Managing chronic hepatitis C acquired through intravenous drug use

We retrospectively reviewed the provision and uptake of hospital services for 253 current and ex-intravenous drug users with hepatitis C virus (HCV). Overall, 237 attended at least one clinic (mean age 32 years, 70% male, 43% on maintenance methadone); 81% had evidence of active viral replication and 137 agreed to a liver biopsy to assess disease severity. Of these 137, 24% had mild chronic hepatitis with a low risk of progression to cirrhosis, but 9% had cirrhosis (mean age 40 years, mean time since initial intravenous drug use 15.8 years). Only 50 of the 100 patients in whom antiviral therapy was indicated, commenced treatment; 18 (36%) have had a sustained virological response. The natural history or response to treatment of chronic HCV in those who acquire it through intravenous drug use is not different to that previously reported for post-transfusion HCV. However, a substantial proportion default from follow-up or decline further intervention. As intravenous drug use is now the main risk factor for acquisition of HCV, these data have implications for future delivery of care aimed at limiting the morbidity of chronic HCV, and limiting the spread of hepatitis C virus infection amongst intravenous drug users.     

Effect of tumour and chemoradiotherapy on oesophageal motility

Background The contribution of dysmotility to dysphagia in oesophageal cancer is unclear. Aim To examine oesophageal motility in patients with oesophageal carcinoma and to assess the effect of chemoradiotherapy on motility. Methods Stationary manometry and 24-hour pH-metry were performed in 12 patients with oesophageal carcinoma and one week following completion of chemoradiotherapy using 5-fluorouracil (5-FU), cisplatin and 40Gy radiotherapy. Results All patients had abnormal motility prior to treatment. Peristalsis was impaired in 11 patients with a mean (SD) of 25% (9) of waves normally propagated. Eight patients had 20% or more simultaneous waves. Following chemoradiotherapy, the percentage of waves normally propagated increased from 25% (9) to 52% (10) (p < 0.03) and normal peristalsis was restored in four patients. The percentage of simultaneous waves decreased from 38% (11) to 21.6% (10) (p=0.129) while the percentage of dropped or increased waves decreased from 20% (11) to 8.3% (4) (p=0.264). Conclusions Oesophageal motility is disturbed in oesophageal cancer. Dysphagia in oesophageal cancer may be partly explained by oesophageal dysmotility. This is improved by chemotherapy.     

The activity of caspase-3-like proteases is elevated during the development of colorectal carcinoma.

Activated caspase-3-like proteases promote apoptotic cell death by cleaving cellular substrates. Caspase-3-like activity was measured in colonic carcinomas and in matched normal colonic mucosa from 31 patients and was significantly elevated in 25/ 31 colonic carcinomas and adenomas when compared to normal mucosa (P < 0.0001). Caspase-3-like activity was much higher in normal mucosa and tumours of female subjects than of males (P < 0.0001). No correlation was obtained between caspase-3-like activity and location of the tumour, tumour grade, stage, or patient age. The marked increase in caspase-3-like activity in colorectal carcinomas may reflect an increase in the proportion of cells undergoing spontaneous apoptosis.     

Experimental study of peritoneal blood flow and insufflation pressure during laparoscopy

BACKGROUND: Port-site metastases after laparoscopic surgery may occur with greater frequency than would be expected following open resection of intra-abdominal malignancies, but the causal mechanism for this is incompletely understood. The possibility that insufflation may increase peritoneal blood flow producing a wound environment conducive to the formation of metastases was investigated.METHODS: The effects of insufflation gas type and pressure were studied in 30-kg female pigs. Pigs were divided into five groups, which were subjected to insufflation at 12 mmHg pressure with helium, insufflation at 12, 8 or 4 mmHg pressure with carbon dioxide, or laparotomy. A microsphere technique utilizing two distinct radiotracers, 99mTc-labelled macroaggregated albumin (MAA) and 51Cr-labelled MAA, was used to study blood flow to the peritoneum, liver and kidneys.RESULTS: Insufflation with carbon dioxide or helium gases had no effect on renal (P < 0.09) or hepatic blood flow (P = 0.54). However, insufflation significantly increased peritoneal blood flow when carbon dioxide (P < 0.05), but not when helium (P = 0.99), was used as the insufflating gas.CONCLUSION: These data suggest that blood flow within the peritoneum is influenced by insufflation with carbon dioxide. It is conceivable that such hyperaemia could increase the propensity for implanted tumour cells to metastasize in these sites following laparoscopy.     

Serum profiles of insulin-like growth factors and their binding proteins in adults with growth hormone receptor deficiency treated with insulin like growth factor I

Six adult patients with growth hormone receptor deficiency (GHRD) (2 men, 4 women) with an identical defect in the growth hormone receptor (GHR) gene, were treated with recombinant human insulin-like growth factor I (IGF-I), 40 μgikg S.C. twice daily, for 7 days. Serum concentrations of IGF peptide and IGF binding protein-3 (IGFBP-3) were measured by specific radioimmunoassays; serum IGFBPs were also measured by Western ligand blotting. The size distribution of both IGF-I and IGF-II was measured in serum following size-exclusion fast-performance liquid chromatography. IGF-I treatment resulted in a normalization of serum IGF-I levels on days 1–7 of treatment and a decrease in serum IGF-II levels. The fall in IGF-II levels and the simultaneous rise in IGF-I levels, however, resulted in an unchanged total serum IGF level. The low IGFBP-3 values did not significantly change during treatment, whereas there was a slight increase in IGFBP-2 levels. Preliminary analysis of size-fractionated sera suggested an increase in IGF-I levels in the 40 and 150 kDa regions at the expense of IGF-II levels. The results suggest that despite the failure of IGF-I treatment to increase IGFBPs significantly, serum IGFBP concentrations were sufficient to maintain normal levels of IGF-I. 0 Laron syndrome, growth hormone receptor deficiency, insulin-like growth factors, insulin-like growth factor binding protein     

Dural infolding during C1-2 myelography

Inward buckling of the dura at C1-2 may occasionally occur with hyperextension of the neck and can result in a difficult or unsuccessful puncture when the posterior lateral C1-2 approach is used for cervical myelography. In this circumstance, placement of the head in a neutral or slightly flexed position may widen the posterior subarachnoid space and facilitate the needle puncture.     

