Simian immunodeficiency virus (SIV) infection of infant rhesus macaques as a model to test antiretroviral drug prophylaxis and therapy: oral 3'-azido-3'-deoxythymidine prevents SIV infection.

The prophylactic and therapeutic properties of 3'-azido-3'-deoxythymidine (AZT) against simian immunodeficiency virus (SIV) infection were tested in four 3-month-old rhesus macaques. The infant monkeys were inoculated intravenously with a low dose (1 to 10 100% animal infectious doses) of uncloned SIVmac. The monkeys were treated orally with 50 mg of AZT per kg of body weight every 8 h; two animals were started on treatment 2 h prior to virus inoculation, and two animals were started on treatment 6 weeks later. All four animals were treated for a period of 6 to 10 weeks. Outward signs of AZT toxicity were absent, but a mild macrocytic anemia occurred soon after therapy was started and resolved shortly after it was discontinued. The two infants that were begun on AZT treatment 2 h prior to virus inoculation never became infected, as demonstrated by the inability to detect cell-free or cell-associated virus in the blood, proviral DNA in peripheral blood mononuclear cells, or anti-SIV antibodies. AZT administration over a 10-week period had no detectable effect on the course of disease in the two animals that were begun on treatment after the infection had been established. In addition to demonstrating the prophylactic effect of AZT against low-dose SIV exposure, the study demonstrated the ease with which infant rhesus macaques can be used for antiretroviral drug testing.


In vitro activities of fleroxacin against clinical isolates of Legionella spp., its pharmacokinetics in guinea pigs, and use to treat guinea pigs with L. pneumophila pneumonia.

The activities of fleroxacin against 22 clinical Legionella isolates were determined by agar and broth microdilution susceptibility testing. The fleroxacin MIC required to inhibit 90% of strains tested on buffered charcoal yeast extract agar medium supplemented with 0.1% alpha-ketoglutarate was 0.64 micrograms/ml and was 0.04 microgram/ml when testing was done with buffered yeast extract broth supplemented with 0.1% alpha-ketoglutarate. Fleroxacin (0.25 microgram/ml) reduced the bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 1 log10 CFU/ml, but regrowth occurred over a 3-day period; fleroxacin was significantly more active than erythromycin in this assay. Single-dose (10 mg/kg of body weight given intraperitoneally) pharmacokinetic studies performed in guinea pigs with L. pneumophila pneumonia revealed peak levels in plasma and lungs to be 3.3 micrograms/ml and 3.5 micrograms/g, respectively, at 0.5 h and 0.8 microgram/ml and 0.8 microgram/g, respectively, at 1 h. The half-life of the terminal phase of elimination from plasma and lung was approximately 2 h. All 17 infected guinea pigs treated with fleroxacin (10 mg/kg/day) for 2 days survived for 14 days post-antimicrobial therapy, as did all 16 guinea pigs treated with the same dose of fleroxacin for 5 days. Only 1 of 16 animals treated with saline survived. The animals treated with fleroxacin for 2 days lost more weight and had higher temperatures than those treated with the antibiotic for 5 days. Fleroxacin is effective against L. pneumophila in vitro and in a guinea pig model of Legionnaires' disease. Fleroxacin should be evaluated as a treatment for human Legionnaires' disease.


Stability of antimycobacterial drugs in susceptibility testing.

Aqueous solutions of 0.02% isoniazid, 0.2% streptomycin, 0.2% para-aminosalicylate, and 0.5% ethambutol and ethylene glycol solutions of 0.5% ethionamide stored at 3 to 7 degrees C remained stable for 1 year, as did aqueous solutions of 0.05% ethionamide hydrochloride, 0.05% kanamycin, 0.05% viomycin, and 0.1% capreomycin stored at -20 degrees C. The ethambutol and capreomycin solutions were tested by microbiologic methods; the other solutions were tested by both spectrophotometric and microbiologic methods. Prepared susceptibility testing media made with cycloserine, rifampin, and the above solutions incorporated into Middlebrook 7H10 medium showed acceptable stability when stored at 3 to 7 degrees C for 1 month. During incubation of the test medium at 37 degrees C, approximately half of the activity of isoniazid, ethionamide, ethambutol, cycloserine, and rifampin was lost after periods ranging from 2 to 4 days for ethambutol to 2 weeks for rifampin.


Optimal aminoglycoside dosing regimen for penicillin-tobramycin synergism in experimental Streptococcus adjacens endocarditis.

