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Are non-absorbable sutures associated with lower recurrence rates in laparoscopic percutaneous inguinal hernia ligation?

Laparoscopic hernia repair with percutaneous ligation of the patent processes vaginalis is a minimally invasive alternative to open inguinal herniorrhaphy in children. With the camera port concealed at the umbilicus, this technique offers an excellent cosmetic result. It is also faster than the traditional laparoscopic repair with no differences in complication rates or hospital stay. The goal of this study was to describe a series of consecutive patients, emphasizing the impact of suture materials (absorbable vs. non-absorbable) on hernia recurrences. A retrospective review was performed of consecutive transperitoneal laparoscopic subcutaneous ligations of a symptomatic hernia and/or communicating hydrocele by 4 surgeons. Patients > Tanner 2 or with prior hernia repair were excluded. The success of the procedure and number of sutures used was compared between cases performed with absorbable vs. non-absorbable suture. Risk factors for surgical failure (age, weight, number of sutures used, suture type) were assessed with logistic regression. 94 patients underwent laparoscopic percutaneous hernia ligation at a mean age of 4.9 years. Outcomes in 85 (90%) patients with 97 hernia repairs at a mean of 8 months after surgery revealed 26% polyglactin vs 4% polyester recurrences (p = 0.004) which occurred at mean of 3.6 months after surgery, Table 1. Repairs performed with non-absorbable suture required only 1 suture more often than those performed with absorbable suture (76% vs 60%, p = 0.163). Logistic regression revealed suture type was an independent predictor for failure (p = 0.017). Weight (p = 0.249), age (p = 0.055), and number of sutures (p = 0.469) were not significantly associated with recurrent hernia.

Our review of consecutive hernia repairs using the single port percutaneous ligation revealed a significantly higher recurrent hernia rate with absorbable (26%) versus non-absorbable (4%) suture. This finding remained significant in a logistic regression model irregardless of number of sutures placed, age, and weight. Though the authors acknowledge the drawback of the potential for learning curve to confound our data, we still feel these findings are clinically important as this analysis of outcomes has changed our surgical practice as now all providers involved perform this procedure with exclusively non-absorbable suture. We thus suggest that surgeons who perform this technique, especially those newly adopting it, use non-absorbable suture for optimal patient outcomes.

Do depressive symptoms during the first chemotherapy cycle predict mortality in patients with advanced non-small cell lung cancer?

Depressive symptoms are commonly experienced by cancer patients, especially those with advanced disease. The link between depression and survival outcome in cancer patients has received increasing attention. The purpose of this study was to determine, after adjusting the known covariates, whether the depressive symptoms during the first cycle of chemotherapy can predict the mortality of patients with advanced non-small cell lung cancer (NSCLC). Patients with stage III or IV NSCLC were recruited from a large teaching hospital located in northern Taiwan. Depressive symptoms were assessed during the first cycle of chemotherapy using the Hospital Anxiety and Depression Scale-Depression subscale. A cut-off of 7/8 was used to categorize patients into depressed and non-depressed groups. All patients were followed up until the end of the study. The follow-up time ranged from 10 to 30 months. The study sample consisted of 90 NSCLC patients. Twenty patients (22.2%) were categorized as depressed. The median survival time in the depressed group was significantly shorter than that of the non-depressed group (11.83 vs. 24.47 months, P = 0.017). After controlling for demographic and clinical factors, depressive symptoms remained significantly (p = 0.023) associated with a shorter survival time. Compared to the non-depressed group, the depressed group had twice the risk of death (HR = 2.18, 95% CI = 1.11 to 4.28).

The finding supports that depressive symptoms at the early phase of treatment can predict shorter survival in patients with advanced NSCLC.

Do utility of bilateral acoustic hearing in combination with electrical stimulation provided by the cochlear implant?

The aim of the study was to quantify the benefit provided by having access to amplified acoustic hearing in the implanted ear for use in combination with contralateral acoustic hearing and the electrical stimulation provided by the cochlear implant. Measures of spatial and non-spatial hearing abilities were obtained to compare performance obtained with different configurations of acoustic hearing in combination with electrical stimulation. In the combined listening condition participants had access to bilateral acoustic hearing whereas the bimodal condition used acoustic hearing contralateral to the implanted ear only. Experience was provided with each of the listening conditions using a repeated-measures A-B-B-A experimental design. Sixteen post-linguistically hearing-impaired adults participated in the study. Group mean benefit was obtained with use of the combined mode on measures of speech recognition in coincident speech in noise, localization ability, subjective ratings of real-world benefit, and musical sound quality ratings.

Access to bilateral acoustic hearing after cochlear implantation provides significant benefit on a range of functional measures.

Tetracycline and trimethoprim/sulfamethoxazole at clinical laboratory: can they help to characterize Staphylococcus aureus carrying different SCCmec types?

Methicillin-resistant Staphylococcus aureus (MRSA) can be difficult to detect at the clinical practice. We analyzed 140 MRSA isolates from inpatients to correlate the antimicrobial susceptibility with the SCCmec types. Type III (n = 63) isolates were more resistant to ciprofloxacin, clindamycin, cloramphenicol, erythromycin, gentamicin, and rifampin than type IV (n = 65) ones (p<0.05). Moreover, type IV isolates were susceptible to tetracycline (100%) and trimethoprim/sulfamethoxazole (98%), while type III isolates presented resistance to them.

In regions where these SCCmec types are prevalent, the detection of specific resistant phenotypes could help to predict them, mainly when there are no technical conditions to SCCmec typing.

Is post-operative atrial fibrillation associated with a pre-existing structural and electrical substrate in human right atrial myocardium?

Post-operative atrial fibrillation (POAF) is a major health economic burden. However, the precise mechanisms in POAF remain unclear. In other forms of AF, sites of high dominant frequency (DF) in sinus rhythm (SR) may harbour 'AF nests'. We studied AF inducibility in relation to substrate changes using epicardial electrograms and cardiomyocyte calcium handling in the atria of AF naïve patients. Bipolar electrograms were recorded from the lateral right atrial (RA) wall in 34 patients undergoing coronary surgery using a high-density array in sinus rhythm (NSR). RA burst pacing at 200/500/1000ms cycle lengths (CL) was performed, recording episodes of AF>30s. Co-localised RA tissue was snap frozen for RNA and protein extraction. Electrograms prolonged during AF (76.64±29.35ms) vs. NSR/pacing (p<0.001). Compared to NSR, electrogram amplitude was reduced during AF and during pacing at 200ms CL (p<0.001). Electrogram DF was significantly lower in AF (75.87±23.63Hz) vs. NSR (89.33±25.99Hz) (p<0.05), and NSR DF higher in AF inducible patients at the site of AF initiation (p<0.05). Structurally, POAF atrial myocardium demonstrated reduced sarcolipin gene (p=0.0080) and protein (p=0.0242) expression vs. NSR. Phospholamban gene and protein expression was unchanged. SERCA2a protein expression remained unchanged, but MYH6 (p=0.0297) and SERCA2A (p=0.0343) gene expression was reduced in POAF.

Human atrial electrograms prolong and reduce in amplitude in induced peri-operative AF vs. NSR or pacing. In those sustaining AF, high DF sites in NSR may indicate 'AF nests'. This electrical remodelling is accompanied by structural remodelling with altered expression of cardiomyocyte calcium handling detectable before POAF. These novel upstream substrate changes offer a novel mechanism and manifestation of human POAF.

Is estrogen deprivation , rather than age , responsible for the poor lipid profile and carbohydrate metabolism in women?

The protective effect of estrogen against cardiovascular diseases (CVD) in women disappears after menopause. However, it is not clear whether the change in risk factors after menopause is related to aging or estrogen deprivation. To assess the risks for CVD and the contribution of aging in estrogen-deprived women. Forty-one patients with premature ovarian failure (POF) (group 1) and 30 patients with natural menopause (group 2) were investigated with respect to well-known risk factors for CVD. Fifteen young women at reproductive age (group 3) were taken as controls. The median ages (ranges) of the groups were 31 (19-40), 52 (46-67) and 26 (24-29) years, respectively. Family and personal history for CVD, smoking, oral contraceptive usage, physical examination, blood pressure measurement, body mass index (BMI), blood level of fasting insulin, diabetes mellitus, and the levels of lipoprotein proteins were the examined parameters regarding the risks for CVD. The levels of triglycerides and very low density lipoprotein (VLDL) cholesterol were not different in the 3 groups. The levels of fasting insulin (11.3 +/- 6.6 vs. 10.2 +/- 5.8 IU/ml), the ratio of fasting insulin to fasting blood glucose (12.2 +/- 6.3% vs. 10.5 +/- 5.4%), high density lipoprotein (HDL) cholesterol (51.9 +/- 12.9 vs. 51.6 +/- 9.7 mg/d), low density lipoprotein (LDL) cholesterol (113 +/- 47 vs. 127 +/- 37 mg/dl) and the ratio of HDL to total cholesterol (27.2 +/- 9.8% vs. 24.1 +/- 6.9%) were not different in women with POF and natural menopause. These parameters were all better in controls with respect to risk for CVD (respectively, 6.5 +/- 2.0 IU/ml, 7.4 +/- 2.2%, 37.9 +/- 5.3 mg/dl, 80 +/- 40 mg/dl, P < 0.05).

Risk factors for CVD are related to estrogen deprivation. Aging does not have an important impact on CVD within the age range of this study group.

Does delayed ascorbate bolus protect against maldistribution of microvascular blood flow in septic rat skeletal muscle?

Although early administration of ascorbate has been shown to protect against the microvascular dysfunction in sepsis, it is not clear if a delayed introduction of ascorbate also yields beneficial effects. The main objective was to determine the therapeutic window for treatment of an animal model of sepsis with bolus injection of ascorbate. We also determined if sepsis per se affects urinary excretion of ascorbate. Prospective, controlled laboratory study. Animal laboratory in a university-affiliated research institute. Male Sprague-Dawley rats, 300-400 g of body weight. Rats were made septic by cecal ligation and perforation (CLP) and volume resuscitated by continuous saline infusion. Ascorbate bolus (7.6 mg/100 g of body weight) or saline vehicle was injected intravenously at 1, 6, or 24 hrs after CLP. At 24 hrs post-CLP, sepsis caused antidiuresis and decreased plasma ascorbate concentration, but it did not affect urinary excretion of ascorbate in rats that received only saline. Sepsis also caused maldistribution of capillary blood flow in skeletal muscle. This maldistribution of flow was prevented by ascorbate injected at 6 hrs post-CLP. At 48 hrs post-CLP, in addition to the flow maldistribution, sepsis caused systemic arterial hypotension and fever that were prevented by both immediate (1 hr post-CLP) and delayed injections of ascorbate (24 hrs post-CLP).

Despite volume resuscitation, the present model of sepsis resulted in maldistribution of capillary blood flow within 24 hrs and hypotension within 48 hrs. Our finding that intravenous bolus of ascorbate can protect against these deficits even if delayed 6-24 hrs after the septic insult shows, for the first time, that ascorbate can reverse microcirculatory dysfunction after the onset of sepsis.

Diagnosis of gluten-sensitive enteropathy: is exclusive reliance on histology appropriate?

Coeliac disease is a prevalent disorder but frequently remains undiagnosed because of varied modes of clinical presentation. In this study, methods for the detection of coeliac disease were evaluated in a clinical practice setting. Small intestinal histology, IgA anti-endomysial and IgG anti-gliadin antibody tests were performed on 441 unselected, consecutive patients under investigation for small intestinal disease. Response to treatment and other clinical events were monitored over the ensuing years. Untreated coeliac disease was diagnosed in 97 patients and was excluded in 344. At clinical presentation, the endomysial antibody test was positive in 84 of the 97 untreated coeliac patients (sensitivity 87%) and negative in 340 of the 344 non-coeliac patients (specificity 99%). A typical histological lesion was found in 83 of the 97 coeliac patients (sensitivity 86%) but was absent in all 344 non-coeliacs (specificity 100%). The sensitivity of the gliadin antibody test was 69% and the specificity was 71%.

In unselected patients attending a gastroenterology clinic, small bowel histology and endomysial antibody serology show similar predictive value in the diagnosis of coeliac disease. These results emphasize that a combination of clinical, histological and serological criteria are required for effective diagnosis of this disorder. Exclusive reliance on histology or serology will result in failure to make a diagnosis in a significant proportion of patients.

Does dexamethasone protect airway epithelial cell line NCI-H292 against lipopolysaccharide induced endoplasmic reticulum stress and apoptosis?

Endoplasmic reticulum (ER) stress and ER stress-mediated apoptosis were reported to be involved in the pathogenesis of several diseases. In a recent study, it was reported that the ER stress pathway was activated in the lungs of lipopolysaccharide (LPS)-treated mice. It was also found that the C/EBP homologous protein (CHOP), an apoptosis-related molecule, played a key role in LPS-induced lung damage. The aim of this study was to verify whether LPS could activate the ER stress response in airway epithelial cells and which molecule was involved in the pathway. This study was also aimed at finding new reagents to protect the airway epithelial cells during LPS injury. ER stress markers were observed in LPS-incubated NCI-H292 cells. SiRNA-MUC5AC was transfected into NCI-H292 cells. The effects of dexamethasone and erythromycin were observed in LPS-induced NCI-H292 cells. LPS incubation increased the expression of ER stress markers at the protein and mRNA levels. The knockout of MUC5AC in cells attenuated the increase in ER stress markers after incubation with LPS. Dexamethasone and erythromycin decreased caspase-3 activity in LPS-induced NCI-H292 cells.

LPS may activate ER stress through the overexpression of MUC5AC. Dexamethasone may protect human airway epithelial cells against ER stress-related apoptosis by attenuating the overload of MUC5AC.

Does multi-locus sequence typing of Salmonella enterica serovar Typhimurium isolates from wild birds in northern England suggest host-adapted strain?

Recent studies have suggested that Salmonella Typhimurium strains associated with mortality in UK garden birds are significantly different from strains that cause disease in humans and livestock and that wild bird strains may be host adapted. However, without further genomic characterization of these strains, it is not possible to determine whether they are host adapted. The aim of this study was to characterize a representative sample of Salm. Typhimurium strains detected in wild garden birds using multi-locus sequence typing (MLST)to investigate evolutionary relationships between them. Multi-locus sequence typing was performed on nine Salm. Typhimurium strains isolated from wild garden birds. Two sequence types were identified, the most common of which was ST568. Examination of the public Salmonella enterica MLST database revealed that only three other ST568 isolates had been cultured from a human in Scotland. Two further isolates of Salm. Typhimurium were determined to be ST19.

Results of MLST analysis suggest that there is a predominant strain of Salm. Typhimurium circulating among garden bird populations in the United Kingdom, which is rarely detected in other species, supporting the hypothesis that this strain is host adapted.

Is mir-17-92 cluster required for and sufficient to induce cardiomyocyte proliferation in postnatal and adult hearts?

Cardiomyocytes in adult mammalian hearts are terminally differentiated cells that have exited from the cell cycle and lost most of their proliferative capacity. Death of mature cardiomyocytes in pathological cardiac conditions and the lack of regeneration capacity of adult hearts are primary causes of heart failure and mortality. However, how cardiomyocyte proliferation in postnatal and adult hearts becomes suppressed remains largely unknown. The miR-17-92 cluster was initially identified as a human oncogene that promotes cell proliferation. However, its role in the heart remains unknown. To test the hypothesis that miR-17-92 participates in the regulation of cardiomyocyte proliferation in postnatal and adult hearts. We deleted miR-17-92 cluster from embryonic and postnatal mouse hearts and demonstrated that miR-17-92 is required for cardiomyocyte proliferation in the heart. Transgenic overexpression of miR-17-92 in cardiomyocytes is sufficient to induce cardiomyocyte proliferation in embryonic, postnatal, and adult hearts. Moreover, overexpression of miR-17-92 in adult cardiomyocytes protects the heart from myocardial infarction-induced injury. Similarly, we found that members of miR-17-92 cluster, miR-19 in particular, are required for and sufficient to induce cardiomyocyte proliferation in vitro. We identified phosphatase and tensin homolog, a tumor suppressor, as an miR-17-92 target to mediate the function of miR-17-92 in cardiomyocyte proliferation.

Our studies therefore identify miR-17-92 as a critical regulator of cardiomyocyte proliferation, and suggest this cluster of microRNAs could become therapeutic targets for cardiac repair and heart regeneration.

Is stroke volume increase to exercise in chronic obstructive pulmonary disease limited by increased pulmonary artery pressure?

This study was designed to investigate the mechanisms by which the right ventricle is able to increase stroke volume (SV) during exercise in chronic obstructive pulmonary disease (COPD). A second aim was to determine whether resting pulmonary artery pressure (Ppa) is predictive of exercise SV. 16 COPD patients (GOLD stages II-IV) underwent right heart catheterisation at rest and during exercise. In this group and eight age-matched controls resting and exercise right ventricular SV, end-diastolic volume (RVEDV) and end-systolic volume (RVESV) were assessed by magnetic resonance imaging (MRI). The exercise protocol during both measurements consisted of 3 minutes of cycling in supine position at 40% of maximal workload. In all patients mean Ppa increased significantly in response to exercise (21 (8) vs 33 (11) mm Hg, p<0.01), whereas pulmonary vascular resistance did not change. In the patient group, RVEDV (129 (42) vs 135 (42) ml, p<0.05) and SV (63 (13) vs 69 (14) ml, p<0.05) increased significantly from rest to exercise, but RVESV and RV ejection fraction remained unaltered. In contrast, in healthy controls SV is augmented (81 (22) vs 101 (28) ml, p<0.05) by both increased RVEDV (123 (33) vs 134 134) ml, p<0.05) and reduced RVESV (37 (9) vs 27 (10) ml, p<0.05). Resting mean Ppa was related to SV during exercise (r = -0.59, p<0.02).

As a consequence of unaltered pulmonary vascular resistance to exercise in COPD patients, Ppa increases and SV response to exercise is limited and results from an increased preload only. Ppa at rest predicts exercise SV.

Does symptomatic Reactivation of HSV Infection correlate with Decreased Serum Levels of TNF-α?

