LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis.

The function of the Laccase domain-containing 1 (LACC1) gene is unknown, but genetic variation at this locus has been reported to consistently affect the risk of Crohn's disease (CD) and leprosy. Recently, a LACC1 missense mutation was found in patients suffering from monogenic forms of CD, but also systemic juvenile idiopathic arthritis. We tested the hypothesis that LACC1 single nucleotide polymorphisms (SNPs), in addition to CD, are associated with juvenile idiopathic arthritis (JIA, non-systemic), and another major form of inflammatory bowel disease, ulcerative colitis (UC). We selected 11 LACC1 tagging SNPs, and tested their effect on disease risk in 3855 Swedish individuals from three case-control cohorts of CD, UC and JIA. We detected false discovery rate corrected significant associations with individual markers in all three cohorts, thereby expanding previous results for CD also to UC and JIA. LACC1's link to several inflammatory diseases suggests a key role in the human immune system and justifies further characterization of its function(s).

New treatments for hepatitis C virus (HCV): scope for preventing liver disease and HCV transmission in England.

New direct-acting antivirals have the potential to transform the hepatitis C (HCV) treatment landscape, with rates of sustained viral response in excess of 90%. As these new agents are expensive, an important question is whether to focus on minimizing the consequences of severe liver disease, or reducing transmission via 'treatment as prevention'. A back-calculation model was used to estimate the impact of treatment of mild, moderate and compensated cirrhosis on incident cases of HCV-related end-stage liver disease/hepatocellular carcinoma (ESLD/HCC). In addition, a dynamic model was used to determine the impact on incidence and prevalence of chronic infection in people who inject drugs (PWID), the main risk group in England. Treating 3500 cirrhotics per year was predicted to reduce ESLD/HCC incidence from 1100 (95% CrI 970-1240) cases per year in 2015 to 630 (95% CrI 530-770) in 2020, around half that currently expected, although treating moderate-stage disease will also be needed to sustain this reduction. Treating mild-stage PWID was required to make a substantial impact on transmission: with 2500 treated per year, chronic prevalence/annual incidence in PWID was reduced from 34%/4.8% in 2015 to 11%/1.4% in 2030. There was little overlap between the two goals: treating mild stage had virtually no impact on ESLD/HCC within 15 years, but the long timescale of liver disease means relatively few PWID reach cirrhosis before cessation of injecting. Strategies focussing on treating advanced disease have the potential for dramatic reductions in severe morbidity, but virtually no preventative impact.

Retrospective cohort study of liver transplantation in the United Kingdom between 1994 and 2010: the impact of hepatitis C infection.

BACKGROUND: Liver transplantation is an important and established treatment option for chronic hepatitis C virus (HCV) related end-stage liver disease (HCV-related ESLD). This study describes trends in elective liver transplantation among persons with HCV-related ESLD. STUDY DESIGN: Retrospective cohort. METHODS: Analyses of United Kingdom (UK) Transplant Registry data for the period 1994 to 2010, with follow-up information extending to 2011. RESULTS: Annual registrations for liver transplantation increased linearly and alcoholic liver cirrhosis (2075, 24%) and HCV-related ESLD (1213, 14%) were the most common indications. HCV-related ESLD patients were mainly aged 40-49 years (32%) and 50-59 years (43%); males (76%); and of white ethnicity (74%). Overall, 75% (956/1213) received a liver transplant with a linear increase over the period (OR 1.11, 95% CI 1.08, 1.13). Pre transplant mortality was unchanged (adjusted OR 1.0, 95% CI 0.96, 1.05) and post-transplant mortality decreased in both HCV-related (adjusted OR 0.77, 95% CI 0.68, 0.88) and non-HCV-related ESLD (adjusted OR 0.82, 95% CI 0.75, 0.89) patients. CONCLUSION: The increase in demand for and receipt of liver transplants among persons with HCV-related ESLD requires coordinated efforts to increase not only organ donation, but investment in HCV prevention programmes and improved access to hepatitis C treatment services.

IL-1ß/HMGB1 complexes promote The PGE2 biosynthesis pathway in synovial fibroblasts.

