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Does intracerebroventricular injections of dronabinol , a cannabinoid receptor agonist , attenuate serotonin-induced apnea in Sprague-Dawley rats?

Evidence suggests that vagal nerve activity may play a role in sleep apnea induction. In anesthetized rats, dronabinol, a cannabinoid (CB) receptor agonist, injected into the nodose ganglia attenuates reflex apnea and increases genioglossus activity, and reflex apnea attenuation is blocked by systemic pre-treatment with cannabinoid type 1 and/or type 2 receptor antagonists. However, it is unclear whether dronabinol has similar effects in the central nervous system; CB receptors are widely distributed in the brain, especially on neuronal circuitry important for respiration and upper airway activation. Here, we examine the effects of intracerebroventricular (ICV) injection of dronabinol on serotonin (5-HT)-induced apnea. Adult male Sprague-Dawley rats were anesthetized and instrumented with bilateral electrodes to monitor genioglossi EMG and with a piezoelectric strain gauge to monitor respiratory pattern. Serotonin was intravenously infused into a femoral vein to induce reflex apnea. After baseline recordings, rats were placed in a stereotaxic apparatus. A unilateral osteotomy was made to allow access for injection to the right lateral ventricle, and the dura were carefully removed. Dronabinol (100, 10, 1, or 0.1 μg/3 μl DMSO) or control (3 μl DMSO) was injected into the right lateral ventricle and 5-HT infusion was repeated. Data (mean ± SEM) were analyzed using a mixed model analysis with a repeated/fixed measure. There was no main effect in 5-HT-induced apnea or breath duration, or in breath instability, between ICV dronabinol injected and ICV vehicle control injected groups. Moreover, there was no main effect in phasic or tonic genioglossus activity between ICV dronabinol injected and ICV vehicle control injected groups.

Our data show that ICV injection of dronabinol did not decrease 5-HT-induced apneas, and did not increase genioglossus activity. This in contrast to published results of dronabinol's effect on apnea via the vagus nerve. Our results suggest that the effects of dronabinol on reflex apneas are peripherally mediated via suppression of vagal nerve activity.

Does chronic amiodarone therapy impair the function of the superior sinoatrial node in patients with atrial fibrillation?

The mechanisms underlying amiodarone-induced sinoatrial node (SAN) dysfunction remain unclear, so we used 3-dimensional endocardial mapping of the right atrium (RA) to investigate. In a matched-cohort design, 18 patients taking amiodarone before atrial fibrillation (AF) ablation (amiodarone group) were matched for age, sex and type of AF with 18 patients who had undergone AF ablation without taking amiodarone (no-amiodarone group). The amiodarone group had a slower heart rate than the no-amiodarone group at baseline and during isoproterenol infusion. Only the amiodarone group had sick sinus syndrome (n=4, 22%, P=0.03) and abnormal (>550ms) corrected SAN recovery time (n=5, 29%; P=0.02). The median distance from the junction of the superior vena cava (SVC) and RA to the most cranial earliest activation site (EAS) was longer in the amiodarone group than in the no-amiodarone group at baseline (20.5 vs. 10.6mm, P=0.04) and during isoproterenol infusion (12.8 vs. 6.3mm, P=0.03). The distance from the SVC-RA junction to the EAS negatively correlated with the P-wave amplitudes of leads II (r=-0.47), III (r=-0.60) and aVF (r=-0.56) (P<0.001 for all).

In a quarter of the AF patients, amiodarone causes superior SAN dysfunction, which results in a downward shift of the EAS and reduced P-wave amplitude in leads II, III and aVF at baseline and during isoproterenol infusion.

Does sanguis Draconis resin stimulate osteoblast alkaline phosphatase activity and mineralization in MC3T3-E1 cells?

Sanguis Draconis (SD), "Dragon's Blood", is a resin that is obtained from Daemonorops draco (Palmae). Used in traditional medicine, it has shown activity in the prevention of osteoporosis as well as promoting the healing of bone fractures. In this study, the effects of Sanguis Dranonis ethanol extract on β-glycerolphosphate and ascorbic acid induced differentiation using mouse calvaria origin MC3T3-E1 osteoblastic cells was examined. We looked at osteoblast differentiation, proliferation, and mineralization by measuring alkaline phosphatase (ALP) and specific bone marker activities. Osteoblast-like MC3T3-E1 cells were cultured in various concentrations of SD ethanol extract (0.005-1mg/mL) during the osteoblast differentiation period (1, 5, 15, and 25 days). As measured by 3-[4,5-dimethylthiazol-2-y]-2,5-diphenyltetrazolium bromide assay, SD extracts increased cell proliferation as compared to control. The most pronounced effect was observed at the concentration range between 0.01 and 0.1 mg/mL (P<0.01). This SD stimulatory effect for cell proliferation was observed during the whole osteogenic period. Cellular (synthesized) ALP activity was increased during 15 days of culture, and was confirmed by the staining of ALP activity on cell matrix layers for matrix calcification. SD stimulatory effect for cell mineralization we observed in 14 and 21 days. Elevated mRNA or protein levels of bone morphogenetic protein-2(BMP 2), the differentiation marker osteocalcin, osteopontin, collgen I, and a master osteogenic transcription factor, Runx2, were observed in SD-treated cells.

These results suggest that SD may increase osteogenic effect by stimulating cell ALP activity and affect the BMP signaling pathway cascades in osteoblastic cells, then promotes osteoblast differentiation, mineralization, and bone formation.

Is osGRAS23 , a rice GRAS transcription factor gene , involved in drought stress response through regulating expression of stress-responsive genes?

Drought is a major abiotic stress factors that reduces agricultural productivity. GRAS transcription factors are plant-specific proteins that play diverse roles in plant development. However, the functions of a number of GRAS genes identified in rice are unknown, especially the GRAS genes related to rice drought resistance have not been characterized. In this study, a novel GRAS transcription factor gene named OsGRAS23, which is located in a drought-resistant QTL interval on chromosome 4 of rice, was isolated. The expression of OsGRAS23 was induced by drought, NaCl, and jasmonic acid treatments. The OsGRAS23-GFP fused protein was localized in the nucleus of tobacco epidermal cells. A trans-activation assay in yeast cells demonstrated that the OsGRAS23 protein possessed a strong transcriptional activation activity. OsGRAS23-overexpressing rice plants showed improved drought resistance and oxidative stress tolerance as well as less H2O2 accumulation compared with the wild-type plants. Furthermore, microarray analysis showed that several anti-oxidation related genes were up-regulated in the OsGRAS23-overexpressing rice plants. The yeast one hybrid test indicated that OsGRAS23 could bind to the promoters of its potential target genes.

Our results demonstrate that OsGRAS23 encodes a stress-responsive GRAS transcription factor and positively modulates rice drought tolerance via the induction of a number of stress-responsive genes.

Does low-protein diet improve blood and urinary glucose levels and renal manifestations of diabetes in C57BLKS-db/db mice?

Dietary protein content is related clinically to the development of diabetic nephropathy. Here, we investigated how dietary protein content (12-24 % energy) within the range used by humans affected renal manifestations including the expressions of genes involved in the renin-angiotensin (RA) system in control and diabetic mice. Moreover, we examined the effects of dietary protein content on HbA1c and urinary glucose. Control (CT) and leptin receptor-deficient obese (db) mice, 5 weeks old, were fed the diets below. Under ad libitum conditions, mice were fed 12, 18, and 24 % energy from protein (L-, M-, and H-diets) for 8 weeks. Under pair-feeding conditions, db mice were supplied H-diet (db-Hp) to the equivalent energy to that consumed by db-L mice. Renal manifestations and values related to glucose and insulin were examined biochemically and pathologically. Under ad libitum conditions, db mice consumed food and water dose dependently of the dietary protein content, although they were consumed similarly by CT mice. CT-L mice showed lower urinary albumin and kidney weight, in association with lower mRNA levels of angiotensinogen and renin, than CT-H mice. Under pair-feeding conditions, db-L mice showed a lower ratio of kidney/body weight, HbA1(C), and urinary glucose, and a higher β-cell distribution rate in the pancreas than db-Hp mice.

Low-protein intake in the range used by humans may relieve renal manifestations through the suppressed expression of genes in the renal RA system of CT mice. On the other hand, in db mice, low-protein intake improved hyperglycemia and the renal manifestations of diabetes.

Is collaboration in maternity care achievable and practical?

Enhancing collaboration has been highlighted as a marker for future success in maternity care, although this suggestion comes with little methodological guidance. This study assessed the efficacy of a collaborative partnership between obstetric doctors and midwives providing Midwifery Group Practice (MGP) care. A retrospective analysis was undertaken with notes from weekly case review meetings held between the obstetricians and midwives over a 12-month period; audio recordings and a prospective analysis of 16 meetings with verbal contributions of the different professions; the number and types of cases discussed and referred, medical records kept at these meetings and a professional satisfaction questionnaire. Consistency of care was measured against the Australian National Midwifery Guidelines for Consultation and Referral. Of the 337 women booked with MGP, 50% were discussed at least once. Of these, 35% were referred for consultation with an obstetrician. Women as 'Patients' were most commonly discussed, followed by educational discussions and anecdotes with equal verbal contributions from midwives and doctors. Plans for each case were recorded 97% of the time, and adhered to 90% of the time. A high level of consistency of care between similar cases (75% of the time) and with the consultation and referral guidelines (85% of the time) were achieved. Professional satisfaction with this model of care rated highly for both groups.

Inter-professional collaboration between midwifery and obstetric staff is highly attainable within this model of care. This study reinforces the effectiveness of collaboration in the MGP model of care for women of all risk levels and should encourage other maternity care providers to consider adopting this collaborative model.

Does arterial spin-labeled perfusion imaging reflect vascular density in nonfunctioning pituitary macroadenomas?

Angiogenesis is very important in clinical features of pituitary adenomas. We investigated the relationship between the blood flow of nonfunctioning pituitary macroadenomas measured by arterial spin-labeled perfusion imaging and the microvessel attenuation of the tissue. Conventional MR imaging with contrast-enhanced T1WI and arterial spin-labeled perfusion imaging were performed before surgery in 11 consecutive patients with nonfunctioning pituitary macroadenomas. ROIs were drawn on the tumors, and the degrees of enhancement were calculated by dividing the signal intensity on the contrast-enhanced T1WI by that on the nonenhanced TIWI. As an index of tumor perfusion, a quantitative analysis was performed by using normalized tumor blood flow values calculated by dividing the mean value of the tumor region of interest by the mean region of interest values in the 2 cerebellar hemispheres. The relative microvessel attenuation was determined as the total microvessel wall area divided by the entire tissue area on CD-31-stained specimens. The degree of enhancement and the normalized tumor blood flow values were compared with relative microvessel attenuation. Additionally, intra- and postoperative tumor hemorrhages were visually graded. The degree of enhancement was not correlated with relative microvessel attenuation. Statistically significant correlations were observed between normalized tumor blood flow values and relative microvessel attenuation (P < .05). At surgery, 3 cases were visually determined to be hypervascular tumors, and 1 of these cases had symptomatic postoperative hemorrhage. A statistically significant difference in normalized tumor blood flow values was observed visually between the intraoperative hypovascular and hypervascular groups (P < .05).

Arterial spin-labeled perfusion imaging reflects the vascular density of nonfunctioning pituitary macroadenomas, which may be useful in the preoperative prediction of intra- and postoperative tumor hemorrhage.

Is high plasma adiponectin concentration associated with all-cause mortality in patients with carotid atherosclerosis?

The role of adiponectin as a risk factor for mortality and recurrent ischemic cardiovascular events in patients with carotid artery disease is unknown. Consecutive patients (n = 292) undergoing carotid endarterectomy for symptomatic and asymptomatic carotid stenosis were included in the study. Mortality and cardiovascular ischemic events were recorded during a median follow-up of 5.2 years. Baseline plasma concentrations of adiponectin were measured. Cox regression models stratified for gender were used for estimation of risk of events. Fifty-two patients died and 73 had an ischemic event (ischemic stroke, n = 52 and/or MI, n = 28) during follow-up. In univariate analyses, adiponectin was associated with mortality, hazard ratio (HR) per standard deviation (SD) increase of adiponectin, 1.46 (95% confidence interval [CI], 1.14-1.86). In multivariate analysis age, type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), plasma interleukin-6 (IL-6) and plasma adiponectin (HR per SD increase of adiponectin, 1.73 [95% CI, 1.29-2.32]) were independently associated with mortality. T2DM, CHD, fibrinogen, contralateral carotid artery stenosis, systolic blood pressure, symptomatic carotid artery stenosis were independently associated with ischemic events, whereas plasma adiponectin was not (HR per SD increase of adiponectin, 0.96 [95% CI, 0.75-1.23]).

High plasma adiponectin concentration is associated with mortality in patients with established atherosclerosis undergoing surgery for carotid artery stenosis. Further studies to determine the role for adiponectin as a biomarker are warranted.

Is colonoscopic high frequency mini-probe ultrasound more accurate than conventional computed tomography in the local staging of colonic cancer?

Colonoscopic high frequency mini-probe ultrasound was compared prospectively with CT in the local staging of colonic cancer. Consecutive patients undergoing surgical resection for colonic cancer were recruited. Preoperative 64-slice CT staging with multiplanar reconstruction was compared with colonoscopic high frequency mini-probe ultrasound using 12 MHz and 20 MHz probes. The three methods of staging (CT, 12 MHz ultrasound and 20 MHz ultrasound) were compared with the histological stage of the resected specimen. This was done using weighted kappa coefficients where weights of 0.7-0.8 were given to penalize disagreements of one level in either direction and weights of zero were given to penalize disagreements of more than one level in any direction. In total, 38 patients with colonic cancer were included. They were located in the sigmoid (n = 20), descending (n = 5), ascending (n = 2) and transverse colon (n = 1) and in the caecum (n = 7) and splenic (n = 2) and hepatic (n = 1) flexure. Histopathological assessment revealed seven pT1, four pT2, 25 pT3 and two pT4 cancers. In relation to the pathology the weighted kappa coefficients were 0.36 (SE = 0.14), 0.81 (SE = 0.16) and 0.81 (SE = 0.17) for CT, ultrasound 12 MHz and ultrasound 20 MHz. Histopathologically 15 (39.5%) patients were lymph node positive. The sensitivity, specificity and kappa coefficient for detection of nodal disease for CT were 80%, 47.8% and 0.25 (SE = 0.14) compared with 80%, 82.5% and 0.62 for 12 MHz ultrasound (SD = 0.14) and 23%, 90.5% and 0.15 (SD = 0.13) for 20 MHz ultrasound.

Colonoscopic ultrasound is significantly more accurate than CT for T staging of colonic cancers. With respect to nodal status, 12 MHz ultrasound offers superior accuracy to CT or 20 MHz ultrasound.

Does the presence of circulating hepatocellular carcinoma cells indicate a risk of recurrence after resection?

Alpha-fetoprotein messenger RNA (AFP mRNA) in the peripheral blood (PB) of patients with hepatocellular carcinoma (HCC) has been considered to represent isolated tumor cells. We investigated its association with the prognosis after curative resection. Using a reverse-transcription polymerase chain reaction (RT-PCR)-based assay, AFP mRNA in the PB was determined prospectively in control and in 81 patients with curative resection for HCC. Twenty-two (27.2%) and 19 (23.4%) of 81 HCC patients had AFP mRNA in their pre- and postoperative PB. Its presence preoperatively was not associated with an increased risk of HCC recurrence (54.5% vs 40.7%, p= 0.264). In contrast, the postoperative presence associated significantly with a higher incidence of recurrence (89.5% vs 30.6%, p<0.001), irrespective of preoperative status. The odds ratio for HCC recurrence was 19.2 (95% confidence interval [CI]: 4.0- 91.7). The cmulative probability of recurrence-free survival was also much lower in patients with postoperatively positive AFP mRNA (p<0.001). The Cox proportional hazards model also demonstrated a significant association with recurrence (p= 0.002). Preoperative serum AFP is also a significant factor and combination with postoperative AFP mRNA enhances the predictability, sensitivity (75.0%), specificity (93.3%), positive prediction (90.0%), and negative prediction (82.4%).

The postoperative detection of AFP mRNA in PB is associated with an increased risk of earlier HCC recurrence. Combination with preoperative serum AFP is useful in predictability.

Does low-dose irradiation stimulate TNF-alpha-induced ICAM-1 mRNA expression in human coronary vascular cells?

Low-dose irradiation (LDI) is employed to extend the irradiation area in vascular brachytherapy to minimize the edge effect. Stimulation of adhesion molecule 1 (ICAM-1) is one of many mechanisms important in the early stages of atherosclerosis and restenosis. This study investigates the effect of gamma-irradiation on mRNA expression of ICAM-1 in human coronary vascular cells. Human coronary endothelial cells (HCAECs), human umbilical endothelial cells (HUVECs), and human coronary smooth muscle cells (HCMSMCs) were cultured and identified. Twenty-four hours after seeding, gamma-irradiation at doses of 0.5 Gy, 1 Gy, 10 Gy, 20 Gy, and 30 Gy (Linac Philips FL 75/20) was carried out. Twenty hours after irradiation, ICAM-1 expression was stimulated for 6 h with TNF-alpha (20 ng/ml). In Northern blot assays, 10 microg of RNA were used. The relative band density of ICAM-1 mRNA of irradiated and stimulated cells were compared with that of non-irradiated cells after TNF-alpha stimulus only. In HCAECs and HCMSMCs, stimulation of ICAM-1 mRNA was detected after irradiation, no matter which dose was applied. After low-dose irradiation (0.5 Gy and 1 Gy) the stimulating effect was pronounced, significant differences being found in HCAECs after irradiation with 1 Gy.

Stimulation of ICAM-1 mRNA expression after LDI of human coronary vascular cells may be one of the many mechanisms that trigger the edge effect in vivo. If these results are confirmed by further studies and if anti-inflammatory treatment strategies cannot inhibit the stimulatory effects, a major problem exists for the future of vascular brachytherapy.

Does trazodone hydrochloride attenuate thermal hyperalgesia in a chronic constriction injury rat model?

Trazodone hydrochloride is used in the treatment of neuropathic pain. However, the analgesic effects of trazodone on neuropathic pain are controversial. The study was undertaken to determine the analgesic effect of trazodone on a chronic constriction injury model. We tested the effect of trazodone on thermal hyperalgesia due to a chronic constriction injury of the sciatic nerve in rats and examined the effects of lesions in the descending and ascending serotonergic system induced by 5,7-dihydroxytriptamine (5,7-DHT). The analgesic effects of trazodone showed a clear dose dependency. Furthermore, the analgesic effect of trazodone was observed in rats injected with 5,7-DHT into the dorsal raphe nucleus and medial raphe nucleus.

The results suggest that a mainly serotonergic descending pain control pathway mediates the analgesic effects of trazodone.

Does massage in patients undergoing intensive chemotherapy reduce serum cortisol and prolactin?

