bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of cGMP phosphodiesterase 5 suppresses matrix metalloproteinase‐2 production in pulmonary artery smooth muscles cells
Authors: Sun Xiu‐Zhen , Li Zong‐Fang , Liu Yun , Fang Ping , Li Man‐Xiang
Published: September 2009

1. It has been shown that the beneficial effects of phosphodiesterase (PDE) 5 inhibition on pulmonary hypertension (PH) are associated with the induction of vascular relaxation and suppression of the proliferation of pulmonary artery smooth muscle cells (PASMC). In the present study, we investigated whether PDE5 inhibition affects the production and/or secretion of matrix metalloproteinases (MMPs) in PASMC, resulting in extracellular matrix remodelling in the pulmonary vasculature and, thus, the development of PH.

2. Primary cultured PASMC were stimulated with endothelin (ET)‐1 and MMP‐2 production and RhoA activation were then determinded using gelatin zymography and a GTP‐bound RhoA assay, respectively. The effects of the selective PDE5 inhibitor sildenafil and subsequent protein kinase G‐specific inhibitor Rp‐8Br‐cGMPs on MMP‐2 production and RhoA activation were further exmamined.

3. Endothelin‐1 (1–1000 nmol/L) concentration‐dependently stimulated MMP‐2 production and/or secretion in primary cultured PASMC, with 100 nmol/L ET‐1 causing a 2.41‐fold increase in MMP‐2 production compared with control (P < 0.01). This increase in MMP‐2 production was accompanied by RhoA activation, which was abolished by preincubation of cells with 10 μmol/L Y27632, an inhibitor of Rho‐associated kinase (ROCK). Furthermore, 10 μmol/L Y27632 abolished the ET‐1‐induced production of MMP‐2.

4. The selective PDE5 inhibitor sildenafil (0.1–1 μmol/L) concentration‐dependently reduced the increased MMP‐2 production induced by 100 nmol/L ET‐1. Specifically, in the presence of 1 μmol/L sildenafil, the 100 nmol/L ET‐1‐induced increase in MMP‐2 production was only increased 1.3‐fold over that of the control (P < 0.01 vs 100 nmol/L ET‐1‐stimulated cells).

5. Suppression of RhoA activation was found to mediate the inhibitory effect of sildenafil on ET‐1‐induced increases in MMP‐2 production. Furthermore, the protein kinase G‐specific inhibitor Rp‐8Br‐cGMPs reversed the inhibitory effects of sildenafil on RhoA activation and MMP‐2 production.

6. The results of the present study indicate that PDE5 inhibition suppresses RhoA/ROCK‐mediated MMP‐2 production by PASMC, which may contribute to the regulation of pulmonary vascular remodelling. Thus, PDE5 inhibition may benefit patients with PH through multiple mechanisms of action.
Impairment of α1‐adrenoceptor‐mediated contractile activity in caudal arterial smooth muscle from Type 2 diabetic Goto‐Kakizaki rats
Authors: Mita Mitsuo , Kuramoto Takuto , Ito Kazushi , Toguchi‐Senrui Natsuko , Hishinuma Shigeru , Walsh Michael P , Shoji Masaru
Published: September 2009

1. In the present study, we compared the responsiveness of de‐endothelialized caudal artery smooth muscle strips, isolated from Type 2 diabetic Goto‐Kakizaki (GK) and normal Wistar rats, to α1‐adrenoceptor stimulation (cirazoline) and membrane depolarization (K+).

2. The contractile and myosin 20 kDa light chain (LC20) phosphorylation responses to 0.3 μmol/L cirazoline of caudal artery strips isolated from 12‐week‐old GK rats were significantly reduced compared with those of age‐matched Wistar rats, whereas the contractile and LC20phosphorylation responses to 60 mmol/L K+were unaltered.

3. Stimulation of fura 2‐AM‐loaded strips from GK rats with 0.3 μmol/L cirazoline induced a significantly smaller rise in [Ca2+]i(by ∼20%) compared with that in strips from Wistar rats, whereas comparable Ca2+transients were evoked by K+in both.

4. Using quantitative polymerase chain reaction, no significant differences were detected in the mRNA expression of α1A‐, α1B‐ and α1D‐adrenoceptor subtypes between GK and Wistar rats.

5. Cirazoline (1 μmol/L)‐ and caffeine (20 mmol/L)‐induced contractions in the absence of extracellular Ca2+were unaltered in GK rats, suggesting that the release of Ca2+from the sarcoplasmic reticulum in response to cirazoline does not differ between GK and Wistar rats.

6. The results of the present study suggest that Ca2+entry from the extracellular space via α1‐adrenoceptor‐activated, Ca2+‐permeable channels, but not via membrane depolarization and voltage‐gated L‐type Ca2+channels, is impaired in caudal artery smooth muscle of GK rats.
Usefulness of polyethylene glycol solution with dimethylpolysiloxanes for bowel preparation before capsule endoscopy
Authors: Nouda Sadaharu , Morita Eijiro , Murano Mitsuyuki , Imoto Akira , Kuramoto Takanori , Inoue Takuya , Murano Naoko , Toshina Ken , Umegaki Eiji , Higuchi Kazuhide
Published: September 2009

Background and Aim:  Capsule endoscopy (CE) is widely used for diagnosing small intestinal diseases. In some cases, however, observation of target sites is very poor during CE because of residues etc. Herein we report the usefulness of a preparation comprised of polyethylene glycol solution (PEG) for CE.