PGE2 is a potent lipid mediator of pain and oedema found elevated in RA. Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal enzyme of the PGE2 pathway inducible by proinflammatory cytokines. mPGES-1 is markedly upregulated in RA synovial tissue despite antirheumatic treatments, suggesting that multiple inflammatory stimuli contribute to its induction. High-mobility group box chromosomal protein 1 (HMGB1) is known to induce inflammation both by direct interaction with TLR4 and by enhancement of other proinflammatory molecules signalling, through complex formation. The high expression of extracellular HMGB1 within the inflamed synovium, implies its pro-arthritogenic role in RA. We aimed to investigate the effects of IL-1ß/HMGB1 complexes on mPGES-1 and other enzymes of the PGE2 pathway in synovial fibroblasts (SFs) from patients with arthritis. Furthermore, we studied the effect of COX-2 inhibition and IL-1RI antagonism on prostanoid and cytokine production by SFs. Stimulation of SFs with HMGB1 in complex with suboptimal amounts of IL-1ß significantly increased mPGES-1 and COX-2 expressions as well as PGE2 production, as compared to treatment with HMGB1 or IL-1ß alone. Furthermore, NS-398 reduced the production of IL-6 and IL-8, thus indicating that IL-1ß/HMGB1 complexes modulate cytokine production in part through prostanoid synthesis. Treatment with IL-1RA completely abolished the induced PGE2 and cytokine production, suggesting an effect mediated through IL-1RI. IL-1ß/HMGB1 complexes promote the induction of mPGES-1, COX-2 and PGE2 in SF. The amplification of the PGE2 biosynthesis pathway by HMGB1 might constitute an important pathogenic mechanism perpetuating inflammatory and destructive activities in rheumatoid arthritis.

Improved hepatitis C treatment response in younger patients: findings from the UK HCV National Register cohort study.

In a cohort of 272 treatment-naive individuals with chronic hepatitis C infection acquired on a known date who were enrolled in the UK HCV National Register, a progressive improvement in response to treatment was found with the evolution of antiviral therapies from 20% (25/122) for interferon monotherapy to 63% (55/88) for pegylated interferon+ribavirin therapy. Multivariable analysis results showed increasing age to be associated with poorer response to therapy [odds ratio (OR) 0·84, 95% confidence interval (CI) 0·72-0·99, P=0·03] whereas time since infection was not associated with response (OR 0·93, 95% CI 0·44-1·98, P=0·85). Other factors significantly associated with a positive response were non-type 1 genotype (P<0·0001) and combination therapies (P<0·0001). During the first two decades of chronic HCV infection, treatment at a younger age was found to be more influential in achieving a sustained viral response than treating earlier in the course of infection.

Spontaneous loss of hepatitis C virus RNA from serum is associated with genotype 1 and younger age at exposure.

A variety of factors have been associated with spontaneous loss of hepatitis C virus (HCV)-RNA from serum, including infecting HCV type, although results are conflicting. This study aimed to investigate further whether infecting HCV type was linked to spontaneous loss of HCV-RNA. Serum samples from 321 untreated HCV antibody positive patients presenting at the Hepatology clinic at Addenbrooke's Hospital, Cambridge between 2004 and 2007 were tested. These individuals were classified either as HCV antibody and HCV-RNA positive (viremic, n = 219) or HCV antibody positive and repeatedly HCV-RNA negative (non-viremic, n = 102). Infecting HCV type was identified by genotyping (viremic) or serotyping (non-viremic). Binomial regression analysis investigated the independent effect of HCV type on spontaneous loss of HCV-RNA from serum by comparing the two groups. Ninety-one percent of patients were found to be either genotype 1 or genotype 3. The prevalence of type 1 infection was greater among non-viremic (64.5%) than viremic individuals (45%). After controlling for the effects of potential confounding factors, multivariable analyses showed that individuals with type 1 infections were more likely to be non-viremic than genotype 3 infections (RR = 2.07; 95% CI: 1.25, 3.43; P = 0.005). Individuals infected at an older age were also less likely to become HCV-RNA negative spontaneously (RR = 0.42 comparing those infected at ≥20 years of age against those infected at <20 years of age, 95% CI: 0.25, 0.72; P = 0.002). In conclusion, the results suggest that HCV genotype 1 infections are more likely than genotype 3 infections to become spontaneously non-viremic, as are infections acquired at younger age.

Actin from the nematode, Caenorhabditis elegans, is a single electrofocusing species.

We have prepared actin from wild type Caenorhabditis elegans animals by three procedures: a purification dependent on the ability of actin to form F-actin, affinity chromatography which preferentially binds G-actin, and co-precipitation of an actin-myosin complex by antimyosin antibodies. Each preparation yields a single electrofucsing species of actin. Comparison of actin from C. elegans embryos and animals reveals that embryos also have the same single electrofocusing species of actin.

The binary complex of pig plasma gelsolin with Mg2+-G-actin in ATP and ADP.

Pig plasma gelsolin combined with Mg-G-actin at less than 10(-8) M Ca2+ to yield a binary complex. Complexes formed from G-actin with bound ATP or ADP. They contained approx. 1 mol of non-exchangeable nucleotide per mol of actin. ATP hydrolysis was not coupled to binary complex formation, but ATP in the complex hydrolysed very slowly. The nucleotide in the binary complex behaved like one of the two nucleotide molecules in the ternary complex (two actin monomers to one gelsolin), but the actin-gelsolin interaction was weaker in the binary complex.

