Field evaluation of coverall fabrics: heat stress and pesticide penetration. The effect of wearing coveralls on the heat stress of ten professional airblast applicators of ethion to Florida citrus were studied. During the period June 21, 1988 to August 9, 1988, applicators wore protective clothing of the same design, but made of seven different fabrics. Heat stress was evaluated by measuring the mean skin temperature, oral temperature, and heart rate of pesticide applicators. Subjects also provided subjective evaluations. Seven environmental variables were also monitored. Although each fabric was replicated an average of 17 times for thermal comfort and an average of 23 times for penetration, statistical tests for differences among fabrics were usually not significant at the p less than 0.05 level. Observed differences among suits were statistically significant at p = 0.27 for the heat stress experiment, and extended over the range p = 0.003-0.500 for the penetration experiment. Lighter weight, untreated fabrics marginally ameliorated heat stress under severe environmental conditions, but they allowed more pesticide penetration.


Small area pesticides data: multiplicity and variability of pesticide usage on southern row crops. Epidemiologic studies of possible effects of agricultural environments upon human health suffer from lack of reliable pesticides usage data. The Arkansas Reproductive Health Monitoring System has developed a method for estimating specific pesticides usage annually for sub-county regions, including amounts, application method, and months. This method is applied to 39 regions of 8 central Arkansas counties for 1980-82. The hugh variability of pesticides usage on individual crops demonstrates the inaccuracy likely if general survey estimates are employed. Annual usage of pesticides in a single sub-county region of 53,000 hectares (130,880 land acres) was greater than 1/2 million pounds (248,670 kg) of 60 pesticides, 40 of which were applied during a four month period. The multiplicity and variability of pesticides usage indicate the need for locally developed pesticides data for epidemiologic studies and for combined studies across regions with widely differing agricultural practices.


Reproductive output of a meiobenthic copepod exposed to sediment-associated fenvalerate. The benthic harpacticoid copepod, Amphiascus tenuiremis, was cultured through one generation at four concentrations (600, 300, 150, and 0 micrograms/kg) of sediment-associated fenvalerate, a synthetic pyrethroid insecticide, to assess effects on reproductive output and age structure. Two static renewal experiments with four replicates of each treatment were conducted. At the end of 21 days, surviving copepods were sorted and counted into adult males, adult females, copepodites, and nauplii. Fenvalerate was extracted from the sediment and measured by GC-MS. The number of individuals in each life-history stage in fenvalerate treatments was not significantly different from controls, except for increased adult females in fenvalerate in the second experiment. The overall lack of a fenvalerate toxic effect on A. tenuiremis was most likely because fenvalerate tightly binds to sediments and was probably not bioavailable to the copepods. Sediment-associated pesticides with large octanol:water partitioning coefficients (K(ow)'s) such as fenvalerate appear to be less toxic to infaunal copepods than those exhibiting smaller K(ow)'s.


Effects of 2,4-dichlorophenoxyacetic acid on Rhizobium sp. membrane fluidity. The effects of 1 mM 2,4-Dichlorophenoxyacetic acid on Rhizobium sp. in pure culture was studied. In a previous work it was demonstrated that this herbicide produces an alteration on the saturated to unsaturated phospholipid acyl chains ratio. In the present paper, it was found that this alteration produces a modification on the membrane fluidity in bacteria that had achieved the stationary phase. The same results were obtained when determinations were done in liposomes from sonicated lipids of treated bacteria, indicating that changes in phospholipid acyl chains may be the main cause of membrane fluidity alteration. In addition, it was determined that leucine transport as well as Ca(++)-ATPase activity (a membrane enzyme) was affected under the experimental conditions.


Oxidative changes in brain of aniline-exposed rats. Oxidative stress in rat cerebellum, cortex and brain stem after a short-term high-dose exposure to aniline vapors under conditions akin to those after major chemical accidents, was studied. Significant increases in superoxide dismutase isozyme activities and formation of thiobarbituric acid reactive material along with depletion of ascorbic acid and non-protein sulfhydryl content suggest impairment of antioxidant defenses 24 h after single exposure to 15,302 ppm aniline vapors for 10 min.


Benzo(a)pyrene-blood protein adducts in wild woodchucks used as biological sentinels of environmental polycyclic aromatic hydrocarbons contamination. Levels of benzo(a)pyrene-diolepoxide (BaPDE)-albumin and BaPDE-hemoglobin adducts in wild woodchucks (Marmota monax) have been measured to evaluate the potential usefulness of these parameters in the assessment of environmental contamination by polycyclic aromatic hydrocarbons (PAHs). Blood was obtained from nine woodchucks living near an aluminum electrolysis plant, contaminated area (Saguenay region, Québec, Canada), and from eight living in a control area (Saint-Roch-des-Aulnaies, Québec, Canada). Blood samples were collected and plasma separated from red blood cells by centrifugation on site. Isolation of albumin (Alb) and hemoglobin (Hb) was performed in our laboratory and each protein fraction was subjected to mild acid hydrolysis yielding free benzo(a)pyrene (BaP) tetrol from the adducts. The analysis was performed by high performance liquid chromatography (HPLC) using fluorescence detection. For the control and contaminated areas geometric mean (interval) Alb adduct levels were 7.6 (0.8-29.3) and 69.6 (10.0-1,103) pmol tetrol/g protein (p less than 0.01) while the corresponding figures for Hb adduct levels were 0.40 (0.01-2.72) and 1.18 (0.02-12.8) pmol/g protein (p greater than 0.01). Alb but not Hb adduct levels were associated with the measured concentration of BaP in the vegetation samples collected on the site where each animal was found. This is compatible with the short half-life of Alb adducts and with the instantaneous image provided by BaP measurements in the collected vegetation samples. BaPDE-blood protein adducts measured in wild animals appear to be good biomarkers of environmental contamination by PAHs.


Early life stage survival of striped bass in the Delaware River, USA. Four 96-h in situ bioassays were conducted on or near the striped bass spawning grounds in the Delaware River within the States of Delaware, New Jersey and Pennsylvania, USA during 1989 to determine if water quality was sufficient to support larval survival. Tests were accomplished by holding 500 striped bass yolk-sac larvae in each of two 75 L chambers at four locations in the river ranging from north of Philadelphia, PA to Salem, NJ and at one location in the Chesapeake and Delaware Canal. Survival varied significantly among stations; highest survival was in the Chesapeake and Delaware Canal, where it averaged more than 50%. Lowest survival occurred at the station near Salem, NJ, approximately 30 km downriver of the primary spawning grounds, where less than 1% of the larvae survived in any of the tests. Survival at stations closest to the primary spawning grounds was weather-dependent; survival was over 47% during periods of little rainfall, but only 11% following periods of higher than average rainfall.


Effects of acute and chronic acidification on three larval amphibians that breed in temporary ponds. This study explored the effects of acute (7 days) and chronic (4 months) exposure to pH 4.2 on three species of larval amphibians, Ambystoma jeffersonianum, Ambystoma maculatum, and Rana sylvatica. Acute tests were conducted in 24 impermeable enclosures in three temporary ponds. Total dissolved aluminum was higher in acidified enclosures in comparison with controls (pH 4.2, [Al] approximately 10-30 microM and pH greater than 4.7, [Al] approximately 5-15 microM, respectively). Greater mortality of A. jeffersonianum occurred at pH 4.2 than at pH greater than 4.7, whereas survival of A. maculatum and R. sylvatica were unaffected by pH. Mean wet masses of R. sylvatica were significantly lower at pH 4.2 than at pH greater than 4.7, but mean wet masses of surviving A. jeffersonianum and A. maculatum were not influenced by pH. There were no pH-related differences in body sodium concentration in larval R. sylvatica. Chronic acidification of mesocosms to pH 4.2 ([Al] approximately 16 microM) (controls = pH greater than 6, [Al] approximately 0.1 microM) resulted in total mortality of A. jeffersonianum. Survival of A. maculatum and R. sylvatica were not associated with pH, but survival of A. maculatum was low at both pH levels. Time to metamorphosis was longer for R. sylvatica maintained at pH 4.2, but not for A. maculatum. No differences in wet masses at metamorphosis were observed for R. sylvatica or A. maculatum. These results indicate that short and long term acidification of temporary wetlands could dramatically affect amphibians which rely upon them as breeding sites, either by causing mortality or by decreasing growth rates.


Anodontites trapesialis: a biological monitor of organochlorine pesticides. The mussel Anodontites trapesialis (Lam, 1819) was used as an indicator of organochlorine pollutants in the Pardo River, located in the municipality of Ribeirão Preto (21 degrees 07'S and 47 degrees 45'W), State of São Paulo, Brazil. Biological monitoring was performed for one year at the site of a sugar cane grove on the left bank of the river. Forty-three animals were placed in two aluminum enclosures on the river bottom at this site and 4 animals of each enclosure were sacrificed for pesticide analysis at 3-month intervals, each collection corresponding to one season of the year. The animals were found to have been exposed to DDT, lindane, heptachlor, aldrin and dieldrin. Endrin was not detected in any of the analyses.