Methods:  This was a prospective, randomized, and single‐blind study. Forty subjects, fasted for 12 h before CE, were randomized into two groups: 20 subjects in Group A were fasted only, whereas 20 in Group B received 1 liter (L) PEG with 200 mg dimethylpolysiloxane 3 h before CE. For evaluation, the observation period of the small intestine was divided into first and second halves. Subsequently, four investigators, blinded as to which group received the preparation, assessed the condition of the intestine using four rating scales in terms of ‘residue’ and ‘intraluminal gas bubbles’. The effects of the preparation were statistically compared.

Results:  CE images were better in Group B than in Group A with respect to ‘intraluminal gas bubbles’ (P = 0.0038) in the first half of the observation period, as well as residue (P = 0.0087) and intraluminal gas bubbles (P = 0.0011) in the second half.

Conclusion:  Bowel preparation using 1 L PEG with dimethylpolysiloxane 3 h before CE significantly reduced residue and intraluminal gas bubbles, and was considered to be a useful method for CE.
Outcomes of endoscopic resection of large colorectal neoplasms: An Australian experience
Authors: Salama Muna , Ormonde Donald , Quach Thai , Ee Hooi , Yusoff Ian
Published: September 2009

Background and Aims:  Endoscopic resection of large colorectal neoplasms is increasingly being used as an alternative to surgery. However data on failure rates, safety and long‐term outcomes remain limited. The aim of the study was to report short‐ and long‐term outcomes from endoscopic resection of large colorectal neoplasms from a single centre and use a model to predict mortality had surgery been performed.

Methods:  Consecutive patients referred for endoscopic resection of large (≥ 20 mm) colorectal neoplasms from January 2001 to February 2008 were included. Resection details were recorded in a prospectively maintained database. Data was collected on 30‐day complication rates, and follow‐up colonoscopy findings. The Colorectal‐POSSUM score was used to estimate mortality from open surgery.

Results:  There were 154 large neoplasms in 140 patients. Mean age was 68 years (range 22–94). Mean neoplasm size was 26 mm (range 20–80 mm, 24 ≥ 40 mm). Complete endoscopic removal was achieved in 95% of cases. Twenty patients were referred for surgery (14%). In the endoscopy group, there were no deaths within 30 days. Twelve patients had a complication including two perforations. Endoscopic follow‐up data was available in 90% of cases and five patients (4%) were found to have residual adenoma that was treated endoscopically with subsequent clearance. If surgery had been performed, the mean predicted mortality was 2.2% (range 0.5–10%). There were two deaths (10%) in patients who underwent elective surgery within 30 days.

Conclusion:  Endoscopic resection of large colorectal neoplasms is safe and effective even for very large benign neoplasms. When the lesion is endoscopically resectable this should be the preferred treatment.
Diagnostic role of serum glypican‐3 in differentiating hepatocellular carcinoma from non‐malignant chronic liver disease and other liver cancers
Authors: Tangkijvanich Pisit , Chanmee Theerawut , Komtong Sanpoj , Mahachai Varocha , Wisedopas Naruemon , Pothacharoen Peraphan , Kongtawelert Prachya
Published: September 2009

Background and Aims:  The role of glypican‐3 (GPC3), a novel serum marker, in differentiating hepatocellular carcinoma (HCC) from non‐malignant chronic liver disease and other malignant space‐occupying lesions in the liver is largely unknown. The aims of this study were to evaluate its diagnostic role and clinical correlations in patients with HCC.

Methods:  Six groups were studied which included 40 healthy subjects, 50 patients with chronic hepatitis (CH), 50 patients with liver cirrhosis (LC), 100 patients with HCC, 50 patients with intrahepatic cholangiocarcinoma (ICC) and 50 patients with metastatic carcinoma (MCA). Serum GPC3 levels were measured by using a sandwich enzyme‐linked immunosorbent assay method.

Results:  Fifty‐three percent of HCC patients had elevated serum GPC3 levels with values ranging 35.5–7826.6 ng/mL. The serum marker was undetectable in other groups except one patient (2%) with LC and another patient (2%) with MCA. In most cases of HCC, elevated GPC3 values did not correlate with α‐fetoprotein (AFP) levels. Detectable GPC3 was significantly correlated with the presence of viral hepatitis markers but was not correlated with tumor size and stage of HCC. Serum GPC3 was superior to AFP in detecting small HCC (56.3% and 31.3%, respectively). A combination of serum GPC3 and AFP yielded an improved sensitivity for detecting small HCC to 75%.

Conclusion:  Serum GPC3 is highly specific for detecting HCC. The combined use of serum GPC3 and AFP provides a potentially promising tool to better differentiate HCC from benign liver disorders, as well as from other liver cancers.
Statins for prevention of contrast‐induced nephropathy in patients undergoing non‐emergent percutaneous coronary intervention
Authors: KANDULA PRAVEEN , SHAH RAVISH , SINGH NISHITH , MARKWELL STEPHEN J , BHENSDADIA NISHANT , NAVANEETHAN SANKAR D
Published: September 2009

Aim:  Oxidative stress and ischaemia are suggested as possible mechanisms of contrast‐induced nephropathy (CIN). Statins may offer renoprotection in both acute and chronic kidney diseases because of their antioxidant and anti‐inflammatory properties. We investigated whether use of statins before non‐emergent percutaneous coronary intervention (PCI) reduces the incidence of CIN.

Methods:  We retrospectively evaluated 540 consecutive adult patients who underwent non‐emergent PCI over a 3 year period at a tertiary care centre. CIN was defined as 25% or 44 mmol/L increase from baseline creatinine at 48–72 h. In addition, we classified patients based on Mehran score for risk of development of CIN and analysed the effect of statins.

