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BACKGROUND: Low serum cholesterol has been associated with an increased risk of cancer mortality in various studies, which has led to uncertainty regarding the benefit of lower blood cholesterol. OBJECTIVE: The aim of our study was to evaluate the association between low blood cholesterol (<5.16 mmol/L) and cancer at sites that have rarely been evaluated. We placed special emphasis on the potential confounding effect of antioxidant vitamins. DESIGN: Plasma concentrations of cholesterol and antioxidant vitamins were measured in 1971-1973 in 2974 men working in Basel, Switzerland. In 1990, the vital status of all participants was assessed. RESULTS: Two hundred ninety of the participants had died from cancer, 87 from lung, 30 from prostate, 28 from stomach, and 22 from colon cancer. Group means for plasma cholesterol concentrations did not differ significantly between survivors and those who died from cancer at any of the studied sites. With plasma cholesterol, vitamins C and E, retinol, carotene, smoking, and age accounted for in a Cox model, an increase in total cancer mortality in lung, prostate, and colon but not in stomach cancer mortality was observed in men >60 y of age with low plasma cholesterol. When data from the first 2 y of follow-up were excluded from the analysis, the relative risk estimates remained practically unchanged with regard to lung cancer but decreased for colon, prostate, and overall cancer. CONCLUSIONS: Increased cancer mortality risks associated with low plasma cholesterol were not explained by the confounding effect of antioxidant vitamins, but were attributed in part to the effect of preexisting cancer. Copyright © 2000 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Objective: Our objective was to investigate the clinical pharmacologic characteristics of saquinavir given as a soft gelatin capsule, either alone or in combination with nelfinavir, to children and adolescents with human immunodeficiency virus infection., Methods: The pharmacokinetics of 50 mg/kg saquinavir 3 times a day (tid) alone versus 33 mg/kg saquinavir tid plus 30 mg/kg nelfinavir tid was assessed after single-dose administration and after short- and long-term administration. The single-dose pharmacokinetics of fixed (1200 mg) versus unrestricted weight-adjusted dosing (50 mg/kg) was also investigated., Results: Saquinavir as the sole protease inhibitor resulted in lower saquinavir exposure in children (steady-state geometric mean area under the concentration-time curve from time zero to 24 hours [AUC (0-24 h)], 5790 ng x h/ml; steady-state concentration 8 hours after drug administration [C(8h,SS)], 65 ng/ml) and adolescents [steady-state geometric mean AUC(0-24 h), 5914 ng x h/ml] than that reported in adults treated with 1200 mg tid [steady-state geometric mean AUC(0-24 h), 21,700 ng x h/ml; C(8h,SS), 223 ng/ml]. This finding appeared to be attributable to markedly higher apparent oral clearance, potentially as a result of increased systemic clearance and reduced oral bioavailability. Nelfinavir combined with saquinavir reduced apparent oral clearance, increasing saquinavir exposure in children [steady-state geometric mean AUC(0-24 h), 11,070 ng x h/ml; C(8h,SS), 380 ng/ml] to levels that approach those observed in adults. A significant correlation between average trough concentration and sustained viral load suppression was observed in children. The apparent threshold for maintaining viral load suppression was a mean trough saquinavir concentration above 200 ng/ml., Conclusions: The pharmacokinetics of saquinavir in children is different from that of adults, and administration of saquinavir alone will not give consistently efficacious plasma levels. The best way of improving saquinavir exposure in children is through combination therapy with other protease inhibitors that inhibit saquinavir metabolism.

Objective: The aim of this study was to compare the effect of ketoconazole, erythromycin and rifampicin on the pharmacokinetics of saquinavir soft-gelatin formulation (Fortovase; FTV) in healthy volunteers with that in HIV-infected patients at steady state after administration of 1200 mg three times daily., Methods: In two open-labelled, randomised, crossover studies pharmacokinetic parameters were calculated in healthy volunteers who received on one occasion multiple doses of 1200 mg FTV three times daily alone and on the other occasion in combination with multiple doses of either 400 mg ketoconazole once daily or 600 mg rifampicin once daily. In another open-labelled, multicentre study, 33 HIV-infected patients underwent a pharmacokinetic assessment after 36-51 weeks of treatment with FTV and were then given additionally multiple doses of either 200 mg ketoconazole once daily, 250 mg erythromycin four times daily or 600 mg rifampicin once daily. Pharmacokinetic parameters of saquinavir were determined again at the end of the combination treatment., Results: In healthy volunteers, coadministration of ketoconazole increased saquinavir area under the curve from time 0 to 8 h (AUC0-8 h) by 190% (95% CI: 90-343) whereas coadministration with rifampicin resulted in a decrease for AUC0-8 h by 70% (95% CI: 50-82). In HIV-infected patients, coadministration of ketoconazole and erythromycin increased AUC0-8 h of saquinavir by 69% (95% CI: 14-150) and 99% (95% CI: 33-198), respectively. When saquinavir was given together with rifampicin, exposure of saquinavir in terms of AUC0-8 h was decreased by 46% (95% CI: 18-65) compared with the baseline assessment., Conclusion: Interactions of saquinavir with ketoconazole, erythromycin and rifampicin were observed in healthy volunteers as well as patients. The effects observed in patients, however, appear to be less pronounced. The enzyme induction caused by rifampicin might lead to subtherapeutic levels of saquinavir and this finding appears to be of clinical relevance.

