Search

Netrins can dictate attractive and repulsive responses during axon growth and cell migration, where presence of the receptor UNC-5 on target cells results in Netrin-mediated repulsion. Molecular details of Netrin–UNC-5 interactions and how they signal remain elusive. Here, we show that nematode UNC-5 is a heparin-binding protein, and the UNC-5–heparin affinity can be modulated using directed evolution or via rational design using our novel structure of UNC-5 with a heparin fragment. Furthermore, UNC-5 and nematode UNC-6/Netrin form a large, stable and rigid oligomeric complex in the presence of heparin, which can incorporate the attractive UNC-40/DCC receptor, demonstrating binary and ternary ectodomain complexes at preparative scale. C. elegans with a heparin-binding deficient UNC-5 fail to establish proper gonad morphology due to abrogated distal tip cell migration, which relies on repulsive UNC-5 signaling in response to UNC-6. Our findings establish Netrin responses to be mediated through glycosaminoglycan-regulated large macromolecular complexes.

Men’s experiences of living with and managing the symptoms associated with bipolar disorder are poorly understood. There is also a lack of qualitative studies focused on men’s experiences of bipolar disorder despite the clinical importance of this understanding for successfully supporting men to live well and manage mood symptoms. This qualitative study used a photo-elicitation approach to explore how men made sense of managing their mood symptoms when living with bipolar disorder. Six participants took photographs representing their experiences of managing their diagnosis and mood symptoms, which formed the basis of in-depth participant-led semi-structured interviews. An interpretative phenomenological analysis identified four themes: (1) “managing symptoms: living with the enemy”; (2) “we’re not just managing mood episodes”; (3) “managing goes beyond a list of strategies”; and (4) “medication is a necessary evil”. Common across the sample’s experiences was the importance of accommodating the disruption caused by mood-related triggers and symptoms. Notably, explicit descriptions of masculinity or male identity were absent from the participants’ sense-making. Findings support a clinical focus on promoting idiosyncratic recoveries and living well, focusing on life beyond symptom reduction and relapse prevention, and facilitating “sense making” of men’s bipolar diagnoses and experiences in practice.

INTRODUCTION This study set out to examine the association between deprivation and the incidence of HCC and survival following diagnosis in the West of Scotland. METHODS Data were gathered on patients from the prospective West of Scotland regional HCC database from November 2014 to August 2017. Patients were included if they had a new diagnosis of HCC. Data on deprivation were taken from the Scottish Index of Multiple Deprivation (SIMD) 2016. RESULTS 357 patients were included in the study. There was a higher incidence rate in patients in SIMD quintile 1 (most deprived) compared with quintile 5 (least deprived) (8.4 vs 4.3 per 100,000, respectively, p

P059 Table 1 2019 2020 P VALUE Number of referrals 62 37 Mean age 69 69 Sex (M:F) 53 (85.5%) : 9(14.5%) 30 (81.1%) : 7(18.9%) Mean size largest lesion (cm) 5.8 6.1 0.39 Mean number of lesions 1.96 1.53 0.48 Mean time to MDT discussion (days) 20.8 11.2 0.08 Mean time to first treatment (days) 93.2 53.8 0.03 ConclusionDuring the COVID-19 pandemic there was a 40% reduction in HCC diagnoses referred to the WOS MDT, compared with 2019. However there is no evidence that patients have presented with more advanced disease. Additionally, we have demonstrated a reduction in the referral to treatment time where active treatment was indicated. Given that the incidence of chronic liver disease has continued to rise in our population, we would expect an increased number of patients to present with more advance stage HCC over the coming months.