Herpes simplex viruses (HSV) are human pathogens that establish lytic and latent infections. Reactivation from latency occurs intermittently, which represents a life-long source for recurrent infection. The role of immune factors in the control of recurrent symptomatic HSV lesions is complex and the exact role of cytokines remains unclear. To assess the levels of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) along with anti-herpetic IgG and IgM, in the symptomatic reactivation of HSV infection. Thirty-six patients with recurrent symptomatic herpes infection were selected as the study group and thirty-two healthy individuals with no history of symptomatic labial herpes infection enrolled as the control group. Skin swabs were obtained from lip and skin lesions for viral culture. Confirmation of HSV cytopathic effect was carried out using PCR assay. The levels of TNF-α, IL-10, IgG and IgM were measured using ELISA. The level of TNF-α was significantly lower in individuals with recurrent symptomatic herpes infection in comparison with the controls (p=0.04). Also a significant elevation was observed in the levels of specific IgG in patients compared to controls (p<0.05).

The decreased level of TNF-α and increased levels of IgG in individuals with a history of symptomatic reactivation of HSV infection is suggestive of a probable shift in favor of the Th2 immune response.

Is regular aspirin-use preceding the onset of primary intracerebral hemorrhage an independent predictor for death?

Hematoma volume and impaired level of consciousness are the most potent predictors of outcome after spontaneous intracerebral hemorrhage (ICH). The effect of preceding aspirin-use on outcome after ICH is poorly investigated. We investigated short-term mortality and hematoma enlargement in subjects with ICH to find the predictors for these outcomes. This population-based study included all subjects with ICH during a period of 33 months in the population of Northern Ostrobothnia, Finland. The subjects were identified, and their clinical characteristics and outcomes were checked from hospital records or death records. Three-month mortality of the 208 identified subjects with ICH was 33%. The independent risk factors for death were regular aspirin-use at the onset of ICH (relative risks [RR], 2.5; 95% CI, 1.3 to 4.6; P=0.004), warfarin-use at the onset of ICH (RR, 3.2; 95% CI, 1.6 to 6.1; P=0.001), and ICH score higher than 2 on admission (RR, 13.8; 95% CI, 6.0 to 31.4; P<0.001). Regular aspirin-use preceding the onset of ICH associated significantly with hematoma enlargement during the first week after ICH (P=0.006).

We observed poor short-term outcomes and increased mortality, probably attributable to rapid enlargement of hematomas, in the subjects with ICH who had been taking regularly moderate doses of aspirin (median 250 mg) immediately before the onset of the stroke.

Do isotopic evidence for dietary niche overlap between barking deer and four-horned antelope in Nepal?

Morphologically similar sympatric species may have a high degree of niche overlap. Barking deer Muntiacus vaginalis and four-horned antelope Tetracerus quadricornis are solitary ungulates of the Indian sub-continent. Limited information is available regarding their trophic ecology, particularly of the endemic four-horned antelope. We present stable carbon (δ(13)C), nitrogen (δ(15)N), and sulphur (δ(34)S) isotopic values, and nitrogen content (%N) of faeces from barking deer and four-horned antelope living in lowland Nepal to assess trophic niche differentiation of these herbivores along the browser-grazer continuum. We also describe trophic differences between those two species in ecological niches and seasonal effects on their diets. We found that the barking deer and four-horned antelope consumed C3 plant sources exclusively. The niche partitioning in their diet was reflected by δ(34)S values. Some seasonal effects observed were: δ(13)C and δ(15)N were significantly lower in the dry season diet of four-horned antelope than that of barking deer, while δ(34)S values were significantly higher in the winter diet; monsoon diet was similar for both species. Faecal N levels for barking deer and four-horned antelope were similar throughout all the seasons, indicating that both species adapted their feeding behaviour so as to maximize protein intake, in accordance with season and environment.

Barking deer and four-horned antelope both are browsers; their dietary sources overlapped during monsoon but differed during the dry season. Conservation actions focused on resource management during the dry season to reduce food scarcity and competition over limited resources is likely to be the most effective.

Are both STAT1 and STAT3 favourable prognostic determinants in colorectal carcinoma?

Aberrant activities of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathways have been implicated in the development and spread of various cancer entities, among them colorectal carcinoma (CRC). Transcription factors STAT3 and STAT1, both downstream effectors of interleukin (IL)-6 and its receptor, are involved in growth and developmental control of CRC cells. Constituents of the signalling network around IL-6 and STAT activation are discussed as potential biomarkers and therapeutic targets in CRC. By immunohistochemical analysis of a tissue microarray covering >400 CRC biopsies, the expression and activity status of STAT1, STAT3 as well as of IL-6 and the IL-6 receptor α-chain was determined. The outcome was correlated with clinical information and patients' survival data. Colorectal carcinoma biopsies were also analysed for specific DNA-binding activity of STATs. Statistical analysis showed tendential associations between individual STATs, IL-6/IL-6 receptor-α and clinicopathological parameters. The study revealed a significant correlation of high STAT1 activity with longer patient overall survival. Surprisingly, strong STAT3 expression in surgical specimens was correlated with an increase in median overall survival by about 30 months. Statistical analysis revealed that high expression levels of STAT1 and STAT3 were associated. This finding was backed up by biochemical data that showed simultaneous STAT1 and STAT3 DNA-binding activity in randomly selected CRC biopsies.

By multivariate data analysis, we could show that STAT3 expression and activity constitutes an independent favourable prognostic marker for CRC.

Do physicians ' reports of their experience with health plan care management practices?

To determine the availability of care management practices in various practice settings, the degree to which physicians report that these practices are useful, and whether physicians' reports vary by their relationships with health plans. Cross-sectional survey. In 2001, we surveyed generalist and specialist physicians serving commercial, Medicaid, and Medicare patients. This report focuses on the responses of 2134 physicians (1252 generalists, 882 specialists) who contracted with independent practice associations and preferred provider organizations. Physicians were asked about the availability, accuracy, and usefulness of specified care management practices. The responses were analyzed according to their relationships with their health plan. Generalists, physicians with a higher percentage of health plan patients, and physicians who reported that health plans sought their views were more likely to report that they used care management practices. The majority who used these practices found them somewhat or very useful. Guidelines and disease management were among the most commonly available and most highly rated care management practices. Physicians' ratings of the usefulness of practice reports were associated with their perceptions of the reports' accuracy and with whether health plans sought their views on other aspects of the care management process.

The stronger a physician's relationship with a health plan, the more positive the physician's experience with care management practices and policies was. The concordance between the types of available practices and physicians' ratings suggests that health plans and physicians agree about how to improve the quality of care.

Does imatinib mesylate-incorporated nanoparticle-eluting stent attenuate in-stent neointimal formation in porcine coronary arteries?

The use of currently marketed drug-eluting stents (DES) presents safety concerns, including an increased risk for late thrombosis in the range of 0.6% per year in patients, including acute coronary syndrome, which is thought to result from delayed endothelial healing effects. A new DES system targeting vascular smooth muscle cells without adverse effects on endothelial cells is therefore needed. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of restenosis; therefore, we hypothesized that imatinib mesylate (PDGF receptor tyrosine kinase inhibitor) encapsulated bioabsorbable polymeric nanoparticle (NP)-eluting stent attenuates in-stent neointima formation. Effects of imatinib-incorporated NP-eluting stent on neointima formation and endothelial healing were examined in a pig coronary artery stent model. Effects of imatinib-NP were also examined in cultured cells. In a cultured cell study, imatinib-NP attenuated the proliferation of vascular smooth muscle cells associated with inhibition of the target molecule (phosphorylation of PDGF receptor-β), but showed no effect on endothelial proliferation. In a pig coronary artery stent model, imatinib-NP-eluting stent markedly attenuated in-stent neointima formation and stenosis by approximately 50% as assessed by angiographic, histopathological, and intravascular ultrasound imaging analyses. Imatinib-NP-eluting stent also attenuated MAP kinase activity, but did not affect inflammation and re-endothelialization.

These data suggest that suppression of neointima formation by a imatinib-NP-eluting stent holds promise as a molecular-targeting NP delivery system for preventing in-stent restenosis.

Does serum low-density lipoprotein cholesterol level predict hematoma growth and clinical outcome after acute intracerebral hemorrhage?

Lower serum low-density lipoprotein cholesterol (LDL-C) levels have been associated with increased risk of death after intracerebral hemorrhage (ICH). Nevertheless, their link with hematoma growth (HG) is unknown. Therefore, we aimed to investigate the relationship between LDL-C levels, HG, and clinical outcome in patients with acute ICH. We prospectively studied 108 consecutive patients with primary supratentorial ICH presenting within 6 hours from symptoms onset. National Institutes of Health Stroke Scale score and ICH volume on computed tomography scan were recorded at baseline and at 24 hours. Lipid profile was obtained during the first 24 hours. Significant HG was defined as hematoma enlargement >33% or >6 mL at 24 hours. Early neurological deterioration as well as mortality and poor long-term outcome (modified Rankin Scale score >2) at 3 months were recorded. Although LDL-C levels were not correlated with ICH volume (r=-0.18; P=0.078) or National Institutes of Health Stroke Scale score (r=-0.17; P=0.091) at baseline, lower LDL-C levels were associated with HG (98.1±33.7 mg/dL versus 117.3±25.8 mg/dL; P=0.003), early neurological deterioration (89.2±31.8 mg/dL versus 112.4±29.8 mg/dL; P=0.012), and 3-month mortality (94.9±37.4 mg/dL versus 112.5±28.5 mg/dL; P=0.029), but not with poor long-term outcome (109.5±31.3 mg/dL versus 108.3±30.5 mg/dL; P=0.875). Moreover, LDL-C levels were inversely related to the amount of hematoma enlargement at 24 hours (r=-0.31; P=0.004). In multivariate logistic regression analysis, LDL-C level <95 mg/dL emerged as an independent predictor of HG (OR, 4.24; 95% CI, 1.26-14.24; P=0.020), early neurological deterioration (OR, 8.27; 95% CI, 1.66-41.16; P=0.010), and 3-month mortality (OR, 6.34; 95% CI, 1.29-31.3; P=0.023).

Lower serum LDL-C level independently predicts HG, early neurological deterioration, and 3-month mortality after acute ICH.

Deep partial rotator cuff tear: transtendon repair or tear completion and repair?

The purpose of this study is to compare the clinical and subjective difference between transtendon repair or complete/repair in two homogeneous groups of patients affected by deep partial articular supraspinatus tear. Seventy-four patients were randomized in two groups of 37 patients each. The first group (A) was treated with arthroscopic transtendon repair while the second group (B) was treated with an arthroscopic completion of the tear and formal repair. All the patients were revaluated at a minimum 2 years of follow-up with Constant score and Visual Analogic Scale (VAS). Constant score improved by a mean value of 25 (95 % CI 21-28) (p<0.0001) and of 29 (95 % CI 26-31) (p<0.0001), respectively; VAS score decreased by a mean value of 3.4 (95 % CI 2.9-3.9) (p<0.0001) and of 3.6 (95 % CI 3.3-4.0) (p<0.0001), respectively. The improvement was higher in both groups for the ADL, and in Group B, the improvement in strength was higher than in Group A. There were no statistical differences between the two different techniques.

Both repairing techniques of deep partial supraspinatus tear provide good results in terms of function and pain. There were no statistically significant differences between the two techniques.

Do microRNA-206 and its down-regulation of Wilms'Tumor-1 dictate podocyte health in adriamycin-induced nephropathy?

Focal segmental glomerulosclerosis (FSGS) is a frequent and severe glomerular disease characterized by destabilization of podocyte foot processes. Emerging evidence suggests that microRNAs play crucial roles in podocyte homeostasis. The aim of the present study was to determine the role of miR-206 in podocyte injury and to elucidate the mechanisms responsible for the damage to podocyte. FSGS nephropathy model was induced by a single intravenous injection of Adriamycin (ADR) in BALB/c mice and the levels of proteinuria were measured on week of 1,3,5. The conditionally immortalized mouse podocyte cell line 5 was either transfected with microRNA mimics or negative control. Real-time PCR analysis was conducted to demonstrate the microRNA level in the glomeruli. Expression of Wilms' tumor-1 (WT1) and synaptopodin were detected by immunofluorescence and western blotting. The results revealed that miR-206 was up-regulated in ADR nephropathy mice, which led to severe podocyte injury and inhibited the expression of WT1 and synaptopodin. Using luciferase reporter assays, WT1 was identified as a target gene of miR-206. In vitro, over expression of miR-206 induced WT1 and synaptopodin degradation and actin rearrangement, initiating a catastrophic collapse of the entire podocyte-stabilizing system.

Over expression of miR-206 promotes podocyte injury via downregulation of WT1, which provides a new pathogenic mechanism for FSGS and miR-206 may be a potential therapeutic target.

Are postal questionnaire surveys of reported activity valid?

Postal questionnaire surveys are commonly used in general practice and often ask about self-reported activity. The validity of this approach is unknown.AIM: To explore the criterion validity of questions asking about self-reported activity in a self-completion questionnaire. A comparison was made between (a) the self-reported actions of all general practitioner (GP) principals in 51 general practices randomly selected within the nine family health services authorities of the former northern regional health authority, and (b) the contents of the medical records (case notes and computerized records) of patients classified as hypertensive from a 1 in 7 random sample of all patients registered in these practices and aged between 65 and 80. Data were gathered from the GPs by self-completion postal questionnaires. Six comparisons were made for two groups of items: first, target and achieved blood pressure; secondly, patient's weight, smoking status, alcohol consumption, exercise and salt intake. The frequency with which the data items were recorded in patient records was compared with the GPs' self-reported frequency of performing the actions. No relationship was found between achieved blood pressure and stated target levels. For each of the other actions, more than half of the responders reported that they usually or always performed the activity. For four of these (smoking, weight, alcohol and exercise), a significant association was noted, but the size of this varied considerably.

There is a variable relationship between what responders report that they do in self-completion questionnaires, and what they actually do as judged by the contents of their patients' medical records. In the absence of prior, knowledge of the validity of questions on reported activity, or of concurrent attempts to establish their validity, the questions should not be asked.

Can conclusions drawn from phantom-based image noise assessments be generalized to in vivo studies for the nonlinear model-based iterative reconstruction method?

Phantom-based objective image quality assessment methods are widely used in the medical physics community. For a filtered backprojection (FBP) reconstruction-based linear or quasilinear imaging system, the use of this methodology is well justified. Many key image quality metrics acquired with phantom studies can be directly applied to in vivo human subject studies. Recently, a variety of image quality metrics have been investigated for model-based iterative image reconstruction (MBIR) methods and several novel characteristics have been discovered in phantom studies. However, the following question remains unanswered: can certain results obtained from phantom studies be generalized to in vivo animal studies and human subject studies? The purpose of this paper is to address this question. One of the most striking results obtained from phantom studies is a novel power-law relationship between noise variance of MBIR (σ(2)) and tube current-rotation time product (mAs): σ(2) ∝ (mAs)(-0.4) [K. Li et al., "Statistical model based iterative reconstruction (MBIR) in clinical CT systems: Experimental assessment of noise performance," Med. Phys. 41, 041906 (15pp.) (2014)]. To examine whether the same power-law works for in vivo cases, experimental data from two types of in vivo studies were analyzed in this paper. All scans were performed with a 64-slice diagnostic CT scanner (Discovery CT750 HD, GE Healthcare) and reconstructed with both FBP and a MBIR method (Veo, GE Healthcare). An Institutional Animal Care and Use Committee-approved in vivo animal study was performed with an adult swine at six mAs levels (10-290). Additionally, human subject data (a total of 110 subjects) acquired from an IRB-approved clinical trial were analyzed. In this clinical trial, a reduced-mAs scan was performed immediately following the standard mAs scan; the specific mAs used for the two scans varied across human subjects and were determined based on patient size and clinical indications. The measurements of σ(2) were performed at different mAs by drawing regions-of-interest (ROIs) in the liver and the subcutaneous fat. By applying a linear least-squares regression, the β values in the power-law relationship σ(2) ∝ (mAs)(-β) were measured for the in vivo data and compared with the value found in phantom experiments. For the in vivo swine study, an exponent of β = 0.43 was found for MBIR, and the coefficient of determination (R(2)) for the corresponding least-squares power-law regression was 0.971. As a reference, the β and R(2) values for FBP were found to be 0.98 and 0.997, respectively, from the same study, which are consistent with the well-known σ(2) ∝ (mAs)(-1.0) relationship for linear CT systems. For the human subject study, the measured β values for the MBIR images were 0.41 ± 0.12 in the liver and 0.37 ± 0.12 in subcutaneous fat. In comparison, the β values for the FBP images were 1.04 ± 0.10 in the liver and 0.97 ± 0.12 in subcutaneous fat. The β values of MBIR and FBP obtained from the in vivo studies were found to be statistically equivalent to the corresponding β values from the phantom study within an equivalency interval of [ - 0.1, 0.1] (p<0.05); across MBIR and FBP, the difference in β was statistically significant (p<0.05).

Despite the nonlinear nature of the MBIR method, the power-law relationship, σ(2) ∝ (mAs)(-0.4), found from phantom studies can be applied to in vivo animal and human subject studies.

Are neuropeptide Y and Y2-receptor involved in development of diabetic retinopathy and retinal neovascularization?

Neuropeptide Y is a sympathetic neurotransmitter, a potent endothelium-derived angiogenic factor and a vascular mitogen. We have studied the role of the functional leucine7 to proline7 polymorphism of the signal peptide region of preproneuropeptide Y (prepro-NPY) as a genetic susceptibility factor for diabetic retinopathy. In addition, we investigated the role of the NPY Y2-receptor as a putative mediator of angiogenic NPY signaling in the retina. Frequencies of proline7 (Pro7) carriers in the prepro-NPY were determined in type 1 and type 2 diabetes patients having retinopathy, in type 2 diabetes patients without retinopathy and in healthy control subjects. The role of Y2-receptor in hyperoxemia-induced retinal neovascularization was investigated in Y2-receptor knockout mice (Y2-/-) and in rats administered Y2-receptor mRNA antisense oligonucleotide. The carriers having Pro7 in the preproNPY are markedly over-represented among type 2 diabetes patients with retinopathy compared to type 2 diabetes patients without retinopathy and to the population control. Neonatal exposure to hyperoxia resulted in development of retinal neovascularization that was prevented in Y2(-1-) -mice, and significantly inhibited in rats treated with the Y2-receptor antisense oligonucleotide.

NPY and Y2-receptor play important roles in diabetic retinopathy and retinal neovascularization and are thus potential new targets for drug molecules for treatment of retinopathy.

Is postmenopause associated with recurrence of differentiated papillary thyroid carcinoma?

