating and differentiated skeletal muscle cells to various forms of exercise-induced physiological stimuli and measured erythropoietin gene expression. To understand if skeletal muscle cells were able to stimulate erythropoiesis, independent of other cell types found in skeletal muscle, we used myoblast-conditioned media to treat bone marrow and to measure erythropoiesis through flow cytometry. We also measured erythropoietin expression and hypoxia in mice subjected to an exercise protocol designed to induce skeletal muscle oxygen stress. Hypoxia increased erythropoietin expression in C2C12 myoblasts, myotubes, and primary myoblasts in vitro by 50% to 130%. Bone marrow treated with media conditioned with hypoxic myoblasts for 24 h increased the number of Ter-119-positive cells by 32%. An erythropoietin-neutralizing antibody prevented this increase. Compared with unexercised controls, exhaustive exercise increased skeletal muscle HIF1α levels by 50% and HIF2α levels by 20%. Moreover, exercised skeletal muscle erythropoietin expression was 70% higher.

These results demonstrate that skeletal muscle produces erythropoietin in a hypoxia and HIF-dependent manner and that hypoxia-treated muscle is capable of stimulating erythropoiesis in vitro.

Does tumor-infiltrated immune response correlate with alterations in the apoptotic and cell cycle pathways in Hodgkin and Reed-Sternberg cells?

To analyze tumor-microenvironment relationships in Hodgkin lymphoma (HL) as potential determinants in the decision-making process related to the alterations in cell cycle and apoptotic pathways of Hodgkin/Reed-Sternberg (H/RS) cells. Based on a cohort of 257 classic HL patients, we carried out a global descriptive correlational analysis and logistic regression study to identify tumor-infiltrated immune cell rate in HL that could be interconnected with genes involved in the regulation of apoptotic/proliferative pathways in H/RS cells. Our results reveal the existence of a connection between the reactive microenvironment and molecular changes in apoptotic/proliferative pathways in H/RS cells. A lesser incidence of infiltrated cytotoxic cells in the tumor (CD8(+) T lymphocytes, CD57(+) natural killer, and granzyme B(+) cells) was associated with overexpression of antiapoptotic proteins (Bcl-X(L), survivin, caspase-3, and nuclear factor-kappaB) in tumoral cells. Increased incidence of general infiltrated immune cells, such as CD4(+) T lymphocytes, CD57(+) natural killer cells, activated CTL, and dendritic cells, in the microenvironment of the tumor was associated with increased growth fraction of tumoral cells, including G(1)-S checkpoint (cyclin D and cyclin E) and tumor suppressor pathways (p16 and SKP2), and with the presence of EBV (signal transducers and activators of transcription 1 and 3 expression; STAT1/STAT3).

A lower level of cytotoxic cells correlated with an increase of antiapoptotic mechanisms in H/RS cells, whereas the global infiltrated immune population correlated with the growth fraction of the tumor. Our collective data suggest a causal relationship between infiltrated immune response and concurrent changes of the different proliferative checkpoints, tumor suppressor, and apoptotic pathways of H/RS cells in HL.

Lower urinary tract changes after early valve ablation in neonates and infants: is early diversion warranted?

Severe hydronephrosis, high grade reflux and/or renal insufficiency often leads to proximal urinary tract diversion in male infants with posterior urethral valves. Even with this treatment progressive loss of renal function often occurs. Unfortunately with early diversion the bladder, already damaged by in utero obstruction, is also defunctionalized. Alternative treatment with valve ablation in the newborn period and without diversion may facilitate recovery of normal bladder function. We retrospectively reviewed the records of infants treated for posterior urethral valves before age 1 year at our institution in the last 8 years. Treatment comprised primary valve ablation in 23 patients and urinary diversion in 8. Preoperative and serial postoperative voiding cystourethrograms were scored for degree of trabeculation, bladder neck hypertrophy and prostatic urethral dilatation in all patients undergoing primary valve ablation. Recovery of bladder and renal function after primary valve ablation was compared to that of patients treated with urinary diversion. All patients treated with primary valve ablation demonstrated marked improvement or resolution of bladder abnormalities on voiding cystourethrography by 1 year postoperatively. Bladder compliance and volume were statistically better than in patients treated with primary diversion. Upper tract diversion failed to halt progressive renal failure in 5 of the 6 patients who underwent diversion. Similarly primary valve ablation did not stop progressive renal failure in a matched group of patients.

Early ablation of posterior urethral valves results in the recovery of normal bladder appearance and function when performed in the first months of life. Severe renal insufficiency tends to progress even with upper tract diversion. Furthermore, this treatment prevents normal bladder cycling, which may inhibit bladder recovery in the patient with posterior urethral valves.

Does mRI suggest increased tonicity of the levator ani in women with interstitial cystitis/bladder pain syndrome?

In interstitial cystitis/bladder pain syndrome (IC/BPS), pelvic floor dysfunction may contribute significantly to pelvic pain. To determine if pelvic floor hypertonicity manifests alterations on magnetic resonance imaging (MRI) in patients with IC/BPS, we retrospectively compared pelvic measurements between patients and controls. Fifteen women with IC/BPS and 15 age-matched controls underwent pelvic MRI. Two blinded radiologists measured the pelvic musculature, including the H- and M lines, vaginal length, urethral length and cross-sectional area, levator width and length, and posterior puborectalis angle. MRI measures and clinical factors, such as age, parity, and duration of symptoms, were compared using a paired, two-tailed t test. There were no significant differences in age, parity, or symptom duration between groups. Patients with IC/BPS exhibited shorter levator muscles (right: 5.0 ± 0.7 vs. 5.6 ± 0.8, left: 5.0 ± 0.8 vs. 5.7 ± 0.8 cm, P < 0.002) and a wider posterior puborectalis angle (35.0 ± 8.6 vs. 26.7 ± 7.9°, P < 0.01) compared with controls. The H line was shorter in patients with IC/BPS (7.8 ± 0.8 vs. 8.6 ± 0.9 cm, P < 0.02), while M line did not differ. Total urethral length was similar, but vaginal cuff and bladder neck distances to the H line were longer in patients with IC/BPS (5.7 ± 0.6 vs. 5.1 ± 0.9 cm, P < 0.02; 1.9 ± 0.4 vs. 1.4 ± 0.2 cm, P < 0.001, respectively).

Patients with IC/BPS have pelvic floor hypertonicity on MRI, which manifests as shortened levator, increased posterior puborectalis angles, and decreased puborectal distances. We identified evidence of pelvic floor hypertonicity in patients with IC/BPS, which may contribute to or amplify pelvic pain. Future studies are necessary to determine the MRI utility in understanding pelvic floor hypertonicity in patients with IC/BPS.

Does intranasal fluticasone propionate inhibit recovery of chemokines and other cytokines in nasal secretions in allergen-induced rhinitis?

Allergen-induced nasal responses are associated with the recovery of proinflammatory mediators and cytokines. In recent years, a distinct group of chemotactic cytokines, chemokines, has been the focus of intense investigation as to their possible role in the pathogenesis of allergic diseases. Although corticosteroids have been known to be effective in the treatment of allergic diseases, their mechanism(s) of action has not been fully elucidated. To study the effect of topical fluticasone on the recovery of chemokines (IL-8, MIP-1 alpha, and RANTES) and other cytokines (IL-1 beta, IL-6, and GM-CSF) from nasal mucosa following allergen challenge. To correlate the improvement of rhinitis symptoms with cytokine levels during early-phase and late-phase allergic responses. A randomized, double-blind, placebo-controlled crossover study of fluticasone propionate, 200 micrograms q d, was performed in ten subjects with allergic rhinitis. Allergen challenge was administered after 1 week of treatment. Nasal secretions were collected immediately after challenge and during the late-phase reactions; symptom scores were recorded simultaneously. Nasal cytokines were assayed by specific ELISA. The allergen challenge caused early-phase and late-phase allergic reactions and increased recovery of IL-1 beta, IL-6, IL-8, RANTES, MIP-1 alpha, and GM-CSF from the nasal mucosa. Intranasal fluticasone inhibited the allergen-induced increase in nasal symptoms. This was associated with decreases in cytokine recovery. A significant correlation was observed between decreases in cytokine levels and in symptom scores after treatment.

Our results suggest that treatment with topical fluticasone propionate inhibits allergen-induced nasal responses and the associated increase in the production/secretion of chemokines and other proinflammatory cytokines.

Is intensive expression of Bmi-1 a new independent predictor of poor outcome in patients with ovarian carcinoma?

It has been suggested that the B-cell specific moloney leukemia virus insertion site 1 (Bmi-1) gene plays an oncogenic role in several types of human cancer, but the status of Bmi-1 amplification and expression in ovarian cancer and its clinical/prognostic significance are unclear. The methods of immunohistochemistry and fluorescence in situ hybridization were utilized to examine protein expression and amplification of Bmi-1 in 30 normal ovaries, 30 ovarian cystadenomas, 40 borderline ovarian tumors and 179 ovarian carcinomas. Intensive expression of Bmi-1 was detected in none of the normal ovaries, 3% cystadenomas, 10% borderline tumors, and 37% ovarian carcinomas, respectively. Amplification of Bmi-1 was detected in 8% of ovarian carcinomas. In ovarian carcinomas, significant positive associations were found between intensive expression of Bmi-1 and the tumors ascending histological grade, later pT/pN/pM and FIGO stages (P < 0.05). In univariate survival analysis of the ovarian carcinoma cohorts, a significant association of intensive expression of Bmi-1 with shortened patient survival (mean 49.3 months versus 100.3 months, p < 0.001) was demonstrated. Importantly, Bmi-1 expression provided significant independent prognostic parameters in multivariate analysis (p = 0.005).