Shell disease and metal content of blue crabs, Callinectes sapidus, from the Albemarle-Pamlico Estuarine System, North Carolina. Concentrations of 13 elements were determined for three tissues (gill, hepatopancreas, muscle) in diseased crabs from a contaminated estuary (Pamlico River, NC), and in non-diseased crabs from both the contaminated estuary and a relatively uncontaminated area (Albemarle Sound, NC) during the fall 1989 and summer 1990. The diseased crabs had lesions which completely penetrated their dorsal integument, while the non-diseased crabs lacked lesions. Sediments within the contaminated area showed enrichment of arsenic, cadmium, manganese, titanium and vanadium relative to the uncontaminated area. Levels of aluminum, arsenic, cobalt, manganese, nickel, titanium, vanadium and zinc were significantly higher in both gill and hepatopancreas in crabs from the contaminated area. Manganese was always highest in the diseased crabs in all tissues measured. The concentrations of the remaining elements were greater in the gills of diseased crabs, while highest values of these elements in the hepatopancreas varied among the diseased and non-diseased crabs from the polluted area. Conversely, copper levels were always highest in all tissues in crabs from the uncontaminated area, and typically lowest in the diseased crabs. Concentrations of aluminum and arsenic were also significantly greater in the muscle tissue of crabs from the contaminated area, but no distinct trend was evident with regard to diseased versus non-diseased crabs. Arsenic was the only element accumulated by crabs in the contaminated area which has a known toxic affect on the tissue responsible for cuticle synthesis and repair (hypodermis) in crustaceans. Metals also accumulated could possibly act synergetically to compromise normal metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)


Chronic ecotoxicity of copper and cadmium to the zebra mussel Dreissena polymorpha. In order to evaluate ecological consequences of the long-term presence of metals in aquatic ecosystems, we investigated the filtration rate and survival of zebra mussels (Dreissena polymorpha) during chronic exposure to Cu and Cd. The filtration rate was measured once a week in laboratory experiments lasting 9-11 weeks. The lowest Cu concentration tested (13 micrograms/L) did not affect the filtration rate and survival of D. polymorpha, but the lowest Cd concentration (9 micrograms/L) did affect the filtration rate, but had no effect on survival. The EC50 for Cd decreased markedly from 388 micrograms/L to 27 micrograms/L when the exposure time was lengthened from 48 hours to 10 weeks. The largest decrease in EC50 for Cd was observed during the first week of exposure. In contrast, the EC50 for Cu did not decrease with increasing exposure time (chronic EC50: 43 micrograms/L). Since the chronic LC50 for Cd was 130 micrograms/L, the filtration rate appeared to be a far more sensitive endpoint for ecotoxicological laboratory experiments than mortality. D. polymorpha was capable of regulating the body concentration of the essential metal Cu at low concentrations in the water (13 micrograms/L). Cd was accumulated at every Cd concentration in the water, suggesting that Cd could not be regulated by D. polymorpha. It is concluded that the relation between short-term and long-term ecotoxicity was different for each metal and could not be predicted from the results of the short-term experiments.


Temporal and spatial variation in the amount of cadmium in the phantom midge larvae (Chaoborus spp.). Several factors, including body size, age, and temporal and spatial variation, which may influence the amount of cadmium (Cd) in the phantom midge larvae, Chaoborus spp., were examined in eight lakes, four from south-central Ontario (Dorset Region) and four from northwestern Ontario (Experimental Lakes Area). All three species of Chaoborus (C. punctipennis, C. trivittatus, C. flavicans) found in Chub Lake (south-central Ontario), were analyzed seasonally. One species, C. punctipennis, was collected and analyzed from all lakes. Smaller Chaoborus tended to have higher Cd concentrations (micrograms Cd/g dry weight), and lower Cd burdens (ng Cd/Animal) than larger Chaoborus. The Cd concentrations of Chaoborus in Chub Lake were lowest during the summer, which coincided with the fastest growth of the organisms. The Cd burdens differed between species, which was attributed to differences in their asynchronous life histories. Cadmium burdens and concentrations were significantly lower in the organisms from northwestern Ontario than those from south-central Ontario. Lower atmospheric deposition rates, lower Cd concentrations in the lake water, as well as life history differences, may explain these results.


Long-term effects of heavy metals in food on developmental stages of Aiolopus thalassinus (Saltatoria: Acrididae). Newly hatched F1 nymphs of Aiolopus thalassinus (Fabr.) were fed on food treated with various concentrations of HgCl2, CdCl2, and PbCl2 until the end of adult life. Toxicological observations were followed in the F1 generation and in the F2 generation derived from the heavy metal-loaded F1 parents. The highest concentration of the heavy metal caused 100% mortality of the F1 adults within four weeks. The nymphal duration of the F1 and F2 generations was significantly prolonged after Hg and Cd exposure, but the F1 of the group treated with lead was not affected. The fresh body weight of adults was significantly reduced in the F1 generation of most treatments and in the resulting untreated F2. The lifespan of the F1 adults was shortened. In the F2 generation, although the lifespan was somewhat longer, generally it was still shorter than that of the control adults. The mean egg number laid by F1 adults fed on food contaminated with Hg or Cd was decreased. This decrease was more pronounced in the case of Cd than Hg. In the females fed on food treated with Pb the reduction of the number of egg pods was not remarkable. The hatchability of the eggs laid by F1 females was significantly reduced as compared to the control. The viability of the eggs laid by F2 adults was somewhat decreased due to either a reduced number of egg pods or to a lower rate of hatchability, especially in the case of Cd. The treated adults frequently displayed weakness in their legs, difficulties in walking, tremors, and nervous movements.(ABSTRACT TRUNCATED AT 250 WORDS)


Mercury concentrations in seabirds from colonies in the northeast Atlantic. Total mercury concentrations were determined in samples of body feathers from a range of common seabird species breeding at Låtrabjarg, northwest Iceland, St. Kilda, Foula and the Firth of Forth, Scotland and Bleiksøy, Syltefjord, and Hornøy, Norway. Seabirds from Låtrabjarg generally exhibited the highest mercury concentrations, with a trend of decreasing mercury concentrations in a southwest to northeast direction in seabirds at the other colonies; seabirds at Hornøy were generally found to have the lowest mercury concentrations. Some species at the Firth of Forth exhibited relatively elevated mercury concentrations compared to those at Foula and Norwegian sites. Inter-colony differences in diet were thought to be relatively small for most species and unlikely to account for the range of mercury concentrations measured in the seabirds (Låtrabjarg: lowest arithmetic mean mercury concentration in common guillemots Uria aalge, 1.6 micrograms/g, s.d. = 0.6, n = 45; highest arithmetic mean mercury concentration in kittiwakes Rissa tridactyla, 5.5 micrograms/g, s.d. = 1.7, n = 36). The oceanic transport of mercury, together with the effects of anthropogenic inputs of mercury to the northeast Atlantic, and the removal of mercury from the water column via biological activity are discussed as influential factors determining the observed patterns of mercury concentration in seabirds.


Psychosocial correlates of diabetes and renal dysfunction. Psychosocial issues related to diabetes and renal dysfunction are complicated and many times misunderstood. Building relationships and acquiring relevant information from patients will help patients adjust to disease complications and enhance compliance.


Chronic complications of diabetes mellitus: peritoneal dialysis. As the number of patients with diabetes treated by peritoneal dialysis continues to grow, nurses will increasingly be challenged to assist these patients to prevent, manage and adapt to the chronic complications of diabetes, including microangiopathy, macroangiopathies and neuropathies. This article presents nursing assessments and interventions related to these chronic complications to hopefully enhance the quality of life for these patients.


Dietary modifications: impact on diabetic nephropathy. This article encompasses the topic of dietary impact upon the diabetic individual with the condition of diabetic nephropathy. The influence of diet will be addressed in: renal insufficiency, chronic renal failure, and the modalities of hemodialysis, peritoneal dialysis, and renal transplantation. The two-fold purpose of this review is to provide documentation in support of dietary therapy and to underscore the sharp contrast in nutritional needs dependent upon the individual's clinical status.


Long-term effects of hemodialysis in diabetic patients with end stage renal disease. The long-term effects of hemodialysis in diabetic patients with end stage renal disease (ESRD) may seem minor, yet with further examination are seen to touch every aspect of the patients' lives. The long-term effects range from vascular access issues, complications such as limb amputation, to feelings of loss of control as well as hopelessness and powerlessness. This article will highlight how the long-term outcomes and effects of hemodialysis with diabetes cause multisystem problems and multiple complications in patients.


Early transplantation for patients with diabetic nephropathy. Renal transplantation is often the preferred renal replacement modality for individuals with the complex problem of diabetic nephropathy. Referral to a transplant program before renal replacement therapy is needed allows patients an opportunity to make treatment decisions as well as offer the advantages of early transplantation. In addition to routine post-transplantation surveillance, health care after transplantation is directed towards prevention and management of diabetic sequelae.


Kidney-pancreas transplantation: a treatment option for ESRD and type I diabetes. Combined kidney-pancreas transplantation is a safe and effective treatment option for patients with end stage renal disease (ESRD) resulting from type I diabetes. Current 1 year graft survival rates are nearing 80% and evidence is accumulating that improvement occurs in microvascular and neuropathic complications of diabetes after transplantation. This article is a detailed overview based on the current literature and our experience at The University Hospitals of Cleveland of the challenges and benefits of kidney-pancreas transplantation and the nursing care required to prepare the patient for home.


Pancreas transplantation: detecting rejection and patient care. Pancreas transplantation in the type I diabetic patient offers hope for a normoglycemic state and arrest, or in some cases, reversal, of secondary complications of diabetes. Rejection in the pancreas graft can be difficult to detect, but much work is being done on different methods to recognize rejection. Patients report increase in psychological well-being after pancreas transplantation. Because of the benefits, it is a viable option for treatment of the patient with type I diabetes.


Diabetic ESRD patient supported with intradialytic parenteral nutrition. The patient did meet the expected outcomes. She was able to achieve a desired weight and continues to gain weight. Currently, consideration is being given to discontinuing IDPN therapy. The main concern is an exacerbation of her symptoms, which is often a problem with diabetic gastraparesis. BC's outlook on life is more positive. Hopefully, she will continue to be compliant with her diet, experience no increase in symptoms, and maintain this weight. As with all ESRD patients, her fluid status requires monitoring. Fluid gains are removed and she remains free of complications. BC is now able to participate in usual daily activities. She goes out to the hairdresser once a week and attends Sunday morning church service. Her sense of well-being is greatly improved. BC has expressed gratitude on numerous occasions for the treatment that she feels has saved her life. Her deteriorating physical state was severely affecting her emotional well-being. Her quality of life has been favorably altered by the intervention with IDPN therapy.


Nursing guidelines for muromonab-CD3 (OKT3). Muromonab-CD3 is currently being used in transplant patients to prevent or reverse graft rejection. It is important that nursing guidelines for its proper usage are understood before the administration of the drug. This article overviewed dosage considerations, side effect profile, and other nursing implications regarding the use of muromonab-CD3.


Case management of the anemic patient. Epoetin alfa: focus on pediatric dialysis patients. Although pediatric and adult dialysis patients experience similar symptoms, young patients can present special problems for clinicians. This article explores the management of pediatric patients receiving Epoetin alfa.


[Destabilization of emulsions during extraction of antibiotics from natural solutions]. Various means for changing the aggregative stability of emulsions in the system of benzylpenicillin fermentation broth filtrate and butyl acetate were tested. It was shown that the use of desemulgators was more efficient than the use of some means for removing the desemulgating admixtures. Moreover, addition of surface active substances after the preliminary thermocoagulation resulted in maximum decreasing of the emulsion aggregative stability.


