Correlation of hemodynamic and functional variables with the angiographic extent of peripheral arterial occlusive disease.

The aim of the study was to determine whether hemodynamic and functional variables are related to the angiographic extent of lower limb atherosclerosis. In 150 patients with stable intermittent claudication, the Bollinger angiogram score was compared with the resting Doppler pressure values, and the initial claudication distance (ICD) and absolute claudication distance (ACD) with treadmill exercise. The extent of lower limb atherosclerosis correlated significantly with the age of the patients and the duration of the claudication. The angiogram scores of the patients were negatively correlated with the ankle systolic blood pressure (SBP) and the ankle/brachial index (ABI). In a multiple regression analysis, ABI was the most predictive variable for the angiographic severity of disease. ICD, ACD and work on the treadmill failed to correlate with the angiogram summation score. If patients were classified into groups for those with iliac or femoropopliteal disease, a weak correlation between ACD and femoropopliteal angiogram score was found. The comparison between Doppler measurements and treadmill exercise testing showed no significant correlation between SBP/ABI of the more diseased limb and ICD. However, both SBP and ABI did correlate significantly with ACD (r = 0.16, p < 0.05 and r = 0.20, p < 0.01, respectively). In conclusion, SBP and ABI are reliable parameters for indirect assessment of the angiographic extent of lower limb atherosclerosis. In contrast, the walking capacity of claudicant patients is independent of the angiographic severity of the disease.

Cefixime penetration in human renal parenchyma.

The diffusion of cefixime, a new orally active expanded-spectrum cephalosporin, was studied in 12 patients undergoing nephrectomy after receiving 200-mg oral doses every 12 h for 2 days. The patients were divided into two groups according to the time of perioperative sampling after the last dose: 4 h (group 1) and 12 h (group 2). Preoperative blood samples were taken just before administration of the last dose of cefixime. Simultaneous blood and tissue samples were collected perioperatively at 4 h (time to peak level) and 12 h (residual level). The intrarenal concentrations of cefixime were measured by an isocratic reversed-phase high-pressure liquid chromatographic (HPLC) assay. Concentrations in serum were determined by both microbiological and HPLC assays. The mean peak levels in serum were 3.41 +/- 0.43 micrograms/ml (group 1), and the residual levels averaged 1.54 +/- 1.17 micrograms/ml (group 2). The diffusion in renal parenchyma was not significantly different in the cortexes and medullas of both groups of patients: 5.7 to 6.4 micrograms/g in group 1 and 4.6 to 4.7 micrograms/g in group 2. The decrease in cefixime concentrations was slower in tissue than in serum; the ratios of concentrations in tissue to those in serum were 3.5 to 3.6 and 1.7 to 1.9 at 4 and 12 h, respectively. The intrarenal concentrations of cefixime remained higher than the MIC for the most susceptible gram-negative bacteria during the time interval between the administration of two doses.

Complications of varicella pneumonia in adults.

Varicella is predominantly a disease of children, in whom it typically has a benign course and outcome. However, when the disease affects adults, the complications can be life-threatening. Varicella pneumonia, secondary bacterial infection, and opportunistic infection in the immunocompromised host are the most common complications in the adult. Surveillance for these complications is mandatory because appropriate therapy may be life-saving. The introduction of specific antiviral agents may be useful in certain clinical circumstances. The authors describe two representative patients and discuss the diagnosis and treatment. They also discuss this infection in adulthood in general.

Improved classification of proteinuria by semiautomated ultrathin SDS polyacrylamide gel electrophoresis.

The quantitative and qualitative analysis of proteinuria by electrophoretic means proved to be a potent diagnostic tool for differentiation of functional renal impairment. The purpose of this study was to compare the macro scale SDS-PAGE technique, which has been used for the last two decades, with semiautomated electrophoresis using an ultrathin SDS-PAA gel with silver staining (Phast system). The new system proved to be quick and easy to handle. Separation of proteins in the range of 70-320 kD were of comparable quality to the macro scale system (unselective and selective glomerular proteinurias with 68 to 150 and 68 to 350 kD components, respectively, as well as total serum proteins), but there was considerable improvement regarding the quality and visibility of protein bands in the range of 11-70 kD. This improvement led to a new classification of micromolecular protein bands into three groups: the smallest microproteins (11-22 kD), the larger microproteins (23-40 kD) and the largest microproteins (41-68 kD). Thereby it was possible to obtain an improved definition of electrophoretic patterns of urinary proteins, which is described in detail.

Toxicology then and now.

A review of the history of the evolution of the science of toxicology from the original concepts of Paracelsus through the early development of analytical chemistry and its contributions to the detection of toxic substances in foods and drugs as these have led to modern regulatory rules for public protection is presented. The legal actions taken to protect against adulteration of food prior to the early steps by the U.S. Department of Agriculture that concluded with the passage of the 1906 Food and Drug Act are systematically documented. The history is reviewed of the Food and Drug Administration's role in the use of animal toxicity studies to develop reasonable criteria for safety of foods and drugs for man. Modern concepts of molecular distribution, metabolism, and excretion of substances in the animal body are discussed as these impinge on the so-called "protection index." The legal and often litigious controversies over the claimed carcinogenicity of chemical substances is documented with comments on the Delaney dilemma and the role of in vitro tests in toxicology. The review concludes with a discussion of the hazards of use of stochastic mathematical models to assess carcinogenicity and suggests that the criteria employed in the report of the Scientific Committee of the Food Safety Council are properly structured to give a contemporary evaluation of all the currently available data. References give documentation of events over the past 200 years that explain the present state of toxicology as a discipline.