Differentiated papillary thyroid carcinoma (D-PTC) is the most common malignancy arising in the thyroid gland. There are gender differences in the incidence of PTC being mainly observed in females. Low-risk groups consisted of men younger than 40-year-old and women younger than 50-year-old, whereas the high-risk group are older patients. We believe that age is not enough to explain the clinical course of this neoplasm and hypothesize that aggressive behavior of D-PTC may be correlated with hormonal status. Studies that support this idea showed that the follicular neoplastic cells had higher estrogen receptor-alpha in premenopausal (28.1+/-4.5) than in postmenopausal women (14.2+/-2.9). According to author's prior observations, there are evidences correlating recurrence of D-PTC with postmenopause in women. Postmenopause status is characterized by estrogen decrease and FSH increases both associated with EGFR activation. Previous observations identified EGFR over-expression in D-PTC of postmenopause when compared with premenopausal ladies.

Postmenopause is an adverse factor for tumor evolution in women with D-PTC and is associated with EGFR expression. It's introduction in thyroid tumor stratification could be a fine tuning in predicting papillary thyroid carcinoma behavior.

Does health-related quality of life worsen disproportionately to objective signs of psoriasis after withdrawal of adalimumab therapy?

Health-related quality of life (HRQoL) is an important part of the clinical assessment and management of psoriasis. Few studies have investigated the effects of withdrawing treatment on the relationship between HRQoL and objective clinical manifestations of psoriasis. This post hoc subanalysis of a clinical trial (REVEAL) examined the relationship of HRQoL [assessed with the Dermatology Life Quality Index (DLQI)] and objective disease activity [assessed with the Psoriasis Area and Severity Index (PASI)] among patients before and after they underwent protocol-mandated discontinuation of psoriasis therapy. Adult patients with moderate-to-severe plaque psoriasis who received adalimumab from baseline and had 75% or greater improvement in the PASI score at weeks 16 and 33 were re-randomized to adalimumab 40 mg or placebo every other week from weeks 33 to 52. DLQI and PASI scores were compared at baseline (week 0), early in treatment (week 4), directly before randomized withdrawal (week 33), and up to 19 weeks after treatment discontinuation (week 52; last observations carried forward). Correlations between DLQI total score and PASI score at week 4 and week 52 were modeled by linear regression. In the patients (N = 240) who underwent protocol-mandated discontinuation of psoriasis treatment after achieving PASI 75 response, mean PASI scores at week 52 were lower (i.e., better) compared with week 4, yet mean DLQI scores were higher (i.e., worse). An approximately twofold disproportionately greater degree of worsening of DLQI score compared with the degree of worsening of PASI was observed while patients underwent discontinuation of therapy (week 52) compared with early in treatment (week 4). There was a significant interaction (P < 0.0001) between the PASI-DLQI correlation and study period (week 4 or 52).

Discontinuing therapy in patients who initially responded to treatment, as seen in this analysis with adalimumab, disproportionately worsened patient-reported HRQoL relative to the worsening of PASI.

Are long-term safety and efficacy observed after implantation of Zotarolimus-Eluting stent in real-world clinical practice?

Zotarolimus-eluting stents (ZESs) have been shown to be safe and effective in randomised trials. We sought to report the clinical outcomes after implantation of ZES in real-world clinical practice. ZES have been approved for clinical use in Singapore since April 2005. Until December 31, 2007, a total of 219 patients had undergone implantation of ZES. After excluding 11 foreign patients with whom contact was lost, 208 patients (246 lesions, 305 stents) formed the study cohort. A high-proportion of diabetic patients (n=90, 43.3%) was included. Recommended dual antiplatelet therapy was at least 3 months (n=147) for patients treated before or 12 months (n=61) after January 2007. As of January 2008, the median follow-up duration was 19 months (range: 1 to 33 months). There were 10 (4.8%) deaths, including 7 (3.4%) cardiac deaths. Myocardial infarction occurred in 11 (5.3%) patients. The numbers of patients requiring target vessel revascularisation and target lesion revascularisation were 10 (4.8%) and 5 (2.4%) respectively. Using the ARC definition, there were two cases of definite stent thrombosis on days 7 and 17, and one case of probable stent thrombosis on day 15.

In this real-world clinical experience, ZES was associated with a low incidence of adverse cardiac events at a medium follow-up of one and half years.

Do effects of aerosolized class C fly ash in weanling goats?

To determine effects of repeated aerosol exposures to fly ash dust on respiratory tracts of tent-confined goats. 12 weanling Boer-Spanish crossbred goats. Goats were randomly assigned to 2 groups: fly ash treatment group (principal goats, n = 6) or control group (control goats, 6). Aerosolized fly ash dust was provided during a 4-hour period for each of 6 applications given over 3 months and one 2-hour application prior to necropsy. Fly ash particle diameters ranged from 0.1 to 130 microm and averaged 17.8 microm, with 1.5% of fly ash particles in the 0.1- to 5-microm-diameter range. A mean +/- SD of 748 +/- 152 g/treatment was delivered inside a tent containing principal goats; control goats were placed inside a similar tent for 4-hour treatments without dust. Following treatment, rectal temperatures were taken at 0, 4, 6, 8, 24, and 72 hours; Hcts were recorded at 0, 24, and 72 hours. Rectal temperatures were significantly increased at 4, 6, and 8 hours and decreased at 72 hours, compared with 0 hours. Mean +/- SEM Hct values were significantly increased for principal goats (3747 +/- 0.39%), compared with control goats (36.17 +/- 0.42%). A significant increase in the mean area of gross atelectatic lung lesions (1,410 mm2) was found in principal goats (n = 6), compared with control goats (440 mm2; 5).

An increase in atelectatic lung lesions was observed in principal goats, compared with control goats; however, overall, fly ash dust effects were nontoxic.

Does precollegiate Knee Surgery predict Subsequent Injury Requiring Surgery in NCAA Athletes?

The effect of precollegiate orthopaedic surgery on injury risk in the elite collegiate athlete is unknown. To (1) assess the relationship between precollegiate surgery and subsequent injury requiring surgery in National Collegiate Athletic Association (NCAA) Division I athletes at a single institution and (2) compare the risk of subsequent surgery in the ipsilateral versus contralateral extremity in those with a history of precollegiate surgery. Cohort study; Level of evidence, 3. A retrospective chart review was performed of all athletes who began participation from 2003 to 2009 until completion of eligibility. Athletes who received orthopaedic surgery in college were identified through the Sports Injury Monitoring System and were cross-referenced with medical records. The risk of orthopaedic surgery was evaluated using multivariate Cox and Poisson regression models, with sex and sport as additional covariates. Risk of subsequent surgery in the ipsilateral versus contralateral extremity was compared using Kaplan-Meier survival estimates and Cox proportional hazards regression. Hazard ratios (HRs) and rate ratios (RRs) with corresponding 95% confidence intervals were used to compare groups. In total, 1141 athletes were identified for analysis. Of these, 186 athletes (16.3%) had a history of precollegiate orthopaedic surgery. There were 261 documented intracollegiate orthopaedic surgeries in 181 athletes (15.9%). Precollegiate knee surgery was an independent predictor of orthopaedic surgery (HR, 1.85; 95% CI, 1.16-2.83) in college. When examining only surgeries resulting from acute or primary injuries, precollegiate knee surgery was an independent predictor of primary knee injury requiring surgery in college (HR, 4.45; 95% CI, 2.51-7.59). Athletes with a history of precollegiate surgery were more susceptible to subsequent surgery in their ipsilateral extremity compared with their other extremities (HR, 1.89; 95% CI, 1.03-3.53). In contrast, there was no additional risk of receiving subsequent surgery in the contralateral extremity (P = .54).

Precollegiate knee surgery in the Division I athlete is associated with subsequent injury requiring surgery in college. Athletes with a history of precollegiate surgery are at higher risk of subsequent surgery in their ipsilateral extremity compared with other extremities.

Do neuromagnetic responses to vowels vs. tones reveal hemispheric lateralization?

To evaluate whether a simple auditory paradigm could demonstrate a difference in cortical lateralization between right- and left-handed subjects. Such information would be important for later development of clinical noninvasive tests of hemispheric language dominance in candidates for brain surgery. Healthy subjects (10 strongly right-handed, 10 strongly left-handed, 5 weakly right-handed, and two ambidextrous) listened to binaural pairs of tones and pairs of Finnish vowels and decided whether the items in the pair were the same (target probability 20%). Cortical responses were recorded with whole-scalp magnetoencephalography. The laterality index for strengths of the auditory-cortex 100 ms responses (N100m) to vowels vs. tones suggested left-hemispheric dominance in 8 of the 10 strongly right-handed subjects, and right-hemispheric dominance in 7 of the 10 left-handed subjects.

Our results demonstrate difference in hemispheric dominance for processing of vowels between right-handed and left-handed subjects. This difference resembles language lateralization suggested by previous invasive studies as well as by anatomical and functional comparisons in left- and right-handed subjects.

Does prior use of angiotensin-converting enzyme inhibitors affect outcome in patients with intracerebral hemorrhage?

Angiotensin-converting enzyme inhibitors (ACEI) exert protective effects in patients with stroke but their effects remain unknown in patients with intracerebral hemorrhage (ICH). We recruited consecutive patients with acute ICH and analysed pre-admission demographic variables and drug therapy as well as clinical and radiological parameters. Functional and neurological outcomes were determined with the modified Rankin score (mRS) and the NIH Stroke Scale (NIHSS) score administered 90 days after ICH. Three hundred and ninety-nine patients were included over 6 years with a mortality rate of 47.3%. Before ICH, 130 patients (32.6%) used ACEI. ACEI-treated patients more often had vascular co-morbidities and were more frequently treated with anti-platelets. Admission NIHSS scores were significantly higher in ACEI-treated patients but 90 days NIHSS scores were not. Improvement from baseline NIHSS scores was significantly larger in ACEI-treated patients. Pre-ICH use of ACEI was not associated with lower mortality or better functional outcome on univariate analysis. On multivariable logistic regression analysis, controlling for possible confounding variables, ACEI use was not associated with increased chances for good outcome and failed to show an influence on mortality.

In conclusion, our study does not support a possible neuroprotective effect for ACEI use prior to the occurrence of ICH.

Does anterolateral Portal be Less Painful than Superolateral Portal in Knee Intra-Articular Injection?

Intra-articular knee injections are commonly performed in clinical practice for treating various knee joint disorders such as osteoarthritis and rheumatoid arthritis. When selecting the portal for injection, not only intra-articular needle accuracy but also procedural pain should be taken into consideration. The purpose of this study was to determine whether injection through anterolateral portal provokes less pain and provides better pain relief compared to superolateral portal. A total of 60 patients with primary osteoarthritis of the knee receiving intra-articular injections were randomized into 2 groups according to the type of portal approach; anterolateral or superolateral. All patients received hyaluronic acid (20 mg) and triamcinolone (40 mg) as the first injection followed by second and third injections of hyaluronic acid on a weekly basis. Underlying knee pain, procedural pain, and knee pain at 4 weeks were evaluated using visual analogue scale (VAS). Injection through anterolateral portal provoked less pain (VAS, 1.5±1.3) than the superolateral portal (VAS, 1.5 vs. 2.7; p=0.004). No differences were found in the degree of pain relief at weeks between the two groups (p=0.517).

We recommend the use of anterolateral portal for intra-articular knee injection as it provokes less pain and comparably short-term pain relief than the superolateral portal.

Do whole genome analyses suggest ischemic stroke and heart disease share an association with polymorphisms on chromosome 9p21?

Recently independent studies reported an association between coronary heart disease and single-nucleotide polymorphisms (SNPs) located at chromosome 9p21, near CDKN2A and CDKN2B genes. Given that stroke is a common complication after myocardial infarction, we investigated if the same SNPs were associated with ischemic stroke in our population. We recently initiated a whole genome analysis of ischemic stroke and published the first stage of a case control study using >400,000 SNPs from Illumina Infinium Human-1 and HumanHap300 assays. We focused on SNPs recently associated with heart disease by Helgadottir and colleagues and SNPs from the same haplotype block. In analyses both unadjusted and adjusted for stroke risk factors, significant associations with ischemic stroke were observed for SNPs from the same haplotype block previously associated with myocardial infarction. Significant association was also seen between disease and haplotypes involving these SNPs, both with and without adjustment for stroke risk factors (odd ratios: 1.01 to 2.65).

These data are important for 3 reasons: first, they suggest a genetic association for stroke; second, they suggest that this association shares pathogenic mechanisms with heart disease and diabetes; and third, they illustrate, that public release of data can facilitate rapid risk locus discovery.

Does andrographolide inhibit growth of acute promyelocytic leukaemia cells by inducing retinoic acid receptor-independent cell differentiation and apoptosis?

The growth inhibiting potential of andrographolide was evaluated in three acute promyelocytic leukaemia cell line models (HL-60, NB4 and all-trans retinoic acid (ATRA)-resistant NB4-R2). In elucidating the mechanisms of growth inhibition, a special emphasis was placed on assessing the induction of differentiation and apoptosis by andrographolide in the primary acute promyelocytic leukaemia NB4 cells. The compound was 2- and 3-fold more active in inhibiting the growth of HL-60 and NB4-R2 cells compared with NB4 cells, respectively. At IC50 (concentration at which growth of 50% of the cells (compared with medium only treated control cells) is inhibited; 4.5 microM) the compound exhibited strong cell-differentiating activity in NB4 cells, similar to ATRA (IC50 1.5 microM). In the presence of a pure retinoic acid receptor antagonist AGN193109, the growth inhibition of NB4 cells by ATRA was reversed, whereas the activity of andrographolide was not affected. This clearly suggested that andrographolide's cell differentiating activity to induce growth inhibition of NB4 cells most likely occurred via a retinoic acid receptor-independent pathway. At higher concentration (2xIC50), andrographolide was an efficient inducer of apoptosis in NB4 cells.

Taken together, these results suggest andrographolide and its derivatives, apparently with a novel cell differentiating mechanism and with ability to induce apoptosis, might be beneficial in the treatment of primary and ATRA-resistant acute promyelocytic leukaemia.

Do epilepsy patients treated with vigabatrin exhibit reduced ocular blood flow?

Reduced cerebral blood flow and decreased glucose metabolism have been identified in epilepsy patients receiving vigabatrin. It is likely that such a change may extend to the eye and may be linked to previously reported irreversible visual field defects. The aim of this study was to determine whether patients who have undergone anti-epileptic drug (AED) therapy with vigabatrin have altered ocular haemodynamics. The study cohort comprised 11 normal subjects (mean age 42.6 (SD 12.7) years and 17 epilepsy patients, of which 10 were either currently or previously treated with vigabatrin (38.6 (11.7) years) and seven were treated with AEDs excluding vigabatrin (46.0 (9.8) years). The three groups were matched at baseline for pulse rate, diastolic and systolic blood pressure, and intraocular pressure (IOP). At a single visit, the ocular blood flow analyser (OBFA; Paradigm Medical Instruments Inc, UT, USA) was used to measure pulsatile ocular blood flow (POBF) and pulse amplitude (PA) in each eye of all subjects. One way ANCOVA (with age as a covariate) was used to identify differences in POBF and PA between the groups. For the vigabatrin group only, Pearson's product moment correlation coefficient was used to explore potential interactions between ocular blood flow parameters and cumulative vigabatrin dose, duration, and maximum dose. Both the vigabatrin treated epilepsy group and conventionally treated epilepsy group exhibited significantly reduced POBF (p=<0.001, p=0.040) and PA (p=<0.001, p=0.005) compared to normal subjects. Patients treated with vigabatrin exhibited a further reduction in POBF (p=0.046) and PA (p=0.034) compared to conventionally treated epilepsy patients. No significant correlations were found between drug dosage and POBF and PA for the vigabatrin treated epilepsy group.

A significant reduction in POBF and PA is apparent in epilepsy patients treated with AEDs when compared to normal subjects. A further reduction in POBF and PA is apparent between vigabatrin treated and conventionally treated patients. The reduction in ocular perfusion, which is more pronounced in patients previously treated with vigabatrin, may have implications in the impairment of visual function associated with the drug.

Rural placements in Tasmania: do experiential placements and background influence undergraduate health science student's attitudes toward rural practice?

Each year growing numbers of undergraduate health science students, from a variety of disciplines, participate in a University of Tasmania Department of Rural Health supported rural placement program in Tasmania. This study aimed to investigate the influence rural placement and rural background had on students' intentions to live and work in a rural or remote location after graduation. Between January 2005 and December 2006, 336 students participated in the placement program. Students were requested to complete a survey at the completion of their placement. A response rate of 239 was achieved (71%). The survey measured students' stated rural career intentions and rural background status according to location of primary and secondary school attendance. A demographic analysis of respondents was undertaken and results cross tabulated according to the rural, remote and metropolitan area (RRMA) classification system. Statistical analyses, including paired t-tests and a Wilcoxon signed rank test, were conducted to compare reported mean intention to practise rurally both prior to and after placement. The results from this survey show that rural placements in the undergraduate health science programs have a predominantly positive influence on students' intention to work in a rural community post-graduation. While these findings were significant for the disciplines of nursing, medicine and allied health, the results were not significant for pharmacy students. Students' average intention to practise rurally significantly increased after the placement for students from RRMA classifications 1 and 3-5.

The value of rural placements as a method for increasing health science students' intentionality to take up rural practice as a positive and viable career option is considerable.

Is airway hyperresponsiveness associated with airway remodeling but not inflammation in aging Cav1-/- mice?

Airway inflammation and airway remodeling are the key contributors to airway hyperresponsiveness (AHR), a characteristic feature of asthma. Both processes are regulated by Transforming Growth Factor (TGF)-β. Caveolin 1 (Cav1) is a membrane bound protein that binds to a variety of receptor and signaling proteins, including the TGF-β receptors. We hypothesized that caveolin-1 deficiency promotes structural alterations of the airways that develop with age will predispose to an increased response to allergen challenge. AHR was measured in Cav1-deficient and wild-type (WT) mice 1 to 12 months of age to examine the role of Cav1 in AHR and the relative contribution of inflammation and airway remodeling. AHR was then measured in Cav1-/- and WT mice after an ovalbumin-allergen challenge performed at either 2 months of age, when remodeling in Cav1-/- and WT mice was equivalent, and at 6 months of age, when the Cav1-/- mice had established airway remodeling. Cav1-/- mice developed increased thickness of the subepithelial layer and a correspondingly increased AHR as they aged. In addition, allergen-challenged Cav1-/- mice had an increase in AHR greater than WT mice that was largely independent of inflammation. Cav1-/- mice challenged at 6 months of age have decreased AHR compared to those challenged at 2 months with correspondingly decreased BAL IL-4 and IL-5 levels, inflammatory cell counts and percentage of eosinophils. In addition, in response to OVA challenge, the number of goblet cells and α-SMA positive cells in the airways were reduced with age in response to OVA challenge in contrast to an increased collagen deposition further enhanced in absence of Cav1.