[Phage-mediated conjugative transfer of plasmids in Staphylococcus aureus]. It was shown possible to transfer nonconjugative plasmids during joint cultivation of the donor and recipient cells by transduction and phage-mediated conjugation. In the latter case it was necessary that the phage in the medium was free and the prophage was present in the recipient cells. Differences in the regularities of the transfer of the nonconjugative plasmids mobilized by the conjugative plasmid or phage were observed.


[Effects of rifampicin and doxycycline on the production of hydrogen peroxide by macrophages]. The influence of rifampicin and doxycycline on oxidative metabolism of macrophages was estimated in vitro by production of hydrogen peroxide. It was shown that low concentrations of rifampicin and doxycycline stimulated production of hydrogen peroxide by macrophages of guinea pigs. In concentrations of 1 to 10 micrograms/ml corresponding to the mean therapeutic ones doxycycline increased both the spontaneous and zymosan-induced production of hydrogen peroxide by the macrophages. The potentiating activity of doxycycline on the cells activated by opsonized zymosan was higher. The maximum increase in the induced production of hydrogen peroxide (by 40 per cent) was observed when the antibiotic concentration was 1 microgram/ml. Rifampicin in concentrations of 0.1 to 1 microgram/ml corresponding to the mean therapeutic ones stimulated the zymosan-induced production of hydrogen peroxide by the macrophages. The maximum increase in the production of hydrogen peroxide (by 22 per cent) was noted at the rifampicin concentration of 1 microgram/ml.


[Experimental study of human recombinant insulin]. The experimental study of recombinant human insulin revealed its high specific activity. The kinetics of the hypoglycemic effect of various dosage forms of the insulin developed at the National Research Centre of Antibiotics and the dosage forms manufactured by Eli Lilly was similar. The pharmacological investigation of the dosage forms showed that they had no side effects on the vitally important organs and systems. It was concluded that the dosage forms of the gene engineered human insulin developed at the National Research Centre of Antibiotics did not differ by their characteristics from the analogous dosage forms manufactured in other countries.


[Characteristics of pharmacokinetics of liposome-incorporated rifampicin in rats after intratracheal administration]. Pharmacokinetics of rifampicin after its single intratracheal administration in the form of the liposome-encapsulated drug and its aqueous solution was studied on rats. It was shown that after the exposure to the liposome-incorporated rifampicin (10 mg/kg) the concentration-time curve in the blood and lungs was sigmoid with the retarded decrease in the blood drug concentration within 9 hours. The plateau segment of the curve provided at least a 4-fold longer maintenance of the rifampicin concentration in the blood and lungs at 3 to 4 micrograms/ml. The use of the liposome-incorporated antibiotic induced 2- and 1.5-fold increases in the AUC in regard to the lungs and blood, respectively.


[Obtaining liposomal preparations of various biologically active substances by the method of detergent flow analysis]. It was shown that detergent dialysis could be successfully used for liposomal encapsulation of substances belonging to different chemical groups with diverse therapeutic activity such as rifampicin, aclarubicin, amphotericin B, pefloxacin and insulin. Liposome encapsulation of substances poorly soluble or insoluble in aqueous media was likely the most promising. The optimal incorporation depended on both the composition of the lipids forming the liposomes and the properties of the compounds being encapsulated.


[Antibacterial effects of gamma-interferon in experimental Klebsiella infection]. The results of the experimental study on the effect of the natural and recombinant gamma-interferons (gamma-IFs) of mice on the process of the infection caused by Klebsiella sp. are presented. The infection was reproduced by intraperitoneal contamination of mice with a virulent culture of Klebsiella pneumoniae 5055, line SHK. The gamma-IFs were administered to the animals in a dose of 250 units per mouse on days 1 and 3 after the contamination. Survival of the animals, clearance of the pathogen from the blood and liver and functional activity of the phagocytes in the contaminated mice were investigated. It was shown that both the natural and recombinant gamma-IF stimulated the phagocytic activity and oxidative metabolism of the phagocytes in the contaminated mice. Activation of these functions after the use of the natural gamma-IF correlated with its marked protective effect and accelerated elimination of the pathogen from the host which was not observed after the use of the recombinant gamma-IF.


[Gentacycol--a delayed-action form of gentamicin in the treatment of suppurative infection]. Efficacy of gentacycol was studied in the treatment of various purulent infections. It was used in therapy of hematogenic and traumatic osteomyelitis, wound infections, soft tissue abscesses, purulent diffuse peritonitis as a complication of comissural ileus or appendectomy, pyothorax, destructive pneumonia and mediastinitis. Gentacycol ++ was also used for the prophylaxis in cholecystectomy, herniotomy and other conditions. The favourable results were stated in 93 per cent of the cases.


[Antibiotic therapy of children in a gnotobiological unit]. The clinical effect of antibiotics in treatment of children at the age of 2 months to 5 years with acute pneumonia during a gnotobiological department in the wards of the 1st class purity and under the conditions of a routine pediatric hospital was estimated. The course of the antibiotic therapy amounted to 4.7 +/- 0.42 days in the gnotobiological department and 12.0 +/- 0.3 days in the routine hospital. After recovery the patients were discharged in 7.61 +/- 0.76 days from the gnotobiological department and in 15.2 +/- 1.11 days from the routine hospital.


[Antibiotic therapy of Salmonella infection in infants during the first year of life and methods if its correction]. The efficacy of antibiotic therapy of salmonellosis was studied and functional activity of peripheral blood leukocytes from electron microscopic data was estimated in 200 infants. It was shown that the use of antibiotics in combination with immunostimulants such as leukocyte mass, lysozyme and prodigiozan in complex therapy of salmonellosis in infants had a favourable effect on both the time course of the clinical signs and the functional state of the neutrophil leukocytes. The duration of the treatment decreased by 6.14 +/- 0.34 days and repeated isolation of the pathogen from the host appeared to be less frequent.


[Experience with using aclarubicin in the treatment of acute leukemia and blast crisis of chronic myeloid leukemia]. The clinical efficacy of aclarubicin, an anthracycline antibiotic, was studied in 48 patients with leukemia. The antibiotic was used in the following combinations with cytarabine: "7 + 7", "5 + 5" and "7 & 3". A complete remission was stated in 14 (42.4 per cent) out of 33 patients with acute nonlymphoid leukemia, 6 (43 per cent) out of the 14 patients having relapses. The combined therapy was effective in 4 out of 5 pre-resistant patients. The "7 + 3" scheme was the most beneficial. The most common adverse reactions were nausea and vomiting.


[Comparative evaluation of stability of benzylpenicillin in acid media of natural solutions and in culture fluid]. Inactivation of benzylpenicillin in real media i.e. fermentation broths and their filtrates was studied in comparison with the published data on inactivation of commercial benzylpenicillin in aqueous solutions as dependent on the medium pH and temperature. The lowest constant of benzylpenicillin inactivation was shown to be in the fermentation broths.


[Cefoperazone in combination with metronidazole in the prevention of postoperative infectious complications in patients with genital neoplasms]. Cefoperazone and metronidazole were used for the prevention of postoperative infectious complications in 33 patients (Group 1) with cervical cancer who had undergone the Wertheim operation. 29 patients (Group 2) were treated prophylactically with carbenicillin in the routine doses. Postoperative urinary infections developed in 12.1 and 37.9 per cent of the patients in Groups 1 and 2, respectively. Since the incidence of infectious complications in the patients of Group 1 was lower, the radiation therapy was initiated on an average on day 12.4 +/- 0.4, which was much earlier than in Group 2 (day 15.4 +/- 0.8, p < 0.001). Bacteriological examination of the operation materials from the patients of Group 1 revealed the presence of anaerobes in 64.3 per cent of the patients. The incidence of fever (over 37.8 degrees C) developed irrespective of other signs of an infection significantly correlated with the detection rate of anaerobes in the operation materials (p < 0.05).


[Experience with using cefoperazone in cancer patients after bone marrow transplantation]. Cefoperazone is a semisynthetic cephalosporin of the 3rd generation (cefobid, Pfizer, USA). It was used in monotherapy of 12 oncological patients during ++post-cytostatic aplasia of the bone marrow and peripheral pancytopenia after bone marrow transplantation. The results were favourable in 67 per cent of the patients: the body temperature normalized and no signs of any infection were evident. In 25 per cent of the patients the monotherapy failed and it was necessary to combine cefoperazone with aminoglycosides. Therefore, cefoperazone proved to be an efficient antibacterial drug, whose use was possible in the monotherapy of oncological patients after transplantation of the bone marrow.


[Use of cefoperazone in clinical practice]. The bacteriological and clinical efficacy and side effects of cefoperazone were studied in 45 patients with severe and moderate purulent inflammatory diseases. The study showed that its bacteriological and clinical efficacy was high in cases with peritonitis, cholecystitis, respiratory and urinary infections, as well as those of the eye and soft tissues. The general clinical efficacy amounted to 95.6 per cent. The number of the side effects was insignificant. This made it possible to recommend the use of cefoperazone in the therapy of many purulent inflammatory diseases, as well as in empirical therapy.


[Preparation and characteristics of protoplasts from various strains of Streptomyces roseoflavus var. roseofungini]. It was shown that the variants of the roseofungin-producing organism, which differ in their differentiation, antibiotic activity, structure and cell wall composition had different sensitivity to the protoplasting factors. The protoplasting increased the population heterogeneity: in strain 1128 it was evident from an increased frequency of the secondary colonies, in variant 1-68, folding of the colonies increased and their consistency become milder, sectorial colonies and colonies with coremia formed. It was in principle possible to transform the protoplasts of S. roseoflavus var. roseofungini by plasmid DNA, which suggests that the roseofungin-producing culture may be useful in genetic engineering.


[Isolation and evaluation of the structure of the new anthracycline antibiotics rubomycins F and H]. The rubomycin complex produced by Streptomyces coeruleorubidus 4-157 was studied and the two novel anthracyclines i.e. rubomycins F and H were isolated. The study of the physicochemical properties of the novel antibiotics in comparison with rubomycin C (daunomycin) and the specially prepared 3'-N-carbmethoxyrubomycin C showed that rubomycin F was 3'-N-carbethoxydaunomycin and rubomycin H was 3'-N-carbmethoxydaunomycin. Therefore, rubomycins F and H are novel representatives of natural anthracyclines undescribed previously.


