Alcoholic liver disease: from pathophysiology to therapy

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, in October 2004. A salient feature of this symposium was to demonstrate how the striking advances made in our understanding of the pathophysiology of alcoholic liver disease are now raising prospects for better treatment as well. Genetic factors are now being elucidated, and F. Stickel (Germany) has summarized his own studies as well as those of others. M. Salaspuro (Finland) updated the possible role of gut bacteria in the pathogenesis of alcoholic liver disease, bringing us closer to antibacterial therapy as part of the treatment of alcoholic liver disease. Specifically, the gut bacterial flora may be important via the in situ production of acetaldehyde and the associated intestinal injury, which may favor the translocation of toxins from the gut lumen to the systemic circulation and the liver. The analytical progress in the assessment of alterations of phospholipid composition in liver membranes described by H. P. Schlemmer (Germany) may eventually give us an objective method to recognize patients in whom phospholipid therapy might be indicated. Other novel treatment modalities for severe alcoholic hepatitis were described by Y. Horie and H. Ishii (Japan), including plasma exchange. Finally, the pros and cons of nutraceutical therapy were analyzed by C. S. Lieber, with a demonstration that although some nutraceuticals may have toxicity exacerbated by alcohol and must be administered very carefully within a narrow therapeutic window, others are actually beneficial as demonstrated under controlled conditions.     

Interactions between light-induced currents, voltage-gated currents, and input signal properties in Drosophila photoreceptors

Voltage-gated K(+) channels are important in neuronal signaling, but little is known of their interactions with receptor currents or their behavior during natural stimulation. We used nonparametric and parametric nonlinear modeling of experimental responses, combined with Hodgkin-Huxley style simulation, to examine the roles of K(+) channels in forming the responses of wild-type (WT) and Shaker mutant (Sh(14)) Drosophila photoreceptors to naturalistic stimulus sequences. Naturalistic stimuli gave results different from those of similar experiments with white noise stimuli. Sh(14) responses were larger and faster than WT. Simulation indicated that, in addition to eliminating the Shaker current, the mutation changed the current flowing through light-dependent channels [light-induced current (LIC)] and increased the delayed rectifier current. Part of the change in LIC could be attributed to direct feedback from the voltage-sensitive ion channels to the light-sensitive channels by the membrane potential. However, we argue that other changes occur in the light detecting machinery of Sh(14) mutants, possibly during photoreceptor development.     

No evidence of Mycoplasma pneumoniae in acute myringitis

Our aim was to discover Mycoplasma pneumoniae in bullous and hemorrhagic myringitis in children <2 years of age. Middle ear fluid samples (n = 37) and samples taken from the blisters of the tympanic membranes (n = 12) studied by polymerase chain reaction for M. pneumoniae were negative. This study does not support an important role for M. pneumoniae as an etiologic agent in acute myringitis.     

Epidemiology of choriocarcinoma in Finland, 1953 to 1999

OBJECTIVE: Choriocarcinoma is a rare tumor with remarkable differences in the incidence in various parts of the world. The available data do not elucidate recent time trends in the incidence of the disease in Western countries. We studied the epidemiology of choriocarcinoma in Finland over a period of 47 years. METHODS: Incidence rates for choriocarcinoma from 1953 to 1999, according to the population-based Finnish Cancer Registry, were calculated per number of deliveries, obtained from the National Research and Development Center for Welfare and Health. Standardized incidence ratios (SIRs) for the years 1971 through 1995 for women born between 1906 and 1945 were calculated by occupation taken from the 1970 Population Census. RESULTS: The incidence of choriocarcinoma was 40/10(6) deliveries for the study period 1953-1999 as a whole. The respective incidence rate calculated per female population and adjusted for age to the world standard population was 1.3/10(6). The incidence, per number of deliveries, was remarkably higher in women above 40 years as compared to younger women. There was a decline in the incidence of the disease in women between 25 and 39 years of age from 53/10(6) deliveries in 1953-1984 to 26/10(6) deliveries in 1985-1999. High occupation-specific risks were observed for nurses (SIR 7.8; 95% confidence interval 2.1-20) and agricultural workers (SIR 11; 95% confidence interval 1.4-40). CONCLUSION: The incidence of choriocarcinoma in Finland is similar to that reported earlier for other Western countries. The recent decline in the incidence of the disease, the enormous increase in the risk among old fertile women, and clustering of cases to certain occupations should be targets of future studies.     

Growth hormone selectively improves intestinal cholesterol absorption after jejunoileal autotransplantation in pigs

Background/Purpose

Small bowel transplantation impairs enteric function and causes malabsorption of cholesterol and bile acids. Growth hormone stimulates intestinal absorptive function. The authors hypothesized that long-term growth hormone therapy could improve absorption of bile acids and cholesterol after autotransplantation of the jejunoileum.

Methods

Sixteen pigs with similar food, cholesterol, and fat intake underwent either sham laparotomy or a model of jejunoileal autotransplantation, including extrinsic autonomic denervation, lymphatic interruption, and in situ cold ischemia. Five randomly chosen autotransplanted animals received daily growth hormone treatment for 8 weeks. Serum lipids, absorption, and excretion of cholesterol, bile acids, and fat were determined after 8 weeks. Mucosal morphometrics, proliferation, and enzyme activities were determined. Plasma cholesterol precursors and plant sterols, respective markers of cholesterol synthesis and absorption, were measured after 2 and 8 weeks.