These findings provide evidence that intensive expression of Bmi-1 might be important in the acquisition of an invasive and/or aggressive phenotype of ovarian carcinoma, and serve as a independent biomarker for shortened survival time of patients.

Is fatty liver in men associated with high serum levels of small , dense low-density lipoprotein cholesterol?

Our study addressed potential associations between fatty liver and small, dense low-density lipoprotein cholesterol (sd-LDL-C) levels using a cross-sectional analysis. We enrolled 476 male subjects. Serum sd-LDL-C concentrations were determined using precipitation assays. Subjects were divided into four groups based on triglyceride (TG) and LDL-C levels: A, TG < 150 mg/dl and LDL-C < 140 mg/dl; B, TG < 150 mg/dl and LDL-C ≥ 140 mg/dl; C, TG ≥ 150 mg/dl and LDL-C < 140 mg/dl; and D, TG ≥ 150 mg/dl and LDL-C ≥ 140 mg/dl. sd-LDL-C levels and the prevalence of fatty liver were significantly higher in groups B, C, and D than in group A. Subjects were also categorized into four groups based on serum sd-LDL-C levels; the prevalence of fatty liver significantly increased with increasing sd-LDL-C levels. Additionally, logistic regression analysis revealed an independent association between sd-LDL-C concentrations and fatty liver using such potential confounders as obesity and hyperglycemia as variables independent of elevated TG or LDL-C levels.

Fatty liver is a significant determinant of serum sd-LDL-C levels independent of the presence of obesity or hyperglycemia. Fatty liver may alter hepatic metabolism of TG and LDL-C, resulting in increased sd-LDL-C levels.

Does non-steroidal anti-inflammatory drug use appear to be associated with increased cardiovascular mortality in patients with inflammatory polyarthritis : results from a primary care based inception cohort of patients?

There is controversy about the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on cardiovascular disease (CVD) mortality. The aim of this study was to explore associations between NSAID use and mortality in patients with inflammatory polyarthritis (IP). A total of 923 patients with new onset (IP), recruited to the UK Norfolk Arthritis Register (NOAR) between 1990-1994, were followed up to the end of 2004. Current medication was recorded annually for the first 6 years and then every 2-3 years. Rheumatoid factor (RF) and C-reactive protein (CRP) were measured. Logistic regression was used to calculate all cause and CVD mortality odds ratios (OR) for NSAID use at baseline and during follow-up, adjusting for gender and time-varying covariates: RF, CRP, joint counts, smoking, steroid use, DMARD use and other medication use. By 2004 there were 203 deaths, 85 due to CVD. At baseline, NSAIDs were used by 66% of patients. In final multivariate models, baseline NSAID use was inversely associated with all cause mortality (adjusted OR 0.62, 95% CI 0.45 to 0.84) and CVD mortality (adjusted OR 0.54, 95% CI 0.34 to 0.86). Interval NSAID use had weaker mortality associations: all cause mortality (adjusted OR 0.72, 95% CI 0.52 to 1.00), CVD mortality (adjusted hazard ratio (HR) 0.66, 95% CI 0.40 to 1.08).

No excess CVD or all cause mortality was observed in NSAID users in this cohort of patients with IP. This is at variance with the literature relating to NSAID use in the general population. It is unclear whether this represents unmeasured confounders influencing a doctor's decision to avoid NSAIDs in the treatment of IP.

Are salmonella enterica Serovars Typhi and Paratyphi A avirulent in newborn and infant mice even when expressing virulence plasmid genes of Salmonella Typhimurium?

Salmonella enterica serovars Typhi and Paratyphi A are human host-restricted pathogens. Therefore, there is no small susceptible animal host that can be used to assess the virulence and safety of vaccine strains derived from these Salmonella serovars.  However, infant mice have been used to evaluate virulence and colonization by another human host-restricted pathogen, Vibrio cholerae.  The possibility that infant mice host could be adapted for Salmonella led us to investigate the susceptibility of newborn and infant mice to oral infection with S. Typhi and S. Paratyphi A. Salmonella enterica serovar Typhimurium causes enteric fever in adult mice and this system has been used as a model for human typhoid. The pSTV virulence plasmid, not present in S. Typhi and S. Paratyphi A, plays an essential role in S. Typhimurium colonization and systemic infection of mice. We also conjugated pSTV into S. Typhi and S. Paratyphi A serovars and evaluated these transconjugants in newborn and infant mice.   We determined that the spv virulence genes from the S. Typhimurium virulence plasmid are expressed in S. Typhi and S. Paratyphi A in a RpoS dependent fashion. Also, we determined that S. Typhi and S. Paratyphi A with and without pSTV transiently colonize newborn and infant mice tissues.

Newborn and infant mice infected with S. Typhi and S. Paratyphi A do not succumb to the infection and that carriage of the S. Typhimurium virulence plasmid, pSTV, did not influence these results.

Is cancer cell sensitivity to bortezomib associated with survivin expression and p53 status but not cancer cell types?

Survivin is known playing a role in drug resistance. However, its role in bortezomib-mediated inhibition of growth and induction of apoptosis is unclear. There are conflicting reports for the effect of bortezomib on survivin expression, which lacks of a plausible explanation. In this study, we tested cancer cells with both p53 wild type and mutant/null background for the relationship of bortezomib resistance with survivin expression and p53 status using MTT assay, flow cytometry, DNA fragmentation, caspase activation, western blots and RNAi technology. We found that cancer cells with wild type p53 show a low level expression of survivin and are sensitive to treatment with bortezomib, while cancer cells with a mutant or null p53 show a high level expression of survivin and are resistant to bortezomib-mediated apoptosis induction. However, silencing of survivin expression utilizing survivin mRNA-specific siRNA/shRNA in p53 mutant or null cells sensitized cancer cells to bortezomib mediated apoptosis induction, suggesting a role for survivin in bortezomib resistance. We further noted that modulation of survivin expression by bortezomib is dependent on p53 status but independent of cancer cell types. In cancer cells with mutated p53 or p53 null, bortezomib appears to induce survivin expression, while in cancer cells with wild type p53, bortezomib downregulates or shows no significant effect on survivin expression, which is dependent on the drug concentration, cell line and exposure time.

Our findings, for the first time, unify the current inconsistent findings for bortezomib treatment and survivin expression, and linked the effect of bortezomib on survivin expression, apoptosis induction and bortezomib resistance in the relationship with p53 status, which is independent of cancer cell types. Further mechanistic studies along with this line may impact the optimal clinical application of bortezomib in solid cancer therapeutics.

Does periodontal inflammatory burden correlate with C-reactive protein serum level?

The aim of study was to present a new method for evaluation of the periodontal inflammatory burden, to apply the method to the adult population and to correlate it with serum levels of C-reactive protein (CRP). On 515 extracted teeth was measured the neck circumferences (NC). The average values of the NC were obtained for 16 male and 16 female individual tooth types. In the clinical part of this study 238 dentate subjects were included. The subgingival area, inflamed area and periodontal wound size were calculated from NC, probing depth and BOP. The sum of the inflamed and ulcerated subgingival areas of all teeth represented the total periodontal inflammatory burden of an individual. Serum levels of CRP were measured by immunochemical method. The average subgingival area in 238 subjects was calculated to be 13.11 ± 6.35 cm(2) and inflammatory burden area 9.25 ± 5.57 cm(2). The periodontal bleeding wound (p < 0.05) was significantly larger in men. The increased serum levels of CRP correlated with periodontal inflammatory burden (p < 0.05).

This new method quantifies the inflammatory burden caused by periodontal disease. The size of the inflammatory burden is correlated with increased serum levels of CRP.

Does neurotoxicity of intrathecally administered tetracaine commence at the posterior roots near entry into the spinal cord?

Neurotoxicity of intrathecally administered local anesthetics is generating increased interest. This study was designed to examine the histopathologic effects of intrathecally administered tetracaine. Sixty Wistar rats randomly received either 20%, 10%, 5%, 3%, 1%, 0.5%, or 0% tetracaine dissolved in 10% glucose solution or no solution via a chronically implanted intrathecal catheter. The spinal cord at L1, posterior and anterior roots and cauda equina were excised 5 days later, sectioned, processed, and prepared for light and electron microscopic examinations. Rats treated with tetracaine at 10% or 20% developed lesions in the posterior white matter and posterior roots. Rats injected with 3% or 5% tetracaine developed lesions, which began in the posterior roots close to the spinal cord and extended to the posterior white matter. The lesions were characterized by axonal degeneration. Injections of < or =1% of tetracaine did not cause any pathological changes.

Our results suggest that the initial target of intrathecal tetracaine neurotoxicity may be the posterior roots at their entry into the spinal cord, where the axons are devoid of myelin sheath and thus representing a sensitive area for neurotoxic change.