Results:  Three‐hundred and fifty‐three patients met inclusion criteria. Two‐hundred and thirty‐nine patients were taking statins before PCI and 114 were not. Baseline characteristics were similar for both groups. CIN occurred in 75 patients (21.2%). There was a higher incidence of CIN in patients on statins as compared with patients not on statins (24.7% vs 14%; 95% CI: 1.09–3.67; P = 0.02). However, propensity‐based adjustment for receipt of statins revealed no significant differences in CIN between both groups (OR: 1.6; 95% CI: 0.87–3.22; P = 0.12). Multivariate logistic regression revealed Mehran score to be independently predictive of CIN. None of the patients who developed CIN required dialysis.

Conclusions:  Statin use before non‐emergent PCI is not associated with reduction in CIN. Further randomized controlled trials based on proper risk adjustment for development of CIN are needed.
Pediatric eosinophilic esophagitis: Single‐center experience in northwestern USA
Authors: Eroglu Yasemen , Lu Huiying , Terry Annie , Tendler Janice , Knopes Barbara , Corless Christopher , Byrne William J , Zhang Zili
Published: September 2009

Background:  Eosinophilic esophagitis (EE) is an emerging disease. Its incidence and prevalence have been exponentially increasing in the last decade. The clinical manifestations of EE vary especially in children. Allergic reaction is strongly implicated in the disease. The aim of the present study was to retrospectively examine the demographic, clinical, laboratory, and endoscopic features of pediatric patients with EE, in order to better understand the diversity of the disease, thereby improving clinical diagnosis and treatment.

Methods:  The data were retrospectively collected from 20 pediatric patients with biopsy‐proven EE. Demographic information, clinical symptoms and duration, as well as endoscopic findings were correlated and statistically analyzed.

Results:  Median age at diagnosis was 11 years. Male patients had higher prevalence of EE. Thirty‐five percent of the children had food allergy on either skin prick test or IgE radioallergosorbent test, and atopic diseases were common in the group. Gastroesophageal reflux appeared to be the major symptom in younger children, whereas dysphagia and food impaction were more common in older patients. The referral and final diagnosis were often delayed. Esophageal white exudates were the most prominent feature in the younger age group, whereas esophageal ring‐like lesion occurred more often in older children.

Conclusion:  EE is more common in male subjects. The clinical and endoscopic features depend upon the age. Allergic processes are strongly involved in pathogenesis. The present results will improve understanding of the characteristics of the disease in the pediatric population and enhance clinicians' vigilance for the diagnosis of EE.
Effects of ghrelin on growth and cardiac function in infants with congenital heart disease
Authors: Kitamura Tomohiro , Shimizu Toshiaki , Ohkawa Natsuki , Oda Hisayuki , Ohtsuki Masahiro , Kishiro Masahiko
Published: September 2009

Background:  Ghrelin has effects on appetite and growth. Recent reports suggest effects on cardiac function, but no study has evaluated the ghrelin levels of congenital heart disease (CHD) infants with heart failure. The purpose of the present study was therefore to investigate the relationship between ghrelin level and growth and cardiac function in CHD infants.

Methods:  Twenty‐eight infants with CHD were eligible for the study. Blood samples were obtained at the time of insertion of intracardiac catheter and correlation was examined between ghrelin plasma level and anthropometric parameters, including z score of height and weight, body mass index (BMI), and %bodyweight gain rate, severity of heart failure, and the levels of leptin and insulin‐like growth factor‐1.

Results:  In the CHD group, active ghrelin (A‐Ghr) had a significant negative correlation with z score of bodyweight, and a significant positive correlation with cardiac function. There were no correlations, however, with height and BMI. A‐Ghr levels were significantly higher in the high heart failure index score group. Significant correlation between A‐Ghr and desacyl‐ghrelin in the CHD group was observed.

Conclusions:  A‐Ghr is involved in cardiac function and has little effect on their physique in infants with CHD.
Patients' preferences for positioning during phaco‐emulsification under topical‐intracameral anaesthesia
Authors: Tsatsos Michael , Chong Loy , Eke Tom
Published: September 2009

Abstract

In many eye departments it is routine to ask patients to lie completely flat for cataract surgery. However, many patients prefer not to lie completely flat, if given the choice. It is our practice to ensure patients are in a comfortable position before commencing surgery. We conducted a prospective observational study of our routine practice comprising 125 consecutive cataract operations conducted by a single surgeon with local anaesthesia (occasional phaco under general anaesthetic was not included). All patients were initially positioned lying flat on the reclining chair and were given the option of staying in that position throughout the operation or having the chair‐back raised until they were comfortable. Only 27% (34 patients of 125 total) were happy to lie flat (angle between 0° and 5°). The majority of our patients (62% – 78 patients) preferred to sit up slightly, with the chair‐back 10° to 25° above the horizontal; 8% (10 patients) of the patients were sited at an angle of 30° to 35° and 2% (three patients) needed to be sited at 35° or more. Patients who sat up above 30° generally had a medical reason such as orthopnoea (3% – four patients), back pain (5% – six patients), anxiety (2% – two patients), Meniere's disease (1% – one patient). Patients who sat up below 25° chose this position for comfort or preference. Our results show that patient preferences for positioning during cataract phaco‐emulsification under topical‐intracameral anaesthesia should increase overall patient satisfaction without the need to compromise safety.
Revisiting transconjunctival sutureless 25‐gauge vitrectomy: still worthwhile?
Authors: Sandinha Teresa , De Souza Clairton , Essex Rohan , Kelly Theresa‐Lan , Lake Stewart , Phillips Russell
Published: September 2009