Highlights in the history of saccharin toxicology.

Saccharin has successfully survived a half century of scrutiny of its safety. Experience during almost 60 years of common use in foods, as well as several rat feeding studies including that conducted by the FDA, established its GRAS status under the 1958 Food Additives Amendment. Many chronic one-generation and three (unvalidated) two-generation rat studies subsequently conducted by regulatory and independent agencies in the USA and elsewhere have been interpreted by expert committees, especially those of the National Academy of Sciences/National Research Council, as supportive of saccharin's non-carcinogenicity under possible conditions of use. Not convinced of saccharin's safety, because of the (inconsistent) evidence of bladder tumours in saccharin-treated F1 male rats, the FDA proposed a ban on its use as a food additive. This ban has been temporarily postponed by Congressional moratoria, while better designed and executed studies into the mode of action of this unmetabolized non-genotoxic substance are in progress.

Caffeine: an update.

While the total annual volume of caffeine has increased over the years, the actual per capita daily intake has not. This is based on the fact that the quantity of caffeine in a soft drink is about the same or, in the case of diet drinks, less than in 1961 when the original GRAS (Generally Recognized as Safe) determinations were made. Since that time, there have been numerous studies on the effect of caffeine on animals and humans. The Select Committee on GRAS Substances (SCOGS) of the Federation of American Societies for Experimental Biology (FASEB) in 1978 reviewed all the data available at that time and concluded that there is "no evidence in the available information on caffeine [that] demonstrates a hazard to the public when it is used in cola-type beverages at levels that are now current and in the manner now practiced...", although they did suggest further study was necessary. The Flavor and Extract Manufacturers' Association (FEMA) Expert Panel has now reviewed not only the same data s the FASEB (SCOGS) Committee, but several more recent studies. On the basis of this review, the Panel reaffirms the GRAS status of caffeine under conditions of its current use as an international ingredient in nonalcoholic beverages.

Acute oral toxicity of selected flavor chemicals.

The acute oral lethal doses are reported in rats or mice for 63 substances which are used in flavorings. For specific groups of compounds which contain several representatives of one structural class, some effects of structure on acute oral toxicity were observed. For pyrazines, the addition and position of methyl groups affected the toxicity while the substitution of ethyl for methyl had little effect. Toxicity increased with the proximity of the methyl group. The thiazoles and thiazolines tested had similar toxicities regardless of the side groups. The furan thioesters tested were about equally toxic, a fact which would be consistent with hydrolysis to the acid plus thiol.

Long-term and multigeneration toxicity studies with cyclohexylamine hydrochloride.

Cyclohexylamine (CHA), the metabolite of cyclamate produced in varying degree by gastrointestinal microorganisms, was subjected to a 2-year multi-generation feeding study in rats, at dosages of 15, 50, 100, and 150 mg/kg/d. Observations included growth, feed efficiency, clinical and hematological tests, reproduction, teratology, mortality and gross and microscopic pathology. Rats from the first litters of each generation from F0 through F4 were mated to produce the next succeeding generation. Those from the second litters of F1 through F4 were also mated, half the dams being delivered by hysterotomy for teratological examination, while litters from the other half were raised to maturity. Except for some non-progressive growth retardation in the higher dosage groups, due to lower food consumption, the physical and clinical observations in the test groups fell substantially within normal limits and were not significantly different from the untreated controls. Reproduction rates were normal in all groups but at the higher dosages the size of the litters and their weaning weights were slightly reduced. At the 150 mg/kg level, histopathological examination revealed mucosal thickening of the bladder walls and evidence of renal calcification; however, no bladder tumors were seen, such as occurred in the chronic feeding study in which rats received 2500 mg/kg of a cyclamate: saccharin (10 : 1) mixture. A significantly higher incidence of testicular atrophy, characteristic of aged rats, was observed in the F0 group at the highest dosage level; however, these males continued to be fertile, in two cases up to 6 consecutive matings.

Chronic toxicity study of cyclamate: saccharin (10: 1) in rats.

Chronic rat feeding studies were conducted on a 10: 1 cyclamate/saccharin (C/S) mixture to supplement previous investigations which had established the safety of the individual components. The test mixture was fed at dietary levels designed to furnish 500, 1120, and 2500 mg/kg body weight to groups of 35 male and 45 female rats. The protocol included observations of physical condition, growth response, food efficiency, blood, urine, and postmortem pathology. Reproduction and lactation performance was examined through 2 litters. Teratology was also investigated. Since conversion to cyclohexylamine (CHA) was found to occur in many of the rats, particularly in the higher dosage groups, it was included as an added insult in the diets of about half the animals during the last quarter of the 2-year test period. The only positive finding in these studies which proved to have crucial significance was the occurrence of papillary carcinomas in the bladders of 12 of the 70 rats fed the maximum dietary level of the mixture (equivalent to about 2500 mg/kg body weight) for periods ranging from 78 to 105 weeks (except for one earlier death). This finding was the principal reason for the removal of cyclamates from the "generally recognized as safe" (GRAS) group of non-nutritive sweeteners by the U.S. Department of Health, Education and Welfare. In the opinion of the authors, the sequelae following this precipitate ban on cyclamates, prompted by a verbal report of the preliminary findings, warrant placing the study on record for the information of toxicologists and regulatory agencies throughout the world.