The combination of penicillin and aminoglycoside is the recommended therapy for endocarditis caused by nutritionally variant streptococci (NVS). However, the optimal aminoglycoside dosing regimen remains controversial. We compared the efficacies of four regimens of tobramycin alone or combined with procaine penicillin in the therapy of rabbits with endocarditis caused by Streptococcus adjacens, a new species of NVS. Animals were injected intramuscularly for 4 days with procaine penicillin (150,000 U/kg of body weight twice daily) or tobramycin at a low dose (3 mg/kg every 24 h) or a high dose (12 mg/kg every 24 h) either once or three times daily (t.i.d.) alone or in combination with procaine penicillin. Additional groups of animals were treated with the combination regimens for a shorter period of time (2 days) in order to demonstrate a possible difference in the rapidity of efficacy between the regimens. The MICs and MBCs were 0.015 and 1 micrograms/ml and 8 and 16 micrograms/ml for penicillin and tobramycin, respectively. The mean peak tobramycin levels in plasma were 2.4 +/- 1.3 (1 mg/kg t.i.d.), 5.4 +/- 3.7 (4 mg/kg t.i.d.), and 25 +/- 9.3 (12 mg/kg once daily). The mean penicillin levels in serum were always above the MIC. In vitro kill curves plotted at the time that peak concentrations were reached in plasma showed a concentration-dependent killing effect of tobramycin alone but not in combination with penicillin. In vivo, low-dose tobramycin was significantly less effective than the high dose. Results for the combinations of the different dosing regimens of tobramycin with procaine penicillin were not significantly different. Our results suggest that (i) against susceptible strains of streptococci, aminoglycoside alone exhibits a concentration-dependent killing effect both in vitro and in vivo; (ii) against NVS strains, combinations of penicillin and high- or low-dose tobramycin are equally effective; and (iii) aminoglycoside given once daily or at a low dose t.i.d. with penicillin could be a cost-effective alternative with reduced toxic risk for patients with NVS endocarditis when the bacteria are susceptible to the killing activities of both compounds.


Penetration of zidovudine and 3'-fluoro-3'-deoxythymidine into the brain, muscle tissue, and veins in cynomolgus monkeys: relation to antiviral action.

Cynomolgus monkeys had microdialysis probes implanted under ketamine anesthesia into peripheral veins, thigh muscles, and the brain in order to sample the extracellular fluid for the concentrations of unbound nucleoside analogs. A dose of 25 mg of zidovudine or 3'-fluoro-3'-deoxythymidine (FLT) per kg was administered subcutaneously to each of three animals. Relatively high antiviral concentrations of FLT and zidovudine were present in peripheral tissues and in the brain. It was found that the concentration of zidovudine in the brain was approximately one-third of that in muscle and veins; the same relation was observed for FLT. The in vivo unbound concentrations of both drugs in the brain, muscle, and venous blood exceeded those reported to inhibit human immunodeficiency virus replication in vitro. In addition, in a correlative study we found that the appearance of p24 antigen in sera of monkeys infected with simian immunodeficiency virus was significantly delayed by both compounds (15 mg/kg three times daily for 9 days after infection). Thus, we have shown that the extracellular concentrations of unbound FLT and zidovudine in the brain and peripheral tissues attained with in vivo antiviral doses exceed in vitro antiviral concentrations.


Comparison of the antibacterial effects of cefepime and ceftazidime against Escherichia coli in vitro and in vivo.

The efficacies of cefepime and ceftazidime in an experimental Escherichia coli infection in granulocytopenic mice were related to their in vitro activities and their pharmacokinetic profiles. Cefepime had a higher intrinsic activity in vitro than ceftazidime, and it had a different pharmacokinetic profile, resulting in higher peak concentrations in plasma and a longer elimination half-life. To predict the antibacterial efficacy in vivo on the basis of in vitro activity and pharmacokinetics, we applied a mathematical model in which the in vitro effect is expressed as the difference in growth rate between control cultures and cultures grown in the presence of the antibiotic (ER), whereas the in vivo effect is given by the difference in the number of CFU between controls and antibiotic-treated animals (EN). The integral of ER over time, called ERt, was calculated by using in vivo concentrations. A significant linear relationship was found between EN and ERt for different doses at various times up to 4 h after administration, although the slope of this relationship was slightly but significantly less for cefepime (0.44) than for ceftazidime (0.59).


Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses.

The pharmacokinetics and safety of single ascending doses of clarithromycin (6-0-methylerythromycin A) were assessed in a placebo-controlled, double-blind, randomized trial with 39 healthy male volunteers. Subjects were randomized to receive single doses of either placebo or 100, 200, 400, 600, 800, or 1,200 mg of clarithromycin. Blood and urine collections were performed over the 24 h following administration of the test preparation. Biological specimens were analyzed for clarithromycin and 14(R)-hydroxyclarithromycin content by a high-performance liquid chromatographic technique. The pharmacokinetics of clarithromycin appeared to be dose dependent, with terminal disposition half-life ranging from 2.3 to 6.0 h and mean +/- standard deviation area under the concentration-versus-time curve from time 0 to infinity for plasma ranging from 1.67 +/- 0.48 to 3.72 +/- 1.26 mg/liter.h per 100-mg dose over the 100- to 1,200-mg dose range. Similar dose dependency was noted in the pharmacokinetics of the 14(R)-hydroxy metabolite. Mean urinary excretion of clarithromycin and its 14(R)-hydroxy metabolite ranged from 11.5 to 17.5% and 5.3 to 8.8% of the administered dose, respectively. Urinary excretion data and plasma metabolite/parent compound concentration ratio data suggested that capacity-limited formation of the active metabolite may account, at least in part, for the nonlinear pharmacokinetics of clarithromycin. No substantive dose-related trend was observed for the renal clearance of either compound. There were no clinically significant drug-related alterations in laboratory and nonlaboratory safety parameters. In addition, there was no significant difference between placebo and clarithromycin recipients in the incidence or severity of adverse events. Clarithromycin appears to be safe and well tolerated.


Activity of clarithromycin alone or in combination with other drugs for treatment of murine toxoplasmosis.

The activity of the macrolide antibiotic clarithromycin was examined alone or in combination with other drugs for the treatment of acute or chronic infections with Toxoplasma gondii in mice. A dose of 300 mg of clarithromycin per kg per day administered alone for 10 days, beginning 24 hours after infection, protected 10 to 30% of mice infected with lethal inocula of tachyzoites or tissue cysts of different strains of T. gondii, including some strains isolated from patients with both AIDS and toxoplasmosis. Although clarithromycin was protective, a wide variation in its activity against different strains was observed. Survival of infected mice was increased significantly by treatment with clarithromycin in combination with pyrimethamine or with sulfadiazine. Treatment of chronically infected mice with clarithromycin at 300 mg/kg/day administered alone for 8 weeks resulted in significant reduction in the numbers of T. gondii cysts in their brains. The combination of clarithromycin and minocycline resulted in an activity against T. gondii cysts that was significantly greater than the activity of clarithromycin or minocycline administered alone. These results indicate a role for clarithromycin in the treatment of human toxoplasmosis, particularly when this antibiotic is used in combination with other drugs with activity against T. gondii.


Modification of cefixime bioavailability by nifedipine in humans: involvement of the dipeptide carrier system.

We studied the action of nifedipine on the bioavailability of cefixime, a molecule absorbed via the gut wall dipeptide carrier system in the rat, and on the bioavailability of D-xylose, which is absorbed via a pH (and Na(+)-)-dependent transporter. Each compound was administered alone or in combination with 20 mg of nifedipine to eight healthy male volunteers. Nifedipine significantly increased the absorption rate of cefixime (20.7 +/- 4.3 versus 16 +/- 3.5 mg/h in the absence of nifedipine). The absolute bioavailability of cefixime alone was 31% +/- 6% compared with 53% +/- 1% (P < 0.01) in the presence of nifedipine. The observed peak concentrations in serum were significantly different (2.5 +/- 0.3 mg/liter without nifedipine and 3.7 +/- 1.1 mg/liter with nifedipine; P < 0.02). In contrast, nifedipine induced no significant differences in the pharmacokinetic profile of xylose following oral administration. We conclude that (i) cefixime is absorbed in humans by an apparently active process which can be enhanced by a calcium channel blocker, in this case, nifedipine; and (ii) nifedipine does not modify the activity of the pentose transporter.


Intracellular zidovudine (ZDV) and ZDV phosphates as measured by a validated combined high-pressure liquid chromatography-radioimmunoassay procedure.