The objective is to identify whether single 20 min massage sessions were safe and effective in reducing stress levels of isolated haematological oncology patients. Based on a randomised controlled trial, 39 patients were randomised to aromatherapy, massage or rest (control) arm. The measures were serum cortisol and prolactin levels, quality of life (EORTC QLQ-C30) and semi-structured interviews. Primary outcome measure was the fall in serum cortisol levels. A significant difference was seen between arms in cortisol (P=0.002) and prolactin (p=0.031) levels from baseline to 30 min post-session. Aromatherapy and massage arms showed a significantly greater drop in cortisol than the rest arm. Only the massage arm had a significantly greater reduction in prolactin then the rest arm. The EORTC QLQ-C30 showed a significant reduction in 'need for rest' for patients in both experimental arms compared with the control arm, whereas the semi-structured interviews identified a universal feeling of relaxation in patients in the experimental arms.

This pilot study demonstrated that in isolated haematological oncology patients, a significant reduction in cortisol could be safely achieved through massage, with associated improvement in psychological well-being. The implications are discussed.

Does dimerization of soluble HLA-G by IgG-Fc fragment augment ILT2-mediated inhibition of T-cell alloresponse?

Human leukocyte antigen (HLA)-G, a nonclassical HLA class I molecule, induces a wide range of tolerogenic immunological effects by means of interaction with its inhibitory receptors. However, recent studies show that HLA-G dimer formation is essential to bind to its receptors and exhibit its effects. In this study, a soluble divalent HLA-G/IgG molecule (sHLA-G dimer) was constructed. Its inhibitory effect on T-cell alloresponse was studied with mixed lymphocyte reaction in vitro, which was set up by mixing inactivated T1 cells with HLA-mismatched peripheral blood lymphocytes in the presence or absence of the sHLA-G dimer. The results show that sHLA-G dimer inhibits T-cell alloresponse by reducing proliferation of both CD4+ and CD8+ T cells and suppressing generation of alloreactive cytotoxic T lymphocytes at nanomole concentration. The inhibition of the sHLA-G dimer is observed to be more effective than that of sHLA-G monomer. Our results also indicate that sHLA-G dimer up-regulates inhibitory receptor ILT2 on alloreactive CD8+ T cells, which contributes to the significant inhibition on T-cell alloresponse.

The sHLA-G dimer formed by IgG-Fc fragment shows more inhibitory effects on alloreactive T cells, which may have implications for allotransplantation.

Does deficiency of endothelium-specific transcription factor Sox17 induce intracranial aneurysm?

Intracranial aneurysm (IA) is a common vascular disorder that frequently leads to fatal vascular rupture. Although various acquired risk factors associated with IA have been identified, the hereditary basis of IA remains poorly understood. As a result, genetically modified animals accurately modeling IA and related pathogenesis have been lacking, and subsequent drug development has been delayed. The transcription factor Sox17 is robustly expressed in endothelial cells of normal intracerebral arteries. The combination of Sox17 deficiency and angiotensin II infusion in mice induces vascular abnormalities closely resembling the cardinal features of IA such as luminal dilation, wall thinning, tortuosity, and subarachnoid hemorrhages. This combination impairs junctional assembly, cell-matrix adhesion, regeneration capacity, and paracrine secretion in endothelial cells of intracerebral arteries, highlighting key endothelial dysfunctions that lead to IA pathogenesis. Moreover, human IA samples showed reduced Sox17 expression and impaired endothelial integrity, further strengthening the applicability of this animal model to clinical settings.

Our findings demonstrate that Sox17 deficiency in mouse can induce IA under hypertensive conditions, suggesting Sox17 deficiency as a potential genetic factor for IA formation. The Sox17-deficient mouse model provides a novel platform to develop therapeutics for incurable IA.

Does cell density dependent plating efficiency affect outcome and interpretation of colony forming assays?

The usefulness of colony forming assays (CFA) has been established for almost 40 years (Puck and Marcus, J.Exp.Med. 103: 653-666, 1956). Although time-consuming and not successful for all cell lines, it is generally considered to be the gold standard of assays for testing the sensitivity of cell lines to ionizing radiation or other cytotoxic agents in vitro. We recently found for several cell lines that the plating efficiencies of both control and irradiated cells is dependent upon the density of cells seeded for colony formation; that is, increasing cell inoculum levels resulted in a non-linear relationship with colony formation, even at relatively low colony numbers. All data from a human melanoma cell line, transfected with c-myc or N-ras, as well as from normal human diploid fibroblasts, were taken to see how this phenomenon influenced outcome and interpretation of clonogenic assays. Survival was recalculated using all data, or only data with a linear relationship between inoculum level and colony formation. It is found that when data with a non-linear relationship between inoculum level and colony formation are included, survival can be underestimated due to inhibition of colony formation in treated cultures.

For validity, colony forming assays must be standardized to assure a constant relationship between the cell density and colony forming efficiency. This usually requires a much lower density of colonies than has been typically published for many cell survival studies.

Are increases in electroencephalogram and electromyogram variability associated with an increased incidence of intraoperative somatic response?

sBIS, the variability of the Bispectral Index (BIS), sEMG, the variability of facial electromyogram power (EMG), and the Composite Variability Index (CVI) are 3 new measures of electroencephalogram and EMG variability. CVI is a single measure of the combined variability in BIS and EMG. We investigated whether increases in these variables are associated with intraoperative somatic responses. This multicenter study included 120 patients undergoing elective, noncardiac surgery from 4 different sites. General anesthesia was maintained using propofol and remifentanil at 2 of the sites and sevoflurane and remifentanil at the 2 other sites. Propofol or sevoflurane was adjusted to maintain BIS between 45 and 60. Clinicians were blinded to CVI (v2.0) at all times, and remifentanil infusions were adjusted at the discretion of the clinician. The times of all intraoperative somatic events, defined as movement, grimacing, or eye opening, were recorded. Offline, the maintenance phase of each case was divided into consecutive, nonoverlapping, 10-minute segments. Segments were identified as containing a somatic event or containing no events. For each segment, mean sBIS, sEMG, and CVI and the heart rate (HR) range and mean arterial blood pressure range were calculated. To quantify how effectively each variable discriminated between somatic event segments and nonevent segments, we computed the area under the receiver operating characteristic (ROC) curve for each variable. Finally, we observed the time course of sBIS, sEMG, CVI, and the HR range before each somatic event and characterized the earliest time before the somatic event at which each variable was able to discriminate between the somatic events and a specified set of nonevents. The analysis included 33 somatic event segments and 829 nonevent segments from 105 surgical cases. The areas under the ROC curve (±SE) for sBIS, sEMG, and CVI were 0.83 ± 0.04, 0.92 ± 0.02, and 0.89 ± 0.03, respectively. The areas under the ROC curve for HR range and mean arterial blood pressure range were 0.77 ± 0.03 and 0.68 ± 0.05, respectively. CVI, sBIS, and sEMG all demonstrated higher average values before upcoming somatic events when compared with nonevents. HR range only showed a difference within a few seconds before the somatic event.

sBIS, sEMG, and CVI, measures of electroencephalogram and EMG variability, increased when intraoperative somatic events occurred. sBIS, sEMG, and CVI discriminated between 10-minute segments that contained a somatic event and those segments that did not contain an event better than changes in HR and mean arterial blood pressure. Furthermore, CVI increases before somatic events began earlier than HR changes and may provide caregivers with an early warning of potentially inadequate antinociception.

Does basic fibroblast growth factor enema improve experimental colitis in rats?

Growth factors have a potential role in gastrointestinal mucosal repair. Although basic fibroblast growth factor (bFGF) is known to contribute to wound healing, however, the role of bFGF in the treatment of inflammatory bowel disease has not been established. The aim of this study is to investigate the therapeutic effects of intracolonic bFGF administration on both the clinical symptoms and histological mucosal repair in an experimental model of colitis in rats. Acute colitis was induced with 5% dextran sulfate sodium (DSS) given for one week in drinking water. The rats were treated daily with recombinant human bFGF enema (400 microg/kg/day) or vehicle once daily from day 1 to day 7. Clinical score (stool consistency, weight loss and hemoccult/gross rectal bleeding), colon length and histological score of mucosal injury in colonic tissue samples were analyzed. Administration of bFGF enema significantly reduced clinical score (p < 0.01) and histological score (p < 0.01). No specific side effect of bFGF was noted.

These results suggest that bFGF enema is clinically safe and useful in the treatment of inflammatory bowel disease. BFGF enema may contribute as a novel therapy of IBD.

Does response to cold pressor test predict long-term changes in pulse wave velocity in men?

Aortic stiffness is associated with increased cardiovascular mortality. However, the determinants of aortic stiffness progression are not fully established. This study evaluated the predictive value of blood pressure (BP) response to cold pressor test (CPT) in the progression of carotid-femoral pulse wave velocity (PWV) in men and women. A total of 408 individuals (165 men, 243 women) from Vitoria, Brazil, underwent BP evaluation, clinical and laboratorial investigations, and CPT and PWV assessment. Five years later, the studied individuals were re-evaluated, except for the CPT. In men, 5-year PWV change correlated inversely with baseline PWV (P < 0.001) and directly with BP response to CPT (P < 0.05) and 5-year BP change (P < 0.05). In women, 5-year PWV change correlated inversely with baseline PWV (P < 0.001) and directly with age (P < 0.01), glycemia (P < 0.05) and 5-year BP change (P < 0.05) but not with BP response to CPT. Further linear regression analysis showed that 5-year PWV change was associated with baseline PWV, systolic BP response to CPT, and 5-year systolic BP change in men and with baseline PWV, age, glycemia, and 5-year systolic BP change in women.

BP response to CPT was a predictor of PWV progression in men after 5 years of follow-up. These findings provide further insights into the pathophysiologic mechanisms of arterial stiffness, suggesting that elevated sympathetic reactivity may be a predisposing factor for future increases in aortic stiffness, at least in men.

Is off-pump coronary bypass grafting associated with less myocardial injury than coronary bypass surgery with cardiopulmonary bypass?

Excessive myocardial necrosis following coronary artery bypass grafting is associated with adverse outcome. The present study was designed to assess the extent of myocardial injury after conventional coronary artery bypass grafting with cardio pulmonary bypass (ONCAB) compared with off-pump coronary artery bypass (OPCAB). Measurements of serum cardiac troponin T (TnT) were obtained in 137 consecutive, unselected patients who underwent coronary artery bypass grafting. Serial blood sampling was performed at 3 time intervals after surgery: immediately postoperatively, 6 to 12 hours postoperatively, and 18 to 24 hours postoperatively. ONCAB patients totaled 122, and OPCAB patients numbered 15. Ten patients in the ONCAB group suffered perioperative complications, compared with no patients in the OPCAB group. At each time point examined, OPCAB patients exhibited significantly less release of TnT than ONCAB patients (immediately postoperative TnT, 1.99 +/- 4.75 ng/mL versus 0.20 +/- 0.32 ng/mL, P =.004; 6- to 12-hour TnT, 2.28 +/- 3.66 ng/mL versus 0.37 +/- 0.32 ng/mL, P =.001; and 18- to 24-hour TnT 1.59 +/- 3.49 ng/mL versus 0.30 +/- 0.32 ng/mL, P =.01). When ONCAB patients with perioperative ischemic complications were excluded, the differences between the 2 groups remained. The OPCAB patients still demonstrated less TnT release, typically 5- to 6-fold less than for ONCAB patients.

The nearly 6-fold reduction of postoperative TnT associated with OPCAB suggests that off-pump surgery may offer superior cardioprotection than coronary artery bypass grafting with conventional cardiopulmonary bypass. \par

Are all forms of total arterial revascularization equal?

Total arterial revascularization (TAR) with internal thoracic arteries (ITAs) and radial arteries (RA) is associated with greater long-term survival compared with the use of a single internal thoracic artery supplemented by veins. The optimal conduit choice and configuration in achieving TAR remains controversial, with uncertainty regarding the individual prognostic impact of ITAs and RAs. As such, among patients solely undergoing TAR, we compared long-term survival between patients receiving single thoracic arteries and those receiving bilateral ITAs. From 1995 to 2010, 2821 patients with 3-vessel coronary artery disease at 8 centers underwent primary isolated coronary artery bypass with TAR using ITAs and RAs. Bilateral ITAs were used in 912 patients. In 380 cases, bilateral in situ ITAs were grafted to the left coronary system. RAs were used in 848 patients (93%) receiving bilateral ITAs and 1906 patients (99.8%) receiving single ITAs. Survival data were obtained using the National Death Index. Separate 1:1 propensity score-matched analyses were performed for (1) bilateral ITA versus single ITA and (2) bilateral ITA incorporating a free right ITA versus single ITA and RAs. Among the 912 patients with bilateral ITAs, those receiving an in situ right ITA to the left coronary system were compared with those receiving a free right ITA. In the propensity score-matched analysis comparing bilateral versus single ITAs (591 matched pairs), there were similar rates of 30-day mortality and deep sternal wound infection. Bilateral ITA use was associated with greater 15-year survival (79% ± 3.9% vs 67% ± 4.7%, P<.001). In the analysis between bilateral ITA incorporating a free right ITA versus single ITA + RAs (380 matched pairs), bilateral ITA use demonstrated comparable survival at 15 years (79% ± 4.7% vs 67% ± 5.7%, P = .09). Among patients receiving bilateral ITAs, comparison between in situ right ITA versus free right ITA recipients (206 matched pairs) revealed comparable 15-year survival (84% ± 6.1% vs 79% ± 6.7%, P = .13). Multivariable Cox regression found bilateral ITA use to be protective from mortality (hazard ratio, 0.73; 95% confidence interval, 0.59-0.90, P = .004).

The use of bilateral ITAs as an in situ or free conduit is associated with greater survival and seems to offer a prognostic advantage over the use of only a single ITA supplemented by RAs. Therefore, all configurations of TAR are not equivalent.

Does adjunctive GnRH-a treatment attenuate depletion of ovarian reserve associated with cyclophosphamide therapy in premenopausal SLE patients?

We measured antimullerian hormone (AMH), a marker of ovarian reserve, in women with lupus treated with cyclophosphamide (CYC) (group I), CYC plus gonadotropin-releasing hormone agonist (GnRH-a) (group II) or neither (group III). We hypothesized that AMH would be diminished in women exposed to CYC versus women receiving adjunctive GnRH-a treatment or no CYC exposure. Forty-eight premenopausal lupus patients were retrospectively divided into three treatment groups: CYC alone (group I, n = 11), CYC + GnRH-a (group II, n = 10) and neither (group III, n = 27). Serum AMH levels between groups were compared using a nonparametric test (Wilcoxon rank-sum). Multiple linear regression adjusting for age was performed. AMH (ng/mL) levels at the last collection were significantly lower in group I versus group III (mean ± SD: 0.18 ± 0.20 group I vs 1.33 ± 1.59 group III; p = 0.015), and versus group II (mean ± SD: 0.86 ± 1.06; p = 0.018). When centered on age 30 years, average AMH levels for group I, group II and group III were 0.20, 0.44 and 1.00, respectively. When adjusted for age, AMH between all groups was significantly different (p<0.0001).

Posttreatment AMH levels were significantly higher among patients receiving CYC + GnRH-a compared to CYC alone, suggesting that GnRH-a coadministration mitigates CYC-induced ovarian injury.

Are nonalcoholic fatty liver disease markers associated with insulin resistance in type 1 diabetes?

Nonalcoholic fatty liver disease (NAFLD) has been associated with the insulin resistance. To explore the relationship between markers of NAFLD, namely concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALK), γ-glutamyltransferase (GGT), ferritin and bilirubin and insulin resistance in type 1 diabetes. Our study included 353 patients with type 1 diabetes. Insulin sensitivity was measured with estimated glucose disposal rate calculated using the equation: eGDR = 24.31 - (12.22 × WHR) - (3.29 × HT) - (0.57 × HbA1c); WHR = waist to hip ratio, HT = hypertension. Correlations and multiple logistic regressions analysis were performed to identify the relationships between NAFLD associated markers and eGDR, individual components of insulin resistance and risk of insulin resistance. AST, ALT, AST-to-ALT ratio, ALK and ferritin significantly correlated with insulin resistance measured by eGDR (r = -0.13, -0.14, 0.13, -0.18, and -0.24, respectively; all P < 0.05), and with individual components of insulin resistance, most notably WHR. In a multiple logistic regression model adjusted according to age, sex, duration of diabetes and BMI, increased levels of AST, ALT and ALK resulted in an increased risk for the development of insulin resistance in our subjects (OR = 1.03, 1.02, and 1.01, respectively; all P < 0.05).

These findings indicate that higher levels of ALT, AST and ALK are additional markers of insulin resistance in type 1 diabetes and suggest that those subjects must be considered as potentially affected not only by a hepatic but also by a multisystemic disease through altered insulin sensitivity.

Is increased brain gray matter in the primary somatosensory cortex associated with increased pain and mood disturbance in patients with interstitial cystitis/painful bladder syndrome?

Interstitial cystitis is a highly prevalent pain condition estimated to affect 3% to 6% of women in the United States. Emerging data suggest there are central neurobiological components to the etiology of this disease. We report the first brain structural imaging findings from the MAPP network with data on more than 300 participants. We used voxel based morphometry to determine whether human patients with chronic interstitial cystitis display changes in brain morphology compared to healthy controls. A total of 33 female patients with interstitial cystitis without comorbidities and 33 age and gender matched controls taken from the larger sample underwent structural magnetic resonance imaging at 5 MAPP sites across the United States. Compared to controls, females with interstitial cystitis displayed significant increased gray matter volume in several regions of the brain including the right primary somatosensory cortex, the superior parietal lobule bilaterally and the right supplementary motor area. Gray matter volume in the right primary somatosensory cortex was associated with greater pain, mood (anxiety) and urological symptoms. We explored these correlations in a linear regression model, and found independent effects of these 3 measures on primary somatosensory cortex gray matter volume, namely clinical pain (McGill pain sensory total), a measure of urgency and anxiety (HADS).

These data support the notion that changes in somatosensory gray matter may have an important role in pain sensitivity as well as affective and sensory aspects of interstitial cystitis. Further studies are needed to confirm the generalizability of these findings to other pain conditions.

Is house dust mite sublingual tablet effective and safe in patients with allergic rhinitis?

House dust mite (HDM) is the major indoor allergen for allergic diseases such as allergic rhinitis (AR) and asthma. Although sublingual immunotherapy is a curative treatment for HDM-induced AR, data from large-scale studies are limited. We evaluated the efficacy and safety of HDM tablets in adolescent and adult patients (aged 12-64 years) with HDM-induced AR with or without intermittent asthma. In a double-blind trial in Japan, 968 subjects were randomized 1 : 1 : 1 to 300 index of reactivity (IR), 500 IR, or placebo groups. The primary endpoint was the Average Adjusted Symptom Score (AASS) in the last eight weeks of the 52-week treatment. Secondary endpoints included individual nasal and ocular symptom scores, rescue medication use, and the Japanese Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ) scores. The AASS in the last eight weeks of treatment significantly improved in both the 300 IR and the 500 IR groups compared to that in the placebo group (P < 0.001). In the 300 IR group, the onset of action occurred at week 8-10. All four nasal symptoms significantly improved in both active treatment groups; rescue medication use and JRQLQ outcome improved in the 300 IR group. Most adverse events (AEs) were mild, and 16 serious AEs (SAEs) were reported; however, none of them were drug-related.