Does the design of mini slings anchoring systems really matter?

Currently, a sling implant is the standard treatment for stress urinary incontinence in women. To be effective, they require an adequate anchoring system. The aim of this study is compare biomechanical features of fixation systems of two mini slings models available on the market (Ophira™ and Mini Arc™) through a tensile test. Anchoring devices of each sling were surgically implanted in abdominal wall of 15 rats divided into three groups of five animals which were arranged according to the date of post implant euthanasia on 7, 14 and 30 days. Abdominal walls of rats were extracted on bloc containing the anchoring system and were submitted to a tensile strength test to measure the maximum load and elongation until device avulsion from the tissue. The results were compared using Student test t and a 5% cut off was considered significant. The Ophira™ mini sling fixation system demanded a greater maximum load and developed a longer stretch for avulsion from the implanted site at all moments evaluated (p value less than 0.05).

There were significant differences in fixation patterns of the anchoring systems, which were exclusively related to their designs. The Ophira™ mini sling fixation device provided better fixation to the abdominal wall of rats compared to the Mini Arc™ device, even in the late post implant period.

Does neutrophil activation occur in the lower-limbs of patients undergoing elective repair of abdominal aortic aneurysm?

AAA repair is associated with a systemic inflammatory response, mediated in part by neutrophils. The aim of this study was to determine where neutrophil activation occurs. Blood was sampled from the femoral vein, portal vein and radial artery of 10 patients undergoing elective AAA repair at four time-points [induction of anaesthesia (systemic sample only), pre-aortic clamp application, pre-clamp removal and after 30min of reperfusion]. Whole blood was analysed for the white cell count, neutrophil count, and for neutrophil CD11b expression. The white cell count and neutrophil counts increased after aortic clamp release. Neutrophil expression of CD11b was significantly higher in the femoral vein than the portal vein and systemic circulation during ischaemia [P=0.001 (FV vs. PV), P=0.017 (FV vs. systemic)] and reperfusion [P=0.001 (FV vs. PV), P=0.013 (FV vs. systemic)]. There were no significant differences in neutrophil CD11b expression between the systemic and portal vein samples at any time.

Ischaemia and reperfusion during abdominal aortic aneurysm repair are associated with a global increase in the white cell count and neutrophil count, but with increased neutrophil CD11b expression only in the femoral vein. This suggests the lower-limbs are sensitive to aortic clamp-related reperfusion injury and may fuel the inflammatory response.

Does institutional point-of-care glucometer identify population trends in blood glucose associated with war?

Acute physiological stress has been shown to impair glucose homeostasis. War is a period of acute psychological stress, and its effect on glucose control is unknown. In this study random point-of-care (POC) glucose levels were measured using an automated, institutional glucometer in hospitalized adult patients prior to versus during the Israeli Pillar of Defense campaign (November 7-10, 2012). Random POC glucose values measured with the institutional blood glucose monitoring system were obtained 1 week prior to the Pillar of Defense campaign (November 7-10, 2012) and compared with values to those obtained during the first 4 days of the war (November 14-17, 2012). In total, 3,573 POC glucose measures were included: 1,865 during the pre-war period and 1,708 during the campaign. POC glucose measures were significantly higher during the war compared with the week preceding the war: 9.7±4.7 versus 9.3±4.2 mmol/L (P=0.02). In a general linear model, period (pre-war vs. during war) persisted as a significant predictor of POC glucose even after controlling for age, sex, and department type (internal medicine vs. surgical).

Acute stress, such as a wartime situation, is associated with a significant increase in random blood glucose values in a population of hospitalized adults. Long-term follow-up of the individuals hospitalized during these two periods can reveal differences in morbidity and mortality trends.

Do novel Blood Biomarkers Are Associated with White Matter Lesions in Fragile X- Associated Tremor/Ataxia Syndrome?

The need for accessible cellular biomarkers of neurodegeneration in carriers of the fragile X mental retardation 1 (FMR1) premutation (PM) alleles. To assess the mitochondrial status and respiration in blood lymphoblasts from PM carriers manifesting the fragile X-associated tremor/ataxia syndrome (FXTAS) and non-FXTAS carriers, and their relationship with the brain white matter lesions. Oxygen consumption rates (OCR) and ATP synthesis using a Seahorse XFe24 Extracellular Flux Analyser, and steady-state parameters of mitochondrial function were assessed in cultured lymphoblasts from 16 PM males (including 11 FXTAS patients) and 9 matched controls. The regional white matter hyperintensity (WMH) scores were obtained from MRI. Mitochondrial respiratory activity was significantly elevated in lymphoblasts from PM carriers compared with controls, with a 2- to 3-fold increase in basal and maximum OCR attributable to complex I activity, and ATP synthesis, accompanied by unaltered mitochondrial mass and membrane potential. The changes, which were more advanced in FXTAS patients, were significantly associated with the WMH scores in the supratentorial regions.

The dramatic increase in mitochondrial activity in lymphoblasts from PM carriers may represent either the early stages of disease (specific alterations in short-lived blood cells) or an activation of the lymphocytes under pathological situations. These changes may provide early, convenient blood biomarkers of clinical involvements.

Do normal-appearing white matter changes vary with distance to lesions in multiple sclerosis?

Multiple sclerosis (MS) disease processes in normal-appearing white matter (NAWM) may be different close to MR-visible lesions than farther from these lesions. We aimed to investigate the relationship of NAWM changes to the distance to the lesions. We measured B(1)-corrected T1 and magnetization transfer ratio (MTR) maps in 63 patients with MS (11 primary progressive, 34 relapsing-remitting, 18 secondary progressive). We used histogram analyses to assess the global properties of lesions, of 4 consecutive 1-mm pixel layers of NAWM around the lesions, and of distant NAWM located at least 4-mm from lesions in all directions. In 22 healthy controls, we measured white matter MTR and T1 histograms. Histogram parameters were statistically analyzed by using a linear mixed model. The first and second NAWM pixel layers around the lesions had a significantly lower MTR histogram peak position than distant NAWM, whereas T1 histogram peak position was similar between all types of NAWM. Furthermore, MTR histograms of distant NAWM were statistically indistinguishable from those of control white matter, whereas T1 histograms of distant NAWM had significantly decreased peak height for relapsing-remitting MS and secondary progressive MS and significantly increased peak position for secondary progressive MS.

Our results may suggest that axonal damage and demyelination in NAWM mainly arise as a secondary result of visible lesions, with the largest effect close to these lesions. NAWM disease farther from the lesions may be mainly characterized by subtle blood-brain barrier damage, with leakage of fibrinogen into the parenchyma and microplaque formation, processes that are detected with T1 but not with MTR.

Is prostate cancer in patients with metabolic syndrome associated with low grade Gleason score when diagnosed on biopsy?

Studies on the relationship of metabolic syndrome (MS) and prostate cancer are controversial. We evaluated the association between MS and prostate cancer characteristics in patients who underwent transrectal ultrasound-guided prostate biopsy. From October 2003 to May 2011, patients with a prostate-specific antigen (PSA) value≥4 ng/ml or abnormal digital rectal examination (DRE) result underwent transrectal ultrasound-guided prostate biopsy. MS was diagnosed according to the Adult Treatment Panel III. Clinicopathologic factors including PSA, DRE, prostate volume, age, waist circumference, body mass index (BMI), lipid profiles, fasting blood sugar level, and MS were considered for analysis. Three hundred fifty-four patients were enrolled (mean age, 68.86±8.95 years; mean PSA, 13.97±20.42 ng/ml). Seventy-five patients (21.2%) had MS and 90 patients (25.4%) were diagnosed as having prostate cancer, including 27 (30%) with MS and 63 (70%) without MS. Total PSA value and prostate volume were significant predictors for prostate cancer. However, MS and BMI were not significantly related to increased cancer risk. Prostate cancer patients with MS had significantly lower Gleason scores (average, 6.63±1.92) than did prostate cancer patients without MS (average, 7.54±1.71; p=0.029).

Presence of MS was associated with a significantly decreased risk of high-grade prostate cancer. A larger, prospective, multicenter investigation is mandatory to clarify the relationship between MS and prostate cancer.

Pancreatic cancer with paraaortic lymph node metastasis: a contraindication for radical surgery?

The purpose of this study was to determine the operative indications for pancreatic cancer with paraaortic lymph node metastases (No. 16 [+]). Between July 1981 and March 2007, 335 patients with pancreatic cancer including 45 No. 16 (+) patients underwent extended radical surgery at the Department of Surgery II, Nagoya University. The overall survival rates and clinicopathological parameters were analyzed using univariate and multivariate analyses. Although there was no significant difference in survival between the No. 16 (+) patients and the unresectable cases, there were some long-term survivors among the No. 16 (+) patients. Multivariate analysis of the No. 16 (+) patients identified age (59 years or younger), tumor size (>4 cm), and pathologically confirmed portal invasion (pPV[+]) as independent prognostic factors. The survival of No. 16 (+) patients without these factors was significantly better than the unresectable cases. The survival of patients with only 1 metastatic paraaortic lymph node also was significantly better than the unresectable cases, and tended to be better than those with more than 2 metastatic nodes.

No. 16 (+) pancreatic cancer patients with age 60 years or older, tumor size 4 cm or less, and pPV(-) may benefit from resection.