Abstract

To present the outcomes of various retinal conditions treated with the sutureless 25‐gauge (25G) vitrectomy technique. Retrospective case review of 232 eyes of 228 patients who underwent 25G vitrectomy from January 2003 to August 2006. Follow‐up was a minimum of 3 months. Indications for surgery included idiopathic macular hole, rhegmatogenous retinal detachment, epiretinal membrane and proliferative diabetic retinopathy. Main outcome measures included final visual acuity, re‐operation rate and surgical complications such as endophthalmitis, hypotony and retinal (re)detachment. For all cases, the mean overall visual acuity (logMAR) improved from 0.9 preoperatively to 0.5 (P < 0.0001). The improvement in acuity was highest in the rhegmatogenous detachment and diabetic groups. Transient postoperative hypotony was observed in 15 cases (9.2%) on day 1 after surgery but all these cases resolved. In 7.3% of the cases (17 out of 232) additional surgery was performed due to retina (re)detachment but final anatomic success was achieved in all cases; the detachments occurred within the first 3 months. One patients developed endophthalmitis (0.4%) which coincided with subconjunctival antibiotics being discontinued in favour of topical treatment. The 25G system remains a safe and effective technique for a variety of retinal conditions; significant fast visual rehabilitation is an advantage.
The relationship between motivation, learning strategies and choice of environment whether traditional or including an online component
Authors: Clayton Karen , Blumberg Fran , Auld Daniel P.
Published: September 2009

This study examined how students' achievement goals, self‐efficacy and learning strategies influenced their choice of an online, hybrid or traditional learning environment. One hundred thirty‐two post‐secondary students completed surveys soliciting their preferences for learning environments, reasons for their preference, their motivational orientation towards learning and learning strategies used. Findings indicated that most students preferred traditional learning environments. This preference was based on how well the environment matched their personal learning style and engaged them as students. Discriminant analyses indicated significant differences in motivational beliefs and learning strategies; students who preferred traditional environments showed a mastery goal orientation and greater willingness to apply effort while learning. Students who preferred less traditional environments presented as more confident that they could manage a non‐traditional class. These findings have implications for understanding students' motivation for learning in diverse educational settings.
Limited Information and the Sustainability of Unlisted‐Target Acquirers' Returns
Authors: Ekkayokkaya Manapol , Holmes Phil , Paudyal Krishna
Published: September 2009

Abstract:  Relaxed disclosure requirements of unlisted firms, as compared to publicly listed companies, lead to limited quality and quantity of information at bid announcements, causing difficulty in valuing gains from mergers. This raises the question: are the frequently reported superior announcement‐period gains to unlisted‐target acquirers sustainable in the long run? Our results for the UK show that unlisted‐target acquirers gain on announcement, but suffer a substantial loss in the long run. This reversal in fortune of unlisted‐target acquirers is in sharp contrast to the performance of listed‐target acquirers in the UK. Therefore, short‐run gains for unlisted‐target acquirers may result from investors’ excessive optimism when faced with limited and biased information.
What's love got to do with it? Why some marriages succeed and others fail
Authors: HUSTON TED L.
Published: September 2009

This essay summarizes a 13‐year longitudinal study carried out in the United States that challenges conventional wisdom about courtship and the early marital roots of connubial distress and divorce. The study traced relationships from courtship, to the early years of marriage, to parenthood (for most), and to divorce (for some). The essay describes the germination of the study, how it was implemented, and what it reveals about why some marriages succeed and others fail. Couples' courtship and early marital experiences foreshadow: (a) whether they stay married or divorce, (b) whether they sustain satisfying unions if their marriage lasts, and (c) how quickly marriages that end in divorce break apart. Mutually satisfying marriages are differentiable from those that fail in that they both promise marital consanguinity and deliver on the promise.
Cognitions, coercion, and IPV: Sex differences in pursuing resisted physical intimacy
Authors: CVANCARA KRISTEN EIS , KINNEY TERRY A.
Published: September 2009

Communication in close relationships impacts social development and the meeting of personal desires and wants. Since interpersonal violence (IPV) is common in close relationships, this study investigated the extent to which context‐relevant cognitions were associated with use of verbal IPV (e.g., coercion) when communicating for resisted physical intimacy. Based on a convenience sample of U.S. college students, results confirmed that a constellation of cognitions related to the use of coercion and that the rate of use and set of cognitions related to use of coercion differ between males and females. Discussion suggests that examination into the complexities of the cognition–behavior relationship will advance understanding of communication processes related to goal pursuit and use of verbal IPV in interpersonal contexts.
Early exposure to violence, domestic violence, attachment representations, and marital adjustment
Authors: GODBOUT NATACHA , DUTTON DONALD G. , LUSSIER YVAN , SABOURIN STÉPHANE
Published: September 2009

The present study investigates the effects of violent experiences in childhood on current domestic violence and marital adjustment, using adult attachment theory as a conceptual framework. A nonclinical sample of 644 Canadian adults in long‐term romantic relationships completed measures of adult romantic attachment, conflict tactics scales, and dyadic adjustment. Structural equation modeling revealed that early experiences of violence affect adults' intimate violence directly and indirectly through anxiety over abandonment and avoidance of intimacy. The actor–partner interdependence model illustrated the importance of early exposure to violence in predicting both partners' attachment representations, intimate violence, and couple adjustment. Findings are discussed with reference to the clinical issues surrounding minor violence against the intimate partner.
A dyadic exploration of attachment and caregiving in long‐term couples
Authors: MILLINGS ABIGAIL , WALSH JUDI
Published: September 2009

This cross‐sectional study explored associations between attachment style and caregiving patterns in 125 couples with children in the United Kingdom. The Actor–Partner Interdependence Model was used to model for both actor (own) and partner attachment effects on caregiving. Attachment was measured along the dimensions of avoidance and anxiety, and caregiving was measured along the dimensions of proximity, sensitivity, cooperation, and compulsion. Results indicated that different combinations of individual and partner attachment scores predicted different dimensions of caregiving. Own attachment scores best predicted caregiving proximity, cooperation, and compulsion, whereas own and partner attachment predicted caregiving sensitivity. The implications of the findings, limitations, and suggestions for future research are discussed.
Regulation by FK506 and rapamycin of Ca2+ release from the sarcoplasmic reticulum in vascular smooth muscle: the role of FK506 binding proteins and mTOR
Authors: MacMillan D , McCarron JG
Published: September 2009