One-year treatment with 300 IR and 500 IR HDM tablets was effective without major safety concerns. The recommended therapeutic dose for AR is 300 IR.

Is critical COPD respiratory illness linked to increased transcriptomic activity of neutrophil proteases genes?

Gene expression profiling (GEP) in cells obtained from peripheral blood has shown that this is a very useful approach for biomarker discovery and for studying molecular pathogenesis of prevalent diseases. While there is limited literature available on gene expression markers associated with Chronic Obstructive Pulmonary Disease (COPD), the transcriptomic picture associated with critical respiratory illness in this disease is not known at the present moment. By using Agilent microarray chips, we have profiled gene expression signatures in the whole blood of 28 COPD patients hospitalized with different degrees of respiratory compromise.12 of them needed of admission to the ICU, whilst 16 were admitted to the Respiratory Medicine Service. GeneSpring GX 11.0 software was used for performing statistical comparisons of transcript levels between ICU and non-ICU patients. Ingenuity pathway analysis 8.5 (IPA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to select, annotate and visualize genes by function and pathway (gene ontology). T-test showed evidence of 1501 genes differentially expressed between ICU and non-ICU patients. IPA and KEGG analysis of the most representative biological functions revealed that ICU patients had increased levels of neutrophil gene transcripts, being [cathepsin G (CTSG)], [elastase, neutrophil expressed (ELANE)], [proteinase 3 (PRTN3)], [myeloperoxidase (MPO)], [cathepsin D (CTSD)], [defensin, alpha 3, neutrophil-specific (DEFA3)], azurocidin 1 (AZU1)], and [bactericidal/permeability-increasing protein (BPI)] the most representative ones. Proteins codified by these genes form part of the azurophilic granules of neutrophils and are involved in both antimicrobial defence and tissue damage. This "neutrophil signature" was paralleled by the necessity of advanced respiratory and vital support, and the presence of bacterial infection.

Study of transcriptomic signatures in blood suggests an essential role of neutrophil proteases in COPD patients with critical respiratory illness. Measurement and modulation of the expression of these genes could present an option for clinical monitoring and treatment of severe COPD exacerbations.

Does soluble epoxide hydrolase inhibition prevent coronary endothelial dysfunction in mice with renovascular hypertension?

The study addresses the hypothesis that endothelial dysfunction in experimental arterial hypertension can be related to an alteration in epoxyeicosatrienoic acids (EETs) pathway and can be prevented by the inhibition of EETs degradation by soluble epoxide hydrolase (sEH). Arterial hypertension was induced in FVB/N mice by renal artery stenosis ('two-kidney-one-clip', 2K1C). Seven weeks after surgery, increased aortic pressures (Millar tonometer; Millar Instruments, Houston, Texas, USA) and cardiac hypertrophy (echocardiography) were present in 2K1C mice as compared with control mice. Left coronary artery endothelium-dependent relaxations to acetylcholine were decreased in 2K1C mice without modification in the relaxing responses to NS309 and NS1619, the openers of calcium-activated potassium channels mediating the hyperpolarizing effect of EETs. The inhibitors of the EET-synthesizing enzymes cytochrome P450 epoxygenases, fluconazole and N-methylsulfonyl-6-(2-propargyloxyphenyl)-hexanamide (MSPPOH), reduced the coronary relaxations to acetylcholine in control but not in 2K1C mice. The sEH expression was increased in 2K1C mice. The sEH inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid administered for 2 weeks starting 5 weeks after surgery in 2K1C mice (25 mg/l in drinking water) reduced aortic pressures and cardiac hypertrophy, improved the coronary relaxations to acetylcholine and restored the inhibitory effect of fluconazole and MSPPOH on acetylcholine-induced relaxations, without modifying the relaxations to NS309 and NS1619.

These results demonstrate that a reduced EET-mediated relaxations related to an increased degradation by sEH contributes to coronary endothelial dysfunction in 2K1C hypertensive mice. Inhibiting sEH prevents endothelial dysfunction by restoring EET-mediated relaxations and thus, could represent a promising pharmacological intervention to limit cardiovascular morbidity and mortality in arterial hypertension.

Does smoking affect diagnostic salivary periodontal disease biomarker levels in adolescents?

The effects of smoking on periodontal biomarkers in adolescents are unknown. This study investigates matrix metalloproteinase (MMP)-8 and polymorphonuclear leukocyte elastase levels in saliva together with periodontal health indices accounting for body mass index and smoking in a birth cohort from Finland. The oral health of boys (n = 258) and girls (n = 243) aged 15 to 16 years was examined clinically. Health habits were assessed by questionnaire. Saliva samples were collected and analyzed by immunofluorometric and peptide assays for MMP-8 levels and polymorphonuclear leukocyte elastase activities, and investigated statistically with the background factors. Median MMP-8 values of male smokers were 112.03 microg/l compared to 176.89 microg/l of non-smokers (P = 0.05). For female smokers corresponding values were 170.88 microg/l versus 177.92 microg/l in non-smokers (not statistically significant). Elastase values in male smokers were 5.88 x 10(-3) Delta OD(405)/h versus 11.0 x 10(-3) Delta OD(405)/h in non-smokers (P = 0.02), and in female smokers 9.16 x 10(-3) Delta OD(405)/h versus 10.88 x 10(-3) Delta OD(405)/h in non-smokers (P = 0.72). The effect was strengthened by high pack-years of smoking (MMP-8, P = 0.04; elastase, P = 0.01). Both biomarkers increased with gingival bleeding. However, statistically significant associations were observed with bleeding on probing and MMP-8 (P = 0.04); MMP-8 was suggestively associated with probing depth (P = 0.09) in non-smoking boys. In smokers with calculus, MMP-8 increased after adjusting with body mass index (P = 0.03). No corresponding differences were seen in girls.

Smoking significantly decreased both biomarkers studied. Compared to girls, boys seem to have enhanced susceptibility for periodontitis as reflected in salivary MMP-8 values.

Are gSTM1-null and GSTT1-null genotypes associated with essential arterial hypertension in patients with type 2 diabetes?

To evaluate whether the genetic polymorphisms of glutathione S-transferases M1 (GSTM1) and T1 (GSTT1), Ile105Val of the GSTP1 (rs947894), and the Val16Ala polymorphism of the MnSOD (rs4880) are associated with essential arterial hypertension (EAH) in Caucasians with type 2 diabetes. 1015 Slovenian subjects (Caucasians) with type 2 diabetes with/without EAH were enrolled in the cross-sectional study. Genotypes were determined by multiplex PCR amplification and PCR-restriction fragment length polymorphism method. In the cross-sectional study, GSTM1-null genotype and GSTT1-null genotype were associated with EAH in subjects with type 2 diabetes (59.0% vs. 50.3%, p=0.007; 28.5% vs. 20.7%, p=0.008; consequently).

After adjustment for age, body mass index, and hsCRP level, GSTM1-null and GSTT1-null genotypes were found to be independent risk factors for the development of EAH in Slovenian patients with type 2 diabetes.

Is hypercapnia associated with poor prognosis in chronic obstructive pulmonary disease?

To assess whether hypercapnia may predict the prognosis in chronic obstructive pulmonary disease (COPD). Prospective cohort study comparing the survival of patients with COPD and normocapnia to those with chronic hypercapnia. Patients with consecutive COPD were enrolled between 1 May 1993 and 31 October 2006 at two medical centres. Follow-up was censored on 31 October 2011. A total of 275 patients with stable COPD and aged 40-85 years were enrolled. Diagnosis of hypercapnia was confirmed by blood gas analysis. Patients with near-terminal illness or comorbidities that affect PaCO2 (obstructive sleep apnoea, obesity-related hypoventilation, or neuromuscular disease) were excluded. The outcome of 98 patients with normocapnia and 177 with chronic hypercapnia was analysed. Overall survival. Median survival was longer in patients with normocapnia than in those with hypercapnia (6.5 vs 5.0 years, p=0.016). Multivariate COX regression analysis indicated that age (HR=1.043, 95% CI 1.012 to 1.076), Charlson Index, which is a measure of comorbidity (HR=1.172, 95% CI 1.067 to 1.288), use of medication (HR=0.565, 95% CI 0.379 to 0.842), body mass index (BMI) (HR=0.922, 95% CI 0.883 to 0.963), PaCO2 (HR=1.026, 95% CI 1.011 to 1.042), Cor pulmonale (HR=2.164, 95% CI 1.557 to 3.006), non-invasive positive-pressure ventilation (NPPV) (HR=0.615, 95% CI 0.429 to 0.881) and per cent of forced expiratory volume in 1 s (FEV1%) (HR=0.979, 95% CI 0.967 to 0.991), were independent risk factors for mortality.

Increased age, Charlson Index, chronic hypercapnia and Cor pulmonale, and decreased FEV1%, use of medication, BMI and NPPV, were associated with a poor prognosis in patients with COPD.

Does frzA gene protect cardiomyocytes from H2O2-induced oxidative stress through restraining the Wnt/Frizzled pathway?

Lately, there is accumulating evidence that the Wnt/Frizzled pathway is reactivated after myocardial infarction, the inhibition of the pathway is beneficial since it reduce of myocardial apoptosis and prevents heart failure. FrzA/Sfrp-1, a secreted frizzled-related protein and antagonist for the wnt/frizzled pathway. We assessed the hypothesis that FrzA protects cardiomyocytes from H2O2-Induced Oxidative damage through the inhibition of Wnt/Frizzled pathway activity. We used a recombinant AAV9 vector to deliver FrzA gene into neonatal rat ventricle myocytes and developed an oxidative stress model using H2O2. The cell vitality was measured by MTT colorimetric assay. Western blot and RT-PCR were used to evaluate the expressions of Dvl-1, β-catenin, c-Myc, Bax and Bcl-2. Flow cytometry analysis of cardiomyocytes apoptosis. We confirmed that Wnt/frizzled pathway is involved in H2O2-induced apoptosis in cardiomyocytes. Compared with controls, H2O2 induced the upregulation of Dvl-1, β-catenin, and c-Myc. FrzA suppressed the expression of Dvl-1, β-catenin, c-Myc and the activity of the Wnt/frizzled pathway. Furthermore, FrzA over-expression decreased the apoptotic rate, and the Bax/Bcl-2 ratio in cardiomyocytes treated with H2O2.

FrzA, through the inhibition of Wnt/Frizzled pathway activity reduced H2O2-induced cardiomyocytes apoptosis and could be a potential therapeutic target for prevention of cardiac oxidative damage.

Does hDAF porcine cardiac xenograft maintain cardiac output after orthotopic transplantation into baboon -- a perioperative study?

Only limited data are available on the physiological functional compatibility of cardiac xenografts after orthotopic pig to baboon transplantation (oXHTx). Thus we investigated hemodynamic parameters including cardiac output (CO) before and after oXHTx. Orthotopic xenogeneic heart transplantation from nine hDAF transgeneic piglets to baboons was performed. We used femoral arterial thermodilution for the invasive assessment of CO and stroke volume. Baseline CO of the baboons after induction of anesthesia was 1.36 (1.0-1.9) l/min. 30 to 60 min after termination of the cardiopulmonary bypass, CO of the cardiac xenograft was significantly increased to 1.72 (1.3-2.1) l/min (P < 0.01). The stroke volumes of the baboon heart before transplantation and the cardiac xenograft was comparable [14.9 (11-26) vs. 11.8 (10-23) ml]. Thus the higher CO was achieved by an increase in heart rate after oXHTx [75.0 (69-110) vs. 140.0 (77-180)/min; P < 0.01]. Despite the increased CO, oxygen delivery was reduced [256 (251-354) vs. 227 (172-477) ml/min; P < 0.01] due to the inevitable hemodilution during the cardiopulmonary bypass and the blood loss caused by the surgical procedures.

Our results demonstrate that in the early phase after orthotopic transplantation of hDAF pig hearts to baboons, cardiac function of the donor heart is maintained and exceeds baseline CO. However, in the early intraoperative phase this was only possible by using inotropic substances and vasopressors due to the inevitable blood loss and dilution by the priming of the bypass circuit.

Chorioamnionitis: is continuation of antibiotic therapy necessary after cesarean section?

Our purpose was to determine whether the continuation of antibiotics postoperatively after cesarean section in patients whose labors were complicated by chorioamnionitis would reduce the incidence of endometritis. Patients with a clinical diagnosis of chorioamnionitis treated with ampicillin during labor and who required cesarean delivery for obstetric indications received preoperative intravenous clindamycin and gentamicin and were randomized into 2 groups. Group 1 received no scheduled postoperative antibiotics and group 2 continued to receive clindamycin 900 mg every 8 hours and gentamicin 1.5 mg/kg every 8 hours until afebrile for a minimum of 24 hours (temperature</=100 degreesF). Sixty-one patients were randomized to group 1 and 55 patients were randomized to group 2. The duration of labor, the duration of membrane rupture, and the number of intrapartum vaginal examinations were statistically insignificant between the 2 groups. The mean duration of maternal postoperative hospital stay was 4 days for both groups. There were no statistically significant differences in the rate of endometritis for group 1, 9 of 61 (14.8%), versus group 2, 12 of 55 (21.8%), P =.32.

In patients whose labors were complicated by chorioamnionitis and who underwent cesarean section, the continuation of preoperative clindamycin and gentamicin in the postoperative period did not reduce the risk of endometritis compared with a single preoperative dose.

Does correction for heart rate variability improve coronary magnetic resonance angiography?

To address degradation of coronary MR angiography (MRA) image quality due to heart rate variability (HRV)-associated variations in coronary artery position and motion. Free-breathing navigator-gated and -corrected coronary MRA using subject-specific trigger delays and acquisition windows was combined with a real-time HRV correction algorithm, such as commonly used in left ventricular wall motion studies. Ten healthy adults underwent free-breathing navigator-gated and -corrected coronary MRA with and without HRV correction. Signal-to-noise (SNR), contrast-to-noise (CNR), vessel length, diameter, sharpness, and subjective image quality (on a five-point scale) were compared in a blinded fashion. Vessel sharpness improved significantly for both the left (LCA) and right (RCA) coronary artery systems (P = 0.016 and P = 0.015, respectively) with the use of HRV correction. Subjective image quality also improved significantly when HRV correction was used (P = 0.003). There were no significant differences with regard to SNR and CNR (P > 0.1).

Preliminary results suggest that HRV correction improves objective and subjective image quality in coronary MRA. Continued studies in patients with known or suspected coronary artery disease are warranted to investigate the clinical impact of this technique.

Is common neuropeptide Y2 receptor gene variant protective against obesity among Swedish men?

Gut hormones and their receptors are considered important in the control of feeding behavior. The gut hormone peptide-YY (PYY) has anorexic effects via the inhibitory neuropeptide Y2 receptor (Y2R) highly expressed in orexigenic NPY/AGRP neurons within the arcuate nucleus, a major integrator of appetite control in the hypothalamus. Genetic case-control association study of single nucleotide polymorphisms (SNPs) in Y2R and PYY. Swedish Caucasians comprising 148 lean, 129 overweight/obese and 226 morbidly obese men. Genotypes of the common, silent and conserved SNP Y2R 585T>C and the common SNP PYY Arg72Thr, as well as various obesity-related clinical parameters. Obese men had a lower allele and homozygosity frequency of the common allele 585T>C:T which was particularly evident comparing morbidly obese with lean men (P = 0.002), and analyzing dependence between continuous body mass index (BMI) and genotype (P = 0.002). In agreement, systolic blood pressure tended to be lower in those homozygous for allele T, which was not explained by the BMI - genotype dependence. We found no association to obesity for the PYY Arg72Thr polymorphism, which is located nearby the essential carboxy terminal.

A common and conserved variant of the PYY and NPY receptor Y2R is less prevalent among obese compared to among lean Swedish men. This suggests that the common Y2R variant is protective against obesity. Our findings further implicate Y2R in food intake regulation.

Does the effect of doxorubicin on MEK-ERK signaling predict its efficacy in HCC?

Hepatocellular cancer (HCC) is a leading cause of cancer-related death worldwide. Historically, doxorubicin (DOX) has been widely used against unresectable HCC with variable response rates. We hypothesized that DOX combined with mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK) targeted therapy may provide enhanced anti-cancer effects. Human HCC cell lines (HepG2, Hep3B) were treated with DOX and MEK enzyme inhibitors, U0126 or PD184161, alone or in combination. Growth, apoptosis, and ERK expression/MEK activity were respectively determined by proliferation assay, DNA fragmentation enzyme-linked immunoassay or fluorochrome inhibitor of caspases, and Western blot. DOX (0.01-1 microM) decreased cell proliferation in Hep3B cells (IC(50) approximately 0.12 microM) at 48 to 72 h; DOX was less effective in HepG2 cells (IC(50) approximately 0.25 microM). At early time points (30 min) after DOX treatment of Hep3B cells, MEK activity was unchanged at low doses and decreased at higher doses; after 24 h, phospho-ERK levels increased at higher doses. Contrarily, in HepG2 cells, DOX caused a sustained, dose-dependent increase in phospho-ERK levels at early and late time points. The MEK inhibitor U0126 decreased phospho-ERK in both HCC lines. In contrast to DOX, HepG2 cells were more sensitive than Hep3B cells to U0126. The combination of DOX with U0126 (or PD184161) resulted in greater inhibition of proliferation in HepG2 but not in Hep3B cells. This effect may be mediated in part by enhanced apoptosis.

The effect of DOX on early and late induction of MEK activity predicts its chemotherapeutic response in HCC. Furthermore, this effect may also determine the utility of MEK inhibitor combination treatment.

Does vpx rescue HIV-1 transduction of dendritic cells from the antiviral state established by type 1 interferon?

Vpx is a virion-associated protein encoded by SIVSM, a lentivirus endemic to the West African sooty mangabey (Cercocebus atys). HIV-2 and SIVMAC, zoonoses resulting from SIVSM transmission to humans or Asian rhesus macaques (Macaca mulatta), also encode Vpx. In myeloid cells, Vpx promotes reverse transcription and transduction by these viruses. This activity correlates with Vpx binding to DCAF1 (VPRBP) and association with the DDB1/RBX1/CUL4A E3 ubiquitin ligase complex. When delivered experimentally to myeloid cells using VSV G-pseudotyped virus-like particles (VLPs), Vpx promotes reverse transcription of retroviruses that do not normally encode Vpx. Here we show that Vpx has the extraordinary ability to completely rescue HIV-1 transduction of human monocyte-derived dendritic cells (MDDCs) from the potent antiviral state established by prior treatment with exogenous type 1 interferon (IFN). The magnitude of rescue was up to 1,000-fold, depending on the blood donor, and was also observed after induction of endogenous IFN and IFN-stimulated genes (ISGs) by LPS, poly(I:C), or poly(dA:dT). The effect was relatively specific in that Vpx-associated suppression of soluble IFN-β production, of mRNA levels for ISGs, or of cell surface markers for MDDC differentiation, was not detected. Vpx did not rescue HIV-2 or SIVMAC transduction from the antiviral state, even in the presence of SIVMAC or HIV-2 VLPs bearing additional Vpx, or in the presence of HIV-1 VLPs bearing all accessory genes. In contrast to the effect of Vpx on transduction of untreated MDDCs, HIV-1 rescue from the antiviral state was not dependent upon Vpx interaction with DCAF1 or on the presence of DCAF1 within the MDDC target cells. Additionally, although Vpx increased the level of HIV-1 reverse transcripts in MDDCs to the same extent whether or not MDDCs were treated with IFN or LPS, Vpx rescued a block specific to the antiviral state that occurred after HIV-1 cDNA penetrated the nucleus.