In vitro studies of zidovudine (ZDV) phosphorylation may not accurately reflect the in vivo dose-response relationship, which is crucial to determining the relationship between ZDV exposure, efficacy, and toxicity. However, measurement of ZDV phosphorylated anabolites in peripheral blood mononuclear cells (PBMCs) from ZDV-treated human immunodeficiency virus (HIV)-infected patients would be extremely useful in the more appropriate utilization of ZDV in the treatment of HIV infection. We developed a specific and sensitive combined high-pressure liquid chromatography (HPLC)-radioimmunoassay (RIA) procedure for the determination of ZDV, ZDV-monophosphate, ZDV-diphosphate, and ZDV-triphosphate in PBMCs taken from ZDV-treated HIV-infected patients. ZDV and its anabolites were extracted from washed, Ficoll-Paque-isolated PBMCs and then separated by HPLC using a strong anion-exchange column. The anabolites were then hydrolyzed to ZDV with acid phosphatase. ZDV was then measured by using a modified commercially available RIA protocol. Our method was validated by measuring [3H]ZDV anabolites generated in Molt-4 cells radioisotopically and simultaneously by the combined HPLC-RIA procedure. The ZDV determinations correlated well (r2 = 0.97) over the range of 0.037 to 5.2 pmol (10 to 1,400 pg) per assay tube. Furthermore, we defined the stability of ZDV anabolites during ficoll isolation and the recovery after extraction and cleanup. We then measured intracellular parent ZDV and its phosphorylated anabolites in PBMCs from six ZDV-treated HIV-infected patients (PBMCs were taken 2 h after a 300-mg oral dose). The mean concentrations ( +/- standard deviations) of parent and of mono-, di-, and triphosphates were 0.15 +/- 0.08, 1.4 +/-, 0.082 +/- 0.02, and 0.081 +/- 0.03 pmol/10(6) PBMC, respectively (one pmol/10(6) PBMC represents a concentration of approximately 1 microm). Concurrent serum ZDV concentrations were between 1.3 and 7.1 microm. This method should provide a useful tool for evaluating in vivo pharmacokinetics of ZDV anabolites in PBMCs and possibly other cell types, even at the low doses of ZDV currently administered therapeutically.


Pharmacokinetics of a clarithromycin suspension in infants and children.

The single- and multiple-dose pharmacokinetics of clarithromycin and its 14-(R)-hydroxylated metabolite in infants and children were studied after oral administration under fasting and nonfasting conditions. Drug absorption appeared to be rapid following a brief delay in its onset; the mean peak concentrations in plasma (Cmax) for clarithromycin were reached within about 3 h under both conditions. The mean Cmax for the parent drug were 3.59 and 4.58 micrograms/ml in single-dose fasting and nonfasting patients, and the respective Cmax for the metabolite were 1.19 and 1.26 micrograms/ml. Data indicate good absorption and no significant effects by food. There was no unusual accumulation in the area under the concentration-time curve and Cmax in the multiple-dose group.


Comparative pharmacokinetics of SCE-2787 and related antibiotics in experimental animals.

The pharmacokinetic properties of SCE-2787 administered intravenously at a dose of 20 mg/kg of body weight were studied with mice, rats, rabbits, dogs, and monkeys and were compared with those of ceftazidime, cefpirome, and cefclidin in mice and dogs. The area under the concentration-time curve for plasma after intravenous administration was the largest in monkeys, followed by those in dogs, rabbits, rats, and mice, in that order. The elimination half-life ranged from 0.2 to 0.3 h in mice and rats to 0.7 to 1.3 h in rabbits, dogs, and monkeys. In young dogs, the concentrations of SCE-2787 in plasma were somewhat lower than those in the mature dogs. SCE-2787 was distributed well to the tissues, and the highest concentration was found in the kidneys in all species tested; the distribution to the lungs, liver, and spleen was also good, but the concentrations in these tissues were lower than those in the plasma. The pharmacokinetic parameters and urinary excretion of SCE-2787 in mice and dogs were similar to those of ceftazidime, cefpirome, and cefclidin. The maximum concentrations in the cerebrospinal fluid of rats and rabbits were 0.8 and 1.3 micrograms/ml, and the relative percentages of the area under the concentration-time curve of SCE-2787 in the cerebrospinal fluid to that in the plasma were 4.6 and 6.4%, respectively. SCE-2787 was excreted mainly in the urine; the recovery rate ranged from 74% (rats) to 90% (dogs) of the dose. The biliary excretion of SCE-2787, however, was low, amounting to about 1.4% for mice and rats and less than 0.5% for rabbits and dogs. In rats, there was no accumulation in the tissues and no delay in urinary excretion upon multiple intravenous administration of 20 mg of SCE-2787 per kg once daily for 7 days. No active metabolites were found in the plasma or urine of animals given SCE-2787. The binding of SCE-2787 to serum protein in mice, rats, dogs, monkeys, and humans was less than 11% and similar to that of cefclidin.