A lack of Cav1 contributed to the thickness of the subepithelial layer in mice as they aged resulting in an increase in AHR independent of inflammation, demonstrating the important contribution of airway structural changes to AHR. In addition, age in the Cav1-/- mice is a contributing factor to airway remodeling in the response to allergen challenge.

Do the reticulocyte maturation fractions and bone marrow reticulocyte count further help the classification of anemias?

Reticulocyte count plays a major role in anemic evaluation. The conventional method done by the manual supravital staining cannot subclassify the group of less than 2% of corrected reticulocyte count. The newly-developed flow cytometer provides different maturation fractions by measuring its fluorescent intensity. The reticulocytes are believed to shift to the circulation from the bone marrow earlier in more severe anemia. Therefore, the purpose of this study is to evaluate the role of reticulocyte maturation fractions and bone marrow reticulocyte in anemia classification. By using a fully automated counter, the roles of the reticulocyte with maturation and their shifting from bone marrow were evaluated in anemias. Different groups of subjects (243 in total) including aplastic, nutritional, and infiltrative anemias and anemia due to excess destruction and blood loss were studied. Each subject had bone marrow examination for morphologic diagnosis and reticulocyte evaluation. Both the absolute count and the maturation fractions of reticulocytes showed significant difference among marrow infiltration, aplastic anemia, and hemolytic anemia. Both the absolute reticulocyte count and less mature fractions were lowest in aplastic group. The marrow reticulocyte counts and shift ratio to circulating blood added little benefit in the classification of anemias.

The automated reticulocyte count with maturation fractions helps classify anemias, particularly for those with low reticulocyte count by the manual method.

Does inhibition of inducible nitric oxide synthesis ameliorate liver ischemia and reperfusion injury induced transient increase in arterial stiffness?

Hemodynamic instability is a frequent scenario after reperfusion of ischemic liver due to major liver resection and liver transplantation. Previously, we showed that liver ischemia/reperfusion (I/R) injury induced increases in reactive oxygen/nitrogen species and inducible nitric oxide synthase (iNOS) expression impaired cardiac contractility. In addition, nitric oxide (NO) generated via iNOS may have impacts on large arterial smooth muscle tone, causing transient changes in arterial stiffness and ventricular afterload. In this study, we aim to investigate associations between iNOS and transient alternation in arterial stiffness during liver I/R injury, and effects of treatments with 1,400W, a selective iNOS inhibitor, and L-NG nitroarginine methyl ester (L-NAME), a non-specific NOS inhibitor. The arterial stiffness is evaluated using the pulse wave velocity (PWV(2)), measured by finding the means of two high-fidelity micromanometers positioned at the aortic root and left femoral artery. Liver ischemia was conducted by occluding both the hepatic artery and portal vein for 30 minutes, followed by 120 minutes of reperfusion. Studies were performed on male Sprague-Dawley rats in four groups: a sham-operated group, a liver I/R group, and those groups pretreated with 1,400W (N-[3-(aminomethyl)benzyl]acetamidine) or L-NAME. Serum NO metabolites, tumor necrosis factor-α (TNF-α) and methylguanidine (MG) were measured at baseline, 30 minutes of ischemia, and 120 minutes of reperfusion. Post-reperfusion arterial stiffness increased by ∼14% as compared with the baseline, along with increases in serum NO metabolites, TNF-α, and MG level (P < .05); 1,400W and L-NAME treatment reduces post-reperfusion arterial stiffness by ∼5% similarly. Treatments with 1,400W and L-NAME both attenuated I/R induced increases in serum TNF-α, MG, and NO metabolites level (P < .05).

I/R-induced arterial stiffening was strongly associated with increased systemic inflammation. Comparable effects with treatments of 1,400W and L-NAME suggested that iNOS plays a dominant role in I/R-induced transient arterial stiffening.

Is dll4 in the DCs isolated from OVA-sensitized mice involved in Th17 differentiation inhibition by 1,25-dihydroxyvitamin D3 in vitro?

T helper 17 cell (Th17) cells play an important role in neutrophilic asthma, and 1,25(OH)2D3 has been reported to modulate the proliferation and differentiation of T cells. In this study, we examined the effects of 1,25(OH)2D3 on the dendritic cell (DC)-mediated regulation of Th17differentiation from OVA-sensitized mice. DCs were isolated from ovalbumin-sensitized mouse spleens. Lipopolysaccharide (LPS) was administered to stimulate the DCs for 24 h, and dexamethasone or 1,25(OH)2D3 was applied simultaneously. The expression of Notch ligand delta-like ligand 4 (Dll4) in the DCs was detected in each group. All the groups of treated DCs were co-cultured with T cells, and Dll4 was inhibited in these groups. After 24 h, Th17 and Treg cell differentiation and the IL-17A levels were measured. Dll4 expression was increased in LPS-treated DCs compared with the control group (p = 0.05), resulting in increased Th17 cell differentiation (p = 0.002). Treatment with 1,25(OH)2D3 inhibited the Dll4 expression(p = 0.04) and decreased Th17 cell differentiation (p = 0.001) in DCs that was induced by LPS. Directly inhibiting Dll4 reduced Th17 cell differentiation, and Th17 cell differentiation was not further inhibited by 1,25(OH)2D3 once Dll4 was blocked.

These result suggest that Dll4 in the DCs isolated from OVA-sensitized mice is involved in Th17 differentiation inhibition by 1,25(OH)2D3.

Does novel keratin preparation support growth and differentiation of odontoblast-like cells?

To fabricate a keratin hydrogel, characterize its functionality as a biomaterial and investigate the effects of keratin on growth and differentiation of odontoblast-like cells. Keratins were extracted from sheep wool using a well-established technique. The extracted proteins were purified by dialysis, quantified by gel electrophoresis, mass spectrometry, amino acid analysis and inductively coupled mass spectrometry. The microstructure of the fabricated keratin hydrogels was studied by scanning electron microscopy, flow characteristics by rheometer, hydrolytic stability and cytocompatibility by Live/Dead(®) cell assay. Furthermore, the influence of keratin on odontoblast-like cells (MDPC-23) was assessed to confirm their bioactivity at different dilutions. Cell proliferation was studied using alamarBlue(®) assay and differentiation by alkaline phosphatase enzyme activity, alizarin red staining and calcium quantification, reverse transcription polymerase chain reaction (rt-PCR) and immunocytochemical staining for dentine matrix protein- 1 (DMP-1) expression. anova with Tukey's tests was performed for statistical comparison. The characterized hydrogel was injectable with a highly porous architecture that underwent slow degradation, and its cytocompatibility was statistically equivalent to collagen hydrogel (P > 0.05). Cell proliferation and differentiation were enhanced at the optimal keratin concentration of 0.1 mg mL(-1) . At this concentration, the influence of keratin on cell differentiation was demonstrated by marked elevation in alkaline phosphatase activity (P < 0.05), calcium deposition (P < 0.01), gene expression (P < 0.01) and positive immunostaining for DMP-1.

The presence of keratin enhanced odontoblast cell behaviour. Keratin hydrogels may be a potential scaffold for pulp-dentine regen-eration.

Does serum killing of Ureaplasma parvum show serovar-determined susceptibility for normal individuals and common variable immuno-deficiency patients?

Many Gram-negative bacteria, unlike Gram-positive, are directly lysed by complement. Ureaplasma can cause septic arthritis and meningitis in immunocompromised individuals and induce premature birth. Ureaplasma has no cell wall, cannot be Gram-stain classified and its serum susceptibility is unknown. Survival of Ureaplasma serovars (SV) 1, 3, 6 and 14 (collectively Ureaplasma parvum) were measured following incubation with normal or immunoglobulin-deficient patient serum (relative to heat-inactivated controls). Blocking monoclonal anti-C1q antibody and depletion of calcium, immunoglobulins, or lectins were used to determine the complement pathway responsible for killing. Eighty-three percent of normal sera killed SV1, 67% killed SV6 and 25% killed SV14; greater killing correlating to strong immunoblot identification of anti-Ureaplasma antibodies; killing was abrogated following ProteinA removal of IgG1. All normal sera killed SV3 in a C1q-dependent fashion, irrespective of immunoblot identification of anti-Ureaplasma antibodies; SV3 killing was unaffected by total IgG removal by ProteinG, where complement activity was retained. Only one of four common variable immunodeficient (CVID) patient sera failed to kill SV3, despite profound IgM and IgG deficiency for all; however, killing of SV3 and SV1 was restored with therapeutic intravenous immunoglobulin therapy.

Only the classical complement pathway mediated Ureaplasma-cidal activity, sometimes in the absence of observable immunoblot reactive bands.

Can we predict which children with clinically suspected pneumonia will have the presence of focal infiltrates on chest radiographs?

To determine predictive factors for the presence of focal infiltrates in children with clinically suspected pneumonia in a pediatric emergency department. Children (1-16 years) with clinically suspected pneumonia were studied prospectively. The presenting features were compared between the children with and without focal infiltrates using chi2 analysis, t test, and odds ratio with 95% confidence intervals. A multivariate prediction rule was developed using logistic regression. A total of 570 were studied. Risk factors (odds ratio; 95% confidence interval) for the presence of focal infiltrates included history of fever (3.1; 1.7-5.3), decreased breath sounds (1.4; 1.0-2.0), crackles (2.0; 1.4-2.9), retractions (2.8; 1.0-7.6), grunting (7.3; 1.1-48.1), fever (1.5; 1.2-1.9), tachypnea (1.8; 1.3-2.5), and tachycardia (1.3; 1.0-1.6). We then used logistic regression to develop a candidate prediction rule for the variables of fever, decreased breath sounds, crackles, and tachypnea, which had an area under the receiver operating curve of 0.668. This rule had excellent sensitivity (93.1%-98%) yet poor specificity (5.7%-19.4%).

Multiple predictive factors for children with suspected pneumonia have been identified. Patients with focal infiltrates were more likely in our study to have a history of fever, tachypnea, increased heart rate, retractions, grunting, crackles, or decreased breath sounds. A multivariate prediction rule shows promise for the accurate prediction of pneumonia in children. However, the prospective evaluation of this multivariate prediction rule in a clinical setting is still required.

Does vagal nerve stimulation markedly improve long-term survival after chronic heart failure in rats?

Diminished cardiac vagal activity and higher heart rate predict a high mortality rate of chronic heart failure (CHF) after myocardial infarction. We investigated the effects of chronic electrical stimulation of the vagus nerve on cardiac remodeling and long-term survival in an animal model of CHF after large myocardial infarction. Two weeks after the ligation of the left coronary artery, surviving rats were randomized to vagal- and sham-stimulated groups. Using an implantable miniature radio-controlled electrical stimulator, we stimulated the right vagal nerve of CHF rats for 6 weeks. The intensity of electrical stimulation was adjusted for each rat, so that the heart rate was lowered by 20 to 30 beats per minute. The treated rats had significantly lower left ventricular end-diastolic pressure (17.1+/-5.9 versus 23.5+/-4.2 mm Hg, P<0.05) and higher maximum dp/dt of left ventricular pressure (4152+/-237 versus 2987+/-192 mm Hg/s, P<0.05) than the untreated rats. Improvement of cardiac pumping function was accompanied by a decrease in normalized biventricular weight (2.75+/-0.25 versus 3.14+/-0.22 g/kg, P<0.01). Although the 140-day survival of the untreated group was only half, vagal stimulation markedly improved the survival rate (86% versus 50%, P=0.008). Vagal stimulation therapy achieved a 73% reduction in a relative risk ratio of death.

Vagal nerve stimulation markedly improved the long-term survival of CHF rats through the prevention of pumping failure and cardiac remodeling.

Do statins influence platelet reactivity on acetylsalicylic acid therapy in patients with type 2 diabetes?

Type 2 diabetes (T2DM) patients are at increased risk of cardiovascular events despite long-term acetylsalicylic acid (ASA) therapy. This study was performed to establish the prevalence of high platelet reactivity (HPR) on ASA in T2DM and to identify its predictors. The study included 185 T2DM on chronic ASA therapy and to assess platelet reactivity during long-term ASA therapy, we applied the point-of-care method VerifyNow(®) aspirin test (Accumetrics, San Diego, CA, USA). Compared with the low platelet reactivity (LPR) group, patients with HPR had higher triglyceride levels (145 vs. 118 mg/dL, p = 0.041), were less frequently treated with statins (57.1% vs. 75.3%; p = 0.038) and tumor necrosis factor-alpha (TNF-α) concentrations were higher (2.15 vs. 1.74 pg/mL; p = 0.052). In a multivariate analysis only statin therapy (OR 0.375; 95% CI 0.15-0.91; P = 0.030) and lower concentrations of TNF-α (for each 1.0 pg/ml: or 1.3; 95% ci 1.00-1.72; p = 0.046) were predictive of LPR.

Our study provides indirect evidence that the beneficial effect of statins on platelet activity may be related to their non-lipid-mediated, pleiotropic mechanisms of action. This might have been partly related to decreased platelet reactivity in patients receiving statin therapy. In our study in patients with T2DM, platelet reactivity on ASA therapy measured with VerifyNow(®) was associated with TNF-α concentrations and statin therapy. These results may imply a role for subclinical systemic inflammation and a beneficial effect of statins in the development of HPR in T2DM.

Is hairdressing associated with scalp disease in African schoolchildren?

Anecdotal reports suggest that certain disorders are common in African hair and may be associated with hairstyles. A cross-sectional study of 1042 schoolchildren was performed to test this hypothesis. A questionnaire was administered and scalp examinations performed, after ethics approval. Participants included 45% boys and 55% girls. The majority of boys, 72.8%, kept natural hair with frequent haircuts (within 4 weeks). The prevalence of acne (folliculitis) keloidalis nuchae (AKN) was 0.67% in the whole group and highest (4.7%) in boys in the final year of high school, all of whom had frequent haircuts. The majority of girls (78.4%) had chemically relaxed hair, which was usually combed back or tied in ponytails, vs. 8.6% of boys. Traction alopecia (TA) was significantly more common with relaxed than natural hair, with an overall prevalence of 9.4% (98 of 1042) and of 17.1% in girls, in whom it increased with age from 8.6% in the first year of school to 21.7% in the last year of high school. The proportion with TA in participants with a history of braids on natural hair was lower (22.9%), but not significantly, than among those with a history of braids on relaxed hair (32.1%). No cases of central centrifugal cicatricial alopecia were identified.

We found associations between hairstyle and disease in our population of schoolchildren. AKN appears to be associated with frequently cut natural hair and TA with relaxed hair. These associations need further study for purposes of disease prevention.

Does cathepsin S deficiency confer protection from neonatal hyperoxia-induced lung injury?

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that adversely affects long-term pulmonary function as well as neurodevelopmental outcomes of preterm infants. Elastolytic proteases have been implicated in the pathogenesis of BPD. Cathepsin S (cat S) is a cysteine protease with potent elastolytic activity. Increased levels and activity of cat S have been detected in a baboon model of BPD. To investigate whether deficiency of cat S alters the course of hyperoxia-induced neonatal lung injury in mice. Newborn wild-type and cat S-deficient mice were exposed to 80% oxygen for 14 days. Histologic and morphometric analysis were performed and bronchoalveolar lavage protein and cells were analyzed. Lung elastin was assessed by real-time polymerase chain reaction, in situ hybridization, desmosine analysis, and Hart's stain. Distribution of myofibroblasts was analyzed by immunofluorescence. Hydroxyproline content of lung tissues was measured. Hyperoxia-exposed cat S-deficient mice were protected from growth restriction and had improved alveolarization, decreased septal wall thickness, lower number of macrophages, and lower protein concentration in bronchoalveolar lavage fluid. alpha-Smooth muscle actin-expressing myofibroblasts accounted for at least some of the increased interstitial cellularity in hyperoxia-exposed mouse lungs and were significantly less in cat S-deficient lungs. Lung hydroxyproline content was increased in hyperoxia-exposed wild-type, but not in cat S-deficient lungs. Desmosine content was significantly reduced in both genotypes with hyperoxia.

Cathepsin S deficiency improves alveolarization, and attenuates macrophage influx and fibroproliferative changes in hyperoxia-induced neonatal mouse lung injury.

Is eR stress in rodent islets of Langerhans concomitant with obesity and β-cell compensation but not with β-cell dysfunction and diabetes?

The objective of this study was to determine whether ER stress correlates with β-cell dysfunction in obesity-associated diabetes. Quantitative RT-PCR and western blot analysis were used to investigate changes in the expression of markers of ER stress, the unfolded protein response (UPR) and β-cell function in islets isolated from (1) non-diabetic Zucker obese (ZO) and obese female Zucker diabetic fatty (fZDF) rats compared with their lean littermates and from (2) high-fat-diet-fed fZDF rats (HF-fZDF), to induce diabetes, compared with age-matched non-diabetic obese fZDF rats. Markers of an adaptive ER stress/UPR and β-cell function are elevated in islets isolated from ZO and fZDF rats compared with their lean littermates. In islets isolated from HF-fZDF rats, there was no significant change in the expression of markers of ER stress compared with age matched, obese, non-diabetic fZDF rats.

These results provide evidence that obesity-induced activation of the UPR is an adaptive response for increasing the ER folding capacity to meet the increased demand for insulin. As ER stress is not exacerbated in high-fat-diet-induced diabetes, we suggest that failure of the islet to mount an effective adaptive UPR in response to an additional increase in insulin demand, rather than chronic ER stress, may ultimately lead to β-cell failure and hence diabetes.

Does lysophosphatidylcholine induce platelet-derived growth factor gene expression in a human mesangial cell line?

Oxidized low-density lipoprotein (oxLDL) has been considered important in the pathogenesis of progressive renal injury. Lysophosphatidylcholine (lysoPC) is a major phospholipid component of oxLDL. On the other hand, platelet-derived growth factor (PDGF) has also been implicated in proliferative disease of the kidney. This study investigated the difference in the potential of PC and lysoPC to induce DNA synthesis and PDGF gene expression in a human glomerular mesangial cell line (HMCL). DNA synthesis in HMCL was measured by [3H] thymidine incorporation. The mRNA expression levels of the PDGF A chain and B chain genes were measured using reverse transcription-polymerase chain reaction. LysoPC treatment up-regulated the [3H] thymidine incorporation level in a dose-dependent fashion. The [3H] thymidine incorporation level in HMCL coincubated with lysoPC started to increase after 4 hours of treatment, peaked at 24 hours, and decreased thereafter. The level in HMCL incubated with 100 microM of lysoPC (palmitoyl or stearoyl) increased to 7- or 10-fold of the control at peak time, respectively. However, PC treatment did not increase [3H] thymidine incorporation in HMCL. PC treatment did not induce mRNA expression of either PDGF A or B chain genes. LysoPC did not induce PDGF A chain mRNA expression either. The only B chain mRNA expression was induced by lysoPC. The mRNA expression level in HMCL treated with 50 microM lysoPC for two hours increased to 1.6-fold that of the control.