Summary Twelve weeks sofosbuvir/velpatasvir (SOF/VEL) is a highly effective pan‐genotypic regimen for hepatitis C. Phase 2 data suggest 8 weeks of treatment may be sufficient for previously untreated noncirrhotic patients with genotype 3 (GT3) infection. To maximize the number of patients potentially cured within a fixed treatment budget, we elected to treat such patients locally eligible for treatment (F2/3), with 8 weeks of SOF/VEL. By local protocol, treatment‐naive patients with F2 (LSM > 6.9kPa

Direct‐acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C virus (HCV) infection. We describe UK real‐world DAA experience. Individuals commencing HCV treatment containing a DAA regimen (Mar 2014‐Nov 2016), participating in the National HCV Research UK (HCVRUK) Cohort Study were recruited from 33 UK HCV centers. The data were prospectively entered at sites onto a centralised database. The data were reported as median (Q1‐Q3). Of the 1448 treated patients, 1054 (73%) were males, the median age being 54 years (47‐60), 900 (62%) being genotype 1 and 455 (31%) genotype 3. The majority, 887 (61%) had cirrhosis, and 590 (41%) were treatment‐experienced. DAA regimens utilised: genotype1 sofosbuvir (SOF)/Ledipasvir/±Ribavirin (625/900, 69%) and Ombitasvir/Paritaprevir/Dasabuvir/±RBV (220/900, 24%), and in genotype 3 SOF/Daclatasvir + RBV (256/455, 56%) and SOF/pegylated interferon/RBV (157/455, 35%). Overall, 1321 (91%) achieved sustained virological response (SVR12), genotype 1 vs 3, 93% vs 87%, P

Introduction Hepatocellular carcinoma (HCC) causes more than 5,400 deaths per year in the UK and is rising in incidence. Previously in the UK, HCC in non-cirrhotic livers was felt to be uncommon. We sought to establish the proportion of HCC occurring in patients without cirrhosis in our region of the UK and compare characteristics of those with cirrhosis. Methods Data was collected from our prospectively collected database on patient demographics, liver aetiology, stage at presentation and outcome for patients diagnosed with HCC at our regional MDT from 2009 to 2015. Results A total of 638 patients with HCC were included. 140 (21.9%) had no underlying cirrhosis. Non-cirrhotic HCCs were older at diagnosis (72 years vs 68 years, p = 0.001), with a similar male to female ratio. Alcohol related liver disease (ArLD) was the most common underlying aetiology in patients with cirrhosis (59%; see table 1), and along with Viral hepatitis was significantly more common than patients without cirrhosis. In contrast, unknown aetiology represented the majority of diagnoses, and was significantly greater in the non-cirrhotic cohort. Patients with non-cirrhotic HCC had more advanced malignant disease at diagnosis compared to cirrhotic HCC using Barcelona Clinic Liver Cancer (BCLC) staging, p Conclusion In our study nearly 22% of HCCs occurred in patients without underlying cirrhosis. A high proportion of non-cirrhotic HCC patients had unknown aetiology of liver disease. Patients with non-cirrhotic HCC were diagnosed at an older age with more advanced disease but lower mortality compared to patients with cirrhotic HCC.

Introduction Hepatocellular carcinoma (HCC) is rising in incidence both in Scotland and the UK.1 This study set out to examine whether there is an association between deprivation and the incidence of HCC and survival following diagnosis in the West of Scotland. Methods Data was collected on patients from the prospectively collected West of Scotland regional HCC database from November 2014 to August 2017. Patients were included if they had a new diagnosis of HCC not previously diagnosed or treated elsewhere. Data on deprivation was taken from the Scottish Index of Multiple Deprivation (SIMD) 2016 Data was collected on Excel and the statistical analysis was performed using R. Chi squared, unpaired t-test and log rank tests were used as appropriate. Incidence rates were age adjusted using the European standard population. Results 357 patients were included in the study. 45% of all new cases of HCC were in patients living in the most deprived 20% postcodes. There was a higher incidence rate in patients in SIMD quintile 1 (most deprived) compared with quintile 5 (least deprived) (10.3 vs 5.5 per 100,000, respectively, p Patients in SIMD quintile 1 were younger compared with those in SIMD quintile 5, with a mean age 65.4 yrs vs 69.5 yrs respectively, p = 0.027). A significantly higher proportion of people in SIMD quintile 1 had HCV as the aetiology of their cirrhosis compared with SIMD quintile 5 (30% vs 7%, respectively, p = 0.01). There was no significant difference in patients with alcohol as the aetiology between SIMD quintile 1 and 5 (48% vs 50%, respectively, p = 0.6). Following diagnosis there was no significant difference in survival between patients in the most deprived and least deprived quintiles (median survival 368 days vs 325 days, p = 0.8). The only predictors of survival after diagnosis of HCC were BCLC stage (p Conclusions In contrast to previous studies, we found a higher incidence of HCC in both men and women living in the most deprived areas.1 The proportion of HCC patients with HCV (but not alcohol) as the aetiology of cirrhosis was higher in the most deprived compared with least deprived quintile. Following diagnosis of HCC, we found no difference in survival between patients living in the most and least deprived areas. Reference Cancer Research UK. Liver cancer incidence statistics. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/liver-cancer/incidence (accessed 19/1/2020). Age adjusted incidence ratesSave