Background and purpose:  The sarcoplasmic reticulum (SR), regulates the cytoplasmic Ca2+ concentration ([Ca2+]cyto) in vascular smooth muscle. Release from the SR is controlled by two intracellular receptor/channel complexes, the ryanodine receptor (RyR) and the inositol 1,4,5‐trisphosphate receptor (IP3R). These receptors may be regulated by the accessory FK506‐binding protein (FKBP) either directly, by binding to the channel, or indirectly via FKBP modulation of two targets, the phosphatase, calcineurin or the kinase, mammalian target of rapamycin (mTOR).

Experimental approach:  Single portal vein myocytes were voltage‐clamped in whole cell configuration and [Ca2+]cyto measured using fluo‐3. IP3Rs were activated by photolysis of caged IP3 and RyRs activated by hydrostatic application of caffeine.

Key results:  FK506 which displaces FKBP from each receptor (to inhibit calcineurin) increased the [Ca2+]cyto rise evoked by activation of either RyR or IP3R. Rapamycin which displaces FKBP (to inhibit mTOR) also increased the amplitude of the caffeine‐evoked, but reduced the IP3‐evoked [Ca2+]cyto rise. None of the phosphatase inhibitors, cypermethrin, okadaic acid or calcineurin inhibitory peptide, altered either caffeine‐ or IP3‐evoked [Ca2+]cyto release; calcineurin did not contribute to FK506‐mediated potentiation of RyR‐ or IP3R‐mediated Ca2+ release. The mTOR inhibitor LY294002, like rapamycin, decreased IP3‐evoked Ca2+ release.

Conclusions and implications:  Ca2+ release in portal vein myocytes, via RyR, was modulated directly by FKBP binding to the channel; neither calcineurin nor mTOR contributed to this regulation. However, IP3R‐mediated Ca2+ release, while also modulated directly by FKBP may be additionally regulated by mTOR. Rapamycin inhibition of IP3‐mediated Ca2+ release may be explained by mTOR inhibition.
The Scar‐in‐a‐Jar: studying potential antifibrotic compounds from the epigenetic to extracellular level in a single well
Authors: Chen CZC , Peng YX , Wang ZB , Fish PV , Kaar JL , Koepsel RR , Russell AJ , Lareu RR , Raghunath M
Published: September 2009

Background and purpose:  Fibrosis, a pathological accumulation of collagen in tissues, represents a major global disease burden. Effective characterization of potential antifibrotic drugs has been constrained by poor formation of the extracellular matrix in vitro, due to tardy procollagen processing by collagen C‐proteinase/BMP‐1, and difficulties in relating this matrix to cell numbers in experimental samples.

Experimental approach:  The Scar‐in‐a‐Jar model provided, in vitro, the complete biosynthetic cascade of collagen matrix formation including complete conversion of procollagen by C‐proteinase/BMP‐1, its subsequent extracellular deposition and lysyl oxidase‐mediated cross‐linking, achieved by applying the biophysical principle of macromolecular ‘crowding’. Collagen matrix deposition, velocity and morphology can be controlled using negatively charged ‘crowders’ in a rapid (2 days) mode or a mixture of neutral ‘crowders’ in an accelerated (6 days) mode. Combined with quantitative optical bioimaging, this novel system allows for in situ assessment of the area of deposited collagen(s) per cell.

Key results:  Optical evaluation of known and novel antifibrotic compounds effective at the epigenetic, post‐transcriptional/translational/secretional level correlated excellently with corresponding biochemical analyses. Focusing on quantitation of deposited collagen, the Scar‐in‐a‐Jar was most effective in assessing novel inhibitors that may have multiple targets, such as microRNA29c, found to be a promising antifibrotic agent.

Conclusions and implications:  This novel screening system supersedes current in vitro fibroplasia models, as a fast, quantitative and non‐destructive technique. This method distinguishes a reduction in collagen I deposition, excluding collagen cross‐linking, and allows full evaluation of inhibitors of C‐proteinase/BMP‐1 and other matrix metalloproteinases.
Alosetron, cilansetron and tegaserod modify mesenteric but not colonic blood flow in rats
Authors: Painsipp Evelin , Shahbazian Anaid , Holzer Peter
Published: September 2009

Background and purpose:  As the use of the 5‐HT3 receptor antagonist alosetron (GlaxoSmithKline) and the 5‐HT4 receptor agonist tegaserod (Novartis) in patients with irritable bowel syndrome has been associated with cases of ischaemic colitis, the effects of alosetron, cilansetron (Solvay) and tegaserod on the rat splanchnic circulation were evaluated.

Experimental approach:  Phenobarbital‐anaesthetised rats were instrumented to record blood flow in the superior mesenteric artery and transverse colon and to calculate mesenteric and colonic vascular conductance.

Key results:  Intravenous alosetron (0.03–0.3 mg·kg−1) did not alter blood pressure or heart rate but reduced mesenteric blood flow and vascular conductance by 15–20%. This activity profile was also seen after intraduodenal alosetron and shared by the 5‐HT3 receptor antagonist cilansetron. In contrast, blood flow, vascular conductance and intraluminal pressure in the colon were not modified by alosetron and cilansetron. Intravenous or intraduodenal tegaserod (0.3–1.0 mg·kg−1) had no inhibitory effect on mesenteric and colonic blood flow. Peroral treatment of rats with alosetron or tegaserod for 7 days did not modify mesenteric haemodynamics at baseline and after blockade of nitric oxide synthesis. Mild inflammation induced by dextran sulphate sodium failed to provoke a vasoconstrictor effect of cilansetron in the colon.