[Search for inhibitors of West Nile virus among antibiotics]. The activity of 24 antibiotics was studied in treatment of albino mice with experimental encephalitis caused by West Nile virus. The antiviral activity of gentamicin and kanamycin was stated. The survival rate of the animals 19. contaminated with 10-100 LD50 of the West Nile virus and treated parenterally with gentamicin in a dose of 80 to 400 micrograms/mouse was higher than that in the controls by 29.5 to 100 per cent and depended on the drug regimen. The efficacy of kanamycin was lower. The chemotherapeutic indices of gentamicin and kanamycin amounted to 100 and 10, respectively. Since there are no schemes for chemotherapy of the infection caused by the West Nile virus and the respective vaccines are not available the use of the antibiotics and gentamicin in particular appears to be promising in the disease prevention and treatment.


[Effect of doxorubicin on the functional state of the mononuclear phagocyte system]. The response of the system of mononuclear phagocytes (SMP) to doxorubicin, an antitumor antibiotic, most widely used in oncological care, was studied. It was shown that a single intraperitoneal administration of doxorubicin to CBA mice in the maximum tolerance doses induced suppression of absorptive SMP capacity and increased IL-I secretion by the bone marrow and peritoneal macrophages both in the stimulated and spontaneous tests in early periods after cytostatic administration. There was a significant rise in the ability of SMP bone marrow elements to respond to the macrophage activating factor, as well as an increase in the cytotoxic activity of bone marrow and peritoneal macrophages.


[Sensitivity of the pathogen of Campylobacter infection to various antibiotics]. Antibiotic sensitivity of 21 Campylobacter strains isolated from humans, monkeys and birds with diarrhea was assayed and the findings are presented. It was shown that all the isolates were highly sensitive to ofloxacin, pefloxacin, ciprofloxacin, josamycin, pipemidinic acid and amoxyclav (a combination of amoxycillin and clavulanic acid). The predominating majority of the strains were resistant to rifampicin, amoxycillin and phosphomycin. The majority of the cultures were sensitive to erythromycin and roxithromycin while some of the isolates were resistant to them which could be used as an additional biological characteristic of Campylobacter cultures and considered in choosing agents for antibiotic therapy.


[Use of a physiological model of gentamicin pharmacokinetics for individual dosage of the antibiotic]. A new approach to fixing the initial doses of gentamicin (GM) for its intramuscular administration (the most commonly used anyway) is discussed. The approach is based on the physiological model reproducing the individual patterns of GM concentration change in patient's blood. Such parameters of the model as blood flow velocity and actual average volume of specific tissues as well as the tissue to the blood partition coefficient (Kp) are constant. They were used to calculate the volume of distribution in the body specific organs (Vs). The apparent distribution volume (Vd) and total clearance (Cl) are individual parameters. The Vd value was calculated individually for every particular patient depending on the body weight by the known equations. The difference between Vd and Vs was used to calculate the individual Kp for the organs and tissues which were not specially examined. When calculating Cl of GM, the patient's sex, age, weight and creatinine concentrations were taken into account. To evaluate the local velocity of blood flow after antibiotic intramuscular administration, it was important to consider the patient's sex and age. The approach was used to reproduce the individual patterns of GM concentration change after the initial administration of the antibiotic, 80 mg, to 19 male patients (age range, 21 to 73 years; weight range, 50 to 94 kg; blood creatinine concentration, 0.4 to 1.6 mg/dl). The GM concentrations attained with the use of the model were afterwards compared to the data on FPIA. (TDx, Abbott) by measuring the GM concentrations in the blood of the patients 0.5, 1, 5 and 7 hours after the administration.(ABSTRACT TRUNCATED AT 250 WORDS)


[Effect of combined preventive use of quadevit with antibiotics on the survival and humoral immune response in experimental studies]. An attempt to correct with quadevit immunodepression due to prophylactic administration of benzylpenicillin and gentamicin for 6 days provided positive results. There was a significant increase in the quantities of Ig 19S and Ig 7S after the animal immunization with the bacterial antigen, an increase in the number of the AFCs in the spleen of the albino mice in response to administration of sheep erythrocytes and an increase in the survival rate of the animals with salmonellosis. The simultaneous use of quadevit with cefamezine and erythromycin did not lower the unfavourable influence of the antibiotics on the immune status of the animals.


[Microbial ecology of laboratory animals as a model in evaluation of the immunomodulating and antimicrobial agents]. Rats with altered microbial ecology and decreased colonization resistance due to neutropenia induced by cyclophosphamide were used as a model for estimating the effect of bacterial polysaccharides (lactulose and exopolysaccharide from Bacillus polymyxa) and fluoroquinolones (pefloxacin). Monotherapy with pefloxacin had a favourable effect both on normalization on the intestinal microflora in the rats and their hemopoiesis (decreased neutropenia). The highest correcting effect with respect to the lowered colonization resistance was observed when pefloxacin was used in combination with exopolysaccharide.


[Therapeutic form of doxycycline hydrochloride for intravenous administration in the treatment of suppurative-septic diseases]. Efficacy of doxycycline hydrochloride administered intravenously was studied in treatment of severe purulent inflammatory diseases such as pneumonia, lung abscesses, pyothorax, skin and soft tissue infections, peritonitis, purulent cholangitis, etc.. Doxycycline showed significant advantages over tetracyclines: prolonged action, higher efficacy and good tolerance. Favourable results were observed in 85 per cent of the cases.


[Cefoperazone in a multi-profile surgical clinic]. The results of the clinical trials of cefoperazone (cefobid, Pfizer, USA), a 3rd generation cephalosporin, carried out at the Research Centre of Surgery are presented. The antibiotic was used to treat and prevent postoperative infections in 44 patients. Good and satisfactory results were observed in 43 out of the 44 patients (99.9 per cent). Antimicrobial activity of cefoperazone against 182 bacterial strains isolated from the patients was assayed and compared with that of other cephalosporins i.e. cefotaxime, ceftriaxone and ceftazidime. The cefoperazone pharmacokinetics was studied in the patients with normal renal functions after surgical operations on the organs of the chest and abdominal cavity. The antibiotic was shown useful in the monotherapy of mixed infections involving anaerobic pathogens.


[Prevention and treatment with cefoperazone of postoperative suppurative complications in heart surgery]. Clinical trials of cefoperazone (cefobid, Pfizer, USA) were carried out in 49 patients with cardiovascular diseases who had undergone surgical operations. The pathogens of infectious complications were investigated bacteriologically. Good results of the treatment were observed in 43 patients. Allergic reaction developed in 1 patient. Cefoperazone was shown advantageous in treatment of pulmonary complications in the operated patients. It was found possible to use cefoperazone in combination with aminoglycosides. Cefoperazone was found to be one of the drugs of choice in the treatment of aerobic and anaerobic bacteriemia, as well as sepsis after surgical operations on the heart and great vessels. The results on the use of cefoperazone for short-term "perioperative" prophylaxis in cardiosurgery (in accordance with the WHO instructions) are also presented.


The hypoosmotic swelling test: an update. The hypoosmotic swelling (HOS) test is a relatively new assay used to evaluate the functional integrity of the sperm's plasma membrane. In fact, more studies have been published on the applicability of the HOS test than any other new sperm indicator. The assay is based on the fact that fluid transport occurs across an intact cell membrane under hypoosmotic conditions until equilibrium is reached. Due to the influx of fluid, the cell will expand and bulge, especially in the tail, and this change can be readily observed with a phase contrast microscope. Earlier studies have yielded some confusion regarding the interpretation of the data. This review is an attempt to clarify and update the usefulness of the HOS test as a tool to evaluate the sperm function.


Antigenic differences in human sperm samples related to various morphological abnormalities. Sperm samples were collected from male partners of fertile and infertile couples having unexplained and male factor infertility and analyzed for morphological abnormalities. After a staining procedure, sperm samples of these infertile men showed a variety of abnormalities. The sperm samples were also studied for their binding with the Abs directed against protamine (the nuclear protein), fertilization antigen (FA-1, sperm surface antigen), and the lithium diiodosalicylate- (LIS-) solubilized sperm preparation, and the binding was correlated with the percentage of morphologically abnormal sperm in the sample. Abs used in the present study were raised in female rabbits and had high titers (ELISA titers, 1:4096 to 1:8196), and recognized no band (anti-protamine), one 49,000- +/- 2000-dalton band (anti-FA-1), and at least 8 bands of various molecular identities in the 14,000- to 92,000-dalton range (anti-LIS sperm) on the Western blot of LIS-solubilized human sperm. The affinity-purified Fab' antibodies were iodinated and used in a radioimmunobindingassay for testing their binding with the sperm cells. Anti-protamine Fab's showed minimal binding and the binding activity (cpm bound/10 x 10(6) sperm cells) did not correlate (head defect, r = .12; midpiece defect, r = .07; tail defect, r = .11) significantly with percentage of abnormal cells in the sample. The binding of the anti-FA-1 Fab's also did not show a significant correlation (head defect, r = .29; midpiece defect, r = .48; tail defect, r = .23), though a positive trend (p = .05) was observed with the midpiece defect. In contrast, the binding of anti-LIS sperm Fab's demonstrated a significant correlation with the percentage of abnormal sperm cells in the sample (head defect, r = .51, p = .04; midpiece defect, r = .80, p less than .0001; tail defect, r = .23, p = .039). With an increased percentage of abnormal sperm cells, especially those with midpiece defect, there was an increased binding of anti-LIS sperm Fab's. These results suggest that with an increase in percentage of abnormal sperm, there is a change in antigenicity of the sperm cells. An increase in structural abnormality may enhance antibody binding to an abnormal sperm cell, thus causing a further decrease in its fertilizing capacity.


Effect of different types of textile fabric on spermatogenesis: electrostatic potentials generated on the surface of the human scrotum by wearing different types of fabric. This study was conducted to evaluate the effect of the electrostatic potentials generated on the surface of the scrotal area when different types of textile fabric were worn. Twenty-one healthy volunteers were divided into three equal groups. The first group was dressed in underpants made of 100% polyester, the second wore underpants of 100% cotton, and the third wore a 50/50% polyester/cotton mixture. With an electrostatic kilovoltmeter, the electrostatic potentials were measured 1 h after wearing the pants once during the day and a second time at night. The test was repeated 4 times, each on a separate day. No electrostatic potentials were detected on the cotton underpants. The polyester pants showed the highest potentials (mean 338.9 +/- 25 SD V/cm2), while the mixed polyester/cotton pants produced less than half that level (mean 148.3 +/- 16 SD V/cm2). The readings during the day were higher than those at night, probably due to the higher temperature during the day. This study could explain the cause of diminished spermatogenesis in dogs dressed in polyester pants. A new theory is put forward holding that the polyester underpants create an "electrostatic field" across the scrotal sac that disturbs the testicular and/or epididymal function.