The fragmentation of natural habitats is generally considered to be a major threat to biodiversity. We investigated short-term responses of vascular plants (grasses and forbs) and four groups of invertebrates (ants, butterflies, grasshoppers and gastropods) to experimental fragmentation of calcareous grassland in the north-western Jura mountains, Switzerland. Three years after the initiation of fragmentation - which was created and maintained by mowing the area between the fragments - we compared species richness, diversity and composition of the different groups and the abundance of single species in fragments of different size (area: 20.25 m 2 , 2.25 m 2 and 0.25 m 2 ) with those in corresponding control plots. The abundances of 19 (29%) of the 65 common species examined were affected by fragmentation. However, the experimental fragmentation affected different taxonomic groups and single species to a different extent. Butterflies, the most mobile animals among the invertebrates studied, reacted most sensitively: species richness and foraging abundances of single butterfly species were lower in fragments than in control plots. Of the few other taxonomic groups or single species that were affected by the experimental fragmentation, most had a higher species richness or abundance in fragments than in control plots. This is probably because the type of fragmentation used is beneficial to some plants via decreased competition intensity along the fragment edges, and because some animals may use fragments as retreats between foraging bouts into the mown isolation area.

Background: Prostate cancer has one of the highest incidence rates of all cancers. Vitamin intake and tobacco use may have an impact on incidence and mortality, but epidemiologic evidence is scarce and inconsistent., Methods: Plasma vitamins C, E, retinol, and carotene were measured in 1971-1973 in 2,974 men working in Basel, Switzerland. In 1990, the vital status of all participants was assessed., Results: Two hundred and ninety men had died from cancer, including 30 with prostate cancer. On average, prostate cancer cases were 15 years older and smoked slightly more frequently than survivors. The mean values of plasma carotene, and of vitamin C, were nonsignificantly lower in prostate cancer cases than in survivors. After calculation of relative risk using the Cox model with exclusion of mortality during the first 2 years of follow-up, low vitamin E levels in smokers were related to an increased risk for prostate cancer. Relative risks of low vitamin C and carotene levels were about 1. A slightly but nonsignificantly increased risk was observed for low levels of retinol., Conclusions: Given the profound implication if the risk of prostatic cancer could be reduced, the relationship with vitamin E and smoking requires further study.

Plasma vitamins C, E, retinol and carotene were measured in 1971-1973 in 2,974 men working in Basel Switzerland. In 1990, the vital status of all participants was assessed. A total of 290 men had died from cancer during the 17 years of follow-up, including 87 with lung cancer, 30 with prostate cancer, 28 with stomach cancer and 22 with colon cancer. Overall mortality from cancer was associated with low mean plasma levels of carotene (adjusted for cholesterol) and of vitamin C. Lung and stomach cancers were associated with low mean plasma carotene level. After calculation of the relative risk, using the Cox model, with exclusion of mortality during the first 2 years of follow-up, simultaneously low levels of plasma carotene (below quartile I) and lipid-adjusted retinol were related to a significantly increased mortality risk for all cancers and for lung cancer. Simultaneously, low levels of plasma vitamin C and lipid-adjusted vitamin E also were associated with a significantly increased risk for lung cancer. Additionally, low vitamin E levels in smokers were related to an increased risk for prostate cancer. It is concluded that low plasma levels of the vitamins C, E, retinol and carotene are related to increased risk of subsequent overall and lung-cancer mortality and that low levels of vitamin E in smokers are related to an increased risk of prostate-cancer mortality.

Several parameters (pH, osmotic pressure) influencing the local tolerance of injectable drugs have been well-documented; however, little attention has been paid to pain following an injection--a common problem in clinical practice. A pain questionnaire was used to record pain up to 24 h after a deep ventrogluteal injection. Two groups of healthy volunteers were recruited: the first group (n = 6) received 3 different cotrimoxazole preparations and placebo and the second group (n = 10) received 4 different multivitamin preparations and placebo (double-blind, cross-over). Parameters monitored during and after injection included pain localization (line drawing), pain intensity (visual-analog scale: VAS) and verbal description of pain (pain rating index: PRI). In both groups, the equality of pain (VAS, PRI) induced by the preparations was rejected in all cases (Friedman's test, p < or = 1%). The pairwise comparisons of the groups showed significant differences (p < or = 5%) between various preparations. The correlation (Spearman's rank correlation) between pain parameters VAS and PRI was high. The present investigations have shown that the pain questionnaire is a valuable tool to investigate the subjective pain symptoms during and after the injection of different preparations.