Lack of nucleotide cleavage on the binding of G-actin-ATP to plasma gelsolin.

G-Actin-ATP bound to plasma gelsolin to form a 2:1 complex. The complex contained approximately equivalent amounts of nucleotide and actin. More than 84% of this nucleotide was ATP. Half of the bound nucleotide was displaced by cold chase and the remainder did not exchange, implying that the two actins in the complex are not equivalent.

Plasma gelsolin caps and severs actin filaments.

Plasma gelsolin caps actin filaments at their 'barbed' ends and severs them along their length. Capping has been demonstrated both by direct visualization using gold-labeled gelsolin and by inhibition of actin polymerization onto the barbed ends of fragments of the acrosomal process of Limulus sperm. Severing activity is demonstrated by the fact that actin filaments nucleated off acrosomal fragments are shortened or removed within a few seconds by added plasma gelsolin without any obvious disruption of the actin bundles in the acrosomal processes themselves.

Relative importance of heritable characteristics and lifestyle in the development of maternal obesity.

STUDY OBJECTIVE: To assess the relative importance of heritable characteristics and lifestyle in the development of "maternal obesity" after pregnancy. SETTING: South east London, in the homes of mothers who had delivered their babies at either Guy's, Lewisham or St Thomas's hospitals. PARTICIPANTS: Seventy four mothers of low antenatal risk who had been enrolled in the Antenatal Care (ANC) Project (a previous trial of antenatal care) during the first trimester of pregnancy, and who had subsequently been followed up 2.5 years after delivery. DESIGN: Information on parental obesity, psychosocial and sociodemographic factors as well as lifestyle, was gathered during a semi-structured interview at each mother's home. Additional anthropometric and psychosocial data were taken from the existing ANC Project database. These data were used to assess the relative importance of heritable characteristics and lifestyle on changes in maternal body weight from the beginning of pregnancy to the follow up interview. MAIN RESULTS: After adjusting for the effects of potential confounders and known risk factors for maternal obesity, women who selected larger silhouettes to represent their biological mothers were significantly more likely to have higher long term weight gains than those who selected thinner maternal silhouettes (r = 0.083, p = 0.004). Women who were less satisfied with their bodies postpartum had significantly greater long term weight gains than those women who displayed no increase in dissatisfaction with their bodies after pregnancy (r = 0.067, p = 0.010). CONCLUSIONS: A heritable predisposition to gain weight together with changing attitudes to body size, both had an independent role in the development of maternal body weight after pregnancy. Differences in each woman's heritable predisposition to gain weight and any changes in body image that occur after pregnancy might explain why some women gain weight in association with pregnancy.

Binding, pharmacological and immunological profiles of the delta-selective opioid receptor antagonist HS 378.

HS 378 is a recently developed indolomorphinan with high selectivity and antagonist potency at the delta-opioid receptor. The present study was performed to characterize the opioid binding properties and pharmacological and immunological activity of HS 378 and to compare them with those of two well-known delta-opioid receptor antagonists, naltrindole (NTI) and naltriben (NTB). In vitro opioid receptor binding profiles were determined in rat brain homogenates. HS 378 showed 4.7- and 2.4-fold higher mu/delta selectivity compared to NTI and NTB, respectively. In the [35S]GTPgammaS functional assay carried out in cell lines expressing cloned human opioid receptors, HS 378 was found to be a pure delta-opioid receptor antagonist. In vitro, exposure of HS 378 resulted in an apparent dose-related suppression of concanavalin A induced rat T-lymphocyte proliferation with an IC50 value of 0.54 microM. NTI showed also immunosuppression with an IC50 value of 6.93 microM, whereas NTB had no effect. The IC50 of HS 378 was 13 times lower than that of NTI and 8 times higher than that of cyclosporin A. Taken together, our findings indicate that the small molecule HS 378 has properties that may be of therapeutic value in the setting of human inflammatory diseases.

Do the psychosocial and behavioral changes that accompany motherhood influence the impact of pregnancy on long-term weight gain?