Vpx provides a tool for the characterization of a potent, new HIV-1 restriction activity, which acts in the nucleus of type 1 IFN-treated dendritic cells.

Can an arch bar replace a second lag screw in management of anterior mandibular fractures?

To evaluate the efficacy of using a single lag screw combined with an arch bar in the management of anterior mandibular fractures and to compare this method with the traditional application of 2 lag screws. We designed and implemented a randomized clinical trial and enrolled a sample of patients with anterior mandibular fractures. Twenty adult male patients were randomly divided into 2 equal groups according to the number of lag screws used for fracture fixation after securing the occlusion with intermaxillary fixation. In group A, the fractures were treated using 2 lag screws. In group B, the fractures were treated using a single lag screw and an arch bar on the teeth, spanning the fracture line. Clinical and radiographic evaluations were used to evaluate the efficacy of each fixation method immediately and at 2 and 4 months postoperatively. The clinical examination showed stable fixation with no mobility or infection in all cases. One patient in group A showed a slight occlusal discrepancy that was managed with occlusal adjustment. The pretraumatic occlusal relationship of all other patients was re-established. Postoperative radiographs showed properly reduced fracture segments with gradual bone healing. No significant difference was noted (P>.05) between the 2 groups in the development of postoperative complications.

The use of 1 lag screw in conjunction with an arch bar across the fracture line is rigid and stable enough to manage anterior mandibular fractures without the need for supplemental intermaxillary fixation. The use of a single lag screw offers several advantages compared with the traditional use of 2 lag screws. These advantages include decreased cost, use of materials, healing time, and risk of associated morbidity.

Is [ The finding of glucose in the fluid obtained by epidural catheter after its insertion during combined intradural-epidural anaesthesia with hyperbaric bupivacaine a usual occurrence ]?

To determine whether the appearance of glucose in the fluid spontaneously obtained by the epidural catheter after its insertion during combined intradural-epidural anaesthesia with hyperbaric bupivacaine is a usual occurrence. A prospective, observational study was conducted on 34 patients with combined intradural-epidural anaesthesia in whom an epidural catheter was introduced, after locating the epidural space with a saline solution, inserting a spinal needle and injecting hyperbaric bupivacaine. After observing whether any fluid was spontaneously dripping from it, it was determined if this contained glucose. Withdrawal of the needle and washing its lumen with saline solution, it was checked whether there was glucose in washout. The samples were analysed using a glucose meter. When the motor block disappeared a dose of local anaesthetic was administered through the epidural catheter. The relationship of the demographic parameters with the spontaneous dripping of the epidural catheter was evaluated. Spontaneous dripping by the epidural catheter after its insertion was observed in 22 patients. All the samples obtained contained glucose. There was glucose in 9 out of 34 epidural needle wash samples. None of the patients suffered from excessive motor-sensory block. There was a statistically significant relationship between patient age (P<.05) and spontaneous dripping by the catheter (the higher the age, more dripping).

The finding of glucose in the fluid obtained by the epidural catheter is a frequent occurrence and is of no clinical significance. We propose that it could be due to a leak of cerebrospinal fluid by the dural puncture needle during or after the administering of the hyperbaric bupivacaine and the spillage of this into the epidural space.

Does treatment of non-malignant hypertension reduce the incidence of renal dysfunction?

It remains controversial whether non-malignant 'benign' hypertension causes renal dysfunction. The effect of lowering blood pressure on the incidence of renal dysfunction among patients with non-malignant hypertension is not clear. This meta-analysis was conducted to determine whether antihypertensive drug therapy reduces the incidence of renal dysfunction in patients with non-malignant hypertension. Randomised, controlled trials of antihypertensive drug therapy of more than 1 year duration that reported renal dysfunction as an outcome were identified through MEDLINE search and literature review. A random effects model was used to obtain summary estimates. Ten trials were identified, involving 26, 521 individuals and 114 000 person-years. All excluded subjects with advanced baseline renal disease. Definition of renal dysfunction outcome varied among trials but within each trial was applied similarly to both treatment and control groups. Drug treatment consisted mostly of diuretics and adrenergic blockers. Overall, treated patients had lower blood pressure and fewer cardiovascular events. There were a total of 317 cases of renal dysfunction. Patients randomised to antihypertensive therapy (or more intensive therapy) did not have a significant reduction in their risk of developing renal dysfunction (relative risk = 0.97; 95% confidence interval (CI) 0.78-1.21; P = 0.77).

Among patients with non-malignant hypertension enrolled in randomised trials, treated patients did not have a lower risk of renal dysfunction. The 95% CI suggests that a 25% or more true protective effect of antihypertensive drugs is unlikely.

Knowledge about sports-related concussion: is the message getting through to coaches and trainers?

An online knowledge survey was widely promoted across Australia in May-August 2012 targeting community Australian Football (AF) and Rugby League (RL) coaches and sports trainers. 260 AF coaches, 161 AF sports trainers, 267 RL coaches and 228 RL sports trainers completed the survey. Knowledge scores were constructed from Likert scales and compared across football codes and respondent groups. General concussion knowledge did not differ across codes but sports trainers had higher levels than did coaches. There were no significant differences in either concussion symptoms or concussion management knowledge across codes or team roles. Over 90% of respondents correctly identified five of the eight key signs or symptoms of concussion. Fewer than 50% recognised the increased risk of another concussion following an initial concussion. Most incorrectly believed or were uncertain that scans typically show damage to the brain after a concussion occurs. Fewer than 25% recognised, and>40% were uncertain that younger players typically take longer to recover from concussion than adults.

The key messages from published concussion management guidelines have not reached community sports coaches and sports trainers. This needs to be redressed to maximise the safety of all of those involved in community sport.

Do unrecognised psychological problems impair quality of life and increase consultation rates in Chinese elderly patients?

Studies have shown that psychological problems in elderly patients are often unrecognised in primary care. The aim of this study was to investigate the quality of life and consultation rates of Chinese elderly patients with unrecognised psychological problems in primary care. The prevalence and risk factors of unrecognised psychological problems were also determined. A cross-sectional study on consecutive patients aged > or =60 with no known psychological diseases were screened by the Hospital Anxiety and Depression Scale (HADS) when they consulted at two primary care clinics in Hong Kong. Data on socio-demographic characteristics, chronic morbidity, consultation rates, and health-related quality of life (HROQL) were collected. Multivariable regressions were used to determine the effect of a positive HADS score on HRQOL scores and consultation rates, and the risk factors of unrecognised psychological problems. One thousand eight hundred and fifty-four subjects (mean age 72.6 years and 52% male) were screened and the estimated prevalence of unrecognised psychological diseases was 23% (95% CI = 13.1-33.8%). A positive screening result was associated with poorer SF-36 HROQL scores and higher episodic consultation rates. An increased risk of unrecognised psychological problems was associated with the presence of more than two chronic diseases. Other risk factors included female gender, no formal education and having chronic pulmonary disease or heart disease. Living with a spouse increased the risk in elderly women.

Unrecognised psychological problems are common in Chinese elderly patients in primary care. They are clinically important because they impair quality of life and increase the utilization of consultations.

Does electrical stimulation facilitate rat facial nerve recovery from a crush injury?

To study the effect of electrical stimulation on accelerating facial nerve functional recovery from a crush injury in the rat model. Experimental. The main trunk of the right facial nerve was crushed just distal to the stylomastoid foramen, causing right-sided facial paralysis in 17 Sprague-Dawley rats. An electrode apparatus was implanted in all rats. Nine rats underwent electrical stimulation and eight were sham stimulated until complete facial nerve recovery. Facial nerve function was assessed daily by grading eyeblink reflex, vibrissae orientation, and vibrissae movement. An electrical stimulation model of the rat facial nerve following axotomy was established. The semi-eyeblink returned significantly earlier (3.71 + 0.97 vs 9.57 + 1.86 days post axotomy) in stimulated rats (P = 0.008). Stimulated rats also recovered all functions earlier, and showed less variability in recovery time.

Electrical stimulation initiates and accelerates facial nerve recovery in the rat model as it significantly reduces recovery time for the semi-eyeblink reflex, a marker of early recovery. It also hastens recovery of other functions.

Is chronic restraint stress after injury and shock associated with persistent anemia despite prolonged elevation in erythropoietin levels?

Following severe traumatic injury, critically ill patients have a prolonged hypercatacholamine state that is associated with bone marrow (BM) dysfunction and persistent anemia. However, current animal models of injury and shock result in a transient anemia. Daily restraint stress (chronic stress [CS]) has been shown to increase catecholamines. We hypothesize that adding CS following injury or injury and shock in rats will prolong the hypercatecholaminemia and prolong the initial anemia, despite elevated erythropoietin (EPO) levels. Male Sprague-Dawley rats (n = 6-8 per group) underwent lung contusion (LC) or combined LC/hemorrhagic shock (LCHS) followed by 6 days of CS. CS consisted of a 2-hour restraint period interrupted with repositioning and alarms every 30 minutes. At 7 days, urine was assessed for norepinephrine (NE) levels, blood for EPO and hemoglobin (Hgb), and BM for erythroid progenitor growth. Animals undergoing LC or combined LCHS predictably recovered by Day 7; urine NE, EPO, and Hgb levels were normal. The addition of CS to LC and LCHS models was associated with a significant elevation in NE on Day 6. The addition of CS to LC led to a persistent 20% to 25% decrease in the growth of BM hematopoietic progenitor cells. These findings were further exaggerated when CS was added following LCHS, resulting in a 20%q to 40% reduction in BM erythroid progenitor colony growth and a 20% decrease in Hgb when compared with LCHS alone.

Exposing injured animals to CS results in prolonged elevation of NE and EPO, which is associated with worsening BM erythroid function and persistent anemia. Chronic restraint stress following injury and shock provides a clinically relevant model to further evaluate persistent injury-associated anemia seen in critically ill trauma patients. Furthermore, alleviating CS after severe injury is a potential therapeutic target to improve BM dysfunction and anemia.

Do subtypes of hypoxia-responsive cells differentiate into neurons in spinal cord of zebrafish embryos after hypoxic stress?

Neuron stem/progenitor cells (NSPCs) of zebrafish central nervous system (CNS) are known to thrive during oxygen recovery after hypoxia, but not all cell types have been fully characterised due to their heterogeneities. In addition, an in vivo model system is not available that can help us to identify what type-specific cell populations that are involved in neural regeneration and to track their cell fate after regeneration. To solve these issues, we employed a zebrafish transgenic line, huORFZ, which harbours an inhibitory upstream open reading frame of human chop mRNA fused downstream with GFP reporter and driven by cytomegalovirus promoter. When huORFZ embryos were exposure to hypoxic stress, followed by oxygen recovery, GFP was exclusively expressed in some particular cells of CNS. Unlike GFP-negative cells, all GFP-expressing cells were not apoptotic, indicating that cell populations that are able to survive after hypoxia can be identified through this approach. When GFP-expressing cells of spinal cord were studied, we found mostly NSPCs and radial glia cells (RGs), along with a few oligodendrocyte progenitor cells and oligodendrocytes, all termed as hypoxia-responsive recovering cells (HrRCs). After hypoxic stress, these GFP-positive HrRCs did not undergo apoptosis, but GFP-negative neurons did. Prolonged recovery time after hypoxia was correlated with higher proportions of GFP(+)-NSPCs and GFP(+)-RGs, in contrast to lower proportions of proliferating/differentiating GFP(-)-NSPCs and GFP(-)-RGs. Among HrRCs subtypes, only GFP(+)-NSPCs and GFP(+)-RGs proliferated, migrated and differentiated into functional neurons during oxygen recovery. When some HrRCs were ablated in the spinal cord of hypoxia-exposed huORFZ embryos, swimming performance was impaired, suggesting that HrRCs are involved in neuronal regeneration.

We demonstrated type-specific cell populations able to respond sensitively to hypoxic stress in the spinal cord of zebrafish embryos and that these type-specific populations play a role in neural regeneration.

Is chronic obstructive pulmonary disease and allied conditions a strong independent risk factor for osteoporosis and pathologic fractures : a population-based cohort study?

Chronic obstructive pulmonary disease and allied conditions (COPD) is frequently associated with various comorbidities. This study examined the association between osteoporosis and pathologic fractures in a sample of patients with COPD. In this cohort study, claims data from the National Health Insurance Research Database of Taiwan were used to evaluate the risk between COPD and osteoporosis. Using data from the Longitudinal Health Insurance Database 2000, we conducted a retrospective cohort study by investigating patients aged 20 years and older who were newly diagnosed with COPD and comparing them with controls without COPD during 2000-2010. In addition, we used univariable and multivariable Cox proportional hazards regression models to measure the association between COPD and the risk of osteoporosis. Our results revealed that COPD was significantly associated with a high risk of osteoporosis, regardless of whether the patients with COPD were corticosteroid users and irrespective of age and sex. After adjustment for covariates, the COPD patients exhibited a 1.54-fold higher risk of developing osteoporosis (hazard ratio 1.54, 95% confidence interval 1.44-1.64). COPD was a stronger risk factor for osteoporosis in men. Moreover, patients with severe COPD had a higher risk of osteoporosis or pathologic fractures.

This study revealed that COPD, which shares the characteristics of inflammatory diseases, is associated with a higher risk of osteoporosis after adjustment for comorbidities.

Skin involvement and breast cancer: are T4b lesions of all sizes created equal?

Nonmetastatic, noninflammatory, invasive breast cancers with skin involvement (SI) are classified as T4b, regardless of size. This study evaluated disease-specific survival (DSS) to determine whether size should be considered for these lesions rather than grouping them all into stage III. Surveillance, Epidemiology, and End Results data linked to Medicare claims were reviewed. Skin involved and non-SI tumors were reclassified using the American Joint Committee on Cancer, 7(th) edition groupings using tumor size and nodal involvement alone without considering SI (neostage). Disease-specific survival was adjusted for demographics, histology, and treatment using competing risk methods with propensity score-based weighting and bootstrap standard errors. Among 924 SI patients diagnosed between 1992 and 2005, tumors were 0.1 to 2.0 cm, 2.1 to 5.0 cm, and>5.0 cm in 11.6%, 51.1%, and 37.3% of patients, respectively. There were no nodal metastases in 22.3%, 1 to 3 positive nodes in 31.7%, 4 to 9 positive in 28.6%, and ≥10 positive in 17.4% of patients. For SI patients, adjusted 5-year DSS was 95.8% (95% CI, 95.6-96.0) for neostage I, declining progressively to 36.4% (95% CI, 33.8-39.2) for neostage IIIC patients. Adjusted 5-year DSS for SI and non-SI tumors (n = 66,185) was similar for neostage I, IIA, and IIB, and markedly lower for IIIA and IIIC. Adjusted DSS for SI IIIA was similar to non-SI IIIC.

Noninflammatory SI breast cancers have widely varied DSS that differs by tumor size and nodal involvement and therefore should not all be stage III. Skin involvement should be subordinate to T and N groupings to classify SI with non-SI lesions having similar prognoses.

Does glycaemic control modify the haptoglobin 2 allele-conferred susceptibility to coronary artery disease in Type 1 diabetes?

We aimed to assess whether the association of the haptoglobin 2 allele with coronary artery disease is modified by glycaemic control in a prospective cohort study of individuals with childhood-onset Type 1 diabetes. Coronary artery disease events (death from coronary artery disease, confirmed myocardial infarction, stenosis ≥50%, revascularization) were assessed between 1986 and 2013 among 480 individuals with Type 1 diabetes (baseline age 28 years; diabetes duration 19 years). Better glycaemic control was defined as an updated mean HbA In crude models, the incidence of coronary artery disease increased with the number of haptoglobin 2 alleles (hazard ratio 1.34, 95% CI 1.05-1.71). This association was more pronounced in those with better than in those with worse glycaemic control (P interaction = 0.05) and remained essentially unaltered after multivariable adjustments (hazard ratio 2.65, 95% CI 1.30-5.41 in those with better glycaemic control and hazard ratio 1.20, 95% CI 0.93-1.56 in those with worse glycaemic control).

These results suggest that, although better control may reduce the incidence of coronary artery disease in Type 1 diabetes, a residual risk related to the haptoglobin 2 allele remains.

Are increased visceral fat and serum levels of triglyceride associated with insulin resistance in Japanese metabolically obese , normal weight subjects with normal glucose tolerance?

The purpose of this study was to investigate the association between visceral adiposity or triglyceride (TG) metabolism and insulin resistance in metabolically obese, normal weight (MONW) Japanese individuals with normal glucose tolerance. We evaluated body fat areas, lipid profiles, and the glucose infusion rate (GIR) during a euglycemic-hyperinsulinemic clamp study in 20 MONW subjects (BMI <25 kg/m(2)and visceral fat areas 100 cm(2)) with normal glucose tolerance. Body fat areas were measured by computed tomography scans. Control data were obtained from 20 normal subjects (BMI <25 kg/m(2) and visceral fat areas <100 cm(2)). MONW subjects showed a significant increase in fasting serum levels of TG (P < 0.01) and a decrease in GIR (P < 0.01) compared with normal subjects. There were significant correlations between visceral fat areas (r = -0.563, P < 0.01) or serum levels of TG (r = -0.474, P < 0.05) and GIR in MONW subjects. Multiple regression analyses showed that visceral fat areas (F = 7.702, P < 0.02) and serum levels of TG (F = 7.114, P < 0.05) were significantly associated with GIR in all (MONW and normal) subjects.

Increased visceral fat and serum levels of TG are associated with insulin resistance in Japanese MONW subjects with normal glucose tolerance. Excess visceral fat and elevated TG levels may play important roles in the development of insulin resistance in Japanese MONW subjects with normal glucose tolerance.

Is plasma choline depletion associated with decreased peripheral blood leukocyte acetylcholine in children with cystic fibrosis?