LysoPC may induce DNA synthesis in a mesangial cell through the induction of PDGF BB as an autocrine and paracrine growth factor.

Preoperative portal vein embolization: is it useful?

Portal vein embolization (PVE) before hepatectomy is aimed to induce an atrophy of the embolized lobe to be resected, with a compensatory hypertrophy of the counterlobe to be preserved. To answer the question "Is it useful?," we reviewed the clinical outcome in 161 patients undergoing major hepatectomy after PVE for various hepatobiliary tumors. All the patients tolerated PVE well, and hepatic functional data returned to the baseline levels within a week. The left liver volume increased by a median of 8% (range 2%-14%) after the right PVE. The 20 patients undergoing right hepatectomy for hepatocellular carcinoma had a mean indocyanine green retention rate at 15 min of 16% (SD 4%), and the 24 patients with liver metastases underwent right hepatectomy with additional left liver resection. Hepatectomy procedures comprised right or extended right hepatectomy (n=105), left or extended left hepatectomy (n=13), hepatopancreato duodenectomy (n=12), and less extensive hepatectomies (n=31). As a whole, the operative morbidity and mortality rates were 19% and 1.2%, respectively. Hepatopancreato duodenectomy carried no operative mortality. The cumulative 5-year survival rates were 44% in patients with hepatocellular carcinoma and 60% in patients with metastatic tumor.

PVE is useful for performing extensive hepatectomy in patients with mild hepatic dysfunction, in those with bilobar tumors, or in those undergoing hepatopancreato duodenectomy.

Are amniotic fluid interleukin-6 determinations of diagnostic and prognostic value in preterm labor?

The purpose of this study was to determine if amniotic fluid concentrations of the interleukin-6 (IL-6) are of value in diagnosis of microbial invasion of the amniotic cavity and in the prediction of failure of tocolysis, preterm delivery and perinatal morbidity and mortality. Amniotic fluid was obtained by transabdominal amniocentesis from 146 consecutive patients admitted with the diagnosis of preterm labor and intact membranes. Fluid was cultured for aerobic and anaerobic bacteria as well as for mycoplasmas. Amniotic fluid IL-6 levels were measured using a monoclonal antibody-based enzyme-linked immunosorbent assay with a sensitivity of 0.03 ng/ml. Logistic regression and Cox's proportional hazards model were used to examine the effect of several variables on dichotomous outcomes or interval to delivery. Patients with a positive amniotic fluid culture had a significantly higher amniotic fluid IL-6 concentrations than patients with a negative culture (median 91.2 ng/ml, range 0.9 to 437 ng/ml versus median 0.4 ng/ml, range < 0.3 to 195 ng/ml, respectively; P < .0001). An amniotic fluid IL-6 concentration of greater than or equal to 11.3 ng/ml had a sensitivity of 93.3% (14 of 15) and a specificity of 91.6% (120 of 131). All patients with an amniotic fluid IL-6 concentration above 11.3 ng/ml and a negative amniotic fluid culture (N = 11) delivered preterm and all placenta available for examination (N = 7) had histologic evidence of chorioamnionitis. Amniotic fluid concentrations of IL-6 were an independent predictor of preterm delivery, amniocentesis-to-delivery interval and neonatal morbidity and mortality. Moreover, IL-6 concentrations added significant information to the prediction of these outcomes to that provided only by clinical information such as cervical dilatation, gestational age at admission or at delivery.

IL-6 is a sensitive and rapid test for the detection of microbial invasion of the amniotic cavity and for identifying women at risk for spontaneous preterm delivery and neonates at risk for morbidity and mortality.

Does cannabidiol prevent cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism?

Cannabidiol has been reported to be a neuroprotectant, but the neuroprotective mechanism of cannabidiol remains unclear. We studied the neuroprotective mechanism of cannabidiol in 4-hour middle cerebral artery (MCA) occlusion mice. Male MCA occluded mice were treated with cannabidiol, abnormal cannabidiol, anandamide, methanandamide, cannabidiol plus capsazepine, and cannabidiol plus WAY100135 before and 3 hours after MCA occlusion. The infarct size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining). Cerebral blood flow (CBF) was measured at, before and 1, 2, 3, and 4 hours after MCA occlusion. Cannabidiol significantly reduced the infarct volume induced by MCA occlusion in a bell-shaped curve. Similarly, abnormal cannabidiol but not anandamide or methanandamide reduced the infarct volume. Moreover, the neuroprotective effect of cannabidiol was inhibited by WAY100135, a serotonin 5-hydroxytriptamine1A (5-HT1A) receptor antagonist but not capsazepine a vanilloid receptor antagonist. Cannabidiol increased CBF to the cortex, and the CBF was partly inhibited by WAY100135 in mice subjected to MCA occlusion.

Cannabidiol and abnormal cannabidiol reduced the infarct volume. Furthermore, the neuroprotective effect of cannabidiol was inhibited by WAY100135 but not capsazepine, and the CBF increased by cannabidiol was partially reversed by WAY100135. These results suggested that the neuroprotective effect of cannabidiol may be related to the increase in CBF through the serotonergic 5-HT1A receptor.

Does betulinic acid induce apoptosis through a direct effect on mitochondria in neuroectodermal tumors?

We identified BetA as a new cytotoxic agent active against neuroectodermal tumor cells including neuroblastoma, medulloblastoma, glioblastoma and Ewing sarcoma cells, representing the most common solid tumors of childhood. BetA induced apoptosis by a direct effect on mitochondria independent of accumulation of wild-type p53 protein and independent of death-inducing ligand/receptor systems such as CD95. Mitochondrial perturbations on treatment with BetA resulted in the release of soluble apoptogenic factors such as cytochrome c or AIF from mitochondria into the cytosol, where they induced activation of caspases. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L) that blocked loss of the mitochondrial membrane potential and cytochrome c release from mitochondria also conferred resistance to BetA. Most importantly, BetA exhibited potent antitumor activity on neuroblastoma cells resistant to CD95- or doxorubicin-triggered apoptosis and on primary tumor cells from patients with neuroectodermal tumors.

Thus, BetA may be a promising new agent in the treatment of neuroectodermal tumors including neuroblastoma in vivo.

Is albumin concentration determined by the modified bromocresol purple method superior to that by the bromocresol green method for assessing nutritional status in malnourished patients with inflammation?

The controlling nutritional status (CONUT) score (CS), a simple score for assessing nutritional status, is calculated using laboratory data, including serum albumin concentration. Although dye-binding assays such as the bromocresol green (BCG) and modified bromocresol purple (mBCP) methods are widely used for albumin measurement, acute-phase proteins interfere with the BCG method. We aimed to determine whether the choice of albumin assay affects assessment of nutritional status using CONUT scores (CSs). We measured serum albumin concentrations by the BCG (ALBBCG) and mBCP (ALBmBCP) methods in 44 malnourished inpatients, 27 of whom underwent nutritional intervention, and compared them to 30 age-matched healthy volunteers. In treated patients, CSs were calculated by ALBBCG (CS-BCG) and ALBmBCP (CS-mBCP). C-reactive protein (CRP) concentrations were positively correlated with the difference between ALBBCG and ALBmBCP in malnourished inpatients (r = 0.59, p < 0.001). CS-BCG was always lower than CS-mBCP (lower CS indicates superior nutritional status) in treated patients with persistently high CRP levels. However, in patients whose CRP decreased gradually, this difference diminished over the clinical course. CS-BCG and CS-mBCP were similar throughout their courses in patients with normal CRP concentrations. Adding haptoglobin to the human albumin solutions increased ALBBCG in a dose-dependent manner.

The choice of albumin assay affected the assessment of nutritional status using CSs in patients with inflammation. We recommend that the modified BCP assay be used to assess nutritional status, particularly in patients with inflammation.

Are lp-PLA2 activity and mass associated with increased incidence of ischemic stroke : a population-based cohort study from Malmö , Sweden?

Data regarding the association between lipoprotein-associated phospholipase A2 (Lp-PLA(2)) level and incidence of cardiovascular (CV) events are conflicting. This prospective urban population-based study explored the relationship between baseline Lp-PLA(2) activity and mass, respectively, levels and incidence of first coronary heart disease (CHD) and ischemic stroke, respectively. Lp-PLA(2) activity and mass were assessed in 5393 (60% women) subjects who participated in the Malmö Diet and Cancer Study cardiovascular program during 1991-1994. In all 347 subjects had an event (195 CHD and 152 ischemic strokes) during the follow-up period (mean 10.6+/-1.7 years). In an age-, sex- and CV risk factors-adjusted Cox regression analysis, comparing top to bottom tertile of Lp-PLA(2) activity, the relative risk [RR; 95% confidence interval (CI)] for incident CHD and ischemic stroke events were 1.48; 0.92-2.37 and RR: 1.94; 1.15-3.26, respectively. The corresponding figures for Lp-PLA(2) mass were 0.95; 0.65-1.40 and RR: 1.92; 1.20-3.10.

Elevated levels of Lp-PLA(2) activity and mass, respectively, were in this study, independently of established risk factors related to the incidence of ischemic stroke but after adjustment for lipids not significant related to incident CHD.

Are cytochrome P450 enzymes but not NADPH oxidases the source of the NADPH-dependent lucigenin chemiluminescence in membrane assays?

Measuring NADPH oxidase (Nox)-derived reactive oxygen species (ROS) in living tissues and cells is a constant challenge. All probes available display limitations regarding sensitivity, specificity or demand highly specialized detection techniques. In search for a presumably easy, versatile, sensitive and specific technique, numerous studies have used NADPH-stimulated assays in membrane fractions which have been suggested to reflect Nox activity. However, we previously found an unaltered activity with these assays in triple Nox knockout mouse (Nox1-Nox2-Nox4

the cytochrome P450 system accounts for the majority of the signal of Nox activity chemiluminescence based assays.

Does alpha-linolenic acid intake prevent endothelial dysfunction in high-fat diet-fed streptozotocin rats and underlying mechanisms?

Endothelial dysfunction is an important factor in the pathogenesis of diabetes related vascular complications, and acute alpha-linolenic acid (ALA) intake can increase flow-mediated dilation of the diabetic artery at 4 h postprandially. However, whether chronic ALA supplementation may prevent endothelial dysfunction in the process of diabetes and underlying mechanisms remains largely unknown. The high-fat diet-fed streptozotocin (HFD-STZ) rats provided an animal model for T2DM. Age-matched normal and HFD-STZ rats randomly received normal diet or ALA (500 mg/kg per day). After 5 weeks of feeding, endothelial function was determined. Diabetes caused significant endothelial dysfunction (maximal vasorelaxation responses to ACh) in aortic segments, and ALA intake alleviated endothelial dysfunction. Superoxide production and peroxynitrite (ONOO-) formation were reduced with ALA supplement in diabetic vascular segments. Interestingly, ALA intake enhanced eNOS but inhibited iNOS activity in diabetic vessels. Moreover, ALA intake significantly increased eNOS phosphorylation. On the other hand, gp91phox and iNOS overexpression were reduced moderately with ALA intake in diabetic vessels.

We concluded that ALA prevents diabetes-induced endothelial dysfunction by enhancing eNOS activity and attenuates oxidative/nitrative stress by inhibiting iNOS and NADPH oxidase expression and ONOO- production.

Is crinone vaginal gel equally effective and better tolerated than intramuscular progesterone for luteal phase support in in vitro fertilization-embryo transfer cycles : a prospective randomized study?

To compare the efficacy of Crinone vaginal gel and intramuscular progesterone (IMP) for luteal phase support in in vitro fertilization-embryo transfer (IVF-ET) with respect to pregnancy rates and outcomes, and to assess patient satisfaction with both products. Prospective randomized trial. University-affiliated IVF unit. Women under age 40 years with day-3 follicle-stimulating hormone levels <15 mIU/mL undergoing their first, second, or third IVF cycles on gonadotropin releasing-hormone (GnRH) down-regulation protocols. Luteal phase supplementation with either Crinone vaginal gel or IMP; phone survey regarding patient satisfaction with Crinone vaginal gel and IMP. Pregnancy rates, ongoing/delivered, failed pregnancy rates, and product satisfaction scores for patients supplemented with Crinone vaginal gel and with IMP. Four hundred sixty-eight patients were randomized, and 407 completed the study. The patients were randomized on the day of oocyte retrieval to receive either Crinone vaginal gel or IMP for luteal phase support. Pregnancy, ongoing/delivered, and failed pregnancy rates were similar between the Crinone and IMP treatment arms (OR [95% CI]: 1.2 [0.8, 1.8], 1.1 [0.8, 1.7], 1.0 [0.6, 1.7], respectively). On a scale of 1 to 5, patient satisfaction scores were statistically significantly higher with Crinone vaginal gel than with IMP (4.4 ± 0.9 vs. 2.8 ± 1.2).

Crinone vaginal gel and IMP are equally effective for luteal phase support in IVF, but Crinone is better tolerated by patients.

Do lower oxygen saturation alarm limits decrease the severity of retinopathy of prematurity?

To determine whether lowering oxygen saturation alarm limits for infants at risk for retinopathy of prematurity (ROP) reduces its incidence and/or severity. Oximetry alarm limits were lowered to 85% and 93% for all infants with a birth weight 1250 g or less and/or gestational age 28 weeks or less, and maintained until 32 weeks' postmenstrual age or until oxygen saturations were consistently greater than 93% in room air. The new policy was effective for infants born on or after June 1, 2003. ROP data were prospectively collected, and we compared the rate and severity of ROP in the year after the oximeter alarm policy change to the rates in the immediately preceding 3 years. In the year after the oximeter alarm limit policy change, 4 of 72 infants developed prethreshold ROP compared with 44 of 251 infants in the previous 3-year epoch (17.5% vs 5.6%, p=0.01). Similarly, only 6 of 144 eyes developed prethreshold ROP in the year after the policy change, compared with 84 of 502 in the previous 3 years (16.7% vs 4.2%, p=0.001).

A simple change in oximeter alarm parameters in the first weeks of life for infants with a birth weight 1250 g or less may decrease the incidence of prethreshold ROP.

Is sexual functioning impaired in adults with congenital heart disease?

To investigate the overall sexual functioning and disease specific sexual problems in congenital heart disease (ConHD) patients, for both genders and different cardiac diagnostic groups, and compare these with Dutch normative data. Also disease specific sexual problems were investigated. From a longitudinal cohort of patients, operated for ConHD between 1968 and 1980, 254 patients (median age: 40, 53.4% male) were included in this study: atrial septal defect (n = 72), ventricular septal defect (n = 71), pulmonary stenosis (n = 30), tetralogy of Fallot (n = 53) and transposition of the great arteries (n = 28). Patients completed internationally validated, generic questionnaires and also disease specific instruments on sexual functioning. Patients showed a delay in starting sexual activities compared with peers. Females with ConHD scored significantly worse compared with normative data on all scales of sexual functioning, indicating a broad range of sexual problems and 15% showed clinical levels of sexual dysfunction. Of the males, 14% suffered from erectile dysfunction. Males with ConHD scored worse on erectile function, orgasmic function and satisfaction regarding their sexual life compared with normative data. No differences were found between the different cardiac diagnoses. The majority of patients reported disease specific worries and fears about the use of contraceptives, heredity, pregnancy and delivery. Patients indicated to have been suboptimally informed about sexuality in early adolescence.

This study shows that sexual functioning is impaired in adults with ConHD. Providing information to patients about sexuality, pregnancy, delivery and heredity should be improved, and given at young age.

Does emergency department thrombolysis critical pathway reduce door-to-drug times in acute myocardial infarction?

Rapid time to treatment with thrombolytic therapy is an important determinant of survival in acute myocardial infarction (AMI). We hypothesized that establishment of an AMI thrombolysis critical pathway in the Emergency Department could successfully reduce the "door-to-drug" time, the time between patient arrival and start of thrombolysis. Before establishment of the AMI critical pathway, median door-to-drug time was 73 min, which was reduced to 37 min after critical pathway implementation (p < 0.05). The percentage of patients treated within 30 min rose from 0% prior to establishment of the pathway to 43% (p = 0.03). Similarly, the percentage treated in within 45 min rose from 0 to 67% (p = 0.0005). Door-to-drug times were longer for women than for men (median 105 min for women vs. 70 min for men before pathway implementation). The pathway reduced door-to-drug time for both genders, but the median door-to-drug times were higher for women than for men (Mann-Whitney p = 0.013). The difference between men and women was 35 min before establishment of the pathway to 10 min by the end of the study period.

Our critical pathway was successful in reducing door-to-drug times. We observed a "gender gap" in door-to-drug times, with longer mean times for women, which was reduced by the AMI critical pathway. Thus, our data provide support for the use of critical pathways to reduce door-to-drug times, as recommended by the National Heart Attack Alert Program.

Does cyclic adenosine monophosphate-independent tyrosine phosphorylation of NR2B mediate cocaine-induced extracellular signal-regulated kinase activation?

Activation of the extracellular signal-regulated kinase (ERK) in the striatum is crucial for long-term behavioral alterations induced by drugs of abuse. In response to cocaine, ERK phosphorylation (i.e., activation) is restricted to medium-sized spiny neurons expressing dopamine D1 receptor (D1R) and depends on a concomitant stimulation of D1R and glutamate N-methyl-D-aspartate receptor (NMDAR). However, the mechanisms responsible for this activation, especially the respective contribution of D1R and NMDAR, remain unknown. We studied striatal neurons in culture stimulated with D1R agonist and/or glutamate and wild-type or genetically modified mice treated with cocaine. Biochemical, immunohistochemical, and imaging studies were performed. Mice were also subjected to behavioral experiments. Stimulation of D1R cannot activate ERK by itself but potentiates glutamate-mediated calcium influx through NMDAR that is responsible for ERK activation. Potentiation of NMDAR by D1R depends on a cyclic adenosine monophosphate-independent signaling pathway, which involves tyrosine phosphorylation of the NR2B subunit of NMDAR by Src family kinases. We also demonstrate that the D1R/Src family kinases/NR2B pathway is responsible for ERK activation by cocaine in vivo. Inhibition of this pathway abrogates cocaine-induced locomotor sensitization and conditioned place preference.