Conclusions and implications:  Alosetron and cilansetron, not tegaserod, caused a small and transient constriction of the rat mesenteric vascular bed, whereas blood flow in the colon remained unaltered. The relevance of these findings to the treatment‐associated occurrence of ischaemic colitis in patients with irritable bowel syndrome remains open.
The NO donor DETA‐NONOate reversibly activates an inward current in neurones and is not mediated by the released nitric oxide
Authors: Thompson AJ , Mander PK , Brown GC
Published: September 2009

Background and purpose:  It has been previously shown that high levels of nitric oxide (NO), from NO donors, kill neurones, but the mechanisms are unclear.

Experimental approach:  The effects of NO donors on the electrical properties of rat cultured cerebellar granule cells (CGC neurones) were investigated using the whole‐cell patch‐clamp technique.

Key results:  The NO donor (Z)‐1‐[2‐(2‐aminoethyl)‐N‐(2‐ammonioethyl)amino]diazen‐1‐ium‐1,2‐diolate (DETA‐NONOate or NOC‐18) caused a rapid, persistent, but fully reversible inward current that was associated with an increase in baseline noise and was concentration dependent (100 µM–10 mM). The response to 3 mM DETA‐NONOate was completely inhibited by 1 mM gadolinium, but not by NO scavengers (1 mM haemoglobin or 1 mM PTIO) or glutamate receptor antagonists (10 µM MK‐801 or 60 µM CNQX). Application of decomposed 3 mM DETA‐NONOate or 3 mM nitrite had no effect. In contrast, the NO donor S‐nitrosoglutathione (GSNO) caused a rapid, persistent, but fully reversible outward current that was also concentration dependent (1–10 mM). The 3 mM GSNO response was unaltered by NO scavengers, glutamate antagonists or gadolinium, but was mimicked by decomposed 3 mM GSNO and 3 mM oxidized glutathione.

Conclusions and implications:  These results suggest that DETA‐NONOate directly activates cation‐selective channels, causing an inward current in CGCs. In contrast, GSNO causes an outward current in these cells. Some of the effects of these NO donors are independent of NO, and thus caution is required in interpreting results when using high concentrations of these compounds.
α‐Fetoprotein as a modulator of the pro‐inflammatory response of human keratinocytes
Authors: Potapovich AI , Pastore S , Kostyuk VA , Lulli D , Mariani V , De Luca C , Dudich EI , Korkina LG
Published: September 2009

Background and purpose:  The immunomodulatory effects of α‐fetoprotein (AFP) on lymphocytes and macrophages have been described in vitro and in vivo. Recombinant forms of human AFP have been proposed as potential therapeutic entities for the treatment of autoimmune diseases. We examined the effects of embryonic and recombinant human AFP on the spontaneous, UVA‐ and cytokine‐induced pro‐inflammatory responses of human keratinocytes.

Experimental approach:  Cultures of primary and immortalized human keratinocytes (HaCaT) and human blood T lymphocytes were used. The effects of AFP on cytokine expression were studied by bioplexed elisa and quantitative reverse transcriptase polymerase chain reaction assay. Kinase and nuclear factor kappa B (NFκB) phosphorylation were quantified by intracellular elisa. Nuclear activator protein 1 and NFκB DNA binding activity was measured by specific assays. Nitric oxide and H2O2 production and redox status were assessed by fluorescent probe and biochemical methods.

Key results:  All forms of AFP enhanced baseline expression of cytokines, chemokines and growth factors. AFP dose‐dependently increased tumour necrosis factor alpha‐stimulated granulocyte macrophage colony stimulating factor and interleukin 8 expression and decreased tumour necrosis factor alpha‐induced monocyte chemotactic protein 1 and IP‐10 (interferon gamma‐produced protein of 10 kDa) expression. AFP induced a marked activator protein 1 activation in human keratinocytes. AFP also increased H2O2 and modulated nitrite/nitrate levels in non‐stimulated keratinocytes whereas it did not affect these parameters or cytokine release from UVA‐stimulated cells. Phosphorylation of extracellular signal‐regulated kinase (ERK1/2) and Akt1 but not NFκB was activated by AFP alone or by its combination with UVA.

Conclusions and implications:  Exogenous AFP induces activation of human keratinocytes, with de novo expression of a number of pro‐inflammatory mediators and modulation of their pro‐inflammatory response to cytokines or UVA. AFP may modulate inflammatory events in human skin.
Jihad on the Frontier: A History of Religious Revolt on the North‐West Frontier, 1800–1947
Authors: Hopkins B. D.
Published: September 2009

Jihad is an idea and phenomenon receiving increasing popular, policy and scholarly attentions. The current violence in Pakistan’s North West Frontier Province, encompassing much of its borderlands with Afghanistan, is often depicted as a jihad, with many linking it to a larger global ‘war on terror’. Yet religious, or rather rhetorically religious violence has a long history on the Frontier. From at least the advent of British administration in the region in the nineteenth century, there have been repeated jihads against the intrusions of colonial authority, often in the same places with a similar cast of characters. But violence on the Frontier is more than some simplistic outbreak of religious bigotism. This article explores the issues raised by the repeated episodes of jihad on the Frontier and the literature addressing its occurrence.
DIFFERENT PHYSIOLOGICAL RESPONSES OF FOUR MARINE SYNECHOCOCCUS STRAINS (CYANOPHYCEAE) TO NICKEL STARVATION UNDER IRON‐REPLETE AND IRON‐DEPLETE CONDITIONS1
Authors: Qiu Baosheng , Price Neil M.
Published: September 2009