Choline is an important constituent of acetylcholine. Choline is needed for acetylcholine in the nonneuronal acetylcholine system that includes epithelial cells of the lung and intestine, endothelial cells, and immune cells. Plasma free choline concentrations are low in children with cystic fibrosis (CF), but the implications for acetylcholine are unknown. We determined the relation between plasma free choline and related metabolites and leukocyte acetylcholine in children with CF and in a control group of healthy children without CF. This was a cross-sectional study in 34 children with CF who were pancreatic insufficient and taking pancreatic enzyme-replacement therapy and in 16 healthy children. Plasma free choline, betaine, dimethylglycine, methionine, homocysteine, and leukocyte acetylcholine concentrations were quantified by using isotope-dilution HPLC-tandem mass spectrometry. Mean (±SE) plasma free choline was 9.30 ± 0.37 and 6.54 ± 0.38 μmol/L (P < 0.05) and leukocyte acetylcholine was 1.21 ± 0.016 and 0.077 ± 0.011 pmol leukocyte acetylcholine/10(6) cells (P < 0.05) in control children and children with CF, respectively. Leukocyte acetylcholine was positively correlated with plasma free choline concentration in children with CF (r = 0.412, P < 0.05) but not in control children. Plasma betaine, dimethylglycine, and methionine concentrations were also lower in children with CF than in control children (P < 0.05).

A low free choline and methyl status in children with CF is associated with reduced acetylcholine in leukocytes. Whether these changes are explained by a mutation in the CF transmembrane conductance regulator or disturbances in choline metabolism and the implications for immune cell dysfunction in CF are unknown. This trial was registered at clinicaltrials.gov as NCT01150136.

Does cold Atmospheric Plasma induce a Predominantly Necrotic Cell Death via the Microenvironment?

Cold plasma is a partially ionized gas generated by an electric field at atmospheric pressure that was initially used in medicine for decontamination and sterilization of inert surfaces. There is currently growing interest in using cold plasma for more direct medical applications, mainly due to the possibility of tuning it to obtain selective biological effects in absence of toxicity for surrounding normal tissues,. While the therapeutic potential of cold plasma in chronic wound, blood coagulation, and cancer treatment is beginning to be documented, information on plasma/cell interaction is so far limited and controversial. Using normal primary human fibroblast cultures isolated from oral tissue, we sought to decipher the effects on cell behavior of a proprietary cold plasma device generating guided ionization waves carried by helium. In this model, cold plasma treatment induces a predominantly necrotic cell death. Interestingly, death is not triggered by a direct interaction of the cold plasma with cells, but rather via a transient modification in the microenvironment. We show that modification of the microenvironment redox status suppresses treatment toxicity and protects cells from death. Moreover, necrosis is not accidental and seems to be an active response to an environmental cue, as its execution can be inhibited to rescue cells.

These observations will need to be taken into account when studying in vitro plasma/cell interaction and may have implications for the design and future evaluation of the efficacy and safety of this new treatment strategy.

Does rAAV-mediated overexpression of TGF-β stably restructure human osteoarthritic articular cartilage in situ?

Therapeutic gene transfer is of significant value to elaborate efficient, durable treatments against human osteoarthritis (OA), a slow, progressive, and irreversible disorder for which there is no cure to date. Here, we directly applied a recombinant adeno-associated virus (rAAV) vector carrying a human transforming growth factor beta (TGF-β) gene sequence to primary human normal and OA chondrocytes in vitro and cartilage explants in situ to monitor the stability of transgene expression and the effects of the candidate pleiotropic factor upon the regenerative cellular activities over time. Efficient, prolonged expression of TGF-β achieved via rAAV gene transfer enhanced both the proliferative, survival, and anabolic activities of cells over extended periods of time in all the systems evaluated (at least for 21 days in vitro and for up to 90 days in situ) compared with control (reporter) vector delivery, especially in situ where rAAV-hTGF-β allowed for a durable remodeling of OA cartilage. Notably, sustained rAAV production of TGF-β in OA cartilage advantageously reduced the expression of key OA-associated markers of chondrocyte hypertrophic and terminal differentiation (type-X collagen, MMP-13, PTHrP, β-catenin) while increasing that of protective TIMPs and of the TGF-β receptor I in a manner that restored a favorable ALK1/ALK5 balance. Of note, the levels of activities in TGF-β-treated OA cartilage were higher than those of normal cartilage, suggesting that further optimization of the candidate treatment (dose, duration, localization, presence of modulating co-factors) will most likely be necessary to reproduce an original cartilage surface in relevant models of experimental OA in vivo without triggering potentially adverse effects.

The present findings show the ability of rAAV-mediated TGF-β gene transfer to directly remodel human OA cartilage by activating the biological, reparative activities and by regulating hypertrophy and terminal differentiation in damaged chondrocytes as a potential treatment for OA or for other disorders of the cartilage that may require transplantation of engineered cells.

Does tryptanthrin reduce mast cell proliferation promoted by TSLP through modulation of MDM2 and p53?

Atopic dermatitis (AD) results from complex interactions between mast cells and inflammatory mediators. An inflammatory mediator, thymic stromal lymphopoietin (TSLP) is known to promote mast cell proliferation through up-regulation of mouse double minute 2 (MDM2, a negative regulator of p53) and aggravate AD. In this study, we investigated whether tryptanthrin (TR, an anti-inflammatory agent) would regulate TSLP-induced mast cell proliferation and TSLP-induced a pro-inflammatory cytokine, tumor necrosis factor (TNF)-α production from mast cells. Human mast cell line (HMC-1) cells were treated with TR and stimulated with TSLP. Proliferation was measured with a bromodeoxyuridine incorporation assay. And pro- and anti-apoptotic factors were analyzed with quantitative real-time PCR, Western blot analysis, and ELISA. The mRNA expression and production of TNF-α were analyzed with quantitative real-time PCR and ELISA. TR significantly inhibited the proliferation of HMC-1 cells promoted by TSLP. TR inhibited MDM2 expression, whereas TR increased the expression of p53, poly ADP-ribose polymerase, and caspase-3 in the TSLP-stimulated HMC-1 cells. TR significantly inhibited Ki67 mRNA expression as well as mRNA expression and production of interleukin (IL)-13 in the TSLP-stimulated HMC-1 cells. Moreover, TR significantly suppressed mRNA expression and production of TNF-α in the TSLP-stimulated HMC-1 cells. Finally, the mRNA expression of IL-7 receptor α chain and TSLP receptor was inhibited by TR in the TSLP-stimulated HMC-1 cells.

Our results suggest that TR determined with new concept has intensive potential for the treatment of mast cell-mediated allergic diseases, such as AD.

Is profound inhibition of myogenic tone in rat cardiac allografts due to eNOS- and iNOS-based nitric oxide and an intrinsic defect in vascular smooth muscle contraction?

The physiological consequences of inducible NO synthase (iNOS) expression were studied in allograft coronary arteries by pressure myography. Septal coronary arteries (diameter, 200.6+/-3.3 microm) were harvested from allograft and isograft hearts, and their myogenic properties were measured before and after iNOS and nonselective NOS inhibition with aminoguanidine (AG, 100 micromol/L) and N(G)-nitro-L-arginine methyl ester (L-NAME) (200 micromol/L). Fura 2 fluorescence microscopy was used to measure [Ca(2+)](i) in isolated endothelial cells. Monoclonal anti-iNOS immunostains demonstrated iNOS protein in day 2, 7, 14, and 28 allograft vessels, but only in day 2 isograft vessels. Myogenic tone was profoundly inhibited in allograft vessels from day 4 onward. In day 4 allograft vessels, these differences were abolished by L-NAME but not AG, suggesting greater basal release of eNOS-based NO from allograft endothelium. Fluorescence measurements confirmed elevation of [Ca(2+)](i) in day 4 allograft endothelium, providing a mechanism for enhanced eNOS activity. For days 7 to 28, AG potentiated myogenic tone in allograft but not isograft vessels, indicating that vasoactive iNOS-based NO was present. In mature vessels, constriction via agonist- and depolarization-mediated mechanisms showed parallel inhibition, suggesting an intrinsic defect in vascular smooth muscle cell contraction.

Our data indicate that the profound inhibition of myogenic tone in allograft arteries involves direct vasodilation by eNOS- and iNOS-based NO, as well as an intrinsic defect in vascular smooth muscle contraction. The hemodynamic profile resulting from these changes in allograft resistance vessel function would favor movement of extracellular fluid from the intravascular space into the myocardial interstitium, resulting in edema, increased ventricular stiffness, and poor ventricular performance.

Is soluble VEGF receptor-2 increased in sera of subjects with metabolic syndrome in association with insulin resistance?

Metabolic syndrome (MetS) is associated with impaired angiogenesis. Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis through binding to its specific receptor, VEGF receptor-2 (VEGFR-2), whereas the expression of VEGF and VEGFR-2 in the myocardium of insulin-resistant rats is down-regulated. Soluble VEGF receptor-1 (sVEGFR-1) and -2 (sVEGFR-2) have been reported to inhibit angiogenesis both in vitro and in vivo. However, the balance between circulating levels of VEGF and its soluble receptors, which may reflect and/or affect cardiovascular VEGF signaling, in subjects with MetS is unknown. We carried out a cross-sectional study including 272 consecutive, apparently healthy subjects who were not receiving any drugs. Plasma levels of VEGF and serum levels of its soluble receptors were determined using enzyme-linked immunosorbent assays. VEGF and sVEGFR-1 levels did not differ between subjects with and those without MetS. However, sVEGFR-2 levels were significantly increased in MetS compared with non-MetS subjects. Stepwise regression analysis revealed that HOMA-IR was the strongest independent determinant of the sVEGFR-2 level. Accordingly, the mean sVEGFR-2 levels increased in proportion to both the accumulation of components of MetS and quartile of HOMA-IR. Interestingly, multiple regression analyses revealed that independent determinants of VEGF were the body mass index and blood pressure, whereas, in contrast, those of sVEGFR-2 were HOMA-IR and high-sensitivity C-reactive protein.

The correlation of sVEGFR-2 with insulin resistance supports the need for further investigations to define the clinical utility and predictive value of serum sVEGFR-2 levels in cardiovascular dysfunction in MetS.

Hodgkins lymphoma in North Jordan. Does it have a different pattern?

To study the pattern of Hodgkin's lymphoma (HL) in North Jordan, identify the epidemiological features of this disease, and to see if these patterns are unique or follow the patterns seen in developed or developing countries. All of the cases of HL diagnosed at the Department of Pathology, Jordan University of Science and Technology, Irbid, Jordan between January 1996 and September 2002 were retrieved and reviewed histologically. Seventy-five confirmed HL cases were classified according to the WHO classification of hematological malignancies. Data on the age and gender of the patients were correlated with those of the histopathologic types of the disease. Patients range in age from 3-72 years with a median of 20 years. The young adult population (15-34 years) was the largest group in this study accounting for 45.9% of all cases followed by the childhood group (0-14 years), which accounted for 25.6% of the cases. The age distribution displayed only one peak between 11 and 20 years. Classic HL accounted for 91% of the cases, half of these cases belong to the mixed cellularity (MC) type and 46% belong to the nodular sclerosis (NS) type. The overall male to female ratio was 1.7:1; but the ratio was the highest (3.75:1) among children, and reversed among patients with NS type in the young adult group (0.78:1).

The MC and NS types of HL accounted for the vast majority of HL in North Jordan. Similar to other developing countries the MC type of HL was the most common type followed by the NS type. The age distribution displayed a unimodal pattern with a peak between 11 and 20 years of age, which is a decade earlier than the first peak seen in the West. This pattern is also different from developing countries, where HL peaks in children less than 10 years of age. Hodgkin's lymphoma in Jordan appears to have an intermediate pattern between developing countries and the West.

Does glimepiride reduce mononuclear activation of the redox-sensitive transcription factor nuclear factor-kappa B?

Glimepiride has the lowest ratio of insulin release to glucose decrease compared with other sulphonylureas. This prompted us to study in vitro and in vivo in a placebo-controlled study the effect of glimepiride on the redox-sensitive transcription factor nuclear factor-kappa B (NF-kappaB). Fifteen patients with type 2 diabetes on glibenclamide with a stable HbA1c over the last 6 months were included. After sampling for determination of baseline values, 10 patients were changed to an equivalent dose of glimepiride, while the placebo group was maintained at glibenclamide plus placebo. The glimepiride dose in these patients was adjusted so that no change in glucose control occurred, allowing for direct comparison. The others were kept on glibenclamide and received additional placebo. After 4 weeks of glimepiride or glibenclamide plus placebo, a second blood sample was taken. Mononuclear cells were isolated and assayed in a tissue-culture-independent electrophoretic mobility shift assay (EMSA)-based detection system for NF-kappaB binding activity, and by Western Blot for nuclear localization of NF-kappaB-p65, the cytoplasmic content of IkappaBalpha and the NF-kappaB-controlled haemoxygenase-1. Glimepiride dose-dependent inhibition of carboxymethyllysin (CML) albumin or tumour necrosis factor alpha (TNFalpha)- and H2O2-induced activation of NF-kappaB binding were determined, using isolated peripheral blood mononuclear cells from healthy volunteers, and transcriptional activity of bovine aortic endothelial cells either left untreated or induced with CML albumin incubated with or without glimepiride. Furthermore, in-vitro studies were implemented to demonstrate radical quenching properties of glimepiride in the cell-free 2,2'-azo-bis(2-aminopropane)-dihydrochloride system. Baseline glucose and HbA1c remained stable in the patients switched from glibenclamide to a corresponding dose of glimepiride or kept on glibenclamide plus placebo. While in the group of patients only taking glibenclamide plus placebo the NF-kappaB binding activity did not change significantly (p = 0.58), the NF-kappaB binding activity in the group of patients taking glimepiride was reduced from 19.3 relative NF-kappaB-p65-equivalents to 15.5 relative NF-kappaB-p65-equivalents (p = 0.04). The nuclear translocation of NF-kappaB-p65 was reduced from 100% at baseline to 58% after 4 weeks (p = 0.04); the cytoplasmic localization of NF-kappaB-p65 increased from 100% to 129% (p = 0.03) and the cytoplasmic content of IkappaBalpha increased from 100% to 109% (p = 0.06). The redox-sensitive haemoxygenase-1 antigen was reduced from 100% to 82% (p = 0.04). To prove directly that glimepiride reduces NF-kappaB activation, we isolated peripheral blood mononuclear cells (PBMC) from healthy volunteers. In vitro, glimepiride reduced TNFalpha-(1 nmol/l) and CML albumin (800 nmol/l)-induced NF-kappaB activation dose dependently, being half maximal at 120 micromol/l. H2O2-mediated NF-kappaB activation was only partially reduced. In addition, glimepiride reduced NF-kappaB-dependent gene expression using a NF-kappaB-driven luciferase reporter system. Finally, a cell-free detection system showed that glimepiride has radical quenching properties.

Glimepiride can affect the activation of the redox-sensitive transcription factor NF-kappaB in vitro and in vivo.

Abnormal oscillatory brain dynamics in schizophrenia: a sign of deviant communication in neural network?

Slow waves in the delta (0.5-4 Hz) frequency range are indications of normal activity in sleep. In neurological disorders, focal electric and magnetic slow wave activity is generated in the vicinity of structural brain lesions. Initial studies, including our own, suggest that the distribution of the focal concentration of generators of slow waves (dipole density in the delta frequency band) also distinguishes patients with psychiatric disorders such as schizophrenia, affective disorders, and posttraumatic stress disorder. The present study examined the distribution of focal slow wave activity (ASWA: abnormal slow wave activity) in 116 healthy subjects, 76 inpatients with schizophrenic or schizoaffective diagnoses and 42 inpatients with affective (ICD-10: F3) or neurotic/reactive (F4) diagnoses using a newly refined measure of dipole density. Based on 5-min resting magnetoencephalogram (MEG), sources of activity in the 1-4 Hz frequency band were determined by equivalent dipole fitting in anatomically defined cortical regions. Compared to healthy subjects the schizophrenia sample was characterized by significantly more intense slow wave activity, with maxima in frontal and central areas. In contrast, affective disorder patients exhibited less slow wave generators mainly in frontal and central regions when compared to healthy subjects and schizophrenia patients. In both samples, frontal ASWA were related to affective symptoms.

In schizophrenic patients, the regions of ASWA correspond to those identified for gray matter loss. This suggests that ASWA might be evaluated as a measure of altered neuronal network architecture and communication, which may mediate psychopathological signs.

Do ictal high-frequency oscillations on scalp EEG recordings in symptomatic West syndrome?

High-frequency oscillations (HFOs) on intracranial electroencephalography (EEG) recordings have been reported to be useful to identify the epileptogenic zone in intractable epilepsy. We investigated whether the ictal HFOs on scalp EEG seen during spasms contributed to identification of the epileptogenic zone in symptomatic West syndrome (S-WS). In S-WS, ictal scalp EEGs were recorded during a series of spasms. The HFOs associated with spasms were visualized in the temporally expanded EEG traces and subjected to time-frequency analysis. The results on the distribution of HFOs were compared with that of cortical lesions indicated by neuroimaging. In the 4 children examined, HFOs at 80-150 Hz preceded the clinical onsets of spasms. The maximum augmentation of these HFOs was larger than that of HFOs at 20-70 Hz. The regions of the maximum augmentation of HFOs at 80-150 Hz were identical to the lesions detected by neuroimaging. Two patients who underwent dissection of the area including the area with HFOs resulted in Engel class I.

Ictal HFOs of spasms on scalp EEG showed a strong association with neuroimaging abnormalities presumed to be the epileptogenic zone in S-WS. Ictal HFOs can thus be a useful marker for exploring lesions for epilepsy surgery.

Can alcohol intoxication be excluded as the cause of confusion following head injury?

To assess whether there is a breath alcohol level (BrAC) below which confusion in the head injured patient should not be attributed solely to the acute effects of alcohol. Based in the Accident and Emergency Ward in Glasgow Royal Infirmary, a prospective observational study was carried out over a five month period. Patients admitted to the ward were recruited for the study if they had a primary diagnosis of head injury. The outcome measures recorded and analysed were sequential 2 hrly BrAC readings (mg/L) and Glasgow Coma Scale findings (Eye opening, motor and verbal responses). The relationship between these was investigated, which revealed additional relevant factors affecting level of consciousness. The breath alcohol analyser was found to be a useful non-invasive, quick and easy to use tool. The results obtained were consistent with the expected pattern of reducing BrAC levels over a 6 hour period. Within this group of patients, a poor correlation was found between each of the three responses of the Glasgow Coma Scale and BrAC readings. For those patients who remained confused, when their BrAC reading was less than 1 mg/L, other causes of a lowered level of consciousness were identified.

Confusion in the head injured patient with a BrAC of less than 1 mg/L, should alert one to the likelihood of causes other than alcohol intoxication.

Is skin biopsy helpful for the diagnosis of incontinentia pigmenti at late stage ( IV ) : a series of 26 cutaneous biopsies?

Hypochromic streaks can be the only cutaneous sign of incontinentia pigmenti (IP) in adulthood (stage IV). Discovery of such lesions in an adult female with no family history of IP is essential for appropriate genetic counselling. To describe and to validate the histological features of residual skin lesions in adult IP. The analysis and comparison of skin biopsies of 26 women affected with molecularly confirmed IP. Most biopsies showed slight atrophy and some scattered apoptotic cells in the epidermis, epidermal hypopigmentation and reduced melanocyte number. The dermis appeared thickened and homogeneous and revealed a complete absence of hair follicles (23/26) and sweat glands (22/26). There was no melanin incontinence or inflammatory cells, and the elastic network was normal.