Our results show that potentiation of NR2B-containing NMDAR by D1R is necessary and sufficient to trigger cocaine-induced ERK activation. They highlight a new cyclic adenosine monophosphate-independent pathway responsible for the integration of dopamine and glutamate signals by the ERK cascade in the striatum and for long-term behavioral alterations induced by cocaine.

Do treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer?

Recently, histology has emerged as a predictive factor for pemetrexed efficacy in non-small cell lung cancer (NSCLC). These analyses evaluate whether the differential efficacy of pemetrexed by NSCLC histology is reproducible and consistent across three registration studies of different lines of therapy (first-line/second-line and maintenance settings). The reported studies for patients with advanced NSCLC were pemetrexed versus docetaxel in previously treated patients (N = 571), cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (N = 1725), and maintenance pemetrexed plus best supportive care versus placebo plus best supportive care (N = 663). Cox models of overall survival (OS) and progression-free survival (PFS) were used to test for a significant treatment-by-histology interaction (THI). A significant THI indicates that the efficacy benefit for pemetrexed relative to the control arm is greater in patients with nonsquamous histology than in those with squamous histology. Subsequent Cox models were used to estimate hazard ratios for OS and PFS according to histology. Histology was well balanced between treatment arms in each study. Across all three studies, no clinically relevant differences were observed for the safety profile of pemetrexed among histologic groups. THIs were statistically significant in all three studies for OS (p = 0.001, 0.002, and 0.033, respectively) and PFS (p = 0.004, 0.002, and 0.036, respectively).

These analyses demonstrate a statistically significant interaction between treatment effect and NSCLC histology, indicating superior efficacy of pemetrexed in nonsquamous patients compared with other standard treatment options. Thus, histology is consistently predictive of the improved efficacy of pemetrexed in patients with nonsquamous NSCLC.

Can the C-14 urea breath test replace follow-up endoscopic biopsies in patients treated for Helicobacter pylori infection?

The C-14 urea breath test (UBT) is the most specific noninvasive test to detect Helicobacter pylori, with reported sensitivity and specificity rates of 90% and 95%, respectively. This test has not been evaluated for eradication after a therapeutic trial. The goal of this study was to assess the accuracy of C-14 UBT in the diagnosis and eradication of H. pylori infection in patients with duodenal ulcer who were treated with a triple drug regimen. Sixty patients with active duodenal ulcers who tested positive for the rapid urease test had a C-14 UBT at 0 weeks (at enrollment) and at 6 and 12 weeks using 5 microCi (185 KBq) of C-14 urea. A single breath sample was collected at 15 minutes for UBT. H. pylori was eradicated using lansoprazole and two antibiotics. Receiver operator characteristic curves showed that, using a value of 400 counts per minute (cpm), UBT had a sensitivity rate of 91%, specificity rate of 93%, positive predictive value of 77%, and a negative predictive value of 97% in the prediction of H. pylori eradication. The mean + 3 SD of H. pylori-negative patients was 380.1 cpm; at this cutoff value, the sensitivity and specificity rates were 91.3% and 92.8%, respectively.

The C-14 UBT was an accurate, rapid, and easily administered test to diagnose initial H. pylori infection and to monitor its eradication, thereby obviating the need for repeated endoscopic biopsies.

Does dietary restriction modify certain aspects of the postoperative acute phase response?

Lifespan extension is achieved through long-term application of dietary restriction (DR), and benefits of short-term dietary restriction on acute stress and inflammation have been observed. So far, the effects of short-term DR in humans are relatively unknown. We hypothesized that short-term DR in humans reduces the acute phase response following a well defined surgical trauma. Thirty live kidney donors were randomized between 30% preoperative dietary restriction followed by 1 d of fasting (n=17) or a 4 d ad libitum regimen (n=13) prior to surgery. Leukocyte subsets and numbers and serum cytokine levels were determined. Whole blood was stimulated with lipopolysaccharide (LPS) and cytokine production was determined. A clear trend towards lower numbers of postoperative circulating leukocytes was observed in the DR group. IL-8 serum levels were significantly higher in the DR group over the first 6 postoperative d (P=0.018). After LPS stimulation, significantly less TNF-α (P=0.001) was produced by blood obtained postoperatively compared with preoperative blood from the DR group. This was not observed in the control group.

A relatively short preoperative dietary restriction regimen was able to modify certain aspects of the postoperative acute phase response. These data warrant further studies into the dietary conditions that improve stress resistance in humans. (Dutch Trial Registry number: NTR1875).

Are secondary sexual coloration and CSF 5-HIAA correlated in vervet monkeys ( Cercopithecus aethiops sabaeus )?

Identifying indirect markers of the physiology or neuroendocrinology of a primate can provide a powerful tool to scientists. Anecdotal descriptions and recent experimental evidence suggests that the colorful sexual skin in adult male vervet monkeys (Cercopithecus aethiops sabaeus) might be sensitive to social changes, including dominance relationships, which could be related to serotonergic activity. The present study examined whether individual differences in scrotal coloration were related to cisternal cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid (CSF 5-HIAA) in a captive population of vervet monkeys. Darkly colored males had relatively higher CSF 5-HIAA concentrations than paler males, and scrotal color hue was also related CSF 5-HIAA concentrations.

These preliminary data are compatible with the hypothesis that scrotal coloration serves as an indirect marker of serotonergic activity. These findings suggest that color assessments might be useful to consider for study design, as well as for animal welfare and captive management.

Do results of pars plana vitrectomy after complicated phacoemulsification surgery?

To identify the causes and outcomes of pars plana vitrectomy (PPV) in patients undergoing phacoemulsification with intraoperative complication and to analyze whether the interval between phacoemulsification and PPV interferes with best-corrected final visual acuity. This descriptive and retrospective analytical study was conducted in Paraná Eye Hospital in 2013. Data were collected from medical records of 38 patients who underwent complicated phacoemulsification and also required PPV. The most frequent complication as a result of phacoemulsification was posterior capsule rupture, observed in 35 patients (92.10%), followed by capsular bag detachment, in three patients (7.89%). Twenty-eight patients (73.68%) had cortical fragments that were removed during PPV. Twelve patients (31.57%) had their intraocular lens repositioned. PPV was performed on the same day of phacoemulsification in one patient (2.63%), within 1 week in 15 patients (39.47%), between 1 week and 1 month in 13 patients (34.21%), and 1 month after phacoemulsification in 9 patients (23.68%).

This study is in agreement with worldwide literature, asserting that major complications of phacoemulsification are posterior capsule rupture and capsular bag detachment, and in addition, there is an improvement in the final visual acuity in almost half the cases, even when there are complications during modern cataract surgery, when complementary appropriate treatment is provided.

Does survival in Patients With Esophageal Adenocarcinoma Undergoing Trimodality Therapy be Independent of Regional Lymph Node Location?

The American Joint Committee on Cancer Cancer Staging Manual 7th Edition esophageal cancer staging was derived from outcomes of patients undergoing esophagectomy alone and eliminated nodal location from its schema. A limitation of this staging system is that it has not been validated in the setting of multimodality therapy for esophageal cancer. In addition, nodal location continues to influence treatment decisions. The aim of our study was to evaluate outcomes of patients with distal esophageal or gastroesophageal junction (GEJ) adenocarcinoma undergoing trimodality therapy and assess the effect of nodal location on survival. This multiinstitutional retrospective study assessed patients with clinically node-positive (cN+) distal esophageal/GEJ adenocarcinoma treated with trimodality therapy between January 2002 and December 2011. Nodal stations were classified as paratracheal, subcarinal, celiac, lower esophageal, paraaortic, supraclavicular, or perigastric/perihepatic. Overall survival (OS) was estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify variables associated with OS. A total of 196 cN+ patients met the study criteria. The most prevalent metastatic nodal location was in the perigastric region, present in 141 patients (72%); paratracheal nodal involvement was present in 19 patients (10%). None of the nodal stations was significantly associated with OS on univariable analysis. Multivariable analysis identified age (hazard ratio [HR], 1.036; p = 0.001), male sex (HR, 2.39; p = 0.003), pathologic ypT3 (HR, 1.81; p = 0.048), and ypN3 (HR, 2.93; p = 0.003) as being significantly associated with survival.

The location of cN+ regional node disease in patients with distal esophageal or GEJ adenocarcinoma was not predictive of survival after trimodality therapy. Age, sex, pathologic tumor depth, and the number of involved nodes were independent predictors of survival. Patients with cN+ cancers should not be deprived of potentially curative surgical resection based solely on the location of regional nodal disease.

Can Visual Field Progression be Predicted by Confocal Scanning Laser Ophthalmoscopic Imaging of the Optic Nerve Head in Glaucoma?

To determine whether confocal scanning laser ophthalmoscopic imaging (Heidelberg retinal tomography [HRT]) can predict visual field change in glaucoma. The study included 561 patients with glaucoma or ocular hypertension whose clinical course was followed at the Mount Sinai Faculty practice. Humphrey visual fields (HVFs) and HRT images were collected on one randomly selected eye per patient. Glaucoma progression was determined by the presence of two sequential statistically significant negative slopes in mean deviation (MD) or visual field index (VFI) at any point during the study period. Trend-based analysis on HRT parameters was used to determine progressive changes and whether these occurred before or after HVF change. Sensitivity and specificity of HRT to predict HVF change were calculated. HVF rate of change was correlated to the rate of change detected by HRT imaging. Approximately 17% of patients progressed by either MD or VFI criteria. MD and VFI correlated highly and identified overlapping sets of patients as progressing. HRT global parameters had poor sensitivity (∼42%) and moderate specificity (∼67%) to predict HVF progression. Regional stereometric parameters were more sensitive (69%-78%) but significantly less specific (24%-27%). Sensitivity of global stereometric parameters in detecting HVF change was not significantly affected by the level of visual field damage (P=.3, Fisher exact test). HVF rate of change did not correlate with rate of change of HRT parameters.

Trend-based analysis of HRT parameters has poor sensitivity and specificity in predicting HVF change. This may be related specifically to HRT imaging or may reflect the fact that in some patients with glaucoma, functional changes precede structural alterations.

Are skeletal muscle satellite cells located at a closer proximity to capillaries in healthy young compared with older men?

Skeletal muscle satellite cells (SC) are instrumental in maintenance of muscle fibres, the adaptive responses to exercise, and there is an age-related decline in SC. A spatial relationship exists between SC and muscle fibre capillaries. In the present study, we aimed to investigate whether chronologic age has an impact on the spatial relationship between SC and muscle fibre capillaries. Secondly, we determined whether this spatial relationship changes in response to a single session of resistance exercise. Muscle biopsies were obtained from the Type II muscle fibre SC and capillary content was significantly lower in the YM compared with OM (

We demonstrate that there is a greater distance between capillaries and type II fibre-associated SC in OM as compared with YM. Furthermore, quiescent SC are located significantly further away from capillaries than active SC after single bout of exercise. Our data have implications for how muscle adapts to exercise and how aging may affect such adaptations.

Does lactobacillus helveticus-fermented milk improve learning and memory in mice?

To investigate the effects of Calpis sour milk whey, a Lactobacillus helveticus-fermented milk product, on learning and memory. We evaluated improvement in scopolamine-induced memory impairment using the spontaneous alternation behaviour test, a measure of short-term memory. We also evaluated learning and working memory in mice using the novel object recognition test, which does not involve primary reinforcement (food or electric shocks). A total of 195 male ddY mice were used in the spontaneous alternation behaviour test and 60 in the novel object recognition test. Forced orally administered Calpis sour milk whey powder (200 and 2000 mg/kg) significantly improved scopolamine-induced cognitive impairments (P < 0.05 and P < 0.01, respectively) and object recognition memory (2000 mg/kg; P < 0.05).

These results suggest that Calpis sour milk whey may be useful for the prevention of neurodegenerative disorders, such as Alzheimer's disease, and enhancing learning and memory in healthy human subjects; however, human clinical studies are necessary.

Does curcumin disrupt uterine leiomyosarcoma cells through AKT-mTOR pathway inhibition?

Uterine leiomyosarcoma generally has an unfavorable response to standard chemotherapy. The loss of PTEN which results in constitutive AKT-mTOR activation causes an increase in leiomyosarcoma formation in mice. The active ingredient derived from the herb Curcuma longa, curcumin, shows antitumor properties in a variety of cancer cell lines by altering a number of oncogenic pathways. To explore the possibility of curcumin as an alternative to standard chemotherapy, we decided to investigate curcumin's antitumor effect on uterine leiomyosarcoma cells. Human leiomyosarcoma cell lines, SKN and SK-UT-1, were cultured for in vitro experiments. Rapamycin or curcumin was added in different doses and their effect on cell growth was detected by MTS assay. The influence of rapamycin or curcumin on AKT, mTOR, p70S6 and S6 phosphorylation and protein expression was detected by Western Blotting. The ability of rapamycin or curcumin to induce apoptosis was determined by Western blotting using cleaved-PARP specific antibody, Caspase-3 activity assay and TUNEL assay. Both rapamycin and curcumin significantly reduced SKN cell proliferation. Curcumin inhibited mTOR, p70S6 and S6 phosphorylation similar with rapamycin. Cleaved PARP, caspase-3 activity and DNA fragmentation increased proportional with curcumin concentration. At a high concentration, curcumin significantly induced apoptosis in SKN cells, but not rapamycin.

Curcumin inhibited uterine leiomyosarcoma cells' growth by targeting the AKT-mTOR pathway for inhibition. However, rapamycin, a specific mTOR inhibitor, did not induce apoptosis in SKN cells unlike curcumin that also has a pro-apoptotic potential in SKN cells.

Does obstetrician-assessed maternal health at pregnancy predict offspring future health?

We aimed to examine the association between obstetrician assessment of maternal physical health at the time of pregnancy and offspring cardiovascular disease risk. We examined this association in a birth cohort of 11,106 individuals, with 245,000 person years of follow-up. We were concerned that any associations might be explained by residual confounding, particularly by family socioeconomic position. In order to explore this we used multivariable regression models in which we adjusted for a range of indicators of socioeconomic position and we explored the specificity of the association. Specificity of association was explored by examining associations with other health related outcomes. Maternal physical health was associated with cardiovascular disease: adjusted (socioeconomic position, complications of pregnancy, birthweight and childhood growth at mean age 5) hazard ratio comparing those described as having poor or very poor health at the time of pregnancy to those with good or very good health was 1.55 (95%CI: 1.05, 2.28) for coronary heart disease, 1.91 (95%CI: 0.99, 3.67) for stroke and 1.57 (95%CI: 1.13, 2.18) for either coronary heart disease or stroke. However, this association was not specific. There were strong associations for other outcomes that are known to be related to socioeconomic position (3.61 (95%CI: 1.04, 12.55) for lung cancer and 1.28 (95%CI:1.03, 1.58) for unintentional injury), but not for breast cancer (1.10 (95%CI:0.48, 2.53)).

These findings demonstrate that a simple assessment of physical health (based on the appearance of eyes, skin, hair and teeth) of mothers at the time of pregnancy is a strong indicator of the future health risk of their offspring for common conditions that are associated with poor socioeconomic position and unhealthy behaviours. They do not support a specific biological link between maternal health across her life course and future risk of cardiovascular disease in her offspring.

Does novel small molecule α9α10 nicotinic receptor antagonist prevent and reverses chemotherapy-evoked neuropathic pain in rats?

Peripheral neuropathy is a common dose-limiting side effect of chemotherapy. There are no clinically proven analgesics for the treatment of this condition. Drugs from different classes have been tested with mixed results. Identification of novel molecular targets for analgesic(s) is important. Antagonism of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype (absent in brain) is thought to underlie analgesic efficacy of peptide α-conotoxins. We found novel nonpeptide small molecule analogs from a family of tetrakis-, tris-, and bis-azaaromatic quaternary ammonium salts (high potency with selectivity as antagonists at the α9α10 nAChRs) to produce dose-related analgesia in rat models of nerve injury-evoked neuropathy and persistent inflammatory pain. No tests were done in a model of neuropathy induced by drug administration (ie, chemotherapy). In this study, a lead bis-analog, ZZ1-61c, was characterized in a rat model of vincristine-evoked neuropathy. Male Sprague-Dawley rats were repeatedly dosed with the vinca-alkaloid, vincristine (100 μg/kg/day IP, days 1 to 5 and 8 to 12). ZZ1-61c (100 μg/kg/day IP) was given either along with or after completion of vincristine (commencing by day 15 when neuropathy was maximum). Responsiveness was assessed with von Frey hairs and the paw-pressure test. The effects of ZZ1-61c on motor function (rotarod) and muscle strength (grip test) were characterized in naïve rats. The development of neuropathy was demonstrated with repeated dosing of vincristine (pain hypersensitivity in response to mechanical stimulation). ZZ1-61c showed both preventive and restorative effects on this condition: (1) vincristine-evoked sensitivity to pressure was reduced by coadministration of ZZ1-61c; (2) established neuropathy was diminished by ZZ1-61c after cessation of chemotherapy. ZZ1-61c did not cause motor dysfunction (rotarod) or muscular weakness (the grip test).

This study suggests that ZZ1-61c, a novel compound with a unique mechanism of antagonistic action at the α9α10 nAChR, may be a potential drug candidate for prevention and attenuation of neuropathic pain resulting from chemotherapy. Such a strategy may provide effective treatment that circumvents toxicity of centrally acting agonists at nAChR.

Does heart rate turbulence after atrial premature complexes depend on coupling interval and atrioventricular nodal conduction?

Positive Turbulence onset (TO) after atrial premature complexes (APCs) was found temporally related to spontaneous episodes of atrial fibrillation. This study tested the hypothesis that heart rate turbulence (HRT) after APCs is influenced by APC prematurity independently of the prematurity of conducted ventricular complexes. We studied 33 patients (mean age = 58 +/- 16 years, 19 men), 11 of whom had structural heart disease, who were referred for electrophysiological studies of supraventricular or ventricular arrhythmias. Sequences of single right atrial extrastimuli were delivered with coupling intervals adjusted to reach 60% prematurity of conducted ventricular complexes. Descriptors of HRT were compared between patients with slow versus fast atrioventricular (AV) conduction of APCs. The early RR interval dynamics after APCs was prominently modulated by the suppression of sinus node automaticity by the direct effect of APCs. This effect was significantly greater after earlier APCs with longer AV conduction times than after later coupled APCs with shorter AV conduction times.