Ultrastructural parameters of fertile cryopreserved human sperm. Two hundred and forty-four cryopreserved semen samples were used for artificial insemination by donor (AID). All samples were examined for motility and concentration. Thirty of the samples resulted in pregnancies. These samples were further examined ultrastructurally. There was no difference in sperm motility or concentration between the samples that did or did not result in a pregnancy. The ultrastructural characteristics of the samples that resulted in pregnancies revealed that only 15% of sperm (SD = 7.67) possessed normal morphology and had undamaged acrosomes after cryopreservation.


The direct effect of Hochuekki-To on human sperm fertilizability using the hypoosmotic swelling test. The concentration and motility of human sperm increase is examined following the oral administration of a traditional herbal medicine, Hochuekki-To using the hypoosmotic swelling (HOS) test. After 1 h incubation in Hochuekki-To, the motility of sperm and the results of the HOS test improved, particularly for severely abnormal sperm. For both the original and incubated sperm, the results of the HOS test improved when Hochuekki-To was used in the swim-up medium for the swim-up washing method rather than when Whittingham's T6 solution was used. Hochuekki-To had a favorable, direct effect on human sperm functions, suggesting an effect on the physiological integrity of sperm membrane.


Effects of surgical repair of experimental left varicocele on testicular temperature, spermatogenesis, sperm maturation, endocrine function, and fertility in rabbits. To evaluate the effectiveness of surgical correction of varicocele in restoring the function of the varicocelized testicle, experimental varicoceles were created in 16 male rabbits by partly ligating the left lumbotesticular trunk. Five control rabbits received a sham operation (group A). Two months later, eight of the varicocelized rabbits underwent surgical repair by ligation and cutting of the dilated left testicular vein (group B). The remaining eight varicocelized animals did not receive any additional treatment (group C). Five months after the initial operation, group C animals had a significantly lower sperm concentration, sperm motility, bilateral testicular androgen-binding protein activity, bilateral testicular vein testosterone concentration, bilateral testicular versus intraabdominal temperature difference, and fertility when compared with groups A and B. These findings suggested that the surgical repair of an experimental varicocele in the rabbit can significantly improve the parameters indicating the harmful effects of the varicocele on the testicles.


HPLC determination of an oxytocin-like peptide produced by isolated guinea pig Leydig cells: stimulation by ascorbate. Highly purified populations of guinea pig Leydig cells were incubated with a maximally stimulating dose of 100 ng/mL LH for 24 h in the presence of increasing concentrations of sodium ascorbate. Sample supernatants were extracted, concentrated under vacuum, and reconstituted with acidified absolute ethanol. Samples were analyzed for oxytocin using high-performance liquid chromatography with electrochemical detection and known concentrations of an authentic oxytocin standard. Leydig cells stimulated with 0, 25, and 50 microM ascorbate produced and secreted 40.1 +/- 1.23, 77.4 +/- 13.8, 74.2 +/- 26.3 pg of an oxytocin-like peptide, respectively, per 1 x 10(6) cells. These results indicate that guinea pig Leydig cells are capable of producing an oxytocin-like peptide de novo and that low concentrations of ascorbate stimulate the production of this peptide in Leydig cells cultured in vitro.


Blood concentrations of lead, cadmium, mercury, zinc, and copper and human semen parameters. The study consisted of 35 male subjects attending an andrology clinic. The subjects all had poor sperm parameters that could not be attributed to any known medical cause. The objective was to evaluate the relation between various seminal characteristics (volume, total sperm count, sperm viability, proportion of progressively motile sperm, and different sperm morphology) and the blood concentrations of lead, cadmium, mercury, copper, and zinc. The mean blood concentrations of lead, mercury, copper, and zinc were within the normal values; cadmium concentration (1.35 micrograms/L) was much higher than the norms. Asthenozoospermic subjects had significantly (p less than .025) higher blood cadmium levels than normozoospermic subjects. No significant differences were noted between the two groups for mean concentration of mercury, zinc, and copper in blood. Significant correlations were observed between blood cadmium levels and volume of semen, midpiece defects, and immature forms of spermatozoa. High blood cadmium levels may have an effect on spermatogenesis. Possible reasons for the high blood cadmium levels among the subjects are discussed.


Developmental changes in testosterone production by the rat testis in vitro during late fetal life. The age-related evolution of the in vitro capacity of the rat testis to produce testosterone and to respond to luteinizing hormone (LH) during 3 and 24 h incubation was studied from day 18.5 to day 21.5 of fetal life. Basal testosterone production by testes from 18.5-day-old fetuses was significantly higher than production by testes from 20.5- and 21.5-day-old fetuses when secretion was expressed as either per testis or per microgram of testicular protein. When maximal LH-stimulated testosterone secretion was expressed on a per testis basis, it was significantly lower for day 18.5 testes than for day 20.5 and 21.5 testes. However, when it was expressed on the basis of testicular protein content, it decreased significantly between days 18.5 and 20.5. Basal and LH-stimulated secretions displayed the same time-related decrease throughout 24 h of incubation for the three ages studied. The dose-response curves for LH showed that the sensitivity was similar for day 18.5 and 20.5 testes (ED50 = 10 vs. 14 ng/mL, respectively). These results showed an age-related decrease in testicular steroidogenic capacity without a change in the coupling efficiency of LH receptor to testosterone production during late fetal life in rats.


The fate of foreign DNA associated with pig sperm following the in vitro fertilization of zona-free hamster ova and zona-intact pig ova. The aim of this study was to determine the fate of foreign DNA molecules bound to porcine sperm that had been capacitated and acrosome reacted in vitro using calcium ionophore and then used in the in vitro fertilization of zona-free hamster ova and zona-intact pig ova. Fluoresceinated Pisum sativum agglutinin (PSA) labeling was used to differentiate between acrosome-intact and acrosome-reacted sperm. This revealed that up to 80% of the sperm treated with calcium ionophore were acrosome reacted. Up to 70% of these acrosome-reacted sperm were labeled with the foreign DNA at the post-acrosomal region. Following association of DNA with the acrosome-reacted sperm, insemination droplets were prepared and zona-free hamster oocytes or zona-intact pig oocytes were added. The gametes were allowed to interact and then fixed and stained to visualize decondensed sperm heads that had penetrated into the oocytes. The sperm were stained with streptavidin peroxidases to detect the biotinylated foreign DNA bound to the decondensed heads. These studies revealed that 54% of fertilized hamster and pig oocytes contained decondensed sperm that had retained the post-acrosomal pattern of bound foreign DNA. After incubation with DNA-associated sperm, the oocytes were washed and cultured for 15-17 h. After fixation, up to 30% of hamster oocytes and 10% of porcine oocytes were found to contain sperm pronuclei. However, using the streptavidin peroxidase detection system, it was not possible to determine if any of these pronuclei contained the foreign DNA.


Classification of compounds for prevention of NMDLA-induced seizures/mortality, or maximal electroshock and pentylenetetrazol seizures in mice and antagonism of MK801 binding in vitro. Intravenous injection of N-methyl-D,L-aspartic acid (NMDLA) into mice produces characteristic convulsions followed by death. The present study was designed to determine the degree of blockade of these seizures/mortality by compounds acting at various subsites on the N-methyl-D-aspartic acid (NMDA) receptor complex (competitive and noncompetitive antagonists, as well as inhibitors of the strychnine-insensitive glycine subsite, and Zn++ subsite agonists), and also calcium channel blockers, clinically used anticonvulsants, plus selected compounds with activities or structures similar to specific agents chosen. Activity among compounds was correlated to in vitro potency regarding inhibition of binding of MK801 to the ionic channel subsite associated with the NMDA receptor. Furthermore, all compounds were examined for antiseizure properties with respect to tonic hindlimb extension elicited by maximal electroshock (MES) and clonus induced by pentylenetetrazol (PTZ). Drugs were subsequently classified according to their spectra of efficacy in these tests. The following characteristics emerged: 1) agents active at all 3 NMDA mechanisms (convulsions/mortality/MK801 binding) plus MES and PTZ, were MK801 and CPP [3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid]; 2) active at all the NMDA mechanisms and MES were ketamine and dextromethorphan; 3) active against NMDLA-induced convulsions/mortality, MES and PTZ, but not MK801 binding, were doxepin, desipramine and diazepam; 4) active against NMDLA-induced convulsions/mortality and MES were des-Me-doxepin, flunarizine and remacemide; 5) active against NMDLA-induced convulsions/mortality and PTZ was nisoldipine; 6) active against only NMDLA-induced convulsions/mortality were chlorpheniramine and iproniazid; 7) active in the MES and PTZ tests were phenobarbital, pentobarbital and valproate; 8) active in the MES test alone were phenytoin and carbamazepine; 9) active against PTZ only was ethosuximide; 10) active only in the in vitro MK801 binding assay were HA966, 7-Cl-kynurenate and AP7 (2-amino-7-phosphonoheptanoic acid); and 11) no demonstrable actions had AP4 (2-amino-4-phosphonobutyric acid) and mianserin. In conclusion, inhibition of NMDLA-induced convulsions/mortality in vivo is not necessarily correlated to a noncompetitive displacement of MK801 binding to NMDA receptor sites in vitro, nor is inhibition of NMDA-elicited convulsions/mortality correlated with a specific ability of a compound to inhibit either MES or PTZ seizures.


Effects of clonazepam on paired-pulse and frequency potentiation of evoked potentials in rats. Three different monosynaptic evoked potentials (thalamocortical, interhemispheric, i.e. transcallosal, and entorhino-dentate) were used to study the paired-pulse and frequency potentiation in adult rats. A marked potentiation was seen in both neocortical responses under control conditions (up to 200%), whereas potentiation in the dentate gyrus was only moderate. Clonazepam (0.1 and/or 1 mg/kg, i.p.) antagonized the potentiation of the thalamocortical responses only, the frequency potentiation was suppressed in a dose-dependent manner, and the paired-pulse potentiation was significantly attenuated only by the higher dose of clonazepam. The potentiation of the cortical interhemispheric as well as of the entorhino-dentate evoked potentials was not changed by either dose of clonazepam. The present results do not form the hypothesis of frequency potentiation as a mechanism of epileptogenesis.