Is aglR required for addition of the final mannose residue of the N-linked glycan decorating the Haloferax volcanii S-layer glycoprotein?

Recent studies of Haloferax volcanii have begun to elucidate the steps of N-glycosylation in Archaea, where this universal post-translational modification remains poorly described. In Hfx. volcanii, a series of Agl proteins catalyzes the assembly and attachment of a N-linked pentasaccharide to the S-layer glycoprotein. Although roles have been assigned to the majority of Agl proteins, others await description. In the following, the contribution of AglR to N-glycosylation was addressed. A combination of bioinformatics, gene deletion, mass spectrometry and metabolic radiolabeling served to show a role for AglR in archaeal N-glycosylation at both the dolichol phosphate and reporter glycoprotein levels. The modified behavior of the S-layer glycoprotein isolated from cells lacking AglR points to an involvement of this protein in N-glycosylation. In cells lacking AglR, glycan-charged dolichol phosphate, including mannose-charged dolichol phosphate, accumulates. At the same time, the S-layer glycoprotein does not incorporate mannose, the final subunit of the N-linked pentasaccharide decorating this protein. AglR is a homologue of Wzx proteins, annotated as flippases responsible for delivering lipid-linked O-antigen precursor oligosaccharides across the bacterial plasma membrane during lipopolysaccharide biogenesis.

The effects resulting from aglR deletion are consistent with AglR interacting with dolichol phosphate-mannose, possibly acting as a dolichol phosphate-mannose flippase or contributing to such activity.

Do root hydraulic properties change during the early vegetative stage of plant development in barley (Hordeum vulgare)?

As annual crops develop, transpirational water loss increases substantially. This increase has to be matched by an increase in water uptake through the root system. The aim of this study was to assess the contributions of changes in intrinsic root hydraulic conductivity (Lp, water uptake per unit root surface area, driving force and time), driving force and root surface area to developmental increases in root water uptake. Hydroponically grown barley plants were analysed during four windows of their vegetative stage of development, when they were 9-13, 14-18, 19-23 and 24-28 d old. Hydraulic conductivity was determined for individual roots (Lp) and for entire root systems (Lp(r)). Osmotic Lp of individual seminal and adventitious roots and osmotic Lp(r) of the root system were determined in exudation experiments. Hydrostatic Lp of individual roots was determined by root pressure probe analyses, and hydrostatic Lp(r) of the root system was derived from analyses of transpiring plants. Although osmotic and hydrostatic Lp and Lp(r) values increased initially during development and were correlated positively with plant transpiration rate, their overall developmental increases (about 2-fold) were small compared with increases in transpirational water loss and root surface area (about 10- to 40-fold). The water potential gradient driving water uptake in transpiring plants more than doubled during development, and potentially contributed to the increases in plant water flow. Osmotic Lp(r) of entire root systems and hydrostatic Lp(r) of transpiring plants were similar, suggesting that the main radial transport path in roots was the cell-to-cell path at all developmental stages.

Increase in the surface area of root system, and not changes in intrinsic root hydraulic properties, is the main means through which barley plants grown hydroponically sustain an increase in transpirational water loss during their vegetative development.

Do [ Assessment of cochlear implant performance with Mandarin Hearing In Noise Test ]?

To evaluate the abilities speech perception of post-lingual cochlear implant patients by Mandarin Hearing In Noise Test(MHINT), get the performance-intensity function (P-I function). The material was MHINT adults' version, including 12 lists, 20 sentences per list. Twenty-two cochlear implant patients were the subjects, age from 14 to 56. Three adaptive rules were used during the test. Firstly Rule 3 would be done. If subject could finish the test, then Rule 2 and Rule 1 would be used. Got the Reception threshold of sentences and speech recognition score of subjects, then got performance-intensity function (PI function). Among those 22 subjects, 5 of them could be tested in all three rules, 3 could be tested in Rule 2 and Rule 3, 7 of them could be tested with Rule 3, and 7 of the CI users could not be tested even with Rule 3. All of the PI functions for CI users are shifted 10 dB or more above the normal PI functions. Most CI users thought that MHINT was hard for them.

When use new adaptive scoring rules for MHINT, most CI users could be tested with the modified HINT scoring rules, although three subjects could not be tested. Compared with normal hearing subjects, all CI users required positive S/N ratios to perform the HINT measures.

Do multiple independent lineages of HIV-1 persist in breast milk and plasma?

the origin and evolution of HIV-1 in breast milk is unclear, despite the continuing significance of this tissue as a transmitting compartment. To elucidate the evolutionary trajectory of viral populations in a transient mucosal compartment, longitudinal sequences of the envelope glycoprotein (gp120) region from plasma and breast milk spanning the first year after delivery were analyzed in six women infected by HIV-1 subtype C. multiple phylogenetic algorithms were used to elucidate the evolutionary history and spatial structure of virus populations between tissues. overall persistent mixing of viral sequences between plasma and breast milk indicated that breast milk is not a distinct genetic viral compartment. Unexpectedly, longitudinal phylogenies showed multiple lineages defined by long branches that included virus from both the breast milk and the plasma. Plasma was unlikely the anatomical origin of the most recent common ancestor (MRCA) in at least three of the patients, although in other women, the temporal origin of the MRCA of the viral populations following delivery occurred well before the onset of breast milk production.

these findings suggest that during pregnancy/lactation, a viral variant distinct from the plasma virus initially seeds the breast milk, followed by subsequent gene flow between the plasma and breast milk tissues. This study indicates the potential for reactivation or reintroduction of distinct lineages during major immunological disruptions during the course of natural infection.

Does a modified echocardiographic approach improve reliability of superior vena caval flow quantification?

To assess accuracy and repeatability of a modified echocardiographic approach to quantify superior vena cava (SVC) flow volume that uses a short-axis view to directly measure SVC area and a suprasternal view to measure flow velocity, both at the level of the right pulmonary artery. Three tertiary-level neonatal intensive care units. This was a multicentre, prospective, observational study. Accuracy of the traditional and modified approach was first assessed by comparing echo measurements according to both techniques with Phase contrast MRI (PCMRI) assessments, in a cohort of 10 neonates. In a second cohort of 40 neonates, intraobserver scan-rescan repeatability and interobserver analysis-reanalysis repeatability were assessed by repeated SVC flow echo measurements, according to both techniques. The traditional echocardiographic approach to assessment of SVC flow had a moderate agreement with PCMRI (r

Echocardiographic assessment of SVC flow volume by tracing area from a short-axis view and measuring velocity-time integral from a suprasternal view offered an improvement in accuracy and repeatability, building on the traditional approach previously described.

Do effects of high-frequency stimulation on subthalamic neuronal activity in parkinsonian patients?

High-frequency stimulation of the subthalamic nucleus (STN) is a neurosurgical alternative to medical treatment in levodopa-responsive forms of Parkinson disease. The mechanism of action of STN stimulation remains controversial, although an inhibition of overactive STN neurons has been postulated. To determine the effects of high-frequency STN stimulation on the neuronal activity of STN neurons in Parkinson disease patients. Single-unit recordings of the neuronal activity of the STN were obtained before, during, and after the application of intra-STN electrical stimulation in 15 Parkinson disease patients. Changes in firing frequency and pattern were analyzed using various combinations of stimulus frequency (range, 14-140 Hz). Stimulation at a frequency greater than 40 Hz applied within the STN significantly decreased the firing frequency and increased the burst-like activity in the firing pattern of STN neurons. An aftereffect was observed in cells that had been totally inhibited during high-frequency stimulation.

The beneficial effects of high-frequency stimulation result from a change in the firing pattern of cellular discharge and a blockade of the spontaneous overactivity of STN neurons.

Do dustborne and airborne fungal propagules represent a different spectrum of fungi with differing relations to home characteristics?

Exposure to fungi is often assessed by culturing floor dust or air samples. Our objective was to evaluate the relationships between dustborne and airborne fungi and to identify factors that modify these relationships. From November 1994 to September 1996 sequential duplicate 45-l air samples were collected in bedrooms of 496 homes in the Boston area, using a Burkard culture plate sampler. After air sampling, bedroom floors were sampled with a vacuum cleaner that was modified to collect dust in a cellulose extraction thimble. Dust was sieved, and the fine dust was dilution-plated onto DG-18 media. Concentrations of total culturable fungi per gram of bedroom-floor dust were correlated weakly, but significantly, with those of indoor air (r = 0.13, P < 0.05). Concentrations of some individual taxa in the dust and indoor air were also weakly associated. Adjusting for the concentrations of fungi in outdoor air, dustborne fungal concentrations were positively associated with those in indoor air for the taxa Cladosporium and Penicillium, but not for total fungi. The indoor air fungal levels were often predicted by different covariates to those predicting fungal levels in dust. The type of housing (house or apartment) and the presence of carpeting were often predictive factors for dust fungi. In contrast, outdoor fungal levels were often predictive of the indoor air fungal levels.

Because our data do not indicate a strong overall relationship between culturable fungi in dust and indoor air, the results from these two methods (dust and air sampling) likely represent different types of potential fungal exposures to residents. It may be essential to collect both air and dust samples, as well as information on housing characteristics, as indicators for fungal exposure.