The early phase of HRT is strongly influenced by the coupling interval of APCs, independently of the prematurity of conducted ventricular complexes. Consequently, the more positive TO preceding spontaneous atrial fibrillation episodes might be an epiphenomenon of incidental short-coupled APCs with delayed AV conduction, likely to trigger atrial fibrillation.

Does hepatocyte growth factor promote liver regeneration and protein synthesis after hepatectomy in cirrhotic rats?

Hepatocyte growth factor, a potent mitogen for hepatocytes has been reported to be a hepatrophic factor in normal livers. In this study, the effect of exogenous hepatocyte growth factor on liver regeneration in cirrhotic rats was investigated, in vitro and in vivo. Liver cirrhosis was induced by intraperitoneal injections of an emulsion, carbon tetrachloride and olive oil, twice weekly for 10 weeks. In vitro, various amounts of exogenous hepatocyte growth factor; 0, 0.5, 1, 2.5, 5, and 10 ng/mL; were added to the hepatocytes isolated using in situ perfusion method. In vivo, partial hepatectomy (Hx), according to the procedure described by Higgins and Anderson, was performed on cirrhotic rats. Saline solution (control group) or 3 micrograms/kg of exogenous hepatocyte growth factor (HGF group) was then injected through the tail vein at intervals 12 hours after Hx. In vitro, DNA synthesis in hepatocytes obtained from cirrhotic livers increased following exogenous hepatocyte growth factor in dose-dependent fashion. In vivo, the labeling index of 5-bromo-2'-deoxyuridine at 24 hours after Hx was markedly increased by exogenous hepatocyte growth factor (control, 10.0 +/- 3.1%; hepatocyte growth factor, 25.8 +/- 9.8%; P < 0.01). Furthermore, serum albumin at 24 and 72 hours and a normotest at 24 hours after Hx, were significantly higher in the HGF group than in the control group.

These results indicate that exogenous hepatocyte growth factor may promote DNA synthesis and protein synthesis during liver regeneration after Hx with cirrhosis.

Does quantified corticospinal tract diffusion restriction predict neonatal stroke outcome?

Neonatal arterial ischemic stroke occurs in > or =1:4000 births. Many children experience motor deficits but acute predictors of outcome are lacking. Diffusion-weighted MRI changes in descending corticospinal tracts remote from arterial ischemic stroke may represent pre-Wallerian degeneration. We verify and quantify this signal and correlate it with motor outcome. Fourteen neonates with acute arterial ischemic stroke and > or =12 months follow-up with the Pediatric Stroke Outcome Measure were included. Quantitative measurements of descending corticospinal tracts diffusion-weighted MRI signal were developed using Image J software. Ipsilesional descending corticospinal tract diffusion-weighted MRI signal was abnormal in 10 neonates with decreased apparent diffusion coefficients (P<0.001). Poor outcome correlated with: (1) percentage of peduncle (P=0.002); (2) length of descending corticospinal tracts P<0.001); and (3) volume of descending corticospinal tracts (P=0.002). None of: (1) any peduncle; (2) any posterior limb of the internal capsule; or (3) infarct volume correlated with outcome. All children without descending corticospinal tracts signal had normal outcome. Chronic Wallerian degeneration was seen in all children with hemiparesis. Software-assisted analysis was superior to visual inspection with excellent reliability (intra-class correlation coefficient > or =0.9).

Descending corticospinal tracts diffusion-weighted MRI signal is predictive of motor outcome from neonatal arterial ischemic stroke. This accurate, reliable, and simple tool will impact decision making in acute neonatal stroke.

Do cell-cycle alterations underlie cyclophosphamide-induced teratogenesis in the chick embryo?

Cyclophosphamide (CP) embryotoxicity was documented in several studies on different experimental models. We investigate quantitatively the relationship between the embryotoxic effect of CP and the disturbance of the cell-cycle using flow cytometry. Chick embryos on Days 2-4 were treated with 0.5, 1, 2, 4, 8, and 16 microg doses of pure substance of CP by intraamniotic or subgerminal administration routes. Cell-cycle analysis was carried out in the brain, limb buds, hearts, and facial outgrowths dissected from the embryos 6 hr after administration. Samples of nuclear suspensions were obtained by enzymatic and mechanical disintegration of solid tissues in collagenase-dispase, followed by detergent and RNA-ase mediated cytolysis. Nuclei were stained by ethidium bromide. A dose-dependent increase of S-phase cells followed by decrement of G2M cell compartment was observed. The significant block of S-phase cells, however, was not always associated with malformations. The degree of cell-cycle disturbance was expressed more readily by the ratio G2M/S that demonstrated consistently the threshold character of both teratogenic and lethal effects.

CP-induced cytotoxicity manifested by dose-dependent disturbance of cell-cycle resulted in an overall depression of proliferation activity clearly associated with the occurrence of malformations and embryonic death. Although a non-significant depression of mitotic activity appeared sufficient to produce malformations on Day 2, remarkably deeper disturbance was needed to interfere with the development of the embryos in more advanced stages. Changes in proliferation rate appear to be a primary and most important event in teratogenesis induced by general toxic agents.

Is it ADEM, POLG, or both?

To describe a child with apparent brain biopsy-confirmed acute disseminated encephalomyelitis (ADEM) but genetic confirmation of compound heterozygosity for DNA mutations of the polymerase gamma (POLG) gene. Case report. Tertiary referral center. A 4-year-old boy presented with ataxia and encephalopathy. Magnetic resonance imaging demonstrated multiple focal areas of T2 prolongation. The patient's family refused steroid treatment. His symptoms improved then progressed. Magnetic resonance imaging findings also progressed. A cerebrospinal fluid specimen revealed myelin basic protein and oligoclonal bands. A brain biopsy specimen demonstrated demyelination, suggesting progression of ADEM. However, polymerase chain reaction amplification and sequencing revealed 2 heterozygous mutations of the POLG gene, suggesting mitochondrial disease. The patient died 9 months after his initial presentation.

This case raises interesting questions about whether ADEM triggered severe neurologic degeneration in a patient with mitochondrial disease, whether mitochondrial disease predisposed to a pathologic immune response, or whether mitochondrial disease can mimic an autoimmune disease. Mitochondrial disease-causing mutations may help explain the poor outcome in some cases of apparent autoimmune central nervous system disease.

Are rho/ROCK-dependent pseudopodial protrusion and cellular blebbing regulated by p38 MAPK in tumour cells exhibiting autocrine c-Met activation?

The c-Met-dependent, beta-actin-rich, blebbed pseudopodia of MSV-MDCK-INV (invasive Moloney-sarcoma-virus-transformed Madin-Darby canine kidney) cells are induced by Rho/ROCK (Rho kinase) activation, and are morphologically distinct from flat extended lamellipodia. Microtubules were shown to extend to these actin-rich pseudopodial domains, and microtubule depolymerization by nocodazole treatment resulted in progressive cellular blebbing, initiating in the pseudopodial domains and resulting in transient cellular rounding and blebbing after 30 min. The blebbing response was dependent on autocrine HGF (hepatocyte growth factor) activation of c-Met and prevented by inhibition of RhoA, ROCK and p38 MAPK (p38 mitogen-activated protein kinase), but not ERK (extracellular-signal-regulated kinase) or PI3K (phosphoinositide 3-kinase). Phospho-p38 MAPK was present in pseudopodia, localizing activation of this signalling pathway to this protrusive membrane structure. In serum-starved cells, LPA (lysophosphatidic acid) activation of RhoA induced p38 MAPK-dependent pseudopodial protrusions, and inhibition of p38 MAPK prevented pseudopodial protrusion and displacement of MSV-MDCK-INV cells. MSV-MDCK-INV cells exhibited intermittent blebbing and rounding, which may represent an integral part of their motile behaviour.

The localized activation of an autocrine HGF/c-Met loop regulates Rho/ROCK activation of p38 MAPK signalling to stimulate both membrane blebbing and pseudopod formation.

Does chronic Nicotine Treatment During Adolescence attenuate the Effects of Acute Nicotine in Adult Contextual Fear Learning?

Adolescent onset of nicotine abuse is correlated with worse chances at successful abstinence in adulthood. One reason for this may be due to enduring learning deficits resulting from nicotine use during adolescence. Previous work has indicated that chronic nicotine administration beginning in late adolescence (PND38) caused learning deficits in contextual fear when tested in adulthood. The purpose of this study was to determine if chronic nicotine treatment during adolescence would alter sensitivity to nicotine's cognitive enhancing properties in adulthood. C57BL/6J mice received saline or chronic nicotine (12.6mg/kg/day) during adolescence (postnatal day 38) or adulthood (postnatal day 54) for a period of 12 days. Following a 30-day protracted abstinence, mice received either an acute injection of saline or nicotine (0.045, 0.18, and 0.36mg/kg) prior to training and testing a mouse model of contextual fear. It was found that chronic nicotine administration in adult mice did not alter sensitivity to acute nicotine following a protracted abstinence. In adolescent mice, chronic nicotine administration disrupted adult learning and decreased sensitivity to acute nicotine in adulthood as only the highest dose tested (0.36mg/kg) was able to enhance contextual fear learning.

These results suggest that adolescent nicotine exposure impairs learning in adulthood, which could increase the risk for continued nicotine use in adulthood by requiring administration of higher doses of nicotine to reverse learning impairments caused by adolescent nicotine exposure.

Does calcification in major vessel beds relate to vascular brain disease?

Calcification in atherosclerotic plaques is a novel marker of atherosclerosis and is related to cardiovascular disease. However, its relationship with cerebrovascular disease has not been investigated extensively. We investigated the relationship between calcification in various vessel beds outside the brain and imaging markers of vascular brain disease. A total of 885 community-dwelling people (mean age, 66.7 years) underwent computed tomography of the coronary arteries, aortic arch, and extracranial and intracranial carotid arteries to assess arterial calcification. Brain magnetic resonance imaging scans were performed to assess cerebral infarcts, microbleeds, and white matter lesions (WMLs). Calcification in each vessel bed was associated with presence of cerebral infarcts and with larger WML volume. The most prominent associations were found between intracranial carotid calcification and WML volume and between extracranial carotid calcification and infarcts. Adjustment for cardiovascular risk factors or ultrasound carotid plaque scores did not change these results. No associations were found between calcification and cerebral microbleeds.

Arterial calcification in major vessel beds is associated with vascular brain disease on magnetic resonance imaging. Most notably, larger intracranial carotid calcification load relates to larger WML volumes, and larger extracranial carotid calcification load relates to the presence of cerebral infarcts, independently of ultrasound carotid plaque score. This suggests that calcification of atherosclerotic plaque yields other information in addition to merely the presence of plaques, providing novel insights into the etiology of vascular brain disease.

Is angiotensin converting enzyme-independent angiotensin ii production by chymase up-regulated in the ischemic kidney in renovascular hypertension?

Tissue angiotensin II (ANG II) levels are elevated in both kidneys in renovascular hypertension (RVH). It has been demonstrated previously that intrarenal ANG II is augmented by an angiotensin converting enzyme (ACE) dependent mechanism in the non-ischemic kidney, but the role of ACE-independent production of ANG II in the kidney by the enzyme chymase is unknown. This study tested the hypothesis that intrarenal chymase activity is up-regulated in RVH. A two-kidney, one-clip (2K1C) rat model was used to induce RVH (n = 6 rats/group). Regulation of intrarenal chymase activity by plasma ANG II was investigated using an ANG II-infusion model. At sacrifice 14 days post-operatively, steady-state ANG II levels in plasma and kidney were quantified by radioimmunoassay. ANG II production was quantified in kidney homogenates by incubating at 37 degrees C for 60 min with enzyme substrate (200 microm ANG I) alone or substrate containing the chymase inhibitor chymostatin. ANG II was separated and quantitated by HPLC. Chymase activity was defined as the fraction of ANG II production inhibited by Chymostatin. 2K1C and ANG II-infused rats developed significant hypertension, compared to control rats (P = 0.0001 and P = 0.001, respectively). Chymase-dependent ANG II production was increased in the ischemic kidney, but not the non-ischemic kidney, of 2K1C rats compared to control animals (*P < 0.05). Intrarenal chymase activity was unchanged by ANG II infusion (P = NS).

Chymase activity is up-regulated in the ischemic kidney of 2K1C rats. Plasma ANG II does not appear to regulate intrarenal chymase activity, suggesting that ischemia per se up-regulates chymase activity in the kidney. ACE-independent ANG II production by chymase may provide a mechanism for augmenting intrarenal ANG II in the ischemic kidney in RVH.

Do steroid users and the unique challenge they pose to needle and syringe program workers?

Needle and syringe programs (NSP), which provide sterile injecting equipment, are a cornerstone of Australia's drug harm reduction strategy and assist in reducing the spread of blood-borne virus infections, such as HIV and hepatitis C, among people who inject drugs. Some reports suggest that steroid users are an increasing proportion of clientele at NSPs. In this research, we investigate the experience of NSP workers who come into contact with people who use steroids and other performance- and image-enhancing drugs (PIED). Thirteen NSP workers were recruited using purposive sampling strategies. Participants were interviewed using a semi-structured interview guide. Interviews were recorded, transcribed and coded for themes. There are three key findings of this study. Firstly, NSP workers do not feel well informed about the substances that PIED users are injecting. Secondly, they were unsure what equipment PIED users required. Thirdly, PIED users were perceived to differ from other client groups, and these differences impacted upon the level of rapport staff could build with this group.

PIED users pose unique challenges for NSP workers compared with other NSP client groups. The PIEDs used and the way in which they are used are substantially different compared with other NSP clients, and there appears to be a lack of knowledge within the workforce about these substances. This study highlights the need to engage in workforce training, but also the need to more effectively engage with PIED users in relation to effective harm reduction strategies.

Does a novel tandem reporter quantify RNA polymerase II termination in mammalian cells?

Making the correct choice between transcription elongation and transcription termination is essential to the function of RNA polymerase II, and fundamental to gene expression. This choice can be influenced by factors modifying the transcription complex, factors modifying chromatin, or signals mediated by the template or transcript. To aid in the study of transcription elongation and termination we have developed a transcription elongation reporter system that consists of tandem luciferase reporters flanking a test sequence of interest. The ratio of expression from the reporters provides a measure of the relative rates of successful elongation through the intervening sequence. Size matched fragments containing the polyadenylation signal of the human beta-actin gene (ACTB) and the human beta-globin gene (HBB) were evaluated for transcription termination using this new ratiometric tandem reporter assay. Constructs bearing just 200 base pairs on either side of the consensus poly(A) addition site terminated 98% and 86% of transcription for ACTB and HBB sequences, respectively. The nearly 10-fold difference in read-through transcription between the two short poly(A) regions was eclipsed when additional downstream poly(A) sequence was included for each gene. Both poly(A) regions proved very effective at termination when 1100 base pairs were included, stopping 99.6% of transcription. To determine if part of the increased termination was simply due to the increased template length, we inserted several kilobases of heterologous coding sequence downstream of each poly(A) region test fragment. Unexpectedly, the additional length reduced the effectiveness of termination of HBB sequences 2-fold and of ACTB sequences 3- to 5-fold.

The tandem construct provides a sensitive measure of transcription termination in human cells. Decreased Xrn2 or Senataxin levels produced only a modest release from termination. Our data support overlap in allosteric and torpedo mechanisms of transcription termination and suggest that efficient termination is ensured by redundancy.

Does painting Qa-2 onto Ped slow preimplantation embryos increase the rate of cleavage?

Qa-2 protein, the Ped gene product, is linked to the cell surface by a glycosylphosphatidylinositol (GPI) anchor. Some GPI-linked proteins can be spontaneously incorporated into the membranes of cells via a technique called "protein painting."We investigated whether Qa-2 could be painted onto T cells and embryos and whether the painted protein would be functional. Incorporation of Qa-2 into the membranes of T cells and embryos was measured by FACScan and Immuno-PCR, respectively. Function of Qa-2 was measured by cell proliferation. Qa-2 was incorporated by T cells and embryos and was functional.

GPI-linked Qa-2 protein "painted" onto both T cells and preimplantation embryos is functional, as shown by increased proliferation of T cells after cross-linking with anti-Qa-2 antibody, and increased rate of cleavage division of the embryos.

Do telomerase activity in primary and secondary glioblastomas multiforme as a novel molecular tumor marker?

Telomerase activity is responsible for cell immortality. To examine the role of telomerase in the carcinogenesis of human glioblastomas multiforme (GBMs), the authors studied telomerase activity, telomerase component expression, and telomere lengths in 42 GBM samples. In all samples, EGFR and MDM2 amplifications and overexpressions were examined using Southern and Northern blot analyses. The p53 mutation was analyzed using polymerase chain reaction-single strand conformational polymorphism and by direct sequence analysis. Specimens of tissues were immunostained with p53, EGFR, and MDM2 antibodies. Allelic loss on chromosomes 17p and 10 was assessed by loss of heterozygosity (LOH) assays. Telomerase activity, expression of its components (human telomerase reverse transcriptase [hTERT], human telomerase RNA component [hTERC], and telomerase-associated protein [TEP1]), and telomere lengths were analyzed using the telomeric repeat amplification protocol (TRAP)-hybridization protection assay, reverse transcription-polymerase chain reaction, and Southern blot analysis. According to the results of assessments of EGFR and MDM2 amplifications, p53 mutation, LOHs in chromosomes 17p and 10, and the clinical course of the disease, the 42 samples were classified into 22 primary and 20 secondary glioblastomas. Twenty-six (61.9%) of all 42 samples demonstrated detectable telomerase activity during the TRAP assay. Secondary GBMs displayed significantly higher levels of telomerase activity and hTERT expression than primary GBMs. Tumors with a p53 gene mutation demonstrated significantly higher telomerase activity than those without a p53 mutation. Four samples with a codon 175 mutation demonstrated an exceptionally high amount of telomerase activity. In secondary GBMs, the increase in telomerase activity and the hTERT expression level correlated with the increased frequency of p53 mutations. There was no significant difference in telomere length between primary and secondary GBMs.

These results suggest that telomerase activity and p53 mutations both play important roles in the multistep carcinogenesis of GBMs. Telomerase activity and hTERT expression may be considered as novel distinctive factors in human GBMs.

Do a new device in immediately loaded implant treatment in the edentulous mandible?