Penetration of ofloxacin into heart valves, myocardium, mediastinal fat, and sternal bone marrow in humans.

Ofloxacin penetration into heart tissue (valve and myocardium), mediastinal fat, and sternal bone marrow was the object of a prospective nonrandomized study. Thirty-six patients undergoing mitral and/or aortic valve replacement were included. Patients were divided into two groups of 18 patients each. Group 1 patients were administered a single 400-mg intravenous dose of ofloxacin over a 30-min period upon anesthesia (n = 6) or at 1 h (n = 6) or 6 h (n = 6) prior to surgery. Group 2 patients received a 200-mg oral dose of ofloxacin every 12 h during the 48 h preceding surgery. In this group, the final dose of ofloxacin was administered 3 h (n = 9) or 8 h (n = 9) before anesthesia. Plasma and tissue ofloxacin concentrations were assayed by high-pressure liquid chromatography. In group 1 patients, the peak level in plasma was 15.9 +/- 2.5 micrograms/ml. Peak ofloxacin levels in tissue were reached by hour 1 and were 8.89 +/- 2.16 micrograms/g in myocardium and 5 +/- 0.75 micrograms/g in heart valves. A significant decrease in ofloxacin levels in heart valve tissue and sternal bone marrow was observed after hour 3. Nevertheless, ofloxacin myocardial, heart valve, and sternal bone marrow levels remained higher than the MICs for the usually susceptible pathogens for at least 3 h. In group 2 patients, myocardial levels were long lasting (6.46 +/- 1.92 micrograms/g [4 to 8 h] and 5.92 +/- 0.95 micrograms/g [8 to 12 h]) and remained higher than those observed in the other tissues over the entire study period. A progressive but insignificant decrease in ofloxacin heart valve levels was observed (from 2.46 +/- 0.40 micrograms/g [4 to 8 h] to 1.57 +/- 0.22 micrograms/g [8 to 12 h]). In both groups, concentration in mediastinal fat were lower and tended to decrease with time. These were 1.83 +/- 0.61 micrograms/g with the first hour and 0.85 +/- 0.43 micrograms/g between hours 8 and 12 in group 1 and 1.74 +/- 0.52 micrograms/g between hours 4 and 8 and 0.67 +/- 0.11 micrograms/g between hours 8 and 12 in group 2. In conclusion, satisfactory diffusion of ofloxacin into heart tissue seems to favor use of the drug in the treatment of bacterial endocarditis due to susceptible pathogens. Furthermore, the progressively decreasing concentrations observed in heart valve and sternal bone marrow and the poor levels achieved in mediastinal fat suggest the need for renewing injection 3 h following initial infusion if the drug is used as an antibiotic prophylactic agent during cardiovascular surgery.


Transport of pefloxacin across the bacterial cytoplasmic membrane in quinolone-susceptible Staphylococcus aureus.

Binding to phospholipids, uptake by simple diffusion, and an energy-dependent, carrier-mediated efflux are thought to characterize interactions between fluoroquinolones and bacterial cytoplasmic membranes. Here, we have found that an endogenous active efflux is unlikely in quinolone-susceptible Staphylococcus aureus. The protonophore, carbonyl cyanide m-chlorophenylhydrazone (CCCP), increased pefloxacin uptake in different membrane systems under conditions which excluded carrier-mediated transport, i.e., in bacterial cells at 4 degrees C and in protein-free phosphatidylglycerol liposomes. When plotted as a function of outer pH, the CCCP effect, both in S. aureus cells and in phosphatidylglycerol liposomes, correlated with pefloxacin labeling of everted S. aureus membrane vesicles, with all three profiles showing maximal effect at an acidic pH. So the CCCP effect may result not from inhibition of the proton motive force, as previously thought, but rather from acidification of the intramembrane space by the protonophore, leading to enhanced binding of the positive pefloxacin species to the inner leaflet of the bilayer. Moreover, antistaphylococcal potency and uptake profiles of pefloxacin in S. aureus and phosphatidylglycerol liposomes, assayed as a function of outer pH, peaked at a neutral pH. These observations suggest that zwitterionic and positive quinolone species are responsible for diffusion through and binding to the cytoplasmic membrane, respectively.