Synechococcus species are important primary producers in coastal and open‐ocean ecosystems. When nitrate was provided as the sole nitrogen source, nickel starvation inhibited the growth of strains WH8102 and WH7803, while it had little effect on two euryhaline strains, WH5701 and PCC 7002. Nickel was required for the acclimation of Synechococcus WH7803 to low iron and high light. In WH8102 and WH7803, nickel starvation decreased the linear electron transport activity, slowed down QA reoxidation, but increased the connectivity factor between individual photosynthetic units. Under such conditions, the reduction of their intersystem electron transport chains was expected to increase, and their cyclic electron transport around PSI would be favored. Nickel starvation decreased the total superoxide dismutase (SOD) activity of WH8102 and WH7803 by 30% and 15% of the control, respectively. The protein‐bound 63Ni of the oceanic strain WH8102 comigrated with SOD activity on nondenaturing gels and thus provided additional evidence for the existence of active NiSOD in Synechococcus WH8102. In WH7803, it seems likely that nickel starvation affected other metabolic pathways and thus indirectly affected the total SOD activity.
Sensory and Motor Peripheral Nerve Function and Lower‐Extremity Quadriceps Strength: The Health, Aging and Body Composition Study
Authors: Strotmeyer Elsa S. , De Rekeneire Nathalie , Schwartz Ann V. , Resnick Helaine E. , Goodpaster Bret H. , Faulkner Kimberly A. , Shorr Ronald I. , Vinik Aaron I. , Harris Tamara B. , Newman Anne B. ,   for the Health ABC Study
Published: September 2009

OBJECTIVES:To determine whether sensory and motor nerve function is associated cross‐sectionally with quadriceps or ankle dorsiflexion strength in an older community‐based population.

DESIGN:Cross‐sectional analyses within a longitudinal cohort study.

SETTING:Two U.S. clinical sites.

PARTICIPANTS:Two thousand fifty‐nine Health, Aging and Body Composition Study (Health ABC) participants (49.5% male, 36.7% black, aged 73–82) in 2000/01.

MEASUREMENTS:

Quadriceps and ankle strength were measured using an isokinetic dynamometer. Sensory and motor peripheral nerve function in the legs and feet was assessed using 10‐g and 1.4‐g monofilaments, vibration threshold, and peroneal motor nerve conduction amplitude and velocity.

RESULTS:Monofilament insensitivity, poorest vibration threshold quartile (>60 μ), and poorest motor nerve conduction amplitude quartile (<1.7 mV) were associated with 11%, 7%, and 8% lower quadriceps strength (allP<.01), respectively, than in the best peripheral nerve function categories in adjusted linear regression models. Monofilament insensitivity and lowest amplitude quartile were both associated with 17% lower ankle strength (P<.01). Multivariate analyses were adjusted for demographic characteristics, diabetes mellitus, body composition, lifestyle factors, and chronic health conditions and included all peripheral nerve measures in the same model. Monofilament insensitivity (β=−7.19), vibration threshold (β=−0.097), and motor nerve conduction amplitude (β=2.01) each contributed independently to lower quadriceps strength (allP<.01). Monofilament insensitivity (β=−5.29) and amplitude (β=1.17) each contributed independently to lower ankle strength (allP<.01). Neither diabetes mellitus status nor lean mass explained the associations between peripheral nerve function and strength.

CONCLUSION:Reduced sensory and motor peripheral nerve function is related to poorer lower extremity strength in older adults, suggesting a mechanism for the relationship with lower extremity disability.
Cholinesterase Inhibitors and Incidence of Bradycardia in Patients with Dementia in the Veterans Affairs New England Healthcare System
Authors: Hernandez Rohini K. , Farwell Wildon , Cantor Michael D. , Lawler Elizabeth V.
Published: September 2009

OBJECTIVES: To quantify the association between cholinesterase inhibitors (ChE‐Is) and a new diagnosis of bradycardia and to evaluate the clinical significance of bradycardia.

DESIGN: Cox proportional hazards with time‐dependent exposures were used to evaluate the association and examine the dose effect for donepezil and bradycardia.

SETTING: New England Veterans Affairs Healthcare System.

PARTICIPANTS: Patients with dementia who received care between January 1999 and June 2007 (N=11,328).

MEASUREMENTS: Bradycardia was defined using three methods using a combination of International Classification of Diseases, Ninth Revision, codes and recorded heart rates of less than 60 beats per minute.

RESULTS: A greater risk for bradycardia was found in patients taking any ChE‐Is than in the no‐treatment group (adjusted hazard ratio (HR)=1.4, 95% confidence interval (CI)=1.1–1.6). A dose‐response effect was observed for donepezil, with the highest‐dose group at greatest risk (HR=2.1, 95% CI=1.5–2.9). Results were consistent regardless of bradycardia definition. Patients with bradycardia were more likely to fall, experience syncope, or need a pacemaker implantation than those without.

CONCLUSION: Using a large cohort, a modestly greater risk of bradycardia was found in patients with dementia taking ChE‐Is than in those not taking these drugs. In patients taking donepezil, the risk of bradycardia may increase with increasing doses. Because of the potential clinical consequences, monitoring for bradycardia may be warranted in patients with dementia treated with ChE‐Is.
Effects of a Multicomponent Cognitive Behavioral Group Intervention on Fear of Falling and Activity Avoidance in Community‐Dwelling Older Adults: Results of a Randomized Controlled Trial
Authors: Zijlstra G. A. Rixt , Van Haastregt Jolanda C. M. , Ambergen Ton , Van Rossum Erik , Van Eijk Jacques Th. M. , Tennstedt Sharon L. , Kempen Gertrudis I. J. M.
Published: September 2009

OBJECTIVES: To evaluate the effects of a multicomponent cognitive behavioral intervention on fear of falling and activity avoidance in older adults.