These features lead unequivocally to the diagnosis of a stage IV IP skin lesion. Consequently, histology is a major confirmatory criterion for diagnoses of these mild clinical forms of IP. It is therefore a useful tool in genetic counselling and prenatal diagnosis. Moreover, the observations described here may contribute to understanding the physiopathology of the late stages of IP.

Does the key to improving prognosis for aneurysmal subarachnoid hemorrhage remain in the pre-hospitalization period?

Despite advances in neurosurgical management, aneurismal subarachnoid hemorrhage (aSAH) still has high mortality and morbidity. This study aimed to clarify how delaying hospital admission after aSAH contributes to worse prognosis even today and to find the possibility for an improvement of its prognosis by early admission. Four hundred twenty-one consecutive patients are the basis for this study. Cause of delay was classified into 5 categories: patient delay (PD), doctor delay (DD), transportation delay (TD), no delay (ND) (within 2 hours of onset), and others. Condition of each patient was assessed at time of onset and admission using H&K. The relationships between cause of delay and worsening of Hunt and Kosnik grading (H&K) were examined. The median delay time was 1.7 days. Only 41% of patients visited our institution without delay. Admission delay, especially PD and DD, exhibited a significant correlation to worsening of H&K. In addition to nondirect admission, misdiagnosis or delayed diagnosis contributed significantly to worsening of H&K. Incidence of DD has declined in recent years, whereas that of PD has increased. Consequently, no change in total number of delays was found.

There remains much room for an improvement of prognosis for aSAH by early admission. We need to fully realize this reality and to directly face this problem.

Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer?

The pattern of failure (POF) after first-line systemic therapy in advanced non-small cell lung cancer (NSCLC) is unknown. We evaluate the POF in this setting to estimate the potential value of consolidative stereotactic body radiation therapy (SBRT). The records of consecutive NSCLC patients presenting to the University of Colorado, Denver (UCD) between January 2005 and June 2008 were reviewed. Patients with measurable advanced stage NSCLC who received first-line systemic therapy and follow-up at UCD were eligible. In these patients, sites of disease at maximal response were evaluated for theoretical SBRT eligibility, based on institutional criteria. All patients were followed to extracranial progression. The POF was categorized as local (L) for lesions known prior to treatment or distant (D) for new lesions. Among 387 consecutive lung cancer patients (all stages), 64 met the eligibility criteria and 34 were SBRT-eligible. Among all eligible patients, first extra-cranial progression was L-only in 64%, D-only in 9% and L + D in 27%. Among SBRT-eligible patients, POF was L-only in 68%, D-only in 14% and L + D in 18%. In SBRT-eligible patients, time to first progression was 3.0 months in those with L-only failure versus 5.7 month in those with any D failure (HR 0.44; 95% CI 0.22-0.90).

The predominant POF in patients with advanced NSCLC after first-line systemic therapy is local-only. The current analysis suggests that SBRT could improve time to progression in a substantial proportion of patients. The estimated increase in time to progression using this approach would be approximately 3 months.

Is expression of human intestinal mucin modulated by the beta-galactoside binding protein galectin-3 in colon cancer?

Alterations in the production of the beta-galactoside binding protein galectin-3 and of MUC2 intestinal mucin have been independently correlated with the malignant behavior of human colon cancer cells. MUC2 mucin is a major ligand for galectin-3, and colon cancer cells that differ quantitatively in MUC2 expression may also vary in expression of galectin-3. The current study was designed to investigate the relationship between galectin-3 production and MUC2 mucin synthesis by human colon cancer cells. The effect of galectin-3 on MUC2 mucin production was assessed by stable transfection of sense and antisense galectin-3 expression constructs under the control of constitutive or tetracycline-inducible promoters into human colon cancer cells. Galectin-3 and MUC2 expression were determined by fluorescence-activated cell sorter (cell surface galectin-3), Western and Northern analysis (galectin-3, MUC2), and gel filtration of secreted high-weight glycoprotein (MUC2). In vitro results were confirmed in vivo by analysis of cecal xenografts in athymic mice. Colon cancer cells with high levels of galectin-3 also had high levels of MUC2 mucin, whereas those with low galectin-3 levels had low MUC2 levels. Alterations in galectin-3 levels by expression of sense or antisense galectin-3 constructs resulted in parallel alterations of MUC2 protein and RNA. Induction of antisense to galectin-3 in vivo was associated with decreases in both galectin-3 and MUC2 protein in cecal xenografts.

The beta-galactoside binding protein galectin-3 modulates the expression of its major ligand MUC2 mucin in human colon cancer cells. This may have important implications for understanding the role of galectin-3 in colon cancer metastasis.

Is caveolin-1 expression elevated in claudin-low mammary tumor cells?

Caveolin-1 is a scaffolding protein found in plasma membrane invaginations known as caveolae. Caveolin-1 can regulate a number of intracellular processes such as signal transduction, cholesterol metabolism and vesicular transport. With respect to breast cancer caveolin-1 has been observed in both tumor cells and stromal cells surrounding tumors however most of the recent research has focused on how the loss of caveolin-1 in the stromal cells surrounding the tumor alters the tumor microenvironment. Caveolin-1 expression was evaluated in (1) mammary tumors induced by the transgenic overexpression of the type I insulin-like growth factor receptor (IGF-IR), (2) mammary tumors that became independent of IGF-IR signalling and acquired a claudin-low genotype, (3) two murine mammary epithelial tumor cell lines and (4) two murine mammary claudin-low tumor cell lines. We found that mammary tumors induced by IGF-IR overexpression expressed low levels of caveolin-1 while mammary tumors that became independent of IGF-IR signalling expressed considerably higher levels of caveolin-1. Interestingly, pockets of caveolin-1 positive cells could be observed in some of the IGF-IR-induced mammary tumors and these caveolin-1 positive cells were associated with tumor cells that expressed basal cytokeratins (cytokeratins 5 and 14). This caveolin-1 expression pattern was maintained in the murine mammary tumor cell lines in that the epithelial mammary tumor cell lines expressed little or no caveolin-1 while the claudin-low cell lines expressed caveolin-1.

Our model indicates that mammary tumor cells with epithelial characteristics lack caveolin-1 while mesenchymal tumor cells express caveolin-1 suggesting that caveolin-1 may serve as a marker of mammary tumor cells with mesenchymal characteristics such as claudin-low breast tumors.

Does growth hormone-secreting tumor shrinkage after 3 months of octreotide-long-acting release therapy predict the response at 12 months?

The objective of the study was to evaluate whether tumor shrinkage or GH and IGF-I levels achieved after 3 months predicted tumor shrinkage after 12 months of octreotide-long-acting release (LAR) treatment. Patients included 67 patients with de novo acromegaly (33 women, 34 men; aged 20-82 yr) receiving LAR at a dose of 20 mg every 28 d for 3 months. Final LAR dose was 10 mg every 28 d in 4, 30 mg every 28 d in 39, 20 mg every 28 d in 24 patients. The design of the study was analytical, observational, open, and retrospective. Percent change in GH and IGF-I levels and tumor volume after 3 and 12 months of therapy was measured. Stepwise regression and receiving-operator characteristics analysis were used to calculate the optimal cutoff to predict 12 months tumor shrinkage at 12 months. The percent tumor shrinkage after 12 months was significantly correlated with GH, IGF-I, and tumor volume at 3 months and with the dose of LAR administered between 3 and 12 months. There was no correlation with gender, age, baseline GH levels and tumor volume. In a stepwise regression analysis, percent tumor shrinkage after 3 months was the best predictor of tumor shrinkage after 12 months (t = 5.92; P < 0.0001), followed by GH levels after 3 months (t = 2.86; P = 0.0056). To predict 50% or greater tumor shrinkage after 12 months, the best cutoff point of tumor shrinkage at 3 months was 22.1% [sensitivity (95% confidence interval) = 85.5% (71.2-95.4); specificity = 83.3% (65.3-94.3)], whereas that of GH levels after 3 months was 7.8 microg/liter [sensitivity = 70.3% (53.0-84.1); specificity = 93.3% (79.0-99.0)].

Tumor shrinkage achieved after 3 months of LAR treatment at 20 mg/28 d predicted tumor shrinkage at 12 months, provided that dosages were changed according to individual patients requirement.

Can the diagnosis of NF1 be excluded clinically?

Consensus clinical diagnostic criteria for neurofibromatosis type I (NF1) include café-au-lait macules and skinfold freckling. The former are frequently the earliest manifestation of NF1, and as such are of particular significance when assessing young children at risk of the condition. A phenotype of predominantly spinal neurofibromatosis has been identified in a small minority of families with NF1, often in association with a relative or absolute lack of cutaneous manifestations. An association with splicing and missense mutations has previously been reported for spinal neurofibromatosis, but on the basis of molecular results in only a few families. Patients with spinal NF1 were identified through the Manchester nationally commissioned service for complex NF1. Five families with spinal NF1 were identified, with a broad spectrum of NF1 mutations, providing further evidence that this phenotype may arise in association with any genre of mutation in this gene. Pigmentary manifestations were absent or very mild in affected individuals. Several further affected individuals, some with extensive spinal root tumours, were ascertained when additional family members were assessed.

Clinical NF1 consensus criteria cannot be used to exclude the diagnosis of spinal NF1, especially in childhood. This emphasises the importance of molecular confirmation in individuals and families with atypical presentations of NF1.

Is levofloxacin necessary to prevent postoperative infections of auricular second-intention wounds?

Surgeons may prescribe oral quinolones after auricular procedures to prevent postoperative infections, especially those caused by Pseudomonas aeruginosa. This study compares the efficacy of levofloxacin and local wound care to local wound care alone in preventing postoperative infection of auricular second-intention wounds. This study was a prospective, randomized trial of 84 consecutive patients (82 in the final analysis) who underwent Mohs micrographic surgery for an auricular neoplasm and had a wound left to heal by second intention. After surgery, patients were randomly assigned to receive either local wound care or local wound care with concurrent 500 mg of levofloxacin by mouth daily. Overall, 85.4% of patients had no complications. Complications included 12.2% of patients with inflammatory chondritis and 2.4% of patients with infection. No infections with P. aeruginosa were observed. No statistical significance was observed between the two treatment groups.

Levofloxacin is not necessary to prevent postoperative infections of auricular second-intention wounds after Mohs surgery.

Does estrogen administration attenuate bladder outlet obstruction induced oxidative stress in the female rabbit?

Estrogen administration to female rabbits induces a functional hypertrophy of the bladder. The aim of this study was to investigate whether supplementation of estrogen in the female rabbit with partial bladder outlet obstruction (PBOO) would affect the severity of bladder dysfunction. We surgically created PBOO in female New Zealand White rabbits. Group 1 included sham operated rabbits which served as controls. Group 2 received PBOO without estrogen treatment. Group 3 received estrogen treatment after PBOO. Group 4 received estrogen pretreatment before PBOO. The bladders were then removed for contractile, biochemical, and protein expression studies. There were four rabbits per group. (1) PBOO resulted in significant decreases in the contractile responses to all forms of stimulation (field stimulation [FS], carbachol, KCl, ATP). Both pretreatment and post-treatment with estrogen resulted in significantly increased contractile responses to all forms of stimulation, although the responses were still lower than control. (2) PBOO resulted in a significant decrease in the activity of choline acetyltransferase (ChAT). Both pretreatment and post-treatment with estrogen resulted in significant increases in ChAT activity back toward control levels. (3) PBOO resulted in significant increases in both protein oxidation and nitration; both pretreatment and post-treatment with estrogen significantly reduced oxidation and nitration toward control levels.

Estrogen pretreatment and post-treatment in the female rabbit ameliorated contractile and biochemical dysfunctions associated with PBOO. This improvement is likely due to reduced oxidative stress. As expected, pretreatment was generally more effective than post-treatment.

Does empirical assessment suggest that existing evidence could be used more fully in designing randomized controlled trials?

Meta-analyses of randomized controlled trials (RCTs) provide the highest level of evidence regarding the effectiveness of interventions. Less is known about how they are used to inform the design and reporting of RCTs. A sample of RCTs published in leading medical journals in 2007 was assessed to establish whether authors considered previous trials in the design of their trial. An approach to calculate the sample size required for a significant pooled effect in an updated meta-analysis was applied to a subsample of the RCTs to illustrate the ways in which the results of an existing meta-analysis can be incorporated into the planning and reporting of new RCTs. Six of the 27 trials assessed (22%) reported the use of previous trial(s) for sample size calculations. Meta-analyses relating the results of the trial to previous research were cited in 37% (10 out of 27) of the report discussion sections. Previous evidence is formally incorporated into retrospective sample size calculations for three of the trials.

Consulting previous research before embarking on a new trial and basing decisions about future research on the impact on an updated meta-analysis will make the reporting of research more coherent and the design of new RCTs more efficient.

Does global profiling of rice and poplar transcriptomes highlight key conserved circadian-controlled pathways and cis-regulatory modules?

Circadian clocks provide an adaptive advantage through anticipation of daily and seasonal environmental changes. In plants, the central clock oscillator is regulated by several interlocking feedback loops. It was shown that a substantial proportion of the Arabidopsis genome cycles with phases of peak expression covering the entire day. Synchronized transcriptome cycling is driven through an extensive network of diurnal and clock-regulated transcription factors and their target cis-regulatory elements. Study of the cycling transcriptome in other plant species could thus help elucidate the similarities and differences and identify hubs of regulation common to monocot and dicot plants. Using a combination of oligonucleotide microarrays and data mining pipelines, we examined daily rhythms in gene expression in one monocotyledonous and one dicotyledonous plant, rice and poplar, respectively. Cycling transcriptomes were interrogated under different diurnal (driven) and circadian (free running) light and temperature conditions. Collectively, photocycles and thermocycles regulated about 60% of the expressed nuclear genes in rice and poplar. Depending on the condition tested, up to one third of oscillating Arabidopsis-poplar-rice orthologs were phased within three hours of each other suggesting a high degree of conservation in terms of rhythmic gene expression. We identified clusters of rhythmically co-expressed genes and searched their promoter sequences to identify phase-specific cis-elements, including elements that were conserved in the promoters of Arabidopsis, poplar, and rice.

Our results show that the cycling patterns of many circadian clock genes are highly conserved across poplar, rice, and Arabidopsis. The expression of many orthologous genes in key metabolic and regulatory pathways is diurnal and/or circadian regulated and phased to similar times of day. Our results confirm previous findings in Arabidopsis of three major classes of cis-regulatory modules within the plant circadian network: the morning (ME, GBOX), evening (EE, GATA), and midnight (PBX/TBX/SBX) modules. Identification of identical overrepresented motifs in the promoters of cycling genes from different species suggests that the core diurnal/circadian cis-regulatory network is deeply conserved between mono- and dicotyledonous species.

Pulmonary alveolar proteinosis in children on La Réunion Island: a new inherited disorder?

Pulmonary alveolar proteinosis (PAP) is very rare in children. Only a few small series have been published, with little information about long-term progression. The objective of our study was to describe the clinical, radiological and pathological features, and the long-term course of PAP in a cohort of 34 children from La Réunion Island. Data were retrospectively collected from medical files. Radiological and pathological elements were reviewed by two pediatric radiologists and three pathologists, respectively. Thirteen cases were familial and 32/34 (94%) cases were family connected. Disease onset occurred in the first six months of life in 82% of the patients. Thoracic computed tomography scans showed the typical "crazy-paving" pattern in 94% of cases. Respiratory disease was associated with a liver disorder, with the detection of liver enlargement at diagnosis in 56% of cases. The course of the disease was characterized by frequent progression to chronic respiratory insufficiency, accompanied by the appearance of cholesterol granulomas and pulmonary fibrosis. Overall prognosis was poor, with a mortality of 59% and an overall five-year survival rate from birth of 64%. Whole-lung lavages were performed in 21 patients, with no significant effect on survival. Liver disease progressed to cirrhosis in 18% of children, with no severe complication.

PAP in children from la Réunion Island is characterized by an early onset, associated liver involvement, poor prognosis and frequent progression to lung fibrosis, despite whole-lung lavages treatment. The geographic clustering of patients and the detection of many familial links between most of the cases strongly suggest a genetic etiology, with an autosomal recessive mode of inheritance.

Are cTLA4 gene polymorphisms associated with , and linked to , insulin-dependent diabetes mellitus in a Russian population?

The association between the human cytotoxic T lymphocyte-associated antigen-4 (CTLA4) gene and insulin-dependent diabetes mellitus (IDDM) is unclear in populations. We therefore investigated whether the gene conferred susceptibility to IDDM in a Russian population. We studied two polymorphic regions of the CTLA4 gene, the codon 17 dimorphism and the (AT)n microsatellite marker in the 3' untranslated region in 56 discordant sibling pairs and in 33 identical by descent (IBD) affected sibships. The Alal7 allele of the CTLA4 gene was preferentially transmitted from parents to diabetic offspring (p<0.0001) as shown by the combined transmission/disequlibrium test (TDT) and sib TDT (S-TDT) analysis. A significant difference between diabetic and non-diabetic offspring was also observed for the transmission of alleles 17, 20, and 26 of the dinucleotide microsatellite. Allele 17 was transmitted significantly more frequently to affected offspring than to other children (p=0.0112) whereas alleles 20 and 26 were transmitted preferentially to non-diabetic sibs (p=0.045 and 0.00068 respectively). A nonrandom excess of the Ala17 CTLA4 molecular variant (maximum logarithm of odds score (MLS) of 3.26) and allele 17 of the dinucleotide marker (MLS=3.14) was observed in IBD-affected sibling pairs.

The CTLA4 gene is strongly associated with, and linked to IDDM in a Russian population.

Does iVIG immunotherapy protect against synaptic dysfunction in Alzheimer 's disease through complement anaphylatoxin C5a-mediated AMPA-CREB-C/EBP signaling pathway?

Complement component C5-derived C5a locally generated in the brain has been shown to protect against glutamate-induced neuronal apoptosis and beta-amyloid (Aβ) toxicity, but the mechanism is not clear. In this study, we tested the hypothesis that C5a influences upstream signal transduction pathways associated with cAMP-response element-binding protein (CREB) activation, in which alterations of CREB levels are associated with cognitive deterioration in AD. CREB signaling pathway, synaptic plasticity and cognitive function were studied in C5a receptor knockout mice (C5aR(-/-)), C5a over expressing mice (C5a/GFAP) and in Tg2576 mice, an AD mouse model. (1) Cognitive function is severely impaired in C5aR(-/-) mice, coincident with the down-regulated CREB/CEBP pathway in brain. (2) Either the application of recombinant-human-C5a (hrC5a) or exogenous expression of C5a in the brain of a mouse model (C5a/GFAP) enhances this pathway. (3) Application of hrC5a in brain slices from Tg2576 mice significantly improves deficits in long-term potentiation (LTP), while this effect is blocked by a specific AMPA receptor antagonist. (4) Searching for a pharmacological approach to locally mediate C5a responses in the brain, we found that low-dose human intravenous immunoglobulin (IVIG) treatment improves synaptic plasticity and cognitive function through C5a-mediated induction of the CREB/CEBP pathway, while the levels of Aβ in the brain are not significantly affected.