Increased oral bioavailability of ciprofloxacin in cystic fibrosis patients.

The altered pharmacokinetic properties of, e.g., aminoglycosides in cystic fibrosis patients have to be considered when pulmonary exacerbations are treated. Since reported data on ciprofloxacin, a fluorinated quinolone, are conflicting, we compared intravenous and oral administration in cystic fibrosis patients when treating them for mild symptoms of pulmonary infection. All of the patients were colonized with Pseudomonas species. Ciprofloxacin was administered orally (15 mg/kg of body weight) or intravenously (6 mg/kg) twice a day for at least 10 days during separate treatment periods. Five healthy volunteers received single intravenous and oral doses. Pharmacokinetic evaluations were performed at first dose and at steady state. The results showed that cystic fibrosis patients have increased oral bioavailability of ciprofloxacin (80% in cystic fibrosis patients versus 57% in volunteers) and increased total clearance (688 ml/min in CF patients versus 528 ml/min in volunteers). Our data indicate that the pharmacokinetic properties of ciprofloxacin are altered in cystic fibrosis patients with mild symptoms of pulmonary exacerbations and that the changes most probably are due to cystic fibrosis per se or to the impact of chronic infection.


Effects of aggregation and solvent on the toxicity of amphotericin B to human erythrocytes.

In aqueous suspensions of amphotericin B (AmB), a polyene antibiotic and antifungal agent, three forms of AmB coexist: monomers, water-soluble oligomers, and non-water-soluble aggregates. The toxicity of the water-soluble self-associated form of AmB compared with that of the non-water-soluble self-associated form was tested by measuring induction of K+ leakage from human erythrocytes, using different suspensions containing the antibiotic and phosphate-buffered saline. These suspensions were obtained from various stock solutions of the antibiotic in dimethyl formamide or dimethyl sulfoxide. Their circular dichroism spectra around 340 nm, indicative of the degree of AmB self-association, were strongly dependent on the concentration of organic solvent in the suspensions. The nonsoluble self-associated form was separated from the water-soluble form by centrifugation. The nonsoluble form was favored by a high concentration of AmB of the stock solution. The kinetics of AmB-induced K+ leakage from human erythrocytes also appeared to be strongly dependent on the AmB concentration of the stock solution being much weaker with concentrated stock solutions. It was concluded that the only form of AmB toxic to human erythrocytes is the water-soluble self-associated form (in contrast with fungal cells on which the monomeric form is also active). This result may be important in the design of new less toxic AmB derivatives and in the understanding of the mechanism of action of liposomal AmB.


Topical treatment with butenafine significantly lowers relapse rate in an interdigital tinea pedis model in guinea pigs.

Butenafine is a novel antifungal agent of the class of benzylamines. The incidence of relapse after topical treatment with butenafine or bifonazole was investigated in a guinea pig interdigital tinea pedis model. One percent butenafine or bifonazole cream was applied on the infected site of animals for 20 consecutive days starting on day 10 postinfection. On day 30 posttreatment, relapse of the infection occurred in 11 of the 12 feet treated with bifonazole but in only 3 of the 12 feet treated with butenafine. The lower relapse rate after butenafine treatment might be attributable to its potent fungicidal activity and long retention time in the skin.


Influence of high-level gentamicin resistance and beta-hemolysis on susceptibility of enterococci to the bactericidal activities of ampicillin and vancomycin.

The bactericidal activities of ampicillin and vancomycin against 40 recent isolates of Enterococcus faecalis were examined by kill-kinetic studies at concentrations of 4 x the MIC and 20 micrograms/ml. Greater killing was seen with ampicillin (3.57 +/- 0.87 and 2.50 +/- 1.09 log10 CFU/ml, respectively; mean +/- standard deviation) than with vancomycin (1.23 +/- 0.65 and 1.05 +/- 0.57 log10 CFU/ml, respectively). Highly gentamicin-resistant strains showed a tendency toward reduced susceptibility to killing; beta-hemolytic strains were more susceptible than nonhemolytic strains when exposed to ampicillin at 20 micrograms/ml. Within each group, individual isolates demonstrated great variability in susceptibility to killing by the drugs.