DESIGN: Randomized controlled trial.

SETTING: Community‐dwelling adults in the Netherlands.

PARTICIPANTS: Five hundred forty adults aged 70 and older who reported fear of falling and fear‐induced activity avoidance (280 intervention, 260 control).

INTERVENTION: A multicomponent cognitive behavioral group intervention consisting of eight weekly sessions and a booster session. The sessions were aimed at instilling adaptive and realistic views on falls, reducing fall risk, and increasing activity and safe behavior.

MEASUREMENTS: Data on fear of falling, activity avoidance, concerns about falling, perceived control over falling, and daily activity were collected at baseline and at 2, 8, and 14 months.

RESULTS: At 2 months, there were significant between‐group differences in fear of falling (odds ratio (OR)=0.11; P<.001), activity avoidance (OR=0.26; P<.001), concerns about falling (adjusted mean difference=−1.51; P=.02), and daily activity (adjusted mean difference=0.95; P=.01). At 8 months, there were significant between‐group differences in all outcomes and at 14 months in fear of falling (P=.001), perceived control over falling (P=.001), and recurrent fallers (P=.02) but not in activity avoidance (P=.07), concerns about falling (P=.07), daily activity (P=.24), or fallers (P=.08).

CONCLUSION: This multicomponent cognitive behavioral intervention showed positive and durable effects on fear of falling and associated activity avoidance in community‐dwelling older adults. Future research should focus on improving intervention uptake and adherence, reaching frailer populations, and determining potential intervention effects on functional outcomes.
Sleep Disturbances and Frailty Status in Older Community‐Dwelling Men
Authors: Ensrud Kristine E. , Blackwell Terri L. , Redline Susan , Ancoli‐Israel Sonia , Paudel Misti L. , Cawthon Peggy M. , Dam Thuy‐Tien L. , Barrett‐Connor Elizabeth , Leung Ping C. , Stone Katie L. ,   for the Osteoporotic Fractures in Men Study Group
Published: September 2009

OBJECTIVES: To test the hypothesis that sleep disturbances are independently associated with frailty status in older men.

DESIGN: Cross‐sectional analysis of prospective cohort study.

SETTING: Six U.S. centers.

PARTICIPANTS: Three thousand one hundred thirty‐three men aged 67 and older.

MEASUREMENTS: Self‐reported sleep parameters (questionnaire); objective parameters of sleep–wake patterns (actigraphy data collected for an average of 5.2 nights); and objective parameters of sleep‐disordered breathing, nocturnal hypoxemia, and periodic leg movements with arousals (PLMAs) (in‐home overnight polysomnography). Frailty status was classified as robust, intermediate stage, or frail using criteria similar to those used in the Cardiovascular Health Study frailty index.

RESULTS: The prevalence of sleep disturbances, including poor sleep quality, excessive daytime sleepiness, short sleep duration, lower sleep efficiency, prolonged sleep latency, sleep fragmentation (greater nighttime wakefulness and frequent, long wake episodes), sleep‐disordered breathing, nocturnal hypoxemia, and frequent PLMAs, was lowest in robust men, intermediate in men in the intermediate‐stage group, and highest in frail men (P‐for‐trend ≤.002 for all sleep parameters). After adjusting for multiple potential confounders, self‐reported poor sleep quality (Pittsburgh Sleep Quality Index >5, multivariable odds ratio (MOR)=1.28, 95% confidence interval (CI)=1.09–1.50), sleep efficiency less than 70% (MOR=1.37, 95% CI=1.12–1.67), sleep latency of 60 minutes or longer (MOR=1.42, 95% CI=1.10–1.82), and sleep‐disordered breathing (respiratory disturbance index ≥15, MOR=1.38, 95% CI=1.15–1.65) were each independently associated with higher odds of greater frailty status.

CONCLUSION: Sleep disturbances, including poor self‐reported sleep quality, lower sleep efficiency, prolonged sleep latency, and sleep‐disordered breathing, are independently associated with greater evidence of frailty.
Development and Implementation of a Proactive Geriatrics Consultation Model in Collaboration with Hospitalists
Authors: Sennour Youcef , Counsell Steven R. , Jones Jerrlyn , Weiner Michael
Published: September 2009

Acutely ill hospitalized older adults often experience a decline in function that may be preventable using a proactive, interdisciplinary, patient‐centered approach. Hospitalists are treating an increasing number of these patients. A collaborative geriatrics consultation model to prevent functional decline and improve care for older patients with geriatrics syndromes was developed and implemented in partnership with a large hospitalist group in a community teaching hospital. A team of a geriatrician and a geriatrics nurse practitioner led the new consultation service. The team assisted with identifying cases, provided consultation early in the hospital stay, focused its evaluation on functional and psychosocial issues, and assisted in clinical management to optimize implementation of recommendations. In the first 4 years, the consultation service conducted 1,538 consultations in patients with a mean age of 81 (range 56–103). The most frequent geriatrics diagnoses were gait instability, delirium, and depression; recommendations usually included consulting physical therapy, increasing activity, and changing medications. The number of referrals and referring physicians grew steadily each year. Twenty‐eight of 34 (82%) of the referring hospitalists completed a Web‐based satisfaction questionnaire. All responding hospitalists agreed that proactive geriatrics consultation helped them provide better care; 96% rated the service as excellent. Analysis of hospital administrative data revealed a lower length of stay index and lower hospital costs in patients receiving a geriatrics consultation. The Proactive Geriatrics Consultation Service represents a promising model of collaboration between hospitalists and geriatricians for improving care of hospitalized older adults.