Is juvenile myoclonic epilepsy associated with the DRPLA gene in a European population?

Juvenile myoclonic epilepsy (JME), is an early-onset inherited generalized epilepsy which displays genetic heterogeneity, with at least 10 known loci. Another neurogenetic disease, dentato-rubro-pallido-luysian atrophy (DRPLA) presents three clinical phenotypes, one of which in Japanese displays many similarities to JME. The purpose of this study was to investigate whether the DRPLA gene is associated with JME in Caucasians. The CAG repeat polymorphism in the DRPLA gene, which is expanded in patients with DRPLA, was examined with polymerase chain reaction amplification in 107 individuals of Greek origin, including 24 patients with sporadic and 8 with familial JME, 25 healthy relatives and 50 healthy controls. The repeat sizes of all studied individuals were within the normal range.

These results seem to exclude the DRPLA gene as a major candidate gene for JME in this European population.

Are hypertensive patients managed in primary care well evaluated and controlled?

The HICAP study assessed the cardiovascular (CV) global risk and the CV risk factors control in hypertensive patients managed in Primary Care (PC) in Spain. Cross-sectional and multilocated study in which each investigator included data from 5 consecutives hypertensive patients. A routine laboratory test and a ECG from the previous 6 months had to be available for each patients CV global risk evaluation, blood pressure (BP) and diabetes control was based on ESH-ESC 2003; lipid profile evaluation was based on NCEP 2001 (ATP III) 1288 PC physicians included 6719 hypertensive patients, and data from 6375 patients were analyzed.64.5% (CI95%: 63.3-65.7) of the hypertensive patients managed in Primary Care showed a high or very high CV global risk.BP was controlled in 39.3% (CI95%: 38.1-40.5) of patients, 10.5% (CI95%: 9.1-11.9)among diabetics. 37.3% (CI95%: 35-38.7) of diabetics showed HbA1c<6.5% and 18.8% (CI95%: 17.6-20) of dyslipidemic subjects had their LDL-c controlled. The control was lower among the patients at higher CV global risk.

These results demostrate the high proportion of hypertensive patients that present a high CV global risk. The cardiovascular risk factors control, specially among patients at higher CV global risk, is insufficient.

Does genomic Integrity be Favourably Affected by High-Intensity Interval Training in an Animal Model of Early-Stage Chronic Kidney Disease?

Chronic kidney disease (CKD) is an irreversible disease that diminishes length and quality of life. Emerging evidence suggests CKD progression and genomic integrity are inversely and causally related. To reduce health complications related to CKD progression, chronic aerobic exercise is often recommended. To date, appraisals of differing modes of exercise, along with postulations regarding the mechanisms responsible for observed effects, are lacking. In order to examine the ability of aerobic exercise to encourage improvements in genomic integrity, we evaluated the effects of 8 weeks of high-intensity interval training (HIIT; 85 % VO To assess genomic integrity, we examined kidney-specific messenger RNA (mRNA) expression of genes related to genomic repair and stability: Following HIIT, mRNA expression of

Our results suggest that HIIT is superior to SED and LIT as HIIT beneficially influenced the expression of genes related to genomic integrity.

Does malignant melanoma induce migration and invasion of adult mesenchymal stem cells?

To determine if melanoma cells secrete chemotactic factors that result in the migration of multipotent stem cells. In vitro cell culture. Chemotaxis and invasion of human mesenchymal stem cells (hMSCs) was determined using the modified Boyden chamber assay. Quantification of growth factors secreted by melanoma cells (A375) was determined using enzyme-linked immunosorbent assay. Conditioned A375 melanoma media caused significant migration and invasion of hMSCs compared to serum-free controls and conditioned media from normal melanocytes (P < .0001). The migratory effect appeared maximal after the A375 media was conditioned for 48 hours. Physiologically relevant concentrations of fibroblast growth factor-2 (FGF2) (90 pg/mL) secreted by A375 melanoma cells caused significant migration of hMSCs (P < .001) compared to serum-free and normal melanocyte controls. Neutralization of FGF2 inhibited the migration of hMSCs to that of the negative controls (conditioned media from normal melanocytes).

The melanoma tumor microenvironment may be maintained through chemotaxis and invasion of multipotent hMSCs, and this migratory effect appears to be mediated in part through secretion of FGF2 by melanoma cells.

Is lipoprotein ( a ) related to the extent of lesions in the coronary vasculature and to unstable coronary syndromes?

Lp(a) is a highly atherogenic particle with a prothrombotic effect. Until now its relation to the extent and severity of the atheromatic lesions had not been established by standard procedures. This study examined the correlation of Lp(a) to the extent and severity of coronary artery disease (CAD) and its relation to unstable clinical events (not including sudden death). In 202 patients undergoing coronary angiography, plasma lipids were measured with the usual procedures and Lp(a) with the enzyme-linked immunosorbent assay. The extent of CAD was expressed in the number of diseased vessels and its severity in terms of the severity coefficient and the obstruction coefficient. A very strong relationship between LP(a) and the number of diseased vessels (p = 0.0007) signifying diffuse atherosclerosis, but no relation with the severity of the lesions. was found. However, it was the only lipid that correlated significantly with the number of totally occluded vessels (p = 0.0003). The thrombogenic ability of Lp(a) was manifested by increased incidence of myocardial infarction and unstable angina episodes in patients with elevated Lp(a) (p = 0.0157).

Elevated Lp(a) predisposes to the extent of CAD and total occlusions but not to the severity of lesions. Patients with increased Lp(a) levels and unstable angina are at increased danger of suffering myocardial infarction. Thus, Lp(a) may predispose to plaque destabilization and thrombosis of noncritical lesions.

Is intercondylar notch stenosis a risk factor for anterior cruciate ligament tears in professional male basketball players : an 11-year prospective study?

The value of femoral notch size and the notch width index in predicting anterior cruciate ligament injury has been debated. This study examined the relationship between the notch width index and anterior cruciate ligament injury in professional basketball players. No significant difference exists between the notch width index of anterior cruciate ligament-injured and noninjured professional basketball players. Case-control study; Level of evidence, 3. Using a notch view radiograph, the authors prospectively measured the femoral notch and the condylar widths and then calculated the notch width index of 615 male athletes who participated in the National Basketball Association's combine workouts between 1992 and 1999. Players who participated in at least 1 professional game were included. After an 11-year follow-up period, the National Basketball Association's leaguewide injury database was reviewed to identify injured players. The players were then categorized into anterior cruciate ligament-injured or noninjured groups. Notch width, condylar width, and notch width index were compared between the 2 groups. A total of 305 players were followed for a period of up to 11 years. Anterior cruciate ligament trauma was suffered by 14 (4.6%) of the subjects. The average notch width index was 0.235 +/- 0.031 for anterior cruciate ligament-injured players and 0.242 +/- 0.041 for noninjured players (t305=-0.623, P=.534). This difference was not significantly different. Two (3.9%) of the subjects with critical notch stenosis (notch width index 0.20) had noncontact anterior cruciate ligament injuries.

The notch width index did not predict the rate of anterior cruciate ligament injury. A level of critical notch stenosis was not detected. Anterior cruciate ligament injury could not be predicted by the absolute measurement of the femoral inter-condylar notch. Use of a preparticipation notch view radiograph in male professional basketball players as a predictor of anterior cruciate ligament injury is not recommended.

Do amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity?

To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity. Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n = 207). Twelve subjects with Alzheimer disease dementia were included for comparison. Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline.

The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both "amyloid-first" and "neurodegeneration-first" biomarker profile pathways to preclinical AD exist.

Does [ Blood culture result in elderly febrile patients ]?

We retrospectively evaluated blood culture results in elderly patients (≥65 years) with a fever due to infection. We examined the bacteria isolated from blood cultures and compared them to bacteria detected in infected lesions that caused bacteremia. We compared the types of bacteria isolated in the two groups (the community-acquired group and the hospital-acquired group). Blood cultures were obtained from 638 patients. Bacteria were detected in 182 patients (28.5%), including 66 (36.3%) patients in the community-acquired group and 116 (63.7%) patients in the hospital-acquired group. There were 259 positive samples (25.1%). In arterial blood specimens, 153 (30.9%) samples were positive, while in venous blood specimens, there were 106 (19.8%) positive samples (P<0.001). In the community-acquired group, the most common bacteria identified were E. coli compared to S. epidermidis in the hospital-acquired group. More than 50% of the bacteria identified in the blood cultures were of the same species identified in the respective urine samples and central venous catheter tips.

The bacteria detection rate in this study was 28.5% for blood cultures, which is higher than the 17.5% reported by the Japan Nosocomial Infections Surveillance Program conducted by the Japanese Ministry of Health, Labour and Welfare. These results suggest that in elderly patients from whom an insufficient volume of blood can be drawn from a vein, an arterial sample may increase the detection rate. A high percentage of bacterial species isolated from the blood cultures was also detected in urinary tract infections and central venous catheter-related infections, indicating that a blood culture is useful for detecting various infectious diseases, even in elderly febrile patients.

Is wT1 expression in normal and neoplastic cranial and peripheral nerves independent of grade of malignancy?