Pediatric patients supported by ventricular assist devices form a growing and challenging population. They are high-risk, and heterogeneous (in terms of age, neurodevelopment stage, and underlying anatomy) and relatively low-volume. Standardization of care across the various ages and stages is difficult. Multidisciplinary teams managing these patients must have a good understanding of growth and development to provide optimal care and creative options for growth, development, and adherence in order to achieve improved outcomes for pediatric ventricular assist device patients.

Introduction At present, patients with abnormal LFTs referred to secondary care undergo a serological liver screen and Fibroscan at a nurse-led pre-assessment clinic, before being discussed at a multi-disciplinary team meeting (MDT). The outcome is either advice for management in Primary Care or they are offered an appointment at a consultant clinic. ‘Intelligent Liver Function Tests’ (iLFTs) provide a diagnostic pathway and stratification for patients with abnormal LFTs in primary care. When requesting iLFTs, the referrer is asked to include alcohol intake, BMI, and if there are features of the metabolic syndrome. Patients with abnormal LFTs on screen undergo reflex testing without further venepuncture or review. We aimed to assess how long it took from initial abnormal liver enzymes to referral to secondary care and compared the outcomes to what would have happened if iLFTs were the initial test. Methods A retrospective analysis of 93 cases of abnormal LFTsbrought to MDT from February-August 2018 was performed. The MDT result was compared with the diagnosis and outcome had iLFTsbeen used. In addition, the number of times patients had abnormal LFTs and the time period in which the patient had been known to have abnormal LFTs was recorded. Results 37 patients were referred back to primary care from the MDT. 23 (24.7%) would not have been referred if iLFTs were used. 50 patients were offered review at a consultant clinic. Only 2 (2.1%) patients would not have been referred if iLFTs had been used; both had low fibrosis risks. In 41/50 cases (82%), the diagnosis at MDT was the same if the GP had used iLFTs. 6 patients did not attend for nurse review. 3 (50%) did not require referral if the iLFT protocol had been followed. The median number of times a patient had abnormal LFTs before referral was 5 (min 1; max 33). The median duration of abnormal LFTs before referral was 20 months (min 0; max 87), as shown in figure 1. Conclusions iLFTs rapidly and safely identify patients with abnormal LFTs requiring referral to secondary care. If iLFTs were used by referrers, 24.7% of patients would not require referral to secondary care. This represents a substantial cost saving in terms of clinic appointments and unnecessary investigations. In addition, patients would be analysed at the time of the first abnormal LFTs, providing referrers information on how to monitor for disease progression and when to refer. This would save significant time in Primary Care, avoiding repeated venepuncture and ensuring patients are referred before they develop end stage liver disease.