Inhibition of neutrophil chemotaxis by purinoceptor agonists. Adenine nucleotides inhibited fMet-Leu-Phe-activated chemotaxis by rabbit neutrophils in the micromolar concentration range. The sequence of inhibitory effectiveness was ATP[S] greater than ATP greater than ADP greater than AMP greater than adenosine. In the presence of EDTA, inhibition of chemotaxis by ATP occurred to the same degree as in the presence of Ca2+ (and Mg2+), indicating that neither ectonucleotidases nor Ca2+ fluxes across the plasma membrane are of importance for the inhibitory effect. The inhibitory effect of ATP persisted when the nucleotide was removed after preincubation, before the cells were submitted to chemotaxis. Exposure of neutrophils to ApCpp results in desensitization towards inhibition by ATP. Other nucleoside triphosphates, such as XTP, GTP, ITP, CTP and UTP, also inhibited neutrophil migration. The relative potency of the nucleotides, which are used to discriminate between the subtypes of the P2 purinoceptor, was (at a concentration of 50 microM) ATP greater than ApCpp greater than AppNp greater than MeSATP greater than AppCp. The results suggest that inhibition of neutrophil chemotaxis by purinoceptor agonists is mediated by P2 purinoceptors and that the subtype is different from the P2x or P2y purinoceptor.


Distribution of lipid phenotypes in community-living men with coronary heart disease. High prevalence of isolated low levels of high-density lipoprotein cholesterol. Risk factor modification, including treatment of dyslipidemias, has been recommended for the prevention of future coronary events in patients with coronary heart disease (CHD). Since the prevalence of various dyslipidemias among outpatients with CHD has not been well documented, the purpose of this study was to determine the frequency of specific lipid phenotypes among ambulatory men with CHD. Lipid profiles were obtained in 255 men (mean age, 65.5 +/- 9.1 years) with CHD in three Veterans Affairs medical centers. Desirable levels of lipids were defined according to National Cholesterol Education Program guidelines as follows: low-density lipoprotein cholesterol (LDL-C) levels less than 3.36 mmol/L (130 mg/dL); high-density lipoprotein cholesterol (HDL-C) levels equal to or greater than 0.90 mmol/L (35 mg/dL); and triglyceride levels less than 2.83 mmol/L. Seventy-six percent of the group had one or more abnormalities on lipid profile: 51% had high LDL-C levels with or without abnormalities of HDL-C and/or triglyceride levels; 22% had low HDL-C levels with desirable levels of LDL-C; and 3% had hypertriglyceridemia without any cholesterol abnormalities. Normal lipid profiles were significantly more prevalent in subjects over the age of 65 years than in younger patients (40% vs 14%). These data suggest that (1) a high proportion of men with CHD have dyslipidemia, including 50% with LDL-C level elevations. For these men, the potential benefits of therapeutic intervention have been documented in clinical trials, although the cost-efficiency of wide-scale treatment has not been determined; (2) isolated hypertriglyceridemia is rare in this population; and (3) low HDL-C levels in association with desirable LDL-C levels are present in more than one fifth of male patients with CHD. Clinical trials focusing on this large group are urgently needed to determine whether efforts to raise HDL-C levels result in reduced cardiac morbidity and/or mortality.


How useful is the rheumatoid factor? An analysis of sensitivity, specificity, and predictive value. The rheumatoid factor (RF) is frequently ordered in an effort to detect disease, yet its diagnostic utility has not been thoroughly examined. To determine the test's sensitivity, specificity, positive predictive value, and negative predictive value, we analyzed tests ordered in our institution. We performed a retrospective analysis of all 86 patients with a positive RF over a 6-month period identified consecutively soon after the test was ordered. A similar analysis was applied to 86 seronegative patients selected at random from a total seronegative population of 477 during the same period. The patients represented the primary care and subspecialty practices and inpatient wards of a 504-bed university teaching hospital. A positive RF result was strongly associated with rheumatoid arthritis or another rheumatic disease. For rheumatoid arthritis, sensitivity = 0.28 and specificity = 0.87, while for any rheumatic disease, sensitivity = 0.29 and specificity = 0.88. The positive predictive values for rheumatoid arthritis and any rheumatic disease were 0.24 and 0.34, respectively, and the negative predictive values were 0.89 and 0.85, respectively. Seropositive patients were slightly older (55 vs 49 years old), but the incidence of false-positive RFs among the elderly (69%) was not significantly higher than among younger patients (65%). The cost per true-positive RF result was $563. In this study, most positive RF results were not helpful since the majority represented false-positive results. The low positive predictive value of the RF casts doubt on the utility of the RF in the diagnostic evaluation of patients. Contrary to traditional clinical expectations, the diagnostic utility of the RF may be greatest when it is negative. However, the subset of patients with seronegative rheumatic disease reduces the test's power to exclude such disorders even when the RF is negative. Given the test's limitations, clinicians should reconsider their expectations when ordering an RF. The utility of the RF may improve if it is ordered more selectively.


Pumiliotoxin B-like alkaloid in extracts of the skin of the Australian myobatrachid frog Pseudophryne coriacea: effects on blood pressure and heart of the rabbit. Extracts of the skin of the Australian myobatrachid frog Pseudophryne coriacea (PS) displayed striking, reversible and, in part, dose-dependent effects on the systemic blood pressure and the heart of the rabbit. Similarly to the results obtained in the rat, the blood pressure response in the rabbit consisted in an initial short-lasting fall, followed by a significant and persistent rise. The initial hypotensive effect was inhibited by atropine, indicating a cholinergic mechanism. The inhibition of the pressure rise by prazosin or guanethidine, but not by surrenalectomy or hexamethonium, suggests a catecholamine release from adrenergic nerve terminals of the vasculature. PS produced on the heart a variety of rhythm disorders, caused both by a release of acetylcholine and a direct effect on the myocardium. It is worth mentioning that tetrodotoxin, a typical sodium channel blocker, reduced or abolished the effects of PS both on the heart and the blood pressure, suggesting that sodium channels may directly or indirectly participate in the mechanism of action of PS.


Mandated choice. The preferred solution to the organ shortage? A critical shortage of organs is perhaps the major barrier facing transplantation today. Adopting a system of presumed consent or mandated choice are among the solutions proposed. Under presumed consent, organs may be removed after death without explicit consent, unless the deceased had previously objected or the family objects at the time of death. Under mandated choice, all adults would be required to decide for themselves whether they wish to donate on their deaths and their decisions would be controlling. To see if educated young people would support these proposals, I carried out two surveys at the University of Maryland, College Park, Md, of a total of 418 students who were at least 18 years of age. An overwhelming 90% would support mandated choice while a smaller percentage, just over 60%, would support presumed consent. The vast majority believe that the family should not be able to override the previously expressed wishes of their recently deceased loved one. Unfortunately, only a minority of respondents had discussed organ donation with their families and even fewer had signed donor cards. Even young, educated people frequently fail to consider organ donation prospectively and this is a major barrier to organ retrieval. While presumed consent and mandated choice are designed to deal with this serious problem, mandated choice seems preferable and would likely receive widespread support. Therefore, I suggest that a small scale trial of mandated choice be undertaken as soon as possible in the hope of finding an acceptable system that will quickly and efficiently increase the supply of desperately needed organs.


The complications of infective endocarditis. A reappraisal in the 1980s. The frequency of complications of infective endocarditis and their influence on the outcome of the patients changed in the antibiotic era. Therefore, we evaluated the complications in a recent large series of patients with infective endocarditis. We studied 300 episodes of endocarditis in 287 patients in a tertiary cardiology referral center. Predisposing cardiac conditions were valvular heart disease in 147 episodes, congenital heart disease in 37, other heart diseases in five, and prosthetic heart valves in 69. In 69 episodes, there was no previous heart disease. The infecting microorganisms were streptococci in 147 episodes, Staphylococcus aureus in 59, Staphylococcus epidermidis in 14, gram-negative bacteria in 16, other gram-positive bacteria in eight, and fungi in four. In 52 episodes, blood cultures were negative. Seventy-eight patients (26%) died. Complications were defined as any clinically unfavorable event occurring during treatment. A total of 386 complications occurred in 223 episodes (74%); one complication occurred in 128 episodes (57%), two in 57 (26%), three in 18 (8%), four in 13 (6%), five in three (1%), and six or more in three (1%). The complications were as follows: cardiac, 100 occurrences; neurological, 72; septic, 46; associated with medical treatment, 41; renal, 27; extracranial systemic arterial embolism, 16; septic pulmonary embolism, 26; complications related to surgical treatment, 11; acute prosthetic heart valve insufficiency, six; splenic infarction or abscess, three; cardiac rhythm disturbances, three; and other, 19. The distribution of the complications relative to outcome of the patients revealed that fatality exceeded survival rates for neurologic and septic complications. Complications may be common in patients with infective endocarditis. Cardiac complications were the most common ones, but fatality rates were higher for neurologic and septic complications. Hence, heart failure was replaced by neurologic and septic complications as the leading causes of death in patients with infective endocarditis.


Prognosis in ischemic heart disease. Can you tell as much at the bedside as in the nuclear laboratory? BACKGROUND--While the resting left ventricular ejection fraction (LVEF) predicts prognosis in ischemic heart disease, clinical evaluation is also useful. METHODS--To compare the prognostic value of LVEF by resting radionuclide ventriculography with that of clinical signs and symptoms of congestive heart failure (CHF), 170 patients with suspected ischemic heart disease were followed up in this prospective study. Patients had a standardized history and physical examination performed by a study cardiologist immediately before the nuclear scan. Chest roentgenography and radionuclide ventriculography were performed in a standard manner. The diagnosis of CHF was made by validated clinicoradiographic criteria based on the Framingham study. Mortality was determined by means of the National Death Index; median follow-up time was 3 years. RESULTS--There was CHF at baseline in 70 patients, and baseline LVEF was low (< or = 0.4) in 63 patients. Low LVEF was significantly associated with CHF. During follow-up, 55 of the subjects died (overall mortality, 32%). Subjects with CHF had a significantly higher risk of death than those without CHF, and subjects with low LVEF had a higher mortality than those with preserved LVEF. Both CHF and LVEF were independent predictors of mortality. In a Cox model, each percentage increase in LVEF was associated with a 2% decreased mortality, while subjects with CHF had a mortality 2.5 times higher than that of those without CHF. Also, CHF with preserved LVEF had a better prognosis than CHF with depressed LVEF, but this prognosis was worse than that in subjects without CHF. CONCLUSIONS--The clinical diagnosis of CHF, based on clinical evaluation and chest roentgenogram, is a valid predictor of mortality and provides information independent of the radionuclide LVEF in determining prognosis in patients with ischemic heart disease.