Wilms' tumor protein (WT1) expression is usually absent in normal glial cells of the CNS but is highly upregulated in brain tumor cells and its expression correlates with tumor grade. However, knowledge on WT1 expression in tumors of the peripheral nerve system (PNS) is limited. As WT1 antibodies not only serve as biomarker for cancerous tissue but also are considered for cancer immunotherapy, knowledge of WT1 expression in tumorous and normal peripheral nerve tissue is important for therapeutical purposes. We analyze the immunohistochemical expression of WT1 in 101 samples consisting of 13 normal nerves, 10 neurofibromas, 69 schwannomas and 9 malignant peripheral nerve sheath tumors (MPNST). Tumor samples included 14 specimen from patients with a proven neurocutaneous disorder (neurofibromatosis type 1 and 2) and 3 cases of schwannomatosis. In 50 vestibular schwannomas tumor growth extension was correlated to WT1 expression. WT1 expression is present in Schwann cells of the majority of normal human nerves (11/13). In peripheral nerve sheath tumors, cytoplasmic WT1 protein is expressed in the cytoplasm of the neoplastic cells in all tumors, including MPNST, neurofibromas and schwannomas. The WT1 expression is independent of tumor malignancy or tumor growth extension and is not associated with a neurocutaneous disorder.

WT1 expression in normal and neoplastic tissue differs in the peripheral and the central nervous system. These findings may point to a different functional role of WT1 in the PNS and the CNS.

Is tumor size a criterion for resection during the management of giant hemangioma of the liver?

Liver hemangiomas are the most common benign liver tumors. The management of giant (≥5 cm) hemangioma of the liver remains controversial. The aim of this study was to assess the influence of tumor size on postoperative outcomes after hepatectomy in patients with giant hemangioma of the liver. Patients who were subjected to resection because of giant liver hemangioma between December 2006 and July 2012 were grouped by largest tumor size: 5-10 cm (group A) and 10-15 cm (group B). All patients underwent detailed preoperative assessments. Clinicopathologic features were analyzed, and univariate and multivariate analyses were used to determine risk factors that correlated independently with any complication, as well as the intraoperative red blood cell transfusion requirement. Long-term outcomes were assessed with a median follow-up of 56 months. One hundred and ninety patients, mean age 46 years, were included. The 146 patients with tumors 5-10 cm in size were compared with the remaining 44 patients with tumors 5-10 cm in size. The differences in postoperative morbidity (29.86 vs. 41.30%, P=0.150) and duration of hospitalization (11.06±7.02 vs. 12.17±7.74, P=0.465) between group A and group B did not reach statistical significance. Operation time, blood loss, and transfusion volume of group B were greater than those of group A. No perioperative deaths occurred and no recurrences were registered during follow-up in both groups. The results of univariate and multivariate analysis showed that diameter was not an independent risk factor of postoperative complications and intraoperative red blood cell transfusion.

Giant hemangiomas should be monitored regularly. Asymptomatic tumors 5-10 cm in diameter can be managed conservatively even though they grow. When necessary, surgical treatment can be well justified because of low morbidity and mortality.

Is rubella virus associated with fuchs heterochromic iridocyclitis?

To determine whether rubella virus (RV) is involved in the pathogenesis of Fuchs heterochromic iridocyclitis (FHI). Retrospective patient-controlled study. Intraocular immunoglobulin G production against RV, herpes simplex virus (HSV), varicella zoster virus (VZV), and Toxoplasma gondii was determined in the aqueous humor of 14 patients with FHI, 13 control subjects with herpetic uveitis anterior, and 19 control subjects with ocular toxoplasmosis by calculation of the Goldmann-Witmer coefficient (GWC). All patients and control subjects were seropositive for RV. Intraocular antibody production (GWC >3) against RV was found in 13 of 14 patients (93%) with FHI. Intraocular antibody production against HSV, VZV, or T gondii was not detected. None of the control subjects with herpetic uveitis anterior or with toxoplasma chorioretinitis had a positive GWC for rubella virus (P < .0001, Fisher exact test).

Rubella virus, but not HSV, VZV, or T gondii, is associated with FHI.

Does single-molecule sequencing reveal the molecular basis of multidrug-resistance in ST772 methicillin-resistant Staphylococcus aureus?

Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-associated infection, but there is growing awareness of the emergence of multidrug-resistant lineages in community settings around the world. One such lineage is ST772-MRSA-V, which has disseminated globally and is increasingly prevalent in India. Here, we present the complete genome sequence of DAR4145, a strain of the ST772-MRSA-V lineage from India, and investigate its genomic characteristics in regards to antibiotic resistance and virulence factors. Sequencing using single-molecule real-time technology resulted in the assembly of a single continuous chromosomal sequence, which was error-corrected, annotated and compared to nine draft genome assemblies of ST772-MRSA-V from Australia, Malaysia and India. We discovered numerous and redundant resistance genes associated with mobile genetic elements (MGEs) and known core genome mutations that explain the highly antibiotic resistant phenotype of DAR4145. Staphylococcal toxins and superantigens, including the leukotoxin Panton-Valentinin Leukocidin, were predominantly associated with genomic islands and the phage φ-IND772PVL. Some of these mobile resistance and virulence factors were variably present in other strains of the ST772-MRSA-V lineage.

The genomic characteristics presented here emphasize the contribution of MGEs to the emergence of multidrug-resistant and highly virulent strains of community-associated MRSA. Antibiotic resistance was further augmented by chromosomal mutations and redundancy of resistance genes. The complete genome of DAR4145 provides a valuable resource for future investigations into the global dissemination and phylogeography of ST772-MRSA-V.

Physical performance and physical activity in older people: are developmental influences important?

Reduced physical performance and physical activity have serious health consequences, but adult determinants do not fully explain variation in older people. Our objective was to investigate the relationship between early growth, physical performance and physical activity in older people. We studied 349 men and 280 women born 1931-1939 with known birth weight and weight at 1 year who were taking part in the Hertfordshire Cohort Study, UK. Physical performance was measured (3-m walk, chair rises and standing balance) and physical activity was assessed by questionnaire and converted to estimated energy expenditure. Poor balance was associated with lower birth weight (odds ratio [OR] for poor balance per standard deviation [SD]increase in birth weight = 0.68, p=0.01) and weight at 1 year (OR for poor balance per SD increase in weight at 1 year=0.67, p=0.03) after adjustment for age and current size in men, but not in women. There were no significant positive relationships between early size and growth and the other measures of physical performance or physical activity in men or women.

Current lifestyle factors, particularly those affecting adult weight, may be more important than developmental influences on most measures of physical performance and physical activity in older people.

Do liver Label Retaining Cancer Cells Are Relatively Resistant to the Reported Anti-Cancer Stem Cell Drug Metformin?

Recently, we reported that liver Label Retaining Cancer Cells (LRCC) can initiate tumors with only 10 cells and are relatively resistant to the targeted drug Sorafenib, a standard of practice in advanced hepatocellular carcinoma (HCC). LRCC are the only cancer stem cells (CSC) isolated alive according to a stem cell fundamental function, asymmetric cell division. Metformin has been reported to preferentially target many other types of CSC of different organs, including liver. It's important to know if LRCC, a novel class of CSC, are relatively resistant to metformin, unlike other types of CSC. As metformin inhibits the Sorafenib-Target-Protein (STP) PI3K, and LRCC are newly described CSC, we undertook this study to test the effects of Metformin on Sorafenib-treated HCC and HCC-derived-LRCC. We tested various STP levels and phosphorylation status, associated genes' expression, proliferation, viability, toxicity, and apoptosis profiles, before and after treatment with Sorafenib with/without Metformin. Metformin enhances the effects of Sorafenib on HCC, and significantly decreased viability/proliferation of HCC cells. This insulin-independent effect was associated with inhibition of multiple STPs (PKC, ERK, JNK and AKT). However, Metformin increased the relative proportion of LRCCs. Comparing LRCC vs. non-LRCC, this effect was associated with improved toxicity and apoptosis profiles, down-regulation of cell death genes and up-regulation of cell proliferation and survival genes in LRCC. Concomitantly, Metformin up-regulated pluripotency, Wnt, Notch and SHH pathways genes in LRCC vs. non-LRCC.

Metformin and Sorafenib have enhanced anti-cancer effects. However, in contradistinction to reports on other types of CSC, Metformin is less effective against HCC-derived-CSC LRCC. Our results suggest that combining Metformin with Sorafenib may be able to repress the bulk of tumor cells, but as with other anti-cancer drugs, may leave LRCC behind leading to cancer recurrence. Therefore, liver LRCC, unlike other types of CSC, are relatively resistant to the reported anti-cancer stem cell drug metformin. This is the first report that there is a type of CSC that is not relatively resistant to the CSC-targeting drug. Our findings suggest that a drug targeting LRCC may be critically needed to target CSC and prevent cancer recurrence. These may significantly contribute to the understanding of Metformin's anti-cancer effects and the development of novel drugs targeting the relatively resistant LRCC.

Do early career indicators of clinical skill predict subsequent career outcomes and practice characteristics for general internists?

