Hepatitis C virus outside the liver

Observational and some experimental data suggest that hepatitis C virus can manifest in a variety of disease processes outside the liver. The links between hepatitis C virus and membranoproliferative glomerulonephropathy, porphyria cutanea tarda, lichen planus, cryoglobulinemia, diabetes mellitus, B-cell non-Hodgkin’s lymphoma, and thyroiditis are critically reviewed. Based on the available evidence, recommendations for the clinical approach to patients with extrahepatic diseases are discussed.     

Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease.

Previous studies in the MPTP-lesioned primate model of Parkinson's disease have demonstrated that alpha(2) adrenergic receptor antagonists such as idazoxan, rauwolscine, and yohimbine can alleviate L-dopa-induced dyskinesia and, in the case of idazoxan, enhance the duration of anti-parkinsonian action of L-dopa. Here we describe a novel alpha(2) antagonist, fipamezole (JP-1730), which has high affinity at human alpha(2A) (K(i), 9.2 nM), alpha(2B) (17 nM), and alpha(2C) (55 nM) receptors. In functional assays, the potent antagonist properties of JP-1730 were demonstrated by its ability to reduce adrenaline-induced (35)S-GTPgammaS binding with K(B) values of 8.4 nM, 16 nM, 4.7 nM at human alpha(2A), alpha(2B), and alpha(2C) receptors, respectively. Assessment of the ability of JP-1730 to bind to a range of 30 other binding sites showed that JP-1730 also had moderate affinity at histamine H1 and H3 receptors and the serotonin (5-HT) transporter (IC(50) 100 nM to 1 microM). In the MPTP-lesioned marmoset, JP-1730 (10 mg/kg) significantly reduced L-dopa-induced dyskinesia without compromising the anti-parkinsonian action of L-dopa. The duration of action of the combination of L-dopa and JP-1730 (10 mg/kg) was 66% greater than that of L-dopa alone. These data suggest that JP-1730 is a potent alpha(2) adrenergic receptor antagonist with potential as an anti-dyskinetic agent in the treatment of Parkinson's disease.     

Mammalian wound repair environment does not permit skeletal muscle regeneration

Repair and regeneration are mutually exclusive responses to injury. Previous studies have shown that wound fluids promote proliferation, but not differentiation, of myoblasts in vitro. This study explored the ability of the repair environment within polyvinyl alcohol sponges to support cellular events of skeletal muscle regeneration in vivo. Neonatal rat L8 myoblasts were modified to express beta-galactosidase then inoculated into plain sponges or sponges containing minced muscle. Labeled myoblasts were found in myotubes within minced muscle. In contrast, myoblasts inoculated into sponges lacking muscle remained mononucleate. Occurrence of labeled myoblasts within myotubes, which required fusion, represents differentiation of inoculated myoblasts to participate in regeneration. Failure of myoblasts to form myotubes in sponges lacking muscle suggests that this wound repair environment cannot support morphologic differentiation of myoblasts. Although this repair environment can support the survival of myoblasts, it did not support myogenesis, an event necessary to complete skeletal muscle regeneration. Data from this study reinforce earlier studies in vitro and suggest that the properties attributed to wound fluids are inherent in the wound environment. Whether the inability of this environment to support myogenesis is the consequence of the absence of essential factors or the presence of inhibitors remains to be determined.     

Excess mortality attributable to hip fracture in white women aged 70 years and older.

OBJECTIVE: The purpose of this study was to estimate the excess mortality attributable to hip fracture. METHODS: The 6-year survival rate of community-dwelling White female hip fracture patients aged 70 years and older entering one of seven hospitals from 1984 to 1986 (n = 578) was compared with that of White female respondents aged 70 years and older interviewed in 1984 for the Longitudinal Study on Aging (n = 3773). RESULTS: After age, education, comorbidity, and functional impairment were controlled, the mortality differential between the two groups accumulated to an excess among hip fracture patients of 9 deaths per 100 women 5 years postfracture. Among those with three or more functional impairments or one or more comorbidities, the excess was 7 deaths per 100: the effect of the fracture had disappeared in these groups by 4 years. In contrast, those with two or fewer impairments and those with no comorbidities had a continuing trend of increased mortality, with an excess of 14 deaths per 100 by 5 years. CONCLUSIONS: There is an immediate increase in mortality following a hip fracture in medically ill and functionally impaired patients, whereas among those with no comorbidities and few impairments, there is a gradual increase in mortality that continues for 5 years postfracture.     