Results

After jejunoileal autotransplantation, growth hormone treatment significantly increased body weight gain, cholesterol absorption efficiency from 45.1% to 62.1%, plasma campesterol to cholesterol proportions, and biliary secretion of cholesterol. With or without growth hormone treatment, autotransplantation significantly increased fecal bile acid excretion, plasma cholesterol precursors, fecal bacterially modified neutral sterols, mucosal thickness of the ileum (but not jejunum), and intestinal transit time when compared with sham-operated animals. Crypt cell proliferation, mucosal enzyme activities, and microvilli showed no differences between the groups.

Conclusions

These findings suggest that growth hormone treatment selectively improves cholesterol, but not bile acid absorption, after autotransplantation of the jejunoileum.     

Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism

BACKGROUND AND OBJECTIVE: Tizanidine, a centrally acting skeletal muscle relaxant, is metabolized mainly by cytochrome P450 (CYP) 1A2 and has a low oral bioavailability. The fluoroquinolone antibiotic ciprofloxacin is only a moderately potent inhibitor of CYP1A2. Our objective was to study the extent and mechanism of a possible interaction of ciprofloxacin with tizanidine. METHODS: In a double-blind, randomized, 2-phase crossover study, 10 healthy volunteers ingested 500 mg ciprofloxacin or placebo twice daily for 3 days. On day 3, a single dose of 4 mg tizanidine was ingested 1 hour after the morning dose of ciprofloxacin. Plasma concentrations of tizanidine and ciprofloxacin and pharmacodynamic variables were measured. A caffeine test was used as a marker for CYP1A2 activity. RESULTS: Ciprofloxacin increased the area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of tizanidine by 10-fold (range, 6-fold to 24-fold; P < .001) and its peak concentration by 7-fold (range, 4-fold to 21-fold; P < .001), whereas its elimination half-life was only prolonged from 1.5 to 1.8 hours (P = .007). The pharmacodynamic effects of tizanidine were much stronger during the ciprofloxacin phase than during the placebo phase with regard to changes in systolic blood pressure (-35 mm Hg versus -15 mm Hg, P = .001), diastolic blood pressure (-24 mm Hg versus -11 mm Hg, P < .001), Digit Symbol Substitution Test (P = .02), subjective drug effect (P = .002), and subjective drowsiness (P = .009). The AUC(0-infinity) of tizanidine and its change correlated (P < .01) with the caffeine/paraxanthine ratio and its change. CONCLUSIONS: Ciprofloxacin greatly elevates plasma concentrations of tizanidine and dangerously potentiates its hypotensive and sedative effects, mainly by inhibiting its CYP1A2-mediated metabolism, at least when administered 1 hour before tizanidine. Tizanidine seems to be a useful probe drug for measuring presystemic metabolism by CYP1A2. Care should be exercised when tizanidine is used concomitantly with ciprofloxacin.     

Ultrasound attenuation in normal and spontaneously degenerated articular cartilage

High-frequency ultrasound (US) measurements may provide means for the quantification of articular cartilage quality. Bovine patellar cartilage samples (n = 32) at various degenerative stages were studied using US attenuation measurements in the 5- to 9-MHz frequency range. The results were compared with the histologic, biochemical and mechanical parameters obtained for the same samples, to identify which structural or functional factors could be related to the attenuation and its variations. Attenuation, as calculated in the frequency or time domain, correlated significantly with the histologic tissue integrity (i.e., Mankin score, Spearman r = -0.576 or -0.571, p < 0.01), but the slope of attenuation vs. frequency was not related to Mankin score. Ultrasound speed was, however, the most sensitive indicator of Mankin score (r = -0.755, p < 0.01). Cartilage quality index (CQI), a combination of structural and functional parameters, correlated significantly with the attenuation or speed (r = -0.655 or -0.872, p < 0.01). Our results suggest that US attenuation and speed may be suited for the diagnostics of cartilage degeneration. (E-mail: )     

Long-term outcome after intravenous thrombolysis of basilar artery occlusion

Context  Basilar artery occlusion (BAO) is an infrequent disease with high morbidity and mortality. Intra-arterial thrombolysis is advocated for treatment but is limited to use at specialized centers. Objective  To evaluate outcomes for patients with BAO treated with intravenous thrombolytic therapy. Design, Setting, and Participants  During 1995 to 2003, 50 consecutive patients with angiographically proven BAO were treated according to an institutional therapy protocol based on intravenous thrombolysis with recombinant tissue plasminogen activator (alteplase). Patients were treated at an urban university teaching hospital receiving all patients with ischemic stroke who were considered for thrombolysis in a catchment area of 1.5 million inhabitants in Helsinki, Finland. Intervention  Intravenous administration of alteplase (0.9 mg/kg) during a 1-hour infusion. Main Outcome Measures  Basilar artery recanalization determined by magnetic resonance angiography and clinical outcomes at 3 months and at 1 year or longer determined by modified Rankin Scale and Barthel Index scores. Results  Recanalization was studied in 43 patients and verified in 26 (52%) of all patients. By 3 months, 20 patients (40%) had died while 11 had good outcomes (modified Rankin Scale score, 0-2); 12 (24%) reached independence in activities of daily living (Barthel Index score, 95-100), and 6 (16%) were severely disabled (Barthel Index score, 0-50). In the long term (median follow-up 2.8 years), 15 patients (30%) reached good outcomes (modified Rankin Scale score, 0-2) while 23 (46%) died. Conclusions  Intravenous administration of alteplase for patients with BAO appears to be associated with rates of survival, recanalization, and independent functional outcome comparable with those reported with endovascular approaches. These data suggest that a randomized trial is needed to compare these approaches for treatment of BAO.