The aim of the present study was to assess whether the psychosocial and behavioral changes that occur during and after pregnancy influence long-term weight gain. The study examined 74 mothers enrolled in the Antenatal Care (ANC) Project (a randomized controlled trial of antenatal care based in South London), all of whom had volunteered to take part in a subsequent follow-up study. Data on body weight at the beginning of pregnancy; lifestyle and behavior during pregnancy; antenatal care and obstetric history; together with measures of postnatal depression and parenting stress following pregnancy were taken from the existing ANC Project database. Additional measurements of height and weight together with information on a variety of lifestyle changes and psychosocial characteristics, were gathered during semi-structured interviews at each mother's home, two and a half years after their children had been born. The results show that pregnancy-related weight gains are not simply the result of retaining weight that is gained during pregnancy, but that they also originate from gaining additional weight in the postpartum period. Mothers who felt they ate more after their children were born, had significantly greater long-term weight gains (2.78 (1.42) kg) than those who felt that they had not increased their food intake (-1.15 (0.76) kg; t = 2.49, p = 0.016). Similarly, mothers who felt they had greater access to food postpartum, had significantly greater long-term weight gains (1.70 (0.87) kg) than those who felt they did not have greater access to food (-1.37 (1.13) kg; t = 2.18, p = 0.032). There was some evidence that the lifestyle changes which accompany pregnancy and motherhood increase some women's vulnerability to eating disorder psychopathology. Mothers who felt they did less exercise after pregnancy than they did before, were also at greater risk of long-term weight gain (p = 0.028), as were mothers with low numbers of supportive individuals (p = 0.033). Neither the stress of parenting nor maternal depression were significantly associated with an increased risk of long-term weight gain (p > 0.05).

Methodological considerations in the design of an obstetric database abstracted from medical records.

The quality of maternal information contained within contemporary obstetric notes was investigated by abstracting data from the medical records of multiparous women who were admitted to a major city hospital in the South Thames Region. Potential sources of error were identified by comparing information recorded in different sections of each obstetric notes and within the obstetric notes of consecutive pregnancies. The format of the obstetric notes largely determined which variables were recorded and, to some extent, the accuracy of information collected. However, the quality of the data ultimately depended upon whether each variable was self-reported or directly measured. Self-reported variables were subject to selective omission and subjective bias, while measured variables were susceptible to inaccurate equipment and poor measurement practice. By interviewing a sample of midwives currently involved in antenatal care at the Trust it was possible to confirm that extensive variation in measurement and recording procedures routinely occurred.

Adolescents' misperceptions of the dangerousness of acetaminophen in overdose.

Clinical observations suggest that adolescents commonly and naively use acetaminophen in suicide attempts even when they do not wish to die. It is estimated that 18,500-mg acetaminophen tablets can lead to hepatotoxicity, while death is usually associated with ingestion of 50 or more tablets. A sample comprising 569 adolescent students completed an author-designed survey assessing teenagers' knowledge of acetaminophen's therapeutic and harmful effects. The findings support our original data that adolescents have ready access to acetaminophen and use it in suicide attempts, but underestimate its potential for toxicity. Forty-two percent of this sample underestimated the dose to cause harm, believing it would require 20 or more tablets, and 50% underestimated the dose to cause death, stating 100 or more pills would be necessary. Adolescents appear to seriously underestimate the dangerousness of acetaminophen in overdose, and lack knowledge regarding side effects of overdose.

Adolescent psychopathy in relation to delinquent behaviors, conduct disorder, and personality disorders.

The purpose of this study was to explore the relationship between psychopathy as measured by The Revised Psychopathy Checklist (PCL-R) and delinquent behaviors, conduct disorder, and personality disorders in psychiatrically hospitalized adolescents. Thirty adolescent inpatients were assessed for psychopathy, delinquent behaviors, DSM-III-R Axis I disorders, and personality disorders using the Revised Psychopathy Checklist (PCL-R), the Diagnostic Interview for Children and Adolescents (DICA-R), and the Structured Interview for DSM-III-R Personality Disorders (SIDP-R). Significant relationships were noted between elevated PCL-R psychopathy scores and delinquent behaviors, conduct disorder, and narcissistic personality disorder. The validity of the PCL-R as a measure of psychopathy in adolescence was supported. Longitudinal studies are needed to clarify the clinical application of the PCL-R to adolescent populations.

The reliability of hand-written and computerised records of birth data collected at Baragwanath hospital in Soweto.

This study examined the reliability of hand written and computerised records of birth data collected during the Birth to Ten study at Baragwanath Hospital in Soweto. The reliability of record-keeping in hand-written obstetric and neonatal files was assessed by comparing duplicate records of six different variables abstracted from six different sections in these files. The reliability of computerised record keeping was assessed by comparing the original hand-written record of each variable with records contained in the hospital's computerised database. These data sets displayed similar levels of reliability which suggests that similar errors occurred when data were transcribed from one section of the files to the next, and from these files to the computerised database. In both sets of records reliability was highest for the categorical variable infant sex, and for those continuous variables (such as maternal age and gravidity) recorded with unambiguous units. Reliability was lower for continuous variables that could be recorded with different levels of precision (such as birth weight), those that were occasionally measured more than once, and those that could be measured using more than one measurement technique (such as gestational age). Reducing the number of times records are transcribed, categorising continuous variables, and standardising the techniques used for measuring and recording variables would improve the reliability of both hand-written and computerised data sets.