Benzamide potentiation of the cytotoxicity of bifunctional galacticol in resistant P388 leukemia correlates with inhibition of DNA ligase II

Summary Benzamide (BA) enhances the cytotoxicity of 1,2:5,6-dianhydrogalactitol (DAG) in resistant P388 leukemia cell lines but not in the sensitive parent line. To examine the reason for this difference in response, we carried out an alkaline elution assay using proteinase K to study DNA interstrand cross-linking. At early time points, equal concentrations of DAG produced the same level of interstrand cross-linking (ICL) in the resistant and sensitive P388 leukemic cells, although marked differences were observed in their cytotoxicity toward the two cell lines. In the sensitive cells, neither the amount of DNA cross-linking nor the cytotoxicity changed during the observation period (38 h) in either the presence or the absence of BA. In contrast, the elution rate of the DNA of DAG-treated resistant cells increased with time and had reached the control levels by 38 h. However, when these cells were postincubated with BA for 38 h, the elution rate of DNA was much faster than that observed for the untreated resistant cells, indicating an accumulation of DNA singlestrand breaks (SSB). The SSB accumulation caused by BA was associated with an inhibition of the activity of ligase II enzyme, which was stimulated when resistant cells were treated with DAG alone. The potentiating effect of BA on the resistant cells can thus be related to the inhibiting action of BA on the DNA-rejoining enzyme, ligase II. The lack of sensitization by BA of the DAG-treated parent cell line may be attributable to the absence of DNA-SSB formation, which is necessary for ligase II activation through the stimulation of poly(ADP-ribose) synthesis.     

Identification of widespread Helicobacter hepaticus infection in feces in commercial mouse colonies by culture and PCR assay.

The identification of a new murine pathogen, Helicobacter hepaticus, and its association with chronic active hepatitis and liver tumors prompted an evaluation of the prevalence of H. hepaticus in commercially available mice. Of the 28 different strains or stocks, totaling 160 mice from four major commercial vendors, cultured for H. hepaticus, 100% of mice from two outbred strains from one vendor were infected with H. hepaticus, whereas 9 of 13 inbred mouse strains from another vendor were infected. This high prevalence of H. hepaticus established a need for a rapid and reproducible, noninvasive assay for the screening of colony-maintained mice being used for biomedical research. The culturing of fecal material by using 0.45-microns-pore- size filtration for H. hepaticus consistently yielded reproducible results but required extended periods of time. (1 to 3 weeks) to obtain a definitive answer. Although it is rapid, the use of a direct PCR-based detection assay with fecal specimens is restricted by inhibitory agents. to circumvent these inhibitory agents and to augment our H. hepaticus culture technique, we have developed a novel PCR system in which the bacteria are isolated from fecal material in the presence of polyvinylpyropyrollidone and lysed by treatment with Chelex 100. The PCR is performed with Tth polymerase supplemented with a polymerase enhancer. By this PCR method, 24 H. hepaticus culture-positive and 30 H. hepaticus culture-negative fecal samples were correctly identified. Moreover, two samples which were PCR positive and culture negative initially were positive by both methods upon retesting of fresh material. Southern blot hybridizations and sequencing of PCR products showed them to be H. hepaticus specific. A comparison of results obtained under identical conditions indicated a 100-fold increase in sensitivity with Tth polymerase over Taq polymerase. This PCR method can be used as a noninvasive means of rapidly screening large numbers of colony mice for H. hepaticus.     

Becoming a mother — an analysis of women's experience of early motherhood

This paper presents the results of a qualitative study conducted by midwife researchers into women's experience of new motherhood. Data were collected using focus groups involving 55 first-time mothers and analysed using grounded theory method. The analysis produced six categories: 'realizing', 'unready', 'drained', 'aloneness', 'loss' and 'working it out'. The core category, 'becoming a mother', integrates all other categories and encapsulates the process of change experienced by women. Also explained are factors mediating the often distressing experience of becoming a mother. The analysis provides a conceptualization of early motherhood enabling the development of strategies for midwives, nurses and others helping women negotiate this challenge.     

Antenatal education – where next?

The history of antenatal education throws light on why contemporary class attenders represent only a particular section of the childbearing population. Since Victorian times, the non-availability of the women's network to middle class women has forced them to seek knowledge of their own bodies, confidence in their childbearing capacities and the support of other women through formal educational opportunities. Research suggests that antenatal classes often fail to provide women with a realistic account of birth and parenting to replace the lived experience of earlier decades and may not be facilitated in such a way as to create the support groups which class attenders critically need. Teaching approaches often promote dependency amongst clients rather than nurturing the decision-making skills required by a consumer-driven maternity service.     

Empowering research: statistical power in general practice research

BACKGROUND: Statistical power is a measure of the extent to which a study is capable of discerning differences or associations which exist within the population under investigation, and is of critical importance whenever a hypothesis is tested by statistics. Conventionally, studies should reach a power level of 0.8, such that four times out of five a false null hypothesis will be rejected by a study. Statistical power may most easily be increased by increasing sample size. OBJECTIVE: We aimed to assess the level of statistical power of general practice research. METHODS: A total of 1422 statistical tests in 85 quantitative original papers in the British Journal of General Practice were analysed for statistical power. RESULTS: The median power of tests analysed was 0.71, representing a slightly greater than two-thirds likelihood of rejecting false null hypotheses. Of 85 studies, 37 (44%) attained power of 0.8 or more. Ten studies had power of more than 0.99 suggesting 'over-powering'. Twenty- one of the papers surveyed (25%) had a likelihood of gaining significant results poorer than that obtained by tossing a coin when a null hypothesis is false. CONCLUSION: While achieving higher power than studies in similar surveys of other disciplines, the power of general practice research falls short of the 0.8 convention. Adequate power is essential so that effects which exist are not missed. Recommendations are made concerning power calculations prior to the start of research and reporting of results in journal articles.