Introduction Surveillance for hepatocellular carcinoma (HCC) is recommended by national and international guidelines. However, there are limited data on the impact of surveillance on clinical outcome. Our aim was to compare the stage of disease at diagnosis, treatment employed and survival, among those patients complying with, not complying with, or never entered into, a surveillance programme over a 7 year period at our regional centre. Methods We analysed data from our prospectively collected regional HCC MDT database on patients diagnosed with HCC from January 2009 to December 2015. Demographics, Child Pugh score and Barcelona-Clinic Liver Cancer (BCLC) stage at diagnosis were collated, as were the treatment strategy employed and survival. We compared the stage of disease, treatment undertaken and survival across 3 pre-identified groups: 1. Compliant with surveillance (enrolled in surveillance and last ultrasound (US) 9 months); 3. Never enrolled into a surveillance programme. Kaplan-Meier, log rank analysis and chi-squared tests were used as appropriate. Results 641 patients were diagnosed with HCC over this period. Follow up data was available for 638 (99.5%) patients with mean follow-up 15 months. Mean age at diagnosis was 69 years and 82.3% were male. HCC diagnoses increased from 62 in 2009, to 143 in 2015. 52.8% of patients had alcoholic liver diseases, 16.8% NAFLD and 15.4% hepatitis C. 160 (25.1%) patients were from Group 1, 54 (8.5%) from group 2 and 424 (66.5%) from group 3. There was an increase in the proportion of patients with HCC who were diagnosed in a surveillance programme during the study period (p Conclusions The annual number of patients diagnosed with HCC at our regional Centre increased by over 100% during the 7 year study period. A minority of patients diagnosed with HCC were enrolled in a surveillance programme, although the proportion increased over time. HCC Patients enrolled in a surveillance programme had lower BCLC stage at diagnosis, were more likely to receive curative treatment and had improved survival.

Introduction Sodium pentobarbital (Nembutal) is a barbiturate used in research as an anesthetic in many animal models. The injectable form of this drug has lately become difficult to procure and prohibitively expensive. Due to this lack of availability, researchers have begun to compound injectable sodium pentobarbital from so-called “nonpharmaceutical” pentobarbital. Some oversight agencies have objected to this practice, claiming a lack of quality control and degradation of the drug. We sought with this study to establish both: 1) a protocol for the preparation of injectable sodium pentobarbital, and 2) standard operating procedures to monitor the quality of the preparation and degradation of the drug over time. Methods Our preparation consists of a mixture of sodium pentobarbital in alkaline aqueous solution, propylene glycol, and ethanol. Pentobarbital content in this preparation was assayed by high-pressure liquid chromatography (HPLC). We also assayed pentobarbital content over time in preparations of various ages up to 6 years old. Results We determined that the drug degraded at a maximum of 0.5% per year in our preparation (alkaline water/propylene glycol/ethanol) when stored in the dark at room temperature. A yellow discoloration developed after about 2 years, which we have arbitrarily determined disqualifies the preparation from use as an anesthetic. Attempts to spectroscopically assay this discoloration were not successful. Chemicals Pentobarbital sodium (CID: 14075609)

The purpose of this study was to use social cognitive theory to predict human papillomavirus (HPV) vaccination intentions of college men attending a large, southeastern university. Data collection comprised two phases. Phase I established face and content validity of the instrument by a panel of six experts. Phase II assessed internal consistency reliability using Cronbach’s alpha and predicted behavioral intentions applying multiple linear regression. HPV knowledge, expectations, self-efficacy to get HPV vaccine, situational perception, self-efficacy in overcoming barriers to get HPV vaccine, and self-control to get HPV vaccine were regressed on behavioral intentions. Situational perception and self-control to get HPV vaccine were significant predictors, accounting for 22% of variance in behavioral intentions to get vaccinated within the next 6 months. Overall, college men reported low behavioral intentions to getting vaccinated. Future interventions should target situational perception and self-control to increase HPV vaccination intentions.