Reocclusion of infarct-related coronary arteries within 2 weeks of thrombolytic therapy varies from 5% to 45% and neither clinical nor angiographic variables have been proved to be predictive of reocclusion. The goal of the present study was to evaluate whether aspirin could prevent coronary reocclusion and recurrent ischemia after thrombolysis. For this purpose, a meta-analysis including 32 studies was performed. Although the studies showed very similar demographic data, the reocclusion rate assessed by angiography in 419 patients treated with aspirin was 11% compared with 25% in 513 patients without aspirin therapy (p less than 0.001). Recurrent ischemic events were present in 25% of 2,977 patients treated with aspirin and 41% of 721 patients treated without aspirin (p less than 0.001). The effect of aspirin was similar in trials with either streptokinase or recombinant tissue-type plasminogen activator (rt-PA). Thus, aspirin in the presence of heparin might prevent coronary reocclusion after thrombolysis.

The effectiveness of any therapy in acute acoustic trauma or sudden hearing loss of unknown origin has not been demonstrated convincingly. The assessment is difficult because of a relatively high rate of spontaneous recovery. Nevertheless, many different forms of treatment are recommended. We tested one form, treatment with rheoactive substances, in a prospective, randomized, double-blind trial and compared treatment with (a) infusions of dextran-40 with pentoxifylline, (b) saline infusions with pentoxifylline, and (c) saline infusions with placebo medication. Pure-tone hearing thresholds served as control parameters and were taken before treatment and at 1 and 4 weeks after the onset of therapy. Three hundred eighty-two patients were included in the trial, 331 (87%) could be analyzed, 184 patients were treated because of sudden hearing loss, 147 because of acute acoustic trauma. The three treatment groups were comparable in their basic characteristics including the amount of initial hearing loss. In patients with sudden hearing loss, no significant differences of hearing recovery were detected between the three treatment groups. Hearing recovery was also similar in patients with acute acoustic trauma. A power analysis of the study revealed that possible true treatment differences of a hearing recovery of 10 dB would have lead to significance with a probability of over 90%. It is concluded that there were, in fact, no clinically relevant differences in hearing gains of sudden hearing loss or acute acoustic trauma between treatments with saline infusions together with placebo medication and treatment with dextran-40 and/or pentoxifylline.

The influence of the vitamin nutritional status on the immunocompetence of a group of elderly people in the city of Perugia has been investigated. The impairment of some immunological (humoral as well as innate and acquired cell-mediated) functions seemed to be mostly related to age. Statistically significant correlations between the complement component C4 and plasma levels of retinol as well as alpha-tocopherol and an inverse correlation between titers of IgG and plasma retinol have been observed (significance level alpha = 5%).

In 1971-1973 at the third examination of the Basel Study started in 1959, the major antioxidant vitamins and carotene were measured in the plasma of 2974 men. A subsample and their families were reinvestigated in 1977-79. During the 12-y observation period (1973-85) 553 men died, 204 of cancer (lung cancer 68, stomach cancer 20; colon cancer 17, all other malignancies 99). We found significantly lower mean carotene levels for all cancer, bronchus cancer, and stomach cancer (all P less than 0.01) compared with the 2421 survivors. The relative risk of subjects with low carotene (less than 0.23 mumol/L) was significantly elevated (P less than 0.05) for lung cancer (Cox's model). Higher risks were noted for all cancer (P less than 0.01) if both carotene and retinol were low. Low plasma carotene which is known to reflect carotene intake is in our study associated with increased cancer risk.

An interlaboratory study on the reproducibility of the CEA (Roche) RIA Test was carried out. Four different plasma pools of approximately 2, 3, 6, and 12 micrograms/l CEA were tested over a period of 4 weeks with 4 different lots of reagents in order to determine the interassay variances. At the same time we compared the lately introduced column technique with the dialysis and ultrafiltration method. Best results were obtained with the column technique which also showed best reproducibility. Only 1.4% of samples showed deviations greater than 5% between the mean of CEA duplicates and single CEA values, and these were omitted from the evaluation. On the other hand about 15% of the corresponding dialysis results showed deviations greater than 5% and were excluded from the evaluation. The methods compared showed a good correlation with a coefficient of 0.96, but the average values for the CEA determination, using the columns technique were lower than those obtained from dialysis. Interassay variances were greater for the dialysis procedures, i.e. 1.88 +/- 0.81, 3.25 +/- 0.83, 5.81 +/- 1.09, and 11-91 +/- 1.23 compared with 1.77 +/- 0.54, 2.63 +/- 0.68, 4.89 +/- 0.79, and 11.16 +/- 1.23 for the column technique. There were no systematic changes of the CEA values over the period of 4 weeks, thus giving optimal conditions for a follow up of patients.