Cholesterol-lowering effects of calcium carbonate in patients with mild to moderate hypercholesterolemia. In recent years, several authors have noted that oral calcium treatment was associated with a reduction in serum cholesterol level. Calcium carbonate was examined for its ability to lower serum cholesterol levels in hypercholesterolemic patients. Fifty-six patients with mild to moderate hypercholesterolemia were examined in this randomized, double-blind, placebo-controlled crossover study. Patients were treated with a low-fat, low-cholesterol diet targeted at the American Heart Association Step-1 diet for 8 weeks before and while receiving placebo or calcium carbonate (9.98 mmol [400 mg] of elemental calcium) three times daily with meals for 6 weeks. Patients were then crossed over to the alternate treatment for an additional 6-week period. Compared with placebo, calcium carbonate achieved a 4.4% reduction in the low-density lipoprotein cholesterol level, and a 4.1% increase in the high-density lipoprotein cholesterol level. The ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol significantly decreased by 6.5% with calcium carbonate treatment. Calcium carbonate treatment did not significantly affect blood pressure or serum levels of triglycerides, lipoprotein Apo B, or calcium. Relative urinary saturation ratios of calcium oxalate levels were unchanged during calcium carbonate therapy. Compliance with diet and treatment was excellent and no significant adverse effects were noted. Thus, calcium carbonate was a modestly effective and well-tolerated adjunct to diet in the management of mild to moderate hypercholesterolemia in this clinical study.


Prevalence of, and risk factors for, angiographically determined coronary artery disease in type I-diabetic patients with nephropathy. BACKGROUND--Thirty-five percent of type I-diabetic patients are dead of coronary artery disease by age 55 years, and the risk of death is increased eightfold to 15-fold in patients with nephropathy. However, the prevalence of coronary artery disease with respect to age is unknown and few risk factors have been identified. METHODS--One hundred ten insulin-dependent diabetic patients underwent routine pretransplant coronary angiography and cardiac risk factor assessment. Angiograms were evaluated by two angiographers for presence or absence of coronary artery disease (CAD, defined as one or more coronary artery stenoses of 50% or greater in diameter, and no CAD, defined as no stenosis of 25% or greater in diameter, respectively). Prevalence of CAD by age was determined, and associated risk factors were defined. RESULTS--Fifty-two of 110 patients had CAD. Coronary artery disease prevalence increased significantly with age; 13 of 16 patients older than 45 years of age had CAD. For patients 35 years of age or younger, associated risk factors included a family history of premature myocardial infarction, higher hemoglobin A1c level, hypertension for more than 5 years, lower high-density lipoprotein level, and smoking for more than 5 pack-years. For patients between 35 and 45 years of age, associated risk factors included number of years of diabetes, higher hemoglobin A1c levels, and smoking more than 5 pack-years. CONCLUSIONS--In type I-diabetic patients with nephropathy, CAD prevalence increased significantly with age and was found in the majority of patients older than 45 years of age. Coronary artery disease risk factors operative in the general population were significantly associated with CAD in this high-risk group. In addition, a role for hyperglycemia in accelerated atherogenesis was supported by the association of both higher hemoglobin A1c levels and number of years of diabetes with CAD.


The effectiveness of cerebral imaging in the diagnosis of chronic headache. The increasing availability of high-resolution cerebral imaging scanners has fueled enthusiasm for their use to "rule out" brain tumor and other serious neurologic conditions in patients with headache. The effectiveness of this practice, however, has not been tested since the advent of newer scanning equipment. Our objective was to measure the usefulness of cerebral imaging in patients with chronic isolated headache. A retrospective study with a 15- to 27-month follow-up period. A group-model health maintenance organization. Adult patients, 100,800, in a health maintenance organization and an enriched sample of 63 patients with neurosurgical conditions from other health maintenance organization hospitals. During 1990, 1083 cerebral computed tomographic scans were performed on 863 adults (0.9% of health maintenance organization adults). Eighty-nine patients were scanned for chronic isolated headache; none of the scans provided important new information (95% confidence interval, 0%, 3%). Long-term patient follow-up confirmed that this low yield could not be attributed to diagnostic work-up bias. Further attempts to support a policy of imaging patients with isolated headache were also unsuccessful. Review of an enriched sample of patients with malignant brain tumor and patients requiring craniotomy for other reasons (n = 40) demonstrated that no patient had headache alone at the time of diagnosis (95% confidence interval, 0%, 8%) and that only 5% (95% confidence interval, 0%, 12%) of these patients sought medical attention for headache alone. Sampling a second enriched sample of patients who were referred from other hospitals (n = 63) because of conditions requiring neurosurgical procedures demonstrated that only 6% of patients presented with chronic isolated headache alone (95% confidence interval, 0%, 12%). Uncertainty regarding the appropriateness of imaging patients with headache was illustrated by the extreme interphysician variability of this practice. Our study demonstrates the large potential cost and low (although not zero) yield associated with nonselectively imaging patients with chronic isolated headache.


Equal survival rates for first, second, and third episodes of Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Second and subsequent episodes of acute Pneumocystis carinii pneumonia (PCP) are reported to have a worse prognosis than initial episodes in patients with the acquired immunodeficiency syndrome. We tested the hypothesis that survival rates of first, second, and subsequent episodes of acute PCP in patients with the acquired immunodeficiency syndrome are equal. Analysis of the outcomes in prospective series of patients with the acquired immunodeficiency syndrome treated for acute PCP over 5 years. Survival rates of 222 PCP occurrences by episode number were: first, 86%; second, 84%; third, 88%; and fourth, 67%. Survival rates for the first, second, and third episodes were not significantly different. Second and third episodes had a larger proportion of patients with mild disease than initial episodes. Survival rates for first, second, and third episodes of PCP in patients with the acquired immunodeficiency syndrome are not different. In contrast to earlier articles, treatment for second and third episodes of acute PCP may be as successful as in initial episodes.


Frequent hypoglycemic episodes in the treatment of patients with diabetic ketoacidosis. Previous studies of the management of diabetic ketoacidosis have noted a wide range of incidence of hypoglycemia but have not studied the risk factors associated with it. To describe the incidence of hypoglycemia in patients hospitalized with diabetic ketoacidosis, we retrospectively reviewed the charts of all adult patients with the diagnosis of diabetic ketoacidosis at three private, community hospitals in Milwaukee, Wis, between January 1, 1987, and May 31, 1990. Two hundred twenty admissions in 150 patients met our inclusion criteria. In 30% (66/220) of cases of diabetic ketoacidosis, a serum glucose level or Accu-Chek (Boehringer-Mannheim, Indianapolis, Ind) finding was 2.7 mmol/L or less during the first 14 days of hospitalization. No factors could be identified that were associated with a significantly increased risk of early hypoglycemia (within the first 48 hours of admission). The risk of a "late" occurrence of hypoglycemia (after 48 hours of hospitalization) was increased by fever (relative risk, 2.05; 95% confidence interval [CI], 1.16 to 3.63), "nothing orally" status (relative risk, 3.01; 95% CI, 1.88 to 4.83), hepatic disease (relative risk, 2.56; 95% CI, 1.39 to 4.70), and renal disease (relative risk, 2.07; 95% CI, 1.26 to 3.39). A logistic regression analysis showed "nothing orally" status to be associated with an increased risk of any hypoglycemia occurring during the hospitalization (relative risk, 2.39; 95% CI, 1.63 to 3.51). Physicians and nurses documented the first episode of hypoglycemia in their notes 45.5% and 80.3% of the time, respectively. Hypoglycemia is still a common complication of diabetic ketoacidosis, is associated with hepatic and renal disease as well as fever and "nothing orally" status, and is not documented well in physician notes.


Toward improved empiric management of moderate to severe urinary tract infections. Guidelines to show whether a patient hospitalized because of a urinary tract infection (UTI) has a severe infection, and whether he or she is at high risk for harboring a multiresistant pathogen, are scant. The aims of the present study were to find (1) clinical and laboratory variables known within 24 hours of admission that, combined in a logistic model, will point to a high or low probability of bacteremia and (2) variables that can be used to define patients at high risk for the subsequent isolation of a multiresistant uropathogen. In a set of patients consecutively admitted to a department of medicine because of UTI, we compared bacteremic vs nonbacteremic patients, and patients with a multiresistant uropathogen vs others, on logistic regression analysis. The logistic models derived were validated in a second set of patients with UTI. Among 247 patients with UTI (median age, 75 years), 80 of them with bacteremia, five factors were significantly and independently associated with bacteremia: serum creatinine level, leukocyte count, temperature, diabetes mellitus, and low serum albumin level. A logistic model incorporating those factors was used to divide the patients into three groups with increasing prevalence of bacteremia (6%, 39%, and 69%) and of death (3%, 6%, and 20%). Three factors were predictive of the subsequent isolation of a resistant uropathogen: use of antibiotics before admission, advanced age, and male gender. The combination of those factors was used to divide patients into two groups, with resistance to cefuroxime of 9% vs 28%, to gentamicin of 7% vs 20%, and to sulfamethoxazole-trimethoprim of 30% vs 50%. In a second set of 144 patients with UTI, the percentages of bacteremia in the three groups were 5%, 16%, and 55%, and those of death, 2%, 6%, and 17%. When divided by the second model, the resistance to cefuroxime in the two groups was 16% vs 30%; to gentamicin, 16% vs 28%; and to sulfamethoxazole-trimethoprim, 28% vs 59%. If prospectively validated in other settings, the models can be used to define groups of patients with UTI at low and high risk for bacteremia, and to help in the choice of empiric antibiotic treatment.