This study for the first time provides novel evidence suggesting that C5a may beneficially influence cognitive function in AD through an up-regulation of AMPA-CREB signaling pathway. IVIG may systematically improve cognitive function in AD brain by passing Aβ toxicity.

Does a combination of fentanyl-midazolam-propofol provide better intubating conditions than fentanyl-lignocaine-propofol in the absence of neuromuscular blocking agents?

The use of propofol and adjuvants such as opioids, benzodiazepines and local anaesthetic agents, may provide adequate conditions for tracheal intubation without the need for neuromuscular blocking agents. In this randomized, double-blind study, intubating conditions after induction of anaesthesia with propofol, midazolam and fentanyl were compared with those after propofol, lignocaine and fentanyl. In 80 ASA I/II adult patients undergoing elective gynaecological surgery, intubating conditions were compared after induction of anaesthesia with a fentanyl 2 microg/kg, midazolam 0.03 mg/kg, propofol 2.5 mg/kg combination (group FMP) vs. a fentanyl 2 microg/kg, lignocaine 1.5 mg/kg, propofol 2.5 mg/kg combination (group FLP). Intubating conditions were assessed using a qualitative scoring system. Intubation was successful in all patients in group FMP and in 87.5% of patients in group FLP; (P= 0.021). Overall, intubating conditions were clinically acceptable in 77.5% and 55% of patients in group FMP and group FLP, respectively (P= 0.033).

We conclude that the fentanyl, midazolam, propofol combination more reliably provides acceptable conditions for intubation than the fentanyl, lignocaine, propofol combination. Intubation was successful in all patients receiving the fentanyl, midazolam, propofol combination.

Surgical results of arterial switch operation for Taussig-Bing anomaly: is position of the great arteries a risk factor?

A variety of definitive operations have been used to manage patients with double-outlet right ventricle and subpulmonary ventricular septal defect (Taussig-Bing anomaly). This study identifies the impact of the position of the great arteries and use of a staged surgical approach on the outcome after the arterial switch operation in children with Taussig-Bing anomaly. From 1986 through July 2005, 34 patients with Taussig-Bing anomaly underwent the arterial switch operation. The median age at operation was 21 days. Based on position of the great arteries, patients were divided into group I (side by side; n = 16) and group II (anteroposterior; n = 18). Aortic arch obstruction was present in 18 patients (53%), of whom 16 had prior repair with aortic arch reconstruction. Abnormal coronary artery patterns were present in 9 patients (27%). There were 4 early deaths and 1 late death (3 from group I and 2 from group II). The actuarial survival rate was 85% at 15 years (81% in group I and 89% in group II). Right ventricular outflow tract obstruction (mean gradient, 46.0 +/- 5.5 mm Hg) developed in 5 cases (2 from group I and 3 from group II). One patient underwent reoperation for residual aortic arch obstruction. Freedom from reoperation was 80% at 15 years, and thereafter 85% in group I and 75% in group II. Statistical analysis of potential risk factors revealed no significant identifiers for death or need for reoperation between groups.

The arterial switch operation remains our preferred choice of treatment for children with Taussig-Bing anomaly. The position of the great arteries has no effect on postoperative morbidity and mortality. In the presence of aortic arch obstruction, staged arch reconstruction followed soon thereafter by early intracardiac repair has yielded excellent outcomes in our experience.

Does serial positron emission tomography scan following radiation therapy of patients with head and neck cancer?

A single institution study was undertaken to evaluate the role of positron emission tomography (PET) scans with fluorodeoxyglucose (FDG) prior to radiation and following radiation. Forty-five patients with head and neck cancers were evaluated with FDG-PET scans as well as either CT or MRI prior to treatment with definitive radiation (RT). These same scans were obtained following completion of RT at 1 month (36 patients), 4 months (28 patients), 12 months (19 patients), and 24 months (15 patients). Standard uptake values (SUV) normalized for blood glucose and lean body mass were calculated on the initial and 1-month post-treatment PET scans. Fifteen patients are alive without evidence of disease at 24 to 52 months following RT. Initial SUVs were calculated on the primary tumor site and ranged from 2.5 to 28.5. These values did not have any correlation with local control when examined for the entire group, primary site, or T stage. One-month post-RT SUV ranged from 1.8 to 6.24. Of the 36 1-month post-RT PET scans, six were interpreted as positive for residual disease and were confirmed by biopsy. Four of the five scans, which were interpreted as equivocal, were positive on biopsy. Seven of the 25 scans, which were interpreted as negative for tumor, were positive on biopsy. Four-month scans were more accurate for disease with disease noted in 0 of 18 negative scans, 6 of 7 positive scans, and 2 of 3 equivocal scans.

PET is useful for initial imaging of head and neck cancers. SUV does not appear to be useful for predicting outcome following treatment with RT. One-month post-RT scans were inaccurate for predicting the presence of cancer. Four-month post-RT scans were a better predictor for the presence of cancer.

Does olfactory function combined with morphology distinguish Parkinson 's disease?

This study aimed to examine whether the volume of the olfactory bulbs and tracts (OB & T) on magnetic resonance imaging (MRI) is useful for differentiating Parkinson's disease (PD) from PD-related disorders. The study group comprised 13 patients with PD, 11 with multiple system atrophy (MSA), five with progressive supranuclear palsy, and five with corticobasal degeneration (PSP/CBD). All patients were evaluated using the odor stick identification test for Japanese (OSIT-J), (123)I-meta-iodobenzylguanidine (MIBG) scintigraphy, and brain MRI. OB & T areas on 1-mm-thick coronal images were measured and summed for volumes. We examined relationships between olfactory function and volume, and cardiovascular dysautonomia. We defined the cut-off values for OSIT-J score or MIBG uptake and OB & T volume to discriminate PD from PD-related disorders and calculated the proportional rate of PD in four categorized groups. OB & T volume was smaller in PD than in MSA or PSP/CBD (p < 0.05 each). The cut-off for detecting PD patients was OSIT-J score <8, heart/mediastinum ratio <1.6, and OB & T volume <270 mm(3). In the group with OSIT-J score <8 and OB & T volume <270 mm(3), the proportion of PD patients among all patients with PD-related disorders was 91%. The rate of probable PD gradually increased as OSIT-J score and OB & T volume decreased (p < 0.001).

Although preliminary, these data obtained from a combined morphological and functional evaluation of OB or cardiovascular dysautonomia could be useful for further differential of PD and other PD-related disorders.

Do human monocyte-derived suppressor cells control graft-versus-host disease by inducing regulatory forkhead box protein 3-positive CD8+ T lymphocytes?

Adoptive transfer of immunosuppressive cells has emerged as a promising strategy for the treatment of immune-mediated disorders. However, only a limited number of such cells can be isolated from in vivo specimens. Therefore efficient ex vivo differentiation and expansion procedures are critically needed to produce a clinically relevant amount of these suppressive cells. We sought to develop a novel, clinically relevant, and feasible approach to generate ex vivo a subpopulation of human suppressor cells of monocytic origin, referred to as human monocyte-derived suppressive cells (HuMoSCs), which can be used as an efficient therapeutic tool to treat inflammatory disorders. HuMoSCs were generated from human monocytes cultured for 7 days with GM-CSF and IL-6. The immune-regulatory properties of HuMoSCs were investigated in vitro and in vivo. The therapeutic efficacy of HuMoSCs was evaluated by using a graft-versus-host disease (GvHD) model of humanized mice (NOD/SCID/IL-2Rγc(-/-) [NSG] mice). CD33+ HuMoSCs are highly potent at inhibiting the proliferation and activation of autologous and allogeneic effector T lymphocytes in vitro and in vivo. The suppressive activity of these cells depends on signal transducer and activator of transcription 3 activation. Of therapeutic relevance, HuMoSCs induce long-lasting memory forkhead box protein 3-positive CD8+ regulatory T lymphocytes and significantly reduce GvHD induced with human PBMCs in NSG mice.

Ex vivo-generated HuMoSCs inhibit effector T lymphocytes, promote the expansion of immunosuppressive forkhead box protein 3-positive CD8+ regulatory T cells, and can be used as an efficient therapeutic tool to prevent GvHD.

Does fortification of staple foods improve vitamin D intakes and status of groups at risk of deficiency?

More than one-fifth of the United Kingdom population has poor vitamin D status (serum 25-hydroxyvitamin D [25(OH)D] concentration<25 nmol/L), particularly individuals with low sun exposure or poor dietary intake. We identified the fortification vehicle and concentration most likely to safely increase population vitamin D intakes and vitamin D status. Wheat flour and milk were identified as primary fortification vehicles for their universal consumption in population groups most at risk of vitamin D deficiency including children aged 18-36 mo, females aged 15-49 y, and adults aged ≥65 y. With the use of data from the first 2 y (2008-2010) of the National Diet and Nutrition Survey Rolling Program, we simulated the effect of fortifying wheat flour and milk with vitamin D on United Kingdom food consumption. Empirically derived equations for the relation between vitamin D intake and the serum 25(OH)D concentration were used to estimate the population serum 25(OH)D concentration for each fortification scenario. At a simulated fortification of 10 μg vitamin D/100 g wheat flour, the proportion of at-risk groups estimated to have vitamin D intakes below United Kingdom Reference Nutrient Intakes was reduced from 93% to 50%, with no individual exceeding the United Kingdom Tolerable Upper Intake Level; the 2.5th percentile of the population winter serum 25(OH)D concentration rose from 20 to 27 nmol/L after fortification. The simulation of the fortification of wheat flour at this concentration was more effective than that of the fortification of milk (at concentrations between 0.25 and 7 mg vitamin D/100 L milk) or of the fortification of milk and flour combined.

To our knowledge, this study provides new evidence that vitamin D fortification of wheat flour could be a viable option for safely improving vitamin D intakes and the status of United Kingdom population groups at risk of deficiency without increasing risk of exceeding current reference thresholds.

Do interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration?

Interleukin 1 (IL-1) is potentially important in the pathogenesis of intervertebral disc (IVD) degeneration; increasing production of matrix degradation enzymes and inhibiting matrix synthesis. Although IL-1 polymorphisms have been linked to increased risk of IVD degeneration, it is still unclear whether IL-1 drives IVD degeneration in vivo or is a secondary feature of degeneration. Here, we investigated whether IVD degeneration could be induced spontaneously by the removal of the natural inhibitor of IL-1 (IL-1 receptor antagonist) in mice that lack a functional IL-1rn gene. Histological staining and immunohistochemistry was performed on BALB/c IL-1rn(+/+) and IL-1rn(-/-) mice to examine degeneration and to localise and detect IL-1, matrix metalloproteinases (MMP)3, MMP7, a disintigrin and MMP with thrombospondin motifs (ADAMTS)4 protein production. In addition, IVD cells were isolated using collagenase and proliferation potential determined. IL-1rn(-/-) knockout mice displayed typical features of human disc degeneration: loss of proteoglycan and normal collagen structure and increased expression of matrix degrading enzymes: MMP3; MMP7 and ADAMTS4. Histological grade of degeneration increased in IL-1rn(-/-) mice which was more evident within older mice. In addition IVD cells isolated from IL-1rn(-/-) mice displayed reduced proliferation potential.

Here, we show that IL-1rn(-/-) mice develop spinal abnormalities that resemble characteristic features associated with human disc degeneration. The current evidence is consistent with a role for IL-1 in the pathogenesis of IVD degeneration. The imbalance between IL-1 and IL-1Ra which is observed during human IVD degeneration could therefore be a causative factor in the degeneration of the IVD, and as such, is an appropriate pharmaceutical target for inhibiting degeneration.

Does language lateralization correlate with verbal memory performance in children with focal epilepsy?

Assessment of language dominance with functional magnetic resonance imaging (fMRI) and neuropsychological evaluation is often used prior to epilepsy surgery. This study explores whether language lateralization and cognitive performance are systematically related in young patients with focal epilepsy. Language fMRI and neuropsychological data (language, visuospatial functions, and memory) of 40 patients (7-18 years of age) with unilateral, refractory focal epilepsy in temporal and/or frontal areas of the left (n = 23) or right hemisphere (n = 17) were analyzed. fMRI data of 18 healthy controls (7-18 years) served as a normative sample. A laterality index was computed to determine the lateralization of activation in three regions of interest (frontal, parietal, and temporal). Atypical language lateralization was demonstrated in 12 (30%) of 40 patients. A correlation between language lateralization and verbal memory performance occurred in patients with left-sided epilepsy over all three regions of interest, with bilateral or right-sided language lateralization being correlated with better verbal memory performance (Word Pairs Recall: frontal r = -0.4, p = 0.016; parietal r = -0.4, p = 0.043; temporal r = -0.4, p = 0.041). Verbal memory performance made the largest contribution to language lateralization, whereas handedness and side of seizures did not contribute to the variance in language lateralization.

This finding reflects the association between neocortical language and hippocampal memory regions in patients with left-sided epilepsy. Atypical language lateralization is advantageous for verbal memory performance, presumably a result of transfer of verbal memory function. In children with focal epilepsy, verbal memory performance provides a better idea of language lateralization than handedness and side of epilepsy and lesion.

Does a selective cyclooxygenase-2 inhibitor suppress the growth of endometriosis with an antiangiogenic effect in a rat model?

To analyze the antiangiogenic effects of the selective cyclooxygenase-2 (COX-2) inhibitor parecoxib on the growth of endometrial implants in a rat model of peritoneal endometriosis. Pharmacologic interventions in an experimental model of peritoneal endometriosis. Research laboratory in the Federal University of Rio de Janeiro. Twenty female Sprague-Dawley rats with experimentally induced endometriosis. After implantation and establishment of autologous endometrium onto the peritoneum abdominal wall, rats were randomized into groups and treated with parecoxib or the vehicle by IM injection for 30 days. Vascular density, the expression of vascular endothelial growth factor (VEGF) and its receptor Flk-1, the distribution of activated macrophages, the expression of COX-2, and the prostaglandin concentration in the endometriotic lesions treated with parecoxib were analyzed. The treatment significantly decreased the implant size, and histologic examination indicated mostly atrophy and regression. A reduction in microvessel density and in the number of macrophages, associated with decreased expression of VEGF and Flk-1, also were observed. The treatment group showed a low concentration of prostaglandin E(2).

These results suggest that the use of COX-2 selective inhibitors could be effective to suppress the establishment and growth of endometriosis, partially through their antiangiogenic activity.

Do betaine and carnitine uptake systems in Listeria monocytogenes affect growth and survival in foods and during infection?

To establish the relative importance of the osmo- and cryoprotective compounds glycine betaine and carnitine, and their transporters, for listerial growth and survival, in foods and during infection. A set of Listeria monocytogenes mutants with single, double and triple mutations in the genes encoding the principal betaine and carnitine uptake systems (gbu, betL and opuC, respectively) was used to determine the specific contribution of each transporter to listerial growth and survival. Food models were chosen to represent high-risk foods of plant and animal origin i.e. coleslaw and frankfurters, which have previously been linked to major human outbreaks of listeriosis. BALB/c mice were used as an in vivo model of infection. Interestingly, while betaine appeared to confer most protection in foods, the hierarchy of transporter importance differs depending on the food type: Gbu>BetL>OpuC for coleslaw, as opposed to Gbu>OpuC>BetL in frankfurters. By contrast in the animal model, OpuC and thus carnitine, appears to play the dominant role, with the remaining systems contributing little to the infection process.

This study demonstrates that the individual contribution of each system appears dependent on the immediate environment. In foods Gbu appears to play the dominant role, while during infection OpuC is most important.

Does the DNA repair protein ALKBH2 mediate temozolomide resistance in human glioblastoma cells?

Glioblastoma multiforme (GBM; World Health Organization astrocytoma grade IV) is the most frequent and most malignant primary brain tumor in adults. Despite multimodal therapy, all such tumors practically recur during the course of therapy, causing a median survival of only 14.6 months in patients with newly diagnosed GBM. The present study was aimed at examining the expression of the DNA repair protein AlkB homolog 2 (ALKBH2) in human GBM and determining whether it could promote resistance to temozolomide chemotherapy. ALKBH2 expression in GBM cell lines and in human GBM was determined by quantitative real-time PCR (qRT-PCR) and gene expression analysis, respectively. Drug sensitivity was assessed in GBM cells overexpressing ALKBH2 and in cells in which ALKBH2 expression was silenced by small-interfering (si)RNA. ALKBH2 expression following activation of the p53 pathway was examined by western blotting and qRT-PCR. ALKBH2 was abundantly expressed in established GBM cell lines and human GBM, and temozolomide exposure increased cellular ALKBH2 expression levels. Overexpression of ALKBH2 in the U87 and U251 GBM cell lines enhanced resistance to the methylating agents temozolomide and methyl methanesulfonate but not to the nonmethylating agent doxorubicin. Conversely, siRNA-mediated knockdown of ALKBH2 increased sensitivity of GBM cells to temozolomide and methyl methanesulfonate but not to doxorubicin or cisplatin. Nongenotoxic activation of the p53 pathway by the selective murine double minute 2 antagonist nutlin-3 caused a significant decrease in cellular ALKBH2 transcription levels.

Our findings identify ALKBH2 as a novel mediator of temozolomide resistance in human GBM cells. Furthermore, we place ALKBH2 into a new cellular context by showing its regulation by the p53 pathway.

Does elastin in oral connective tissue modulate the keratinization of overlying epithelium?

One of the most discernable differences between keratinized and non-keratinized oral mucosas is the quantity of elastin they contain in the connective tissues. Whether elastin modulates the keratin expression of oral epithelial cells is unknown. Four specimens containing both keratinized and non-keratinized mucosas were processed for immunohistochemical (IHC) stainings for elastin and four keratins. Six keratinized and non-keratinized portions of oral mucosas were dissected and cultured on an organ culture system. Purified elastin and elastase were added separately to the media. After 14 days, the mucosas were examined for four keratin expressions. Cell cultures of keratinized and non-keratinized gingival fibroblasts were established and tested for elastin expression. Oral mucosa equivalents were then engineered and tested for keratin expression. Keratinized epithelium exclusively expressed keratin-1 and -10 (K1/10), while non-keratinized epithelium expressed keratin-4 and -13 (K4/13). Only non-keratinized fibroblasts expressed elastin in cell culture. Both the native and the engineered keratinized gingiva changed phenotypes and expressed K4/13 when treated with exogenous elastin. On the contrary, the native non-keratinized mucosa started to express K1/10 when elastase eradicated inherent elastin.

Our study demonstrated that the elastin in the oral connective tissue is important for the non-keratinized phenotypes of overlaying epithelium.