To study relationships between clinical skill measures assessed at the beginning of general internists' careers and their career outcomes and practice characteristics. General Internist Community Tracking Study Physician Survey respondents (2000-2001, 2004-2005) linked with residency program evaluations and American Board of Internal Medicine board certification examination score records; n = 2,331. Cross-sectional regressions of career outcome and practice characteristic measures on board examination scores/success, residency evaluations interacted with residency type, and potential confounding variables. Failure to achieve board certification was associated with $27,206 (18 percent, p<.05) less income and 14.9 percent more minority patients relative to physicians scoring in the bottom quartile on their initial examination who eventually became certified (p<.01). Other skill measures were not associated with income. Scoring in the top rather than bottom quartile on the board certification examination was associated with 9 percent increased likelihood of reporting high career satisfaction (p<.05). Among physicians trained in community hospital residency programs, lower evaluations were associated with 14.5 percent higher share of minority patients (p<.05). Both skill measures were associated with practice type.

There are associations between early career skill measures and career outcomes. In addition, minority patients are more likely to be treated by physicians with lower early career clinical skills measures than nonminority patients.

Does the use of anticoagulants improve biochemical control of localized prostate cancer treated with radiotherapy?

: Substantial experimental evidence suggests that anticoagulants (ACs) may inhibit cancer growth and metastasis, although the limited data from clinical trials have been inconsistent. The potential antineoplastic effect of ACs was investigated in patients who received radiotherapy for localized prostate cancer. : The study cohort consisted of 662 patients with adenocarcinoma of the prostate who received radiotherapy (RT) with curative intent. Among those 622 men, 243 (37%) were receiving ACs (warfarin, clopidogrel, and/or aspirin). All patients received external-beam RT, permanent seed implantation, or a combination of both. Prostate-specific antigen (PSA) values were monitored for biochemical control of disease. : At a median follow-up of 49 months, the biochemical control rate at 4-years was significantly better in patients who received ACs at 91% compared with 78% in patients who did not receive ACs (P = .0002). The distant metastasis rate at 4 years also was reduced in the AC group compared with the non-AC group (1% vs 5%; P = .0248). In subgroup analysis, the improvement in biochemical control was significant only for patients with high-risk disease. Along with Gleason score, T classification, and initial PSA, the use of AC therapy was associated independently with improved biochemical control in multivariate analysis.

: AC therapy was associated with an improvement in biochemical control in patients with prostate cancer who received RT with curative intent. The effect was most prominent in patients who had high-risk disease. Cancer 2010. (c) 2010 American Cancer Society.

Is endogenous inhibition of somatic pain impaired in girls with irritable bowel syndrome compared with healthy girls?

Endogenous pain inhibition is often deficient in adults with chronic pain conditions including irritable bowel syndrome (IBS). It is unclear whether deficiencies in pain inhibition are present in young children with IBS. The present study compared endogenous pain inhibition, somatic pain threshold, and psychosocial distress in young girls with IBS versus controls. Girls with IBS did not show significant endogenous pain inhibition of heat pain threshold during a cold-pressor task in contrast to controls, who had significant pain inhibition. Girls with IBS did not differ from peers on measures of somatic pain but had more symptoms of depression, somatization, and anxiety than controls. When psychological variables were included as covariates, the difference in pain inhibition was no longer significant, although poor achieved power limits interpretation of these results. Higher-order cognitive processes including psychological variables may be contributing to observed pain inhibition. In girls with IBS, pain inhibition was positively related to the number of days without a bowel movement. To our knowledge, this is the first study to demonstrate deficiencies of endogenous pain inhibition in young children with IBS. Findings have implications for better understanding of onset and maintenance of IBS and other chronic pain conditions.

This study found that young girls with IBS have deficient endogenous pain inhibition compared to healthy girls, which is consistent with the literature on adults. This information can facilitate clinicians in identification of risk factors for onset/maintenance of IBS and other chronic pain conditions.

Does hypoxia differentially affect IL-1β-stimulated MMP-1 and MMP-13 expression of fibroblast-like synoviocytes in an HIF-1α-dependent manner?

To further understand the expression regulation of MMP-1 and MMP-13 under physiological and pathological conditions, we investigated the combined effects of hypoxia and pro-inflammatory stimuli on the expression of MMP-1 and MMP-13 in rheumatoid synovial fibroblasts. Synovial fibroblasts were cultured under either hypoxic or normoxic conditions in the presence of IL-1β stimulation. The culture supernatant was analysed for secreted levels of VEGF, MMP-1 and MMP-13. Their gene expression was quantified with real-time and semi-quantitative PCR. Another group of cells was transfected with small-interfering RNA (siRNA) specific for hypoxia-inducible factor-1 α (HIF-1α). The protein levels of HIF-1α were detected by western blot analysis. In response to 10 ng/ml of IL-1β under normoxia, the levels of MMP-1 and MMP-13 increased compared with the levels observed under hypoxia. IL-1β stimulation under hypoxia induced a 2-fold increase in the level of MMP-1 and a 2-fold decrease in the level of MMP-13 compared with cells cultured under normoxia. A similar pattern of differential expression for MMP-1 and MMP-13 was observed with 1 and 5 ng/ml IL-1β, but not at 0.1 ng/ml. The differential expression of MMPs under the combined effect of IL-1β and hypoxia was significantly attenuated by silencing HIF-1α with siRNA.

Hypoxia in arthritic joints may differentially affect the IL-1β-stimulated expression of MMP-1 and MMP-13 in rheumatoid synovial fibroblasts. This effect is dependent on HIF-1α expression. This hypoxia-mediated differential effect should be taken into consideration when testing the efficiency of therapies that target HIF-1α.

Is a remedial intervention linked to a formative assessment effective in terms of improving student performance in subsequent degree examinations?

Intervention may help weaker medical students improve their performance. However, the effectiveness of remedial intervention is inconclusive due to small sample sizes in previous studies. We asked: is remedial intervention linked to a formative assessment effective in terms of improving student performance in subsequent degree examinations? This was a retrospective, observational study of anonymous databases of student assessment outcomes. Data were analysed for students due to graduate in the years 2005-2009 (n = 909). Exam performance was compared for students who received remediation versus those who did not. The main outcome measure was summative degree examination marks. After adjusting for cohort, gender, overseas versus home funding, previous degree and previous performance in the corresponding baseline third year summative exam, students receiving a remedial intervention (after poor performance on a formative objective structured clinical examination and written exams mid-fourth year) were significantly more likely to obtain an improved mark on end-of-fourth year summative written (p = 0.005) and OSCE (p = 0.001) exams compared to those students who did not receive remediation.

A remedial intervention linked to poor assessment performance predicted improved performance in later examination. There is a need for prospective studies in order to identify the effective components of remedial interventions.

Should we consider an acceptable drinking level specifically for postmenopausal women?

There are substantial neuroendocrine differences between postmenopausal (PMP) women and women with cyclic ovarian function; thus there are differences in hormonal responses to 'acceptable' levels of drinking, i.e. 7 total weekly drinks (TWD). The aim is to evaluate whether alcoholic beverage consumption for PMP women should be the same for all women, as is currently the case, or different from that for women with cyclic ovarian function. Carefully collected and cross-checked current drinking data in 318 PMP women from a spectrum of racial and ethnic groups have been analysed to determine if a plateau in estradiol (E2) levels at a particular alcohol consumption level other than 7 TWD can be identified as the drinking level above which no additional benefit in E2 levels occurs. Levels of E2 are significantly different among abstainers and among drinkers within all racial and ethnic groups, with the disturbing exception of black PMP women. Although there are significant differences among racial and ethnic groups in the proportions of women who drink, there are no differences in TWD consumed during the previous month. Between<or =5 TWD and<or =6 TWD, a plateau in the correlation of E2 with increasing drinks/week occurs, and the range of the unstandardized multiple regression coefficient +/- the standard error do not overlap between these same two drinking levels (P<0.05).

Consideration should be given to lowering the acceptable level of drinking for PMP women 5 TWD. Additional studies in which sample sizes for each minority racial and ethnic are larger need to be performed in the future.

Does neuronal Sirt3 protect against excitotoxic injury in mouse cortical neuron culture?

Sirtuins (Sirt), a family of nicotinamide adenine nucleotide (NAD) dependent deacetylases, are implicated in energy metabolism and life span. Among the known Sirt isoforms (Sirt1-7), Sirt3 was identified as a stress responsive deacetylase recently shown to play a role in protecting cells under stress conditions. Here, we demonstrated the presence of Sirt3 in neurons, and characterized the role of Sirt3 in neuron survival under NMDA-induced excitotoxicity. To induce excitotoxic injury, we exposed primary cultured mouse cortical neurons to NMDA (30 µM). NMDA induced a rapid decrease of cytoplasmic NAD (but not mitochondrial NAD) in neurons through poly (ADP-ribose) polymerase-1 (PARP-1) activation. Mitochondrial Sirt3 was increased following PARP-1 mediated NAD depletion, which was reversed by either inhibition of PARP-1 or exogenous NAD. We found that massive reactive oxygen species (ROS) produced under this NAD depleted condition mediated the increase in mitochondrial Sirt3. By transfecting primary neurons with a Sirt3 overexpressing plasmid or Sirt3 siRNA, we showed that Sirt3 is required for neuroprotection against excitotoxicity.

This study demonstrated for the first time that mitochondrial Sirt3 acts as a prosurvival factor playing an essential role to protect neurons under excitotoxic injury.

Does sphingosine-1-phosphate analogue FTY720 cause lymphocyte redistribution and hypercholesterolemia in ApoE-deficient mice?