Myocardial ischemia damages cardiac myocytes in part via opening of the mitochondrial permeability transition pore. Preventing this poreʼs opening is therefore a useful therapeutic goal in treating cardiovascular disease. Hydroxysafflor yellow A has been proposed as a nontoxic alternative to other agents that modulate mitochondrial permeability transition pore opening. In this study, we proposed that hydroxysafflor yellow A prevents mitochondrial permeability transition pore formation in anoxic cardiac myocytes, and thus protects the cell from damage seen during reoxygenation of the cardiac myocytes. Experiments with hydroxysafflor yellow A transport in aerobic myocytes show that roughly 50% of the extracellular dye concentration crosses the cell membrane in a 2-h incubation. In our anoxia/reoxygenation protocol, hydroxysafflor yellow A modulated both the reduction of viability and the loss of rod-shaped cells that attend anoxia and reoxygenation. Hydroxysafflor yellow Aʼs protective effect was similar to that of cyclosporin A, an agent known to inhibit mitochondrial permeability transition pore opening. In additional experiments, plated myocytes were loaded with calcein/MitoTracker Red, then examined for intracellular dye distribution/morphology after anoxia/reoxygenation. Hydroxysafflor yellow A-containing cells showed a cardioprotective pattern similar to that of cyclosporin A (an agent known to close the mitochondrial permeability transition pore). We conclude that hydroxysafflor yellow A can enter the cardiac myocyte and is able to modulate anoxia/reoxygenation-induced damage by interacting with the mitochondrial permeability transition pore.

Objectives: The purpose of this research was to systematically analyze human papillomavirus (HPV) interventions targeting college students. Methods: Completed interventions targeting general HPV prevention, HPV vaccine uptake, or antecedents of HPV vaccination uptake that used any quantitative design, published from January 2000 to January 2014 in the English language, were reviewed. Results: Twelve interventions met the criteria. Ten interventions produced 1 or more significant outcomes on primary or secondary variables of interest. Conclusions: Efficacy of interventions can be enhanced through tailoring materials and pretesting by sex, operationalizing theories, incorporating process evaluations, employing HPV vaccine uptake outcome measures, and utilizing Web-based delivery of programs.

This lesson plan is designed to stimulate awareness and reflection on personal attitudes toward gender expression and sexual orientation. Participants are guided to identify and analyze how external influences from various socialization agents shape gender and sexual orientation norms and, consequently, personal attitudes about gender expression and sexual orientation. This lesson introduces a box as a metaphor for a human being, with the intention of enlightening participants that humans are dynamic beings with unique characteristics that do not necessarily fit in neat boxes. This lesson plan describes how to achieve these goals in college classrooms and with other adult learners.

Menisci are two crescent shaped fibrocartilaginous structures that provide fundamental load distribution and support within the knee joint. Their unique shape transmits axial stresses (i.e. "body force") into hoop or radial stresses. The menisci are primarily an inhomogeneous aggregate of glycosaminoglycans (GAGs) supporting bulk compression and type I collagen fibrils sustaining tension. It has been shown that the superficial meniscal layers are functionally homogeneous throughout the three distinct regions (anterior, central and posterior) using a 300 μm diameter spherical indenter tip, but the deep zone of the meniscus has yet to be mechanically characterized at this scale. Furthermore, the distribution and content of GAG throughout the human meniscal cross-section have not been examined. This study investigated the mechanical properties, via indentation, of the human deep zone meniscus among three regions of the lateral and medial menisci. The distribution of GAGs through the cross-section was also documented. Results for the deep zone of the meniscus showed the medial posterior region to have a significantly greater instantaneous elastic modulus than the central region. No significant differences in the equilibrium modulus were seen when comparing regions or the hemijoint. Histological results revealed that GAGs are not present until at least ~600 μm from the meniscal surface. Understanding the role and distribution of GAG within the human meniscus in conjunction with the material properties of the meniscus will aid in the design of tissue engineered meniscal replacements.