Efforts to improve compliance with the National Cholesterol Education Program guidelines. Results of a randomized controlled trial. We compared three approaches for improving compliance with the practice guidelines of the National Cholesterol Education Program (NCEP). A randomized controlled trial. Academic group practices of a major urban teaching hospital. Study physicians were three equivalent groups of PG-2 and PG-3 residents (N = 33) seeing patients in equivalent outpatient clinics. Continuity patients of these residents were included (N = 240) if they were younger than 66 years, saw their primary physician during the intervention period, were not pregnant, and had no serious life-shortening noncardiac illnesses. Three interventions were implemented over a 5-week period. Control group physicians (group 1) were offered only a standard lecture provided through the Physician Cholesterol Education Program (PCEP). Group 2 physicians were offered the PCEP lecture and also received generic chart reminders of the NCEP guidelines on each eligible patient's chart. Group 3 physicians were offered the PCEP lecture and also received timely patient-specific feedback, including acknowledgement of recent lipid values and management, and explicit recommendations for further action. Knowledge of lipid disorders was tested before and after the PCEP lecture, and physicians' attitudes were surveyed following the intervention period. The three groups were similar in baseline (preintervention) compliance with NCEP recommendations (average, 39%) and physicians' knowledge. Patients were similar across groups in number of coronary artery disease risk factors and cholesterol values. Significant within-group improvements in compliance were noted for groups 2 and 3 (7.6% and 10.6%, respectively), but not for group 1 (4.5%). Importantly, there were no differences observed in improvements across groups. In exploratory analyses, however, there was a significant correlation between improved compliance and the number of patients seen by each provider in group 3 that was not observed in groups 1 or 2. Notably, changes in compliance were unrelated to PCEP lecture attendance (8.6% vs 8.1% for attenders vs nonattenders, respectively), level of postgraduate training, baseline or later tests of knowledge, or patient factors. The postintervention survey revealed marked overestimation by physicians of their personal compliance with NCEP guidelines, although there was strong support for clinic efforts that would screen patients for lipid disorders independent of physician initiative. This study raises questions about the effectiveness of education alone for improving compliance with NCEP guidelines. The effectiveness and efficiency of timely, individualized feedback should be explored in studies over a longer period. Innovative alternative approaches are suggested by the responses to our survey and other research in preventive practices.


Treatment of cryptosporidiosis with paromomycin. A report of five cases. Cryptosporidiosis continues to be one of the most devastating complications of the acquired immunodeficiency syndrome, causing severe, chronic diarrhea that is largely refractory to treatment. More than 60 drugs have been tried in the treatment of cryptosporidiosis, none of which have been consistently successful. We describe the successful treatment of cryptosporidiosis in five patients with acquired immunodeficiency syndrome with oral paromomycin at a dose of 1500 to 2000 mg/d. All five patients had resolution of symptoms and normalization of bowel movements, although one patient later relapsed while receiving paromomycin. Three of five patients cleared Cryptosporidium from the stool. Paromomycin is a promising therapy for cryptosporidiosis in acquired immunodeficiency syndrome and further prospective clinical trials are warranted.


Carbamazepine neurotoxic reaction after administration of diltiazem. A patient with epilepsy controlled by carbamazepine developed a carbamazepine neurotoxic reaction after being given an increased dosage of diltiazem hydrochloride as adjunctive therapy. Abrupt withdrawal of diltiazem reduced the circulating carbamazepine concentration and resulted in an epileptic attack. Awareness of the interaction between diltiazem and carbamazepine and careful monitoring of carbamazepine blood levels is recommended to prevent the dangerous neurotoxic effect associated with this combination.


Atherosclerotic lesions. Natural history, risk factors, and topography. This article describes the development of human atherosclerosis as a framework on which to integrate and incorporate the research on thrombosis and hemostasis of participants in the 1992 College of American Pathologists Conference XXII on Hemostasis and Atherosclerotic Disease. Included are the early classic studies of the morphological features of atherosclerosis, atherosclerosis in different populations, the distribution of atherosclerotic lesions among arterial segments, the topography of atherosclerotic lesions within arterial segments, and the relationship of risk factors for coronary heart disease to the arterial lesions of atherosclerosis. Special attention is given to the development of atherosclerosis in young people, including findings from the Pathobiological Determinants of Atherosclerosis in Youth study. The data in this review provide confirmation of the development of atherosclerosis at an early age and relate atherosclerotic lesions to certain coronary heart disease risk factors. Any role of thrombosis or hemostasis in atherosclerosis must be integrated into this framework.


Factors controlling smooth-muscle cell proliferation. Injury to the arterial wall normally elicits a rapid and significant increase in smooth-muscle cell (SMC) replication with the subsequent development of intimal lesions. A variety of factors have been proposed to control SMC replication, but recent work has highlighted the role of basic fibroblast growth factor (bFGF) and platelet-derived growth factor in this process. In the carotid artery of the uninjured rat, we have shown that the SMCs express mRNA for bFGF and that bFGF can be readily extracted from these arteries. Following mechanical injury to the artery, ie, after balloon injury, we suggested that bFGF is released from damaged cells and then stimulates adjacent SMCs. In support of this concept, the infusion of a blocking antibody to bFGF was found to significantly inhibit the early SMC replication induced by use of a balloon catheter. The addition of the antibody at the time of injury, however, did not inhibit the development of intimal lesions. In contrast, studies by us and other investigators have shown that platelet-derived growth factor is not directly important for SMC replication after balloon injury, but that it plays a key role in stimulating the migration of SMCs into the intima. Intimal SMC replication was not inhibited with antibodies to either bFGF or platelet-derived growth factor. Therefore, while significant inroads have been made in understanding the initial events, we still do not fully understand all the processes involved in the proliferation of arterial intimal lesions.


Theories and new horizons in the pathogenesis of atherosclerosis and the mechanisms of clinical effects. In this report, I relate some of the major new concepts of the cellular and humoral pathological changes of atherosclerosis to the many observations that have been made recently in the clinicopathological study of the Pathobiological Determinants of Atherosclerosis in Youth, in some of the more human lesion-related animal models, and in epidemiological studies. An effort is made to explain the transition from the many important gross findings to the microscopical, immunohistochemical, and micromorphometric observations that have been made in a number of recent large-scale autopsy studies that are still under way in a number of countries.


Cytokines and growth factors in atherogenesis. The development of laboratory techniques for the culturing of vascular endothelial and smooth-muscle cells during the 1970s, followed by the rapid advances in molecular and cell biology during the 1980s, provided the foundation for the identification of growth factor and cytokine networks involved in maintenance of the normal vasculature as well as participating in diverse pathologic processes involving blood vessels. Vascular cells can produce and respond to a vast array of biochemical messengers that control cell replication, differentiation, and many specific cell functions. Investigators are beginning to explore the changes in the patterns of messengers exchanged between the vascular cells and infiltrating leukocytes during the initiation and progression of atherosclerosis. A variety of in vitro and in vivo studies have indicated that growth factors and cytokines that mediate the critical processes of inflammation and wound healing also play a central role in vascular disease. Indeed, many view atherosclerosis as the result of excessive or prolonged chronic inflammation and wound healing in response to diverse injurious stimuli to cells of the vessel wall. Vascular injury may result from many varied and interacting forces, including nutritional and metabolic abnormalities such as hyperlipidemias or elevated homocysteine, mechanical forces associated with hypertension, exogenous toxins including those found in cigarette smoke, abnormally glycated proteins associated with diabetes mellitus, oxidatively modified lipids or proteins, and, possibly, viral infections. Ultimately, a greater understanding of the activated cytokine and growth factor networks within the vascular wall following injury and during atherogenesis will allow clinical scientists to identify steps susceptible to therapeutic intervention using recombinant cytokines, antibodies, soluble receptors, or receptor antagonists. Other therapeutic strategies may involve the transfection of specific genes, which may inhibit atherosclerosis, into vascular cells at sites prone to lesion formation.


Hemodynamic forces and vascular cell communication in arteries. As the interface between the blood and the rest of the vessel wall, the endothelium is directly affected by hemodynamic shear stress (frictional) forces that locally regulate vascular tone and are implicated in the localization of atherosclerosis. There are many diverse responses of endothelial cells to hemodynamically related mechanical stresses ranging from ion channel activation to gene regulatory events. The processes of force transmission from the blood to the cell, and force transduction within the endothelium to electrophysiologic, biochemical, and transcriptional responses are poorly understood. This article reviews the principal mechanisms currently thought to be involved and outlines the signal pathways from the endothelium to underlying smooth-muscle cells.


Thrombosis and cardiovascular risk in the elderly. Current concepts of cardiovascular disease pathophysiology include a prominent role for thrombosis as a key factor. Thrombosis is not only the usual precipitant to a clinical event, but it may also be involved in atherosclerotic plaque development throughout most of the adult years. However, our understanding of thrombotic risk factors, especially in the elderly, is poor and research has just begun in this area. Fibrinogen has been clearly established as an independent risk factor in the middle aged, but there are conflicting data concerning older persons. Factor VII and plasminogen activator inhibitor-1 look promising as risk factors in the middle aged, but there are no data currently available concerning the status of these factors in the elderly. Many associations exist between the thrombotic risk factors and other cardiovascular risk factors such as plasma lipids and glucose intolerance, making the establishment of independence difficult, and little is known about how these different factors may interact in older individuals. Ongoing studies should provide many answers in the near future.


Hemostatic factors and risk of cardiovascular disease in women. An overview. This report presents an overview of epidemiologic and clinical studies on the relationship between plasma levels of hemostatic factors and risk of cardiovascular disease in women. In addition, research on an association between hemostatic factor levels and gender, as well as estrogen status, is briefly reviewed. Only the Framingham Heart Study has published prospective results showing elevated fibrinogen levels to be associated with excess risk of coronary heart disease among women. However, taken together, the evidence to date from epidemiologic and clinical studies suggests potentially important hemostatic effects of aging, gender, and sex hormone levels on risk of cardiovascular disease in women.


Hemostasis and cardiovascular risk. The British and European experience. There is evidence that increased reactivity of blood plasma to thrombogenic surfaces (hypercoagulability) may contribute to the risk of thrombotic occlusion of a coronary artery in coronary heart disease. The Northwick Park Heart Study found raised levels of factor VII coagulant (VIIc) activity and fibrinogen in men at high risk of a coronary event. Several other European studies have confirmed the latter finding, but the Northwick Park Heart Study is the only study to report formally on VIIc to date. Plasma VIIc is increased in the presence of hyperlipidemia and on a high fat diet, and falls with lipid-lowering therapy and a reduction in fat intake. Fibrinogen concentration is raised in smokers and decreases when the habit is given up. Thus, these markers of thrombogenic risk are readily controlled by standard preventive measures against coronary heart disease. Unresolved issues include: (1) whether the distinctive features of the Northwick Park VII bioassay improve the value of VIIc as a predictor of coronary heart disease; (2) the separate extent to which activation of factor VII and increases in factor VII concentration account for the raised VIIc in hyperlipidemia; (3) the basis of the raised fibrinogen in men at high coronary heart disease risk, even among nonsmokers; and (4) the usefulness of plasma levels of activation peptides of factors IX, X, and prothrombin as markers of thrombogenic risk.