This article reports preliminary clinical results of the Speed Master system, a method for immediate loading of implants for the treatment of mandibular edentulism. Fifteen patients with edentulous mandibles were consecutively included in the study. Each received 4 implants between the mental foramina placed using the system's surgical guides. Permanent fixed prostheses fabricated over premanufactured titanium bars were attached to the implants on the day of implant placement. The patients were followed for 15 to 27 months (mean, 19 months). Peri-implant tissues were periodically evaluated. Marginal bone loss was monitored with periapical radiographs using a computerized technique. Satisfaction was assessed by means of a questionnaire. The overall implant and prosthetic survival rates were 100%. At the time of the final follow-up visit, mean marginal bone loss was 1.11 mm, and bleeding on probing was not observed. Only 6.7% of the patients reported any discomfort during treatment, and all patients would recommend the procedure to others.

The immediate loading of implants placed in the edentulous mandible with the Speed Master surgical and prosthetic protocol reduces treatment time and number of surgical procedures in comparison to classic delayed loading protocols.

Does thromboxane A2 induce blood flow recovery via platelet adhesion to ischaemic regions?

Thromboxane A2 (TXA2) induces platelet adhesion through thromboxane prostanoid (TP) receptor. Platelets contain many pro-angiogenic factors and are recruited to the site of vascular injury. However, the cellular and molecular mechanisms of platelet-dependent angiogenesis, especially the involvement of TP signalling, have not been fully elucidated. The present study hypothesized that TP-dependent platelet adhesion would contribute to angiogenesis in a mouse hindlimb ischaemic model. Blood flow recovery was suppressed by the TXA2 receptor antagonist (S-1452) and the TXA2 synthase inhibitor (OKY-046) compared with control mice. TP knockout mice (TP(-/-)) showed delayed blood flow recovery from ischaemia and impaired angiogenesis compared with wild-type (WT) mice and prostacyclin receptor knockout mice (IP(-/-)). Selective platelet adhesion to ischaemic endothelial cells (ECs) via P-selectin was identified in WT and IP(-/-), but not in TP(-/-), via in vivo microscopy. IF analysis showed that P-selectin glycoprotein ligand-1 (PSGL-1) co-localized with endothelial CD31 in ischaemic muscle in WT and IP(-/-) but not diminished in TP(-/-). Platelet-rich plasma levels of stromal cell-derived factor-1 and VEGF were increased after ischaemia in WT, and suppressed by antibody against P-selectin in WT but not in TP(-/-). Furthermore, the blood flow recovery was suppressed by neutralizing antibodies against VEGF or C-X-C chemokine receptor type 4 in WT and IP(-/-) but not in TP(-/-).

These results indicated that TP signalling facilitates ischaemia-induced angiogenesis via P-selectin-mediated platelet adhesion to PSGL-1 on the ECs at ischaemic sites and the supply of pro-angiogenic factors by the adherent platelets.

Is synuclein-γ ( SNCG ) expression in ovarian cancer associated with high-risk clinicopathologic disease?

Synuclein gamma (SNCG) expression is associated with advanced disease and chemoresistance in multiple solid tumors. Our goal was to determine if SNCG protein expression in ovarian cancer was correlated with clinicopathologic variables and patient outcomes. Tissue microarrays from primary tumors of 357 ovarian, fallopian tube, and primary peritoneal cancer patients, who underwent primary surgery at Roswell Park Cancer Institute between 1995 and 2007, were immunohistochemically stained for SNCG. A pathologist blinded to patient data scored tumors as positive if ≥10 % of the sample stained for SNCG. Medical records were reviewed for clinicopathologic and demographic variables. Between the positive and negative groups, Wilcoxon rank-sum test was used to compare the median ages and Fisher's exact test was used to compare groups in categorical variables. Cox proportional hazard models examined associations between SNCG and overall and progression-free survival. The median follow-up was 36 months, median overall survival was 39 months, and median progression-free survival was 18 months. SNCG presence was associated with clinical variables of serous histology, grade 3 disease, suboptimal debulking, ascites at surgery, FIGO stage III-IV cancer, or initial CA-125 level >485. There was no significant difference in overall survival (HR 1.06 95 % CI 0.81-1.39 P 0.69) or progression-free survival (HR 1.16 95 % CI 0.89-1.50 P 0.28) for patients with or without SNCG expression.

SNCG expression in ovarian cancer is frequent in patients with high-risk features, but it does not correlate with chemotherapy response, overall survival, or progression-free survival.

Does procalcitonin biomarker kinetics fail to predict treatment response in perioperative abdominal infection with septic shock?

Procalcitonin (PCT) biomarker is suggested to tailor antibiotic therapy in the medical intensive care unit (ICU) but studies in perioperative medicine are scarce. The aim of this study was to determine whether PCT reported thresholds are associated with the initial treatment response in perioperative septic shock secondary to intra-abdominal infection. This single ICU, observational study included patients with perioperative septic shocks secondary to intra-abdominal infection. Demographics, PCT at days 0, 1, 3, 5, treatment response and outcome were collected. Treatment failure included death related to the initial infection, second source control treatment or a new onset intra-abdominal infection. The primary endpoint was to assess whether PCT thresholds (0.5 ng/ml or a drop from the peak of at least 80%) predict the initial treatment response. We included 101 consecutive cases. Initial treatment failed in 36 patients with a subsequent mortality of 75%. Upon admission, PCT was doubled when treatment ultimately failed (21.7 ng/ml ± 38.7 vs. 41.7 ng/ml ± 75.7; P = 0.04). Although 95% of the patients in whom PCT dropped down below 0.5 ng/ml responded to treatment, 50% of the patients in whom PCT remained above 0.5 ng/ml also responded successfully to treatment. Moreover, despite a PCT drop of at least 80%, 40% of patients had treatment failure.

In perioperative intra-abdominal infections with shock, PCT decrease to 0.5 ng/ml lacked sensitivity to predict treatment response and its decrease of at least 80% from its peak failed to accurately predict treatment response. Studies in perioperative severe infections are needed before using PCT to tailor antibiotic use in this population.

Is a novel role for APOBEC3 : susceptibility to sexual transmission of murine acquired immunodeficiency virus ( mAIDS ) aggravated in APOBEC3 deficient mice?

APOBEC3 proteins are host factors that restrict infection by retroviruses like HIV, MMTV, and MLV and are variably expressed in hematopoietic and non-hematopoietic cells, such as macrophages, lymphocytes, dendritic, and epithelia cells. Previously, we showed that APOBEC3 expressed in mammary epithelia cells function to limit milk-borne transmission of the beta-retrovirus, mouse mammary tumor virus. In this present study, we used APOBEC3 knockout mice and their wild type counterpart to query the role of APOBEC3 in sexual transmission of LP-BM5 MLV - the etiological agent of murine AIDs (mAIDs). We show that mouse APOBEC3 is expressed in murine genital tract tissues and gametes and that genital tract tissue of APOBEC3-deficient mice are more susceptible to infection by LP-BM5 virus. APOBEC3 expressed in genital tract tissues most likely plays a role in decreasing virus transmission via the sexual route, since mice deficient in APOBEC3 gene have higher genitalia and seminal plasma virus load and sexually transmit the virus more efficiently to their partners compared to APOBEC3+ mice. Moreover, we show that female mice sexually infected with LP-BM5 virus transmit the virus to their off-spring in APOBEC3-dependent manner.

Our data indicate that genital tissue intrinsic APOBEC3 restricts genital tract infection and limits sexual transmission of LP-BM5 virus.

Does low dose aminophylline effectively decrease the risk of post-operative apnea in premature infants?

Retinopathy of prematurity (ROP) is the most common reason behind surgical procedures in premature newborns. Anesthesia in these patients is life-threatening due to post-operative apnea of prematurity (POA). This study aimed to determine the predisposing factors to POA in premature infants and to explore the role of prophylactic aminophylline in decreasing the incidence of POA. Fifty patients with prematurity who were candidates for elective eye surgery (less than one hour) were selected and received aminophylline (3 mg/kg) 5 minutes after the induction of anesthesia with sevoflurane. Patients were kept in the recovery room for 2 hours post-operation in an incubator and were monitored for SPO2, apnea, bradycardia and other signs of desaturation and apnea. There were no statistically significant differences in the gestational age and weight, sex, postconceptual age and weight and other demographic characteristics between the experimental and control groups. Gestational age<28 weeks, postconceptual age<60 weeks, birth weight, operation weight and anemia (OR=1.91; 95% CI: 1.24-3.73; P=0.012) were the predisposing factors associated with postoperative apnea. Treatment with aminophylline as compared with the placebo was associated with a significantly decreased risk of post-operative apnea (OR=0.53; 95% CI 0.28-0.98; P=0.034).

Aminophylline can be used prophylactically to decrease the risk of postoperative apnea with no major adverse effects.

Is use of complementary and alternative medicine by cancer patients associated with perceived distress or poor compliance with standard treatment but with active coping behavior : a survey?

Complementary and alternative medicine (CAM) is often used by cancer patients. Data on characteristics of users, concomitant psychologic disturbance, and compliance with standard treatment continue to be controversial. Use of and interest in CAM and their correlation with psychologic disturbance, ways of coping with illness, and compliance with standard treatment were examined in this study. The authors conducted a survey in a consecutive sample of 205 cancer patients undergoing radiotherapy, using a structured questionnaire to record use of and interest in CAM, the Hospital Anxiety and Depression Scale, the Hornheide Questionnaire to assess patient distress and social support, and the Freiburg Questionnaire of Coping with Illness. Of the 172 participants, 24.4% (response rate, 83.9%) reported use of CAM, and 31.4% reported not having used but being interested in such methods. Logistic regression analysis including clinical, demographic, and psychologic characteristics as independent variables yielded 3 predictors of use of or interest in CAM: younger age (P = 0.004; odds ratio (OR), 0.96), progressive cancer (P = 0.064; OR, 1.47), and active coping behavior (P = 0.016; OR, 1.65). Patients interested in or using CAM did not show more psychologic disturbance, poorer social support, or less trust in medicine or compliance with radiotherapy than subjects without such interest.

Use of CAM by cancer patients is not associated with perceived distress or poor compliance with medical treatment but with active coping behavior. Patients seem to consider CAM as supplementary to standard medical methods and one way of avoiding passivity and of coping with feelings of hopelessness.

Does lens-specific expression of PDGF-A in transgenic mice result in retinal astrocytic hamartomas?

To investigate the possibility that platelet-derived growth factor (PDGF) might regulate aspects of mouse retinal development in vivo. In situ hybridization was used to study the expression patterns of PDGF-A and PDGF-B and their receptors during normal mouse eye development. Transgenic mice that express human PDGF-A in the lens under the control of alpha A-crystallin promoter were generated by pronuclear microinjection. The effects of PDGF overexpression on eye development were analyzed by ocular histology, immunohistochemistry and in situ hybridizations. The PDGF genes are expressed by cells in close contact with retinal astrocytes. The PDGF-A messenger RNA is upregulated in the retinal ganglion neurons after birth, and PDGF-B is expressed by the blood vessel cells in the hyaloid vasculature. The authors found that lens-specific expression of PDGF-A in the eye can induce hyperplasia of retinal astrocytes, which express PDGF-alpha receptor (PDGF-alpha R) during development. The retinal alterations in the PDGF-A transgenic mice closely resemble the retinal astrocytic hamartomas found in human tuberous sclerosis (TSC) disease.

These findings suggest that proliferation of retinal astrocytes is regulated by PDGF during normal eye development. The authors speculate that proliferation of retinal astrocytes is mediated through a PDGF signaling pathway, which may involve the TSC gene product.

Does retinol dehydrogenase 13 protect the mouse retina from acute light damage?

To investigate whether retinol dehydrogenase 13 (RDH13) can protect the retina from acute light-induced damage. We generated Rdh13 knockout mice using molecular biologic methods and assessed the associated morphological and functional changes under room-light conditions by hematoxylin-eosin (H&E), transmission electron microscopy (TEM), and scotopic electroretinography. Then, the light-damage model was established by exposure to diffuse white light (3,000 lx) for 48 h. Twenty-four h after light exposure, H&E was used for the histological evaluation. The thickness of the outer-plus-inner-segment and the outer nuclear layer was measured on sections parallel to the vertical meridian of the eye. An electroretinography test was performed to assess the functional change. Furthermore, the impairment of mitochondria was detected by TEM. Finally, the expression of cytochrome c (CytC) and other apoptosis-related proteins was detected by western blot. We found that there was no obvious difference in phenotype or function between Rdh13 knockout and wild-type mice. In Rdh13(-/-) mice subjected to intense light exposure, the photoreceptor outer-plus-inner-segment and outer nuclear layer were dramatically shorter, and the amplitudes of a- and b-waves under scotopic conditions were significantly attenuated. Distinctly swollen mitochondria with disrupted cristae were observed in the photoreceptor inner segments of Rdh13(-/-) mice. Increased expression levels of CytC, CytC-responsive apoptosis proteinase activating factor-1 (Apaf-1) and caspases 3, and other mitochondria apoptosis-related genes (nuclear factor-kappa B P65 [P65] and B-cell lymphoma 2-associated X protein [Bax]) were observed in Rdh13(-/-) mice.

Rdh13 can protect the retina against acute light-induced retinopathy. The mechanism may involve inhibition of the mitochondrial apoptosis pathway.

Is fetuin-A/alpha2-Heremans-Schmid glycoprotein associated with the metabolic syndrome in patients with chronic kidney disease?

Components of the metabolic syndrome are highly prevalent in chronic kidney disease (CKD) patients--some of which paradoxically appear to predict an improved outcome in this population. We hypothesized that the circulating calcification inhibitor fetuin-A/AHSG, which is also a natural inhibitor of the tyrosine kinase insulin receptor, could be one factor explaining the association between increased fat mass and a survival advantage in CKD and thus conducted an explorational study to provide preliminary data to support further research into this hypothesis. In a cross-sectional study, we evaluated 198 CKD stage 5 patients (GFR 6.8 +/- 0.2 ml/min; 62% males, mean age 52 +/- 1 years) close to the start of renal replacement therapy. We studied circulating AHSG (ELISA) and two common functional AHSG gene polymorphisms (at amino acids Thr248Met (C-T) and Thr256Ser (C-G) using Pyrosequencing) and related these to multiple components of the metabolic syndrome. Median circulating AHSG was lower (p<0.01) in type-2 (0.22 g/l) and type-1 (0.16 g/l) diabetics as compared to non-diabetic CKD-5 patients (0.24 g/l). AHSG correlated with both total and truncal fat mass in type-2 diabetics (rho 0.37 and 0.39; p<0.001, respectively), but not in type-1 diabetics or non-diabetics. Both SNPs significantly influenced circulating levels of AHSG, and were also associated with significant differences in serum triglycerides and HDL cholesterol. Furthermore, there were significant differences in the prevalence of metabolic syndrome criteria between the AHSG Thr256Ser (C-G) genotype groups, with a more atherogenic lipid profile in AHSG high producers (Thr/Thr homozygotes). In multivariate analysis, the association between circulating AHSG and fat mass remained significant also after adjustment for age, gender, inflammation (CRP>10 mg/l), and AHSG genotype.

The present, explorational, study supports further, mechanistic, studies into a physiological link between AHSG and body fat mass in patients with CKD. As we observed an association between higher fat mass and elevated AHSG levels, these preliminary results may form the basis of further study to establish if the observed associations may be one reason why obesity has been reported to constitute a survival advantage in CKD.

Is chronic Cystoisospora belli infection in an immunocompetent Myanmar refugee - microscopy sensitive enough?

Cystoisosporiasis is an opportunistic infection seen more commonly in patients with acquired immunodeficiency syndrome. Although uncommon, Cystoisospora infection can occur in immunocompetent individuals but tend to be benign and self-limiting. Chronic infection however, has been described but diagnosis can often be challenging and requires a high clinical index of suspicion. We present a case of delayed diagnosis of Cystoisospora belli (C. belli) in an immunocompetent 28-year-old refugee from Myanmar. She had a history of chronic diarrhea where exhaustive investigations over many years failed to reveal a diagnosis. Cystoisospora belli cysts were finally detected in stool 4 years after investigation commenced, and PCR testing on stored colon biopsies amplified a molecular product with 99 % sequence homology to C. belli. The patient improved promptly with trimethoprim-sulfamethoxazole treatment.

In the appropriate clinical context we suggest molecular testing for C. belli or an empirical therapeutic trial.

Are common two-dimensional echocardiographic estimates of aortic linear dimensions interchangeable?

To compare two echocardiographic methods of measuring aortic diameter in short-axis projections. Right-parasternal short-axis 2-dimensional projections of the left atrium and aorta were obtained from dogs and cats undergoing routine cardiac evaluation. Two investigators measured the aortic valve linear dimension using 2 methods: along the commissure between the non-coronary and right-coronary cusps and along the commissure between the non-coronary and left-coronary cusps. Inter-observer and intra-observer variability and agreement were assessed by comparing blinded measurements with each method by 4 trained observers on a standardized set of images. Measurements were compared for agreement using the limits of agreement analysis. Variability between observers was compared by examining residuals and intraclass correlation. 274 canine and 100 feline aortic valve images were measured in the first part of the study. One observer demonstrated slight proportional bias, while the other observer showed more variability (less agreement). When results were pooled for both investigators, no bias was identified, and 95% limits of agreement were ±10% of the mean measurement for both species. In the second part of the study, 106 images were measured. Intraobserver variability was <4% for all observers. Inter-observer agreement was very high. Individual bias was identified in some observers, but was considered clinically inconsequential. Normalized differences between the 2 methods of measurement were below ±15% of the measured value for all observers.

Our results show sufficient agreement between two common methods used to measure aortic linear dimensions to suggest that these methods are interchangeable.

Does overexpression of CD9 in human breast cancer cells promote the development of bone metastases?

Bone is a preferred target for circulating metastatic breast cancer cells. We found that the CD9 protein was up-regulated in the B02 osteotropic cell line, derived from the aggressive parental MDA-MB-231 breast cancer cell line. Here, we investigated the putative relationship between CD9 expression and the osteotropic phenotype. Overexpression of CD9 was analyzed by immunoblotting in different cell lines. Immunohistochemistry was used to assess CD9 expression in primary tumors and metastatic lesions. In vivo experiments were conducted in mice using a monoclonal antibody against CD9. CD9 overexpression was confirmed in osteotropic cells. CD9 was significantly overexpressed in bone metastases versus primary tumors and visceral metastatic lesions. Finally, in vivo experiments showed that an antibody against CD9 delays homing of B02 cells in bone marrow, slowing down bone destruction.

Our study reveals a potential implication of CD9 in the formation of bony metastases from breast cancer cells.