Greeneria uvicola causes bitter rot on Vitis vinifera (bunch grapes) and Muscadinia rotundifolia (muscadine grapes) in warm moist temperate and subtropical regions. This study investigated the phylogenetic relationship of G. uvicola representatives from Australia (67 isolates), the USA (31 isolates), India (1 isolate) and Costa Rica (1 isolate) and compared their pathogenicity and fungicide sensitivity. Differences in cultural and conidial morphology were observed between the isolates from Australia and the USA. Phylogenetic relationships were determined based on three gene regions: the ribosomal DNA (rDNA) internal transcribed spacer 1 (ITS1–5∙8S–ITS2), 28S large subunit (LSU) nuclear rDNA and β-tubulin-2. Greeneria uvicola isolates were clearly differentiated into four groups: isolates from Australia and India; USA isolates from V. vinifera; USA isolates from M. rotundifolia; and the isolate from Costa Rica. All isolates were pathogenic on V. vinifera (cv. Chardonnay) berries although those originating from M. rotundifolia were not as aggressive as isolates from V. vinifera, irrespective of geographical origin. Sensitivity to pyraclostrobin and salicylhydroxamic acid (SHAM) was studied. Despite differences in fungicide applications, hyphal growth inhibition was not significantly different for geographical location, cultivar, tissue, year of collection or different spray regimes. For the Australian and USA isolates, fungal growth inhibition was significantly greater for pyraclostrobin than for SHAM, and was significantly greater for the combined treatment than for each of the fungicides applied singly. The aetiological and epidemiological knowledge of bitter rot collected through this study will aid better prediction and management strategies of this pathogen.

Background and Aims Whilst hepatitis B (HBV) is historically uncommon in Scotland, anecdotal experience suggests an increasing prevalence of chronic infection. We sought to establish whether the incidence of chronic HBV is increasing in Greater Glasgow, and whether patients are assessed in secondary care. Methods The regional virus centre database identified HBV surface antigen (HBsAg) positive samples. For adult patients tested in Glasgow between 1993–2007 the first positive test was identified and classified as acute or chronic infection serologically. Clinic referral and attendance data was then obtained. Results 1,672 patients tested HBsAg positive; 1051 with chronic infection, 421 acute and 200 indeterminate. New diagnoses of HBV remained stable over time, however falling numbers of acute cases were mirrored by a rise in chronic cases from 40 to 119 per annum between 2000 and 2007. Of 193 patients diagnosed in 2006 and 2007, 51% were not seen in secondary care due to non referral (43%) or non attendance (8%). Conclusion Chronic HBV trebled in Glasgow between 2000 and 2007. Most patients were not assessed in secondary care. Improved levels of clinic referral and attendance are required to ensure best care for HBV patients in Glasgow.

Juvenile dispersal and the exchange of offspring among fish populations in river–tributary networks are difficult to characterize, but they may play a substantial role in the dynamics of fisheries in these systems. We used geochemical signatures in otoliths to identify the natal origins of young-of-year smallmouth bass Micropterus dolomieu in the James River and a tributary, the Maury River, in Virginia. The trace element signatures (Sr:Ca, Rb:Ca, Mg:Ca, and Ba:Ca) in otoliths differed significantly between these two rivers, resulting in approximately 87% accuracy in classifying known-origin fry to their natal rivers. The variation in otolith composition reflected the variation in water chemistry within the system. We subsequently used classification functions and stock mixture analyses based on these signatures to identify the natal origins of age-1 juveniles collected from the same rivers 1 year later. The results indicate that approximately 50% of the age-1 smallmouth bass collected in the Jam...

Summary Background Adalimumab is a second generation humanized anti-tumour necrosis factor (TNF) monoclonal antibody with established efficacy in Crohn’s disease (CD). Aims To evaluate the efficacy and safety of adalimumab on a nationwide clinical setting. Methods We used the Scottish Society of Gastroenterology network to identify and follow up the clinical outcomes of patients with CD treated with adalimumab over a 4-year period (2004–2008). Results A total of 98 patients received adalimumab - 100.5 patient follow-up years were recorded (64.3% females; median age at diagnosis of 20.7 years; 88.8% treated with 80/40 mg induction regimen. Eighty eight (89.8%) had previous infliximab with 29 (32.9%) primary nonresponders; 32 (32.6%) were corticosteroid-dependent; 47 (47.9%) were intolerant/resistant to most immunosuppressive therapies (two or more). In all, 60% of patients were in clinical remission at 1-year follow-up, with 30% and 55% requiring dose escalation to weekly therapy at 1-and 2-year follow-up respectively. Overall, 29 (29.6%) patients developed complications with eight nonfatal serious (8.2%) adverse events and 2 (2.0%) case fatalities (sepsis following perforation and disseminated colorectal cancer, respectively). Conclusions Adalimumab is efficacious in severe and refractory CD in the clinical setting, although there remain significant therapy- and disease-related risks of serious complications.