Resident immune cells are a hallmark of atherosclerotic lesions. The sphingolipid analogue drug FTY720 mediates retrafficking of immune cells and inhibits their homing to inflammatory sites. We have evaluated the effect of FTY720 on atherogenesis and lipid metabolism. ApoE-/- mice on a normal laboratory diet received oral FTY720 for 12 weeks, which led to a 2.4-fold increase in serum cholesterol (largely VLDL fraction) and a 1.8-fold increase in hepatic HMGCoA reductase mRNA. FTY720 increased plasma sphingosine-1-phosphate and induced marked peripheral blood lymphopenia. A discoordinate modulation of B, T and monocyte cell numbers was found in peripheral lymphoid organs. Overall depletion of T cells was accompanied by a relative (2-fold) increase in regulatory T cell content paralleled by a similar increase in effector memory T cells (CD4+ CD44hi CD62lo) as absolute numbers of both subpopulations remained essentially unchanged. Lymphocyte function was unaltered as indicated by anti-OxLDL antibodies and T cell proliferation. There were no changes in atherosclerotic lesions in early and established atherosclerosis.

FTY720 mediated peripheral lymphocyte depletion and retrafficking without altering function and overall balance of pro- and antiatherogenic lymphocyte populations. A net decrease in lymphocyte numbers occurred concomitantly with a more proatherogenic hypercholesterolemia resulting in unaltered atherogenesis.

Is delayed nerve conduction associated with increased self-reported disability in individuals with hand symptoms?

To determine whether, in individuals in the general population with hand symptoms, there is a greater level of disability in those with objective evidence of delayed nerve conduction. A 19 item disability schedule relevant to hand function was developed for this survey. Subjects included 71 individual respondents to a random population survey who reported pain, tingling, numbness, or loss of sensation in the hands during an interview and who agreed to have nerve conduction studies. They were divided into those with (10) and without (61) delayed median nerve conduction. Those with delayed conduction were more likely to report disability for 14 of the 19 items assessed. Half those with delayed conduction reported disability in 7 or more items, compared with 18% of those with normal conduction (chi-squared = 7.49, p = 0.006). Disability items that showed the greatest disparity between the 2 groups were those that relied on hand, although not specifically fine hand, movements.

Individuals with hand symptoms in the general population who have objective evidence of delayed nerve conduction have a greater degree of self-reported disability than those with normal conduction.

Are new-generation flexible ureterorenoscopes more durable than previous ones?

To determine the deterioration in the maximal active deflection and flow capabilities of a new-generation flexible ureteroscope (URS). We performed 50 ureterorenoscopies using the same URS: a Karl Storz 11278 AU1 Flex-X, which is capable of a 270 degree active deflection in the ventral and dorsal directions. Postoperatively, we evaluated the maximal active ventral and dorsal deflection, irrigation flow at 100 cm H2O, and the number of broken optical fibers. The URS was used for a total of 76 hours, 15 minutes (average 95 minutes per procedure). The maximal ventral deflection had deteriorated from 270 degrees to 208 degrees at the last procedure. The maximal dorsal deflection had decreased from 270 degrees to 133 degrees. The irrigation flow at 100 cm H2O had decreased from 50 mL/min initially to 40 mL/min at the last procedure. The number of broken image fibers had reached six at the 50th procedure. One repair was necessary at the 50th procedure because of a laser perforation of the working channel.

The need for repair occurs less frequently with the new-generation of URSs, especially when they are used by an experienced endourologist. In the future, improvements in the durability of the flexible URS will still be key for widespread use of the technique and especially to limit damage by the laser to the working channel.

Is teaching and learning in the operating room a two-way street : resident perceptions?

The transformation of a trainee into a surgeon is influenced strongly by communication patterns in the operating room (OR). In the current era of limited educational opportunities, elucidation of teaching and learning strategies in this environment is critical. The aim of this study was to further understand the elements of an effective communicative instructional interaction (CII) as perceived by surgical residents. Qualitative research methodology was used to explore University of British Columbia surgery residents' perceptions of what constitutes an effective CII in the OR. Purposeful sampling was used to select participants from various years of training. Eighteen residents participated in semistructured interviews to facilitate reflection of their OR experiences. Interviews were transcribed, analyzed, and fed back to residents to confirm their accuracy. Independent coding and analysis led to the development of key emergent themes. Themes represented the interplay of ideals expressed by the residents. The primary emergent theme was that both teacher and learner play a major role in the creation of an effective CII. The ideal teacher had an instructional plan, facilitated surgical independence, and showed support and empathy for the surgical resident. The ideal resident was receptive, prepared, and acknowledged limitations. The contextual constraints of the OR played a central role in learning, and residents identified ways to maintain educational value despite primarily nonmodifiable contextual elements (ie, time constraints).

In a unique environment such as the OR, both teacher and learner may benefit by an enhanced understanding of the elements of an effective CII.

Is aggressive surgery in pleural empyema justified?

High risk and a long hospitalization time are often quoted as negative aspects of aggressive surgery in pleural empyema. We did a retrospective analysis evaluating outcome and duration of hospitalization in patients treated according to an aggressive schedule. Since 1989 we have treated 101 patients with pleural empyema (72 males, 29 females; mean age 50.3 years, range 11-91 years; 77 metapneumonic empyema, 24 empyema following trauma or abdominal surgery). Sixty-nine patients had had unsuccessful conservative pre-treatment (antibiotics, thorcozentses, drainage/irrigation, VATS). Thirty-one were critically ill patients. In eight cases a seropurulent stage of empyema was present, 17 patients had fibrinous membranes, 30 an organizing stage with and 46 without well identifiable dissection plane. Eighty-five patients proceeded to thoracotomy. Pulmonary abscesses or indurative pneumonia necessitated wedge-resection, lobectomy, or pneumonectomy in 29 cases. In the presence of gross necroses or callosities not amenable to decortication primary open-window thoracostomy (n = 22) was carried out. In six cases a secondary open-window thoracostomy was carried out because of persisting putrid secretion and sepsis persisting after decortication or after drainage. The thoracostomy was closed when clean granulative tissue developed. Sixteen patients underwent only drainage and irrigation because of an early stage or because of a general condition not permitting thoracotomy. Three patients died due to severe sepsis not responding to treatment, one had fatal bleeding from a duodenal ulcer (mortality rate 3.9%). The others were able to resume their preoperative activities. The median duration of hospitalization was 14 days (mean 21.1 days; SEM 1.7 days).

Aggressive surgery for pleural empyema beyond the seropurulent stage ensures rapid relief from sepsis at a low mortality rate even in very ill patients.

Comminuted diaphyseal fractures of the radius and ulna: does bone grafting affect nonunion rate?

The recommendation of Anderson and colleagues to bone graft even relatively minor amounts of comminution (a third of the bone diameter) in the treatment of diaphyseal forearm fractures with plate-and-screw fixation has been questioned. This study examines factors related to nonunion in adult patients with comminuted diaphyseal fractures of both the radius and the ulna to determine the relative influence of bone grafting. Over a 15-year period at two hospitals, 41 patients with diaphyseal fractures of both forearm bones satisfied the following criteria: comminution (Orthopaedic Trauma Association grade IV or higher) of at least one fracture; treatment with 3.5- or 4.5-mm dynamic compression plates at least six holes in length; and minimum 12-month follow-up. Multiple logistic regression was used to determine the contribution of the following factors to the risk of nonunion: multiple injuries; ipsilateral upper extremity injury; open wound; and the application of cancellous bone graft at the fracture site. Five patients had nonunion of one or both bones (12%). According to the multiple logistic regression model, none of the factors studied had a statistically significant association with nonunion (p>0.40 for all). The odds ratios were as follows: multiple injuries, 2.1 (95% confidence interval [CI], 0.34-12.9); ipsilateral injury, 0.68 (95% CI, 0.058-7.84); open fracture, 1.46 (95% CI, 0.21-9.89); and bone graft, 0.98 (95% CI, 0.15-6.42).

Nonunion occurred in 12% of comminuted, diaphyseal fractures of both bones of the forearm treated with dynamic compression plates. No single factor was associated with nonunion. In particular, the use of bone graft was not associated with a higher rate of union.

Is abdominosacral resection related to the risk of neurological complications in patients with low-rectal cancer?

Some authors claim that the risk of sacrectomy-related neurological complications is a serious limitation of abdominosacral resection (ASR). We determined the incidence of neurological complications in patients with a low-rectal cancer who were treated by ASR. The clinical records of 54 consecutive patients with low-rectal cancer who were operated on by ASR were analysed. The occurrence of neurological complications in these patients was compared with that of 140 consecutive patients with cancer of the mid- and upper rectum who underwent anterior resection (AR) during the same period. Neurological complications were defined as bowel, bladder or sexual dysfunction, gait abnormalities and local parasthesiae persisting for more than 6 months following surgery. There were no persisting neurological complications after either AR or ASR. At the end of hospitalization, the 16 of 140 and 12 of 54 of those treated with AR and ASR had neurological complications, which fell to five of 140 and three of 53 at 3 months, respectively; at 6 months, no one treated had any complications.

Neurological complications after AR and ASR were similar but recovery was complete at 6 months following surgery.