Higher order aberrations,refractive error development and myopia control: a review

Evidence from animal and human studies suggests that ocular growth is influenced by visual experience. Reduced retinal image quality and imposed optical defocus result in predictable changes in axial eye growth. Higher order aberrations are optical imperfections of the eye that alter retinal image quality despite optimal correction of spherical defocus and astigmatism. Since higher order aberrations reduce retinal image quality and produce variations in optical vergence across the entrance pupil of the eye, they may provide optical signals that contribute to the regulation and modulation of eye growth and refractive error development. The magnitude and type of higher order aberrations vary with age, refractive error, and during near work and accommodation. Furthermore, distinctive changes in higher order aberrations occur with various myopia control treatments, including atropine, near addition spectacle lenses, orthokeratology and soft multifocal and dual-focus contact lenses. Several plausible mechanisms have been proposed by which higher order aberrations may influence axial eye growth, the development of refractive error, and the treatment effect of myopia control interventions. Future studies of higher order aberrations, particularly during childhood, accommodation, and treatment with myopia control interventions are required to further our understanding of their potential role in refractive error development and eye growth.     

Acceptability of the nestorone®/ethinyl estradiol contraceptive vaginal ring: development of a model; implications for introduction

Objectives

Develop and test a theoretical acceptability model for the Nestorone®/ethinyl estradiol contraceptive vaginal ring (CVR); explore whether domains of use within the model predict satisfaction, method adherence and CVR continuation.

Study Design

Four domains of use were considered relative to outcome markers of acceptability, that is, method satisfaction, adherence and continuation. A questionnaire to evaluate subjects' experiences relative to the domains, their satisfaction (Likert scale) and adherence to instructions for use was developed and administered to 1036 women enrolled in a 13-cycle Phase 3 trial. Method continuation was documented from the trial database. Stepwise logistic regression (LR) analysis was conducted and odds ratios (ORs) calculated to assess associations of satisfaction with questions from the four domains. Fisher's Exact Test was used to determine the association of satisfaction with outcome measures.

Results

A final acceptability model was developed based on the following determinants of CVR satisfaction: ease of use, side effects, expulsions/feeling the CVR and sexual activity including physical effects during intercourse. Satisfaction was high (89%) and related to higher method adherence [OR, 2.6 (1.3, 5.2)] and continuation [OR, 5.5 (3.5, 8.4)]. According to the LR analysis, attributes of CVR use representing items from the four domains — finding it easy to remove, not complaining of side effects, not feeling the CVR while wearing it and experiencing no change or an increase in sexual pleasure and/or frequency — were associated with higher odds of satisfaction.

Conclusion

Hypothesized domains of CVR use were related to satisfaction, which was associated with adherence and continuation. Results provide a scientific basis for introduction and future research.

Implications Statement

Acceptability research is important when introducing a new method of contraception and determining whether it can be a successful option in meeting the reproductive health needs of women and men. This study was designed to test a conceptual model of acceptability and identify factors associated with successful use of a new contraceptive delivery modality. Original research was conducted for this publication.     

Modulation of gastrointestinal function by MuDelta,a mixed μ opioid receptor agonist/ μ opioid receptor antagonist

BACKGROUND & PURPOSE

Loperamide is a selective µ opioid receptor agonist acting locally in the gastrointestinal (GI) tract as an effective anti-diarrhoeal but can cause constipation. We tested whether modulating µ opioid receptor agonism with δ opioid receptor antagonism, by combining reference compounds or using a novel compound (‘MuDelta’), could normalize GI motility without constipation.

EXPERIMENTAL APPROACH

MuDelta was characterized in vitro as a potent µ opioid receptor agonist and high-affinity δ opioid receptor antagonist. Reference compounds, MuDelta and loperamide were assessed in the following ex vivo and in vivo experiments: guinea pig intestinal smooth muscle contractility, mouse intestinal epithelial ion transport and upper GI tract transit, entire GI transit or faecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil (post-inflammatory). Colonic δ opioid receptor immunoreactivity was quantified.

KEY RESULTS

δ Opioid receptor antagonism opposed µ opioid receptor agonist inhibition of intestinal contractility and motility. MuDelta reduced intestinal contractility and inhibited neurogenically-mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. Stress up-regulated δ opioid receptor expression in colonic epithelial cells. In stressed mice, MuDelta normalized GI transit and faecal output to control levels over a wide dose range, whereas loperamide had a narrow dose range. MuDelta and loperamide reduced upper GI transit in the post-inflammatory model.

CONCLUSIONS AND IMPLICATIONS

MuDelta normalizes, but does not prevent, perturbed GI transit over a wide dose-range in mice. These data support the subsequent assessment of MuDelta in a clinical phase II trial in patients with diarrhoea-predominant irritable bowel syndrome.