This study has focused on the application of lubricating oil additives in metal V-belt pushing type continuously variable transmission fluids (B-CVTFs) achieve higher friction coefficient and more stable lubricant film formation between the metal-metal contacting surfaces. The metal-metal tribological characteristics of various kinds of antiwear additives and a detergent were experimentally investigated using a ball on plate reciprocating tribometer (Plint TE77), which enables lubricant film formation to be monitored during a rubbing test. Zinc-dithio phosphates (ZnDTPs), a significant difference in instantaneous film formation was observed between primary and secondary type ZnDTP at the moment of increasing step load, due to the variation of the antiwear activity of different ZnDTPs. ZnDTPs in the presence of over-based calcium sulphonate detergent demonstrated slightly less tribofilm formationcompared with ZnDTP alone due to the competition for the rubbing surface. Very interestingly, in the case of phosphonic ester with calcium sulphonate, synergism was observed with more stable film formation and 8 per cent higher friction coefficient than without calcium sulphonate, a positive outcome for a B-CVTF. From surface analysis, it is hypothesized that the tribofilms species composed of iron phosphate, calcium phosphate, and calcium carbonate were generated by the reaction between phosphonic ester and calcium sulphonate, and that the resulting tribofilm plays a dual role in preventingwear and inhibiting the entrainment of lubricant into the interface, resulting in higher friction.

Fatigue crack growth in open holes in aluminium alloys 2024-T351 and 2650 was investigated. Tests were carried out using plates containing plain holes and cold expanded holes in aluminium. The tests explored the influence of the applied stress, the ratio of the minimum to the maximum applied stress, R, and crack closure. Longer fatigue lives of specimens with cold expanded holes were obtained provided that the applied load ratio was less than 0.7, and the maximum applied stress was less than 0.5 of the yield strength. The decrease in fatigue crack growth in cold-expanded specimens was related to higher crack opening stresses which is a consequence of the presence of compressive residual stresses arising from cold expansion. Fatigue crack growth rates were described as a function of an effective stress intensity factor, which was determined using measured crack opening stress. Measured crack opening stress was also compared with opening stress determined from fatigue crack growth rates.

Alpha1-adrenoceptor agonists may potentiate relaxation to beta-adrenoceptor agonists, although the mechanisms are unclear. We compared relaxations induced by beta-adrenoceptor agonists and cyclic AMP-dependent vasodilators in rat pulmonary arteries constricted with prostaglandin F2alpha (PGF2alpha) or the alpha1-adrenoceptor agonist phenylephrine (PE). In addition, we examined whether differences were related to cyclic AMP- or nitric oxide (NO) and cyclic GMP-dependent pathways. Isoprenaline-induced relaxation was substantially potentiated in arteries constricted with PE compared with PGF2alpha. Methoxamine was similar to PE, whereas there was no difference between PGF2alpha and 30 mM KCl. The potentiation was primarily due to a marked increase in the NO-independent component of relaxation, from 9.1+/-1.7% for PGF2alpha to 55.1+/-4.4% for PE. NO-dependent relaxation was also enhanced, but to a lesser extent (50%). Relaxation to salbutamol was almost entirely NO-dependent in both groups, and was potentiated approximately 50% by PE. Relaxation to forskolin (activator of adenylate cyclase) was also enhanced in PE constricted arteries. Part of this relaxation was NO-dependent, but the major effect of PE was to increase the NO-independent component. Propranolol diminished but did not abolish the potentiation. There was no difference in response to CPT cyclic AMP (membrane permeant analogue) between PE and PGF2alpha, suggesting that mechanisms distal to the production of cyclic AMP were unchanged. Relaxation to sodium nitroprusside (SNP) was the same for PE and PGF2alpha, although relaxation to acetylcholine (ACh) was slightly depressed. This implies that potentiation by PE does not involve the cyclic GMP pathway directly. Mesenteric arteries constricted with PE did not show potentiation of isoprenaline-induced relaxation compared to those constricted with PGF2alpha, suggesting that this effect may be specific to the pulmonary circulation. These results clearly show that PE potentiates both the NO-independent and -dependent components of cyclic AMP-mediated relaxation in pulmonary arteries of the rat, although the effect on the former is more profound. We suggest that potentiation of both components is largely due to direct activation of adenylate cyclase via alpha1-adrenoceptors, within the smooth muscle and endothelial cells respectively.