For testing the significance of dose-related effects, a test procedure was developed for the typical situation in toxicological studies where several dosage groups are compared to one control group. Using a closed testing procedure in the sense of Marcus et al. (1976), the algorithm is sensitive to the detection of toxicological effects without increase in type-one errors. Furthermore, all significance tests applied in the algorithm are based on ranks and the calculation of the error probability is performed by a random-permutation technique (Wall 1974, 1985); the algorithm is therefore also applicable to non-normally distributed data. In the case of discrete quantities, this technique takes into account tie-structures of all kinds (Lüdin 1985). An application of the proposed test-procedure is given in the work of Kistler and Hummler (1985).

In a previous study with flucytosine (5-FC) susceptibility of 40 Candida albicans isolates in vitro proved statistically correlated with response in systemic murine candidiasis in vivo, although exceptions occurred with individual isolates. For the present analogous study with ketoconazole, 58 C. albicans isolates were used of which 38 were from the 5-FC study and 20 were added to equalize the numbers of serotype A (n = 30) and B (n = 28) and to make the range of susceptibility in vitro to ketoconazole continuous and wide. The widest range of ketoconazole susceptibility was noted for the minimal inhibitory concentrations on Kimmig and Casitone agars (0.015-256 micrograms/ml) and disk zone diameters on YNB agar (0-54 mm), whereas with disk tests on other media, the range of 50% inhibitory concentrations, relative inhibition factors and MICs on serum agar remained narrow and/or showed strong ties. The Spearman's rank correlation between the in vitro activities determined with the various parameters showed wide variation consistent with p values from less than 0.001 to greater than 0.05. The serotype B isolates generally were more susceptible than the A isolates (p less than 0.02 for the majority of parameters). Evaluation of response in vivo was hampered by the low activity of ketoconazole on the murine infection with any of the isolates, the range of the ED50's being only 10- greater than 100 mg/kg. The serotype B infections exhibited significantly better response (p less than 0.05) than the serotype A infections. The overall correlation (Spearman's rank) of the susceptibility test results in vitro with the response in vivo was poor (p less than 0.05 for almost all parameters) suggesting very limited if any precise predictive values of the susceptibility tests in vitro with ketoconazole against C. albicans. However, the narrow range of the ED50 suggests relatively little variation in the response of the different isolates in vivo and similarly small variation was also noted in some of the tests in vitro.

Three repeated cross-sectional surveys were undertaken among children (1 month to 15 years) of a rural community in southeastern Tanzania. The study was part of a longitudinal project on the interactions among nutrition, parasitic infections and immunity within a primary health care programme emphasizing village health workers. All children underwent interviews and parasitological, anthropometric, anamnestic and clinical examinations. Out of 550-590 children examined each year, a cohort of 170 children could be followed for three consecutive years. Malaria was holo- to hyperendemic in the community, P. falciparum accounting for greater than 90% of the infections. The parasite and spleen rates were 88% and 67%, respectively, and the average enlarged spleen index was 2.0 among children from 2-9 years in 1982. Transmission of malaria was high and stable as indicated by a parasite rate of 80% among infants between 1 month and 1 year during the whole period of study. G. lamblia, hookworm (N. americanus), Strongyloides spp. and Schistosoma haematobium were highly prevalent and annual incidence rates were high, while Entamoeba histolytica, Ascaris and Trichuris were of minor importance. Prevalence and incidence of parasitic infections did not differ by sex. Multiparasitism was very frequent and less than 11% of all children were parasite-free in each year. Not a single child remained parasite-free for three consecutive years. An anthropometric assessment showed a high degree of stunting (35-71%) and a substantial proportion of wasting (3-20%). The growth potential was normal in girls and boys during the whole period of study. There were indications that malaria was the main contributory factor to growth retardation among young children. Hookworm infection did not significantly affect the packed-cell volume of the children, probably owing to the low intensity of infection. Due to the multiparasitism and the lack of parasite-free individuals, single-parasite and single-nutrient effects were difficult to unravel. A latrine campaign followed by a single mass treatment against hookworm (single oral dose of albendazole, 400 mg) and/or G. lamblia (single oral dose of ornidazole, 40 mg/kg) only temporarily affected the prevalence and incidence of G. lamblia, and only resulted in a decrease in the intensity of hookworm infections up to six months after the interventions. As the effects of the latrine campaign and a single mass treatment on the parasite load were only transient, no sustained impact on nutritional variables was observed.(ABSTRACT TRUNCATED AT 400 WORDS)