Facing haematopoietic stem-cell transplantation: do patients and their physicians agree regarding the prognosis?

To evaluate the correlation and concordance between patients' and physicians' estimations of prognoses before initiation of the conditioning regimen for allogeneic haematopoietic stem-cell transplantation. A total of 123 patients and their attending physicians were asked to estimate a prognosis on a six-point scale. The patients were also asked to fill out questionnaires addressing their psychological state and coping. The mean prognostic estimations differed by 1.17 points (p<0.001), with the patients being more optimistic than the physicians. With respect to concordance: Pearson correlation r=0.024 (ns); unweighted kappa and kappa with linear weighting are 0.115 and 0.068, respectively. The prognostic estimates of the patients correlated with their psychological state, but not with the objective disease- or treatment-related variables, whereas the physicians' estimates were partially based on such objective factors.

A clear significant association between actual survival and the physicians' estimates, but not the patients' estimates, was observed. If agreement regarding the prognosis exists, the relationship between physicians' and patients' estimates is probably non-linear. Assessing one's chances of being cured is a highly emotional task, and psychological processes such as denial or repression most likely play a decisive role. Moreover, collusion between the patient and physician may be inevitable in this situation. Whether it is desirable to gain concordance and who will benefit from such efforts must be discussed and empirically studied.

Do linear Gadolinium-Based Contrast Agents Are Associated With Brain Gadolinium Retention in Healthy Rats?

The aim of this study was to evaluate Gd retention in the deep cerebellar nuclei (DCN) of linear gadolinium-based contrast agents (GBCAs) compared with a macrocyclic contrast agent. The brain tissue retention of Gd of 3 linear GBCAs (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) and a macrocyclic GBCA (gadoterate meglumine) was compared in healthy rats (n = 8 per group) that received 20 intravenous injections of 0.6 mmol Gd/kg (4 injections per week for 5 weeks). An additional control group with saline was included. T1-weighted magnetic resonance imaging was performed before injection and once a week during the 5 weeks of injections and for another 4 additional weeks after contrast period. Total gadolinium concentration was measured with inductively coupled plasma mass spectrometry. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data. At completion of the injection period, all the linear contrast agents (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) induced a significant increase in signal intensity in DCN, unlike the macrocyclic GBCA (gadoterate meglumine) or saline. The T1 hypersignal enhancement kinetic was fast for gadodiamide. Total Gd concentrations for the 3 linear GBCAs groups at week 10 were significantly higher in the cerebellum (1.21 ± 0.48, 1.67 ± 0.17, and 3.75 ± 0.18 nmol/g for gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide, respectively) than with the gadoterate meglumine (0.27 ± 0.16 nmol/g, P < 0.05) and saline (0.09 ± 0.12 nmol/g, P < 0.05). No significant difference was observed between the macrocyclic agent and saline.

Repeated administrations of the linear GBCAs gadodiamide, gadobenate dimeglumine, and gadopentetate dimeglumine to healthy rats were associated with progressive and significant T1 signal hyperintensity in the DCN, along with Gd deposition in the cerebellum. This is in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed.

Are androgen receptor mutations associated with Gleason score in localized prostate cancer?

To study human androgen receptor (hAR) mutations and their relationship to the clinical and pathological characteristics of patients with prostate cancer, as the mechanisms by which tumour cells escape androgen control and grow independently of hormone stimulation are unclear. In all, 67 radical prostatectomy specimens were sequenced genomically (mean age of the patients, 64 years; median prostate-specific antigen level 15 ng/mL; 34% T1 and 66% T2). Of the 66 patients who had a valid follow-up, 28 (43%) had biochemical progression during the follow-up. There was mutation in the hAR in 11 patients (16%); nine types of different mutations were identified, only one of which was described previously in patients with prostate cancer. Patients with mutated hAR had statistically lower Gleason scores (P = 0.004) than had patients with native hAR.

hAR mutations have a different effect on the disease course in patients with localized than in those with metastatic prostatic cancer.

Does fatigue predict disease worsening in relapsing-remitting multiple sclerosis patients?

It is unclear whether fatigue is a consequence or a predictive trait of disease worsening. To investigate the predictive value of fatigue toward conversion to confirmed moderate-severe disability in patients with relapsing-remitting multiple sclerosis (RRMS). We retrospectively selected from the Comprehensive Longitudinal Investigations in MS at the Brigham and Women's Hospital (CLIMB) study cohort RRMS patients who converted to confirmed (⩾2 years) Expanded Disability Status Scale (EDSS) score ⩾3 within a follow-up period ⩾3 years. We contrasted the Modified Fatigue Impact Scale (MFIS) score of 33 converters, obtained at least 1 year before conversion to EDSS ⩾3, with that of 33 non-converter RRMS patients matched for baseline characteristics. Total MFIS score was higher in converter versus non-converter MS patients (median 37 vs 13; p < 0.0001). EDSS and Center for Epidemiological Studies Depression scale (CES-D) scores were also higher in the converters (median EDSS 1.5 vs 0, p < 0.0001; median CES-D 30 vs 24, p < 0.0001) and were both associated with MFIS score (EDSS: rho = 0.42, p = 0.0005; CES-D: rho = 0.72, p < 0.0001). After adjusting for EDSS and CES-D in multivariate analysis, MFIS remained a significant predictor of subsequent conversion to confirmed EDSS ⩾3.

Fatigue is a promising indicator of risk for conversion to confirmed moderate-severe disability in RRMS patients.

Does interleukin-33 synergistically enhance immune complex-induced tumor necrosis factor alpha and interleukin-8 production in cultured human synovium-derived mast cells?

Substantial evidence suggests that human synovial mast cells (MCs) are involved in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-33 is believed to play an important role in the pathogenesis of RA. We recently reported that FcγRI is responsible for producing abundant tumor necrosis factor alpha (TNF-α) from cultured synovium-derived MCs (SyMCs) in response to aggregated immunoglobulin G (IgG). However, whether or not IL-33 affects immune complex (IC)-induced synovial MC activation remains unknown. This study sought to evaluate the effect of IL-33 on IC-induced synovial MC activation. Cultured SyMCs were generated by culturing synovial cells with stem cell factor. ST2 expression was analyzed using FACS and immunohistochemical techniques. Mediators released from the MCs were measured using EIAs or ELISAs. SyMCs obtained from patients with RA or osteoarthritis (OA) expressed ST2 on their surfaces. We confirmed the expression of ST2 in MCs using immunofluorescence staining in joint tissue obtained from RA patients. IC-triggered histamine release was not enhanced by IL-33. However, IL-33 synergistically enhanced IC-induced IL-8 and TNF-α production in SyMCs.

ICs and IL-33 may exacerbate inflammation associated with RA by abundantly producing TNF-α and IL-8 from SyMCs.

Does evaluation of platelet storage lesions in platelet concentrate stored for seven days?

Platelet storage lesions (PSL) are detrimental to the post transfusion functional capacity of platelets. As EDTA enhances the storage-induced changes, changes in platelet indices with and without EDTA incubation are promising new tests to monitor the PSL. The present study was undertaken to monitor the PSL in 40 units of pooled platelet concentrates harvested by platelet rich plasma (PRP) method and stored for seven days in second generation platelet storage containers using conventional in vitro tests and platelet indices. Morphological changes in platelets were monitored by automated haematological cell counter for platelet count and mean platelet volume (MPV). Samples were incubated with K2EDTA for 1 h and platelet indices were repeated on the EDTA incubated samples. Difference between pre-and post-EDTA incubation of platelet count (dPLT) and MPV (dMPV) were calculated. Metabolic parameters such as pH, pO2, pCO2 and ATP were measured. There was no significant change in the indices without EDTA during storage, however, after EDTA incubation, significant changes were noted in dPLT and dMPV. The mean dPLT on day 0 was 75.15 x 10(3)/microl decreasing to 44.4 x 10(3)/microl on day 7, while dMPV from 0.76 fl on day 0 increased to 1.34 fl on day 7 (P < 0.05). Metabolic parameters showed a significant decrease in pH and pCO2 concurrent with increasing pO2 during storage (P < 0.05). Average ATP level on day 0 was 21.09 micromol/dl falling to 10.59 micromol/dl on day 7.

The results indicate that storage induced lesions take place even in second generation platelet storage containers under recommended conditions of storage. Platelet indices especially after EDTA incubation are useful in monitoring PSL. However, how much these changes contribute to poor post transfusion survival and haemostatic function of platelets need to be investigated.

Does ovarian stimulation affect the levels of regulatory endometrial NK cells and angiogenic cytokine VEGF?

Endometrial NK cells play a critical role in uterine vascularization producing angiogenic factors. Impact of ovarian stimulation on endometrial expression of NK cells and VEGF in normal fertile oocyte donors and the effect of endometrial injury treatment on these parameters have been investigated. Endometrial tissue was obtained from oocyte donors during natural and stimulated cycles. NK cell subsets were measured by flow cytometry. VEGF was determined by ELISA and flow cytometry. Endometrial angiogenic parameters were determined by ultrasound Doppler. Local injury was induced by scratching endometrial tissue previous to implantation window. Ovarian stimulation decreased endometrial levels of NK cells and vascularization index but increased VEGF levels. Local injury normalized only the CD56(+) NK cell count.

Hormonal therapy for ovarian stimulation may be associated with poor endometrial vascularization. Local injury before the implantation window seems not to influence endometrial angiogenic parameters altered by ovarian stimulation.

Are serum retinol-binding protein 4 levels elevated in non-alcoholic fatty liver disease?

Retinol-binding protein 4 (RBP4) is a recently identified adipokine that is elevated in the serum in several insulin-resistant states. We investigated the relationship between non-alcoholic fatty liver disease (NAFLD) and serum RBP4 in nondiabetic adults. One hundred and fifty-nine nondiabetic, non-alcoholic subjects (95 males and 64 females) participated in this study. Division of subjects into a NAFLD group (n = 73; 45 males and 28 females) or a normal group (n = 86; 50 males and 36 females) was based on the presence of fatty liver disease determined by sonography. Serum RBP4 levels in the NAFLD group were significantly higher than those in the normal group (62.8 +/- 16.0 mg/l vs. 51.7 +/- 14.6 mg/l, P < 0.0001). Multiple logistic regression analysis revealed that the RBP4 level was an independent factor associated with NAFLD (P = 0.0042). In addition, serum RBP4 levels were positively correlated with serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltranspeptidase (GGT) levels. The significant association between serum RBP4 and GGT levels remained even after adjusting for age, gender, body mass index, the homeostasis model of assessment (HOMA) value and the presence of NAFLD (r = 0.3097, P = 0.0002).

Serum RBP4 levels are significantly associated with NAFLD and liver enzymes.

Fusion of circulating blood cells with solid-organ tissue cells in clinical stem cell transplants: a potential therapeutic model?

The clinical model was a male-into-female blood stem cell transplantation setting using the Y-chromosome as a blood-derived cell marker and the patient's BCR/ABL fusion gene. Endometrial cells were chosen as the target cells because of their uniquely female genotype. The Y-chromosome and the BCR/ABL fusion gene were identified by fluorescence in situ hybridization and were colocalized with estrogen receptor-staining endometrial cells. Both donor-derived Y-chromosome and patient-derived fusion gene were identified in the same endometrial cells, thereby indicating cell fusion as the mechanism for genetic material transfer in a clinical setting.

These findings contribute to our understanding of how blood-derived cells interact with solid-organ tissue cells.

Does gene expression profiling identify MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis?

Little is known about the genetic regulation of granulomatous inflammation in sarcoidosis. To determine if tissue gene array analysis would identify novel genes engaged in inflammation and lung remodeling in patients with sarcoidosis. Gene expression analysis was performed on tissues obtained from patients with sarcoidosis at the time of diagnosis (untreated) (n = 6) compared with normal lung tissue (n = 6). Expression of select genes was further confirmed in lung tissue from a second series of patients with sarcoidosis and disease-free control subjects (n = 11 per group) by semi-quantitative RT-PCR. Interactive gene networks were identified in patients with sarcoidosis using Ingenuity Pathway Analysis (Ingenuity Systems, Inc., Redwood, CA) software. The expression of proteins corresponding to selected overexpressed genes was determined using fluorokine multiplex analysis, and immunohistochemistry. Selected genes and proteins were then analyzed in bronchoalveolar lavage fluid in an independent series of patients with sarcoidosis (n = 36) and control subjects (n = 12). A gene network engaged in Th1-type responses was most significantly overexpressed in the sarcoidosis lung tissues, including genes not previously reported in the context of sarcoidosis (e.g., IL-7). MMP-12 and ADAMDEC1 transcripts were most highly expressed (> 25-fold) in sarcoidosis lung tissues, corresponding with increased protein expression by immunohistochemistry. MMP-12 and ADAMDEC1 gene and protein expression were increased in bronchoalveolar lavage samples from patients with sarcoidosis, correlating with disease severity.

Tissue gene expression analyses provide novel insights into the pathogenesis of pulmonary sarcoidosis. MMP-12 and ADAMDEC1 emerge as likely mediators of lung damage and/or remodeling and may serve as markers of disease activity.

Does γ-Actin play a key role in endothelial cell motility and neovessel maintenance?

Angiogenesis plays a crucial role in development, wound healing as well as tumour growth and metastasis. Although the general implication of the cytoskeleton in angiogenesis has been partially unravelled, little is known about the specific role of actin isoforms in this process. Herein, we aimed at deciphering the function of γ-actin in angiogenesis. Localization of β- and γ-actin in vascular endothelial cells was investigated by co-immunofluorescence staining using monoclonal antibodies, followed by the functional analysis of γ-actin using siRNA. The impact of γ-actin knockdown on the random motility and morphological differentiation of endothelial cells into vascular networks was investigated by timelapse videomicroscopy while the effect on chemotaxis was assessed using modified Boyden chambers. The implication of VE-cadherin, VEGFR-2 and ROCK signalling was then examined by Western blotting and using pharmacological inhibitors. The two main cytoplasmic isoforms of actin strongly co-localized in vascular endothelial cells, albeit with some degree of spatial preference. While β-actin knockdown was not achievable without major cytotoxicity, γ-actin knockdown did not alter the viability of endothelial cells. Timelapse videomicroscopy experiments revealed that γ-actin knockdown cells were able to initiate morphological differentiation into capillary-like tubes but were unable to maintain these structures, which rapidly regressed. This vascular regression was associated with altered regulation of VE-cadherin expression. Interestingly, knocking down γ-actin expression had no effect on endothelial cell adhesion to various substrates but significantly decreased their motility and migration. This anti-migratory effect was associated with an accumulation of thick actin stress fibres, large focal adhesions and increased phosphorylation of myosin regulatory light chain, suggesting activation of the ROCK signalling pathway. Incubation with ROCK inhibitors, H-1152 and Y-27632, completely rescued the motility phenotype induced by γ-actin knockdown but only partially restored the angiogenic potential of endothelial cells.

Our study thus demonstrates for the first time that β-actin is essential for endothelial cell survival and γ-actin plays a crucial role in angiogenesis, through both ROCK-dependent and -independent mechanisms. This provides new insights into the role of the actin cytoskeleton in angiogenesis and may open new therapeutic avenues for the treatment of angiogenesis-related disorders.

Is male breast cancer : the scenario changing?

The overall incidence of male breast cancer is around 1% of all breast cancers and is on the rise. In this review we aim to present various aspects of male breast cancer with particular emphasis on incidence, risk factors, patho-physiology, treatment, prognostic factors, and outcome. Information on all aspects of male breast cancer was gathered from available relevant literature on male breast cancer from the MEDLINE database over the past 32 years from 1975 to 2007. Various reported studies were scrutinized for emerging evidence. Incidence data were also obtained from the IARC, Cancer Mondial database.

There is a scenario of rising incidence, particularly in urban US, Canada and UK. Even though more data on risk factors is emerging about this disease, more multi-institutional efforts to pool data with large randomized trials to show treatment and survival benefits are needed to support the existing vast emerging knowledge about the disease.

Is increased visceral adiposity with normal weight associated with the prevalence of non-alcoholic fatty liver disease in Japanese patients with type 2 diabetes?

To investigate the impact of increased visceral adiposity with normal weight (OB[-]VA[+]) on the prevalence of non-alcoholic fatty liver disease in patients with type 2 diabetes. This was a cross-sectional study of 140 Japanese patients with type 2 diabetes (mean age 65 ± 11 year; 44.6% women). Visceral fat area (VFA; cm(2) ) and liver attenuation index (LAI) were assessed by abdominal computed tomography. The patients were divided into four groups by VFA and body mass index (BMI; kg/m(2) ) as follows: BMI <25 kg/m(2) and VFA <100 cm(2) (OB[-]VA[-]), BMI ≥25 kg/m(2) and VFA <100 cm(2) (OB[+]VA[-]), BMI <25 kg/m(2) and VFA ≥100 cm(2) (OB[-]VA[+]), and BMI ≥25 kg/m(2) and VFA ≥100 cm(2) (OB[+]VA[+]). Multivariate linear regression and logistic regression analysis were carried out to determine the impact of OB(-)VA(+) on LAI. In the present study, 25.0% were OB(-)VA(+) patients, where the LAI levels were lower (1.09 ± 0.22) than those in OB(-)VA(-) patients (1.23 ± 0.15), and were equivalent to those in OB(+)VA(+) patients (1.03 ± 0.26). In multivariate linear regression analysis, OB(-)VA(+) was independently associated with LAI (standardized β-0.212, P = 0.014). In multivariate logistic regression analysis, OB(-)VA(+) was a significant predictor of LAI <0.9 (odds ratio 5.88, 95% confidence interval 1.03-33.52, P = 0.046).

The present study provides evidence that increased visceral adiposity with normal weight is a strong predictor for the prevalence of non-alcoholic fatty liver disease in Japanese patients with type 2 diabetes.

Does procyanidin B1 purified from Cinnamomi cortex suppress hepatitis C virus replication?

A combination of pegylated interferon and ribavirin is the current standard therapy for hepatitis C virus (HCV) infection, but this combination provides relatively low efficacy, especially in some patients with HCV genotype 1 infection; therefore, the development of novel therapeutic agents is required for further improvement in the treatment of chronic HCV infection. HCV pseudotype and subgenomic replicon assays were used in this study. The interaction of compounds with HCV receptors was examined using flow cytometry. Intracellular RNA levels were determined by semi-quantitative reverse transcriptase PCR. Procyanidin B1 (PB1), a dimer of (-)-epicatechin and (+)-catechin, purified from Cinnamomi cortex, inhibits infection by vesicular stomatitis virus and HCV pseudotype virus in Huh-7 cells, with 50% effective concentrations of 29 and 15 microM, respectively. No inhibitory effects were observed in each component of PB1. We found that PB1 does not interfere with viral entry or receptor expression, but inhibits HCV RNA synthesis in a dose-dependent manner.

These results indicate that PB1 suppresses HCV RNA synthesis, possibly as a HCV RNA polymerase inhibitor. Our results might contribute towards the development of more effective inhibitors for HCV infection from natural plants.