1. Noradrenaline induces a meagre vasoconstriction in small muscular pulmonary arteries compared to large conduit pulmonary arteries. We have examined whether this may be partially related to differences in the beta-adrenoceptor-mediated vasorelaxation component and, in particular, beta-adrenoceptor-mediated NO release. 2. Noradrenaline induced a bell-shaped concentration-response in large (1202+/-27 microm) and small (334+/-12 microm) pulmonary arteries of the rat. In large arteries tension increased to 95.6+/-1.8% of 75 mM KCl (KPSS; n=8) at 2 microM, above which tension declined. The response in small arteries was meagre (12+/-1.5% KPSS, n=9), peaking at 0.2 microM. N(G)-monomethyl-L-arginine (L-NMMA; 100 microM) abolished the decline in tension induced by higher concentrations of noradrenaline in large arteries, and increased maximum tension (117+/-3.5% KPSS, n=5, P

Treating chronic hepatitis C with pegylated interferon alpha may induce or exacerbate psychiatric illness including depression, mania and aggressive behaviour. There is limited data regarding treatment in the context of chronic schizophrenia. We sought to establish the safety and efficacy of treating patients with schizophrenia. Patient and treatment data, prospectively collected on the Scottish hepatitis C database, were analysed according to the presence or absence of a diagnosis of schizophrenia. Time from referral to treatment, and the proportion of patients commencing treatment in each group, was calculated. Outcomes including sustained viral response rates, reasons for treatment termination and adverse events were compared. Of 5497 patients, 64 (1.2%) had a diagnosis of schizophrenia. Patients with schizophrenia (PWS) were as likely to receive treatment as those without [28/61(46%) vs 1639/4415 (37%) P = 0.19]. Sustained viral response (SVR) rates were higher in PWS [21/25 (84%) vs 788/1453 (54%) P < 0.01]. SVR rates by genotype were similar [4/8 (50%) vs 239/684 (35%) Genotype 1 (P = 0.56), 17/17 (100%) vs 599/742 (81%) non-Genotype 1 (P = 0.09)]. Adverse events leading to cessation of treatment were comparable [2/25(8%) vs 189/1453 (13%) P: 0.66]. Patients with schizophrenia are good candidates for hepatitis C treatment, with equivalent SVR and treatment discontinuation rates to patients without schizophrenia.

An X-ray diffraction technique was employed to determine the residual stresses introduced by cold working a fastener hole in a 6-mm thick 2024-T351 aluminum plate. The radial and tangenital residual stresses were measured at both faces of the plate and the measurements compared with the results from a two-dimensional axisymmetric finite-element model. The comparisons were favorable, although modifying the finite-element model to simulate the X-ray process provided better agreement. Experimental determinations of residual stresses showed differences between the two faces of the plate. This feature was attributed to the directional nature of the cold-working process.

Osteoarthritis (OA) is a dehabilitating condition that is highly prevalent in today’s society, frequently leading to a knee replacement. OA is characterized by loss of articular cartilage. Previous research has shown articular cartilage preservation is dependent on the structural integrity of the menisci [1, 2]. The human menisci are two crescent shaped fibrocartilaginous structures that provide fundamental load distribution within the knee joint, ultimately aiding to attenuate stresses at the tibio-femoral site [3–5].Copyright © 2012 by ASME