Increasing resistance of enterococci to ciprofloxacin.

We determined that resistance to ciprofloxacin has emerged in enterococci over the last 5 years in our hospital, mainly in strains demonstrating the phenotype of high-level gentamicin resistance. All high-level-gentamicin-resistant isolates from 1985 and 1986 were susceptible, whereas 24% of isolates from 1989 and 1990 were resistant to ciprofloxacin. Plasmid and genomic DNA typing showed at least six unique strains exhibiting resistance, but one type accounted for 80% of recent resistant isolates, suggesting a role for cross infection in the emergence of resistance.


Aminoglycoside-modifying enzymes in clinical isolates harboring extended-spectrum beta-lactamases.

The aminoglycoside-modifying enzymes present in the first 120 clinical isolates harboring extended-spectrum beta-lactamases isolated in Spain were studied. Most of these isolates (84%) were gentamicin resistant. The enzymes most frequently associated and cotransferred with SHV-2 or TEM-type beta-lactamases were AAC(3)V, APH(3"), and APH(3')I.


Penetration of vancomycin in uninfected sternal bone.

Concentrations of vancomycin in sternal bones of 10 patients undergoing cardiac surgery were studied at steady state, 48 h after starting intravenous prophylaxis. A sample of sternal bone was taken before (group I) or after (group II) cardiopulmonary bypass. The mean vancomycin concentrations in sternal bones were not significantly different between the groups and were 9.3 +/- 3.0 micrograms/g. The concentrations of vancomycin in sternal bones were always above the MICs for staphylococci, streptococci, and enterococci.


Risk of ventricular dysrhythmias during 1-hour infusions of amphotericin B in patients with preserved renal function.

In order to assess the safety of 1-h infusions of amphotericin B (AMB), we prospectively monitored 213 1-h infusions of AMB (dose range, 0.27 to 0.89 mg/kg of body weight) in 27 patients with creatinine clearances of > 25 ml/min. Holter monitor tracings during 1-h infusions were compared with those during a 4-h baseline period of monitoring. There were no ventricular dysrhythmias during 1-h infusions of AMB that were not present during baseline monitoring. Nausea and/or rigors were noted for 32 (15%) infusions in six (22%) patients. No patient exhibited a temperature rise of > 1 degree C. We conclude that, in doses of up to 0.9 mg/kg, AMB does not appear to induce asymptomatic ventricular dysrhythmias when administered over 1 h to patients with creatinine clearances of > 25 ml/min.


Comparative sequence analysis of the catB gene from Clostridium butyricum.

Sequence analysis of the Clostridium butyricum chloramphenicol acetyltransferase (CAT) gene, catB, showed that it encoded a CAT monomer of 219 amino acids with a molecular weight of 26,114. Comparison of the deduced amino acid sequence of the CATB monomer to those of sixteen other CATs showed that it was most closely related to the CATQ monomer from Clostridium perfringens.


Iontophoresis generates an antimicrobial effect that remains after iontophoresis ceases.

Iontophoresis required chlorine-containing compounds in the medium for effective microbial population reduction and killing. After iontophoresis ceased, the antimicrobial effect generated by iontophoresis remained but slowly decreased. Antimicrobial effects of iontophoresis may be related to the generation of short-lived chlorine-containing compounds.


Duration of the protective effect of polyaspartic acid on experimental gentamicin nephrotoxicity.

It is known that daily polyaspartic acid (PAA) protects the kidney from gentamicin nephrotoxicity in a standardized rat model despite marked cortical accumulation of the aminoglycoside. The present experiments address the duration of PAA protection. When administered every other day, PAA provided functional and histologic protection against gentamicin-induced toxicity. A stepwise reduction in nephroprotection occurred as the dosage interval was prolonged.


In vitro activity of Ro 23-9424 against clinical isolates of Legionella species.

Agar and broth microdilution MICs of Ro 23-9424 that inhibited 90% of 22 Legionella clinical isolates tested were 0.64 and 0.08 micrograms/ml, respectively; respective erythromycin values were 1.0 and 0.12 micrograms/ml. Ro 23-9424 (1 microgram/ml) was slightly more active than the same erythromycin concentration in a macrophage system, for both Legionella pneumophila strains studied.


Occurrence of the nfxB type mutation in clinical isolates of Pseudomonas aeruginosa.

Seven spontaneous norfloxacin (NFLX)-resistant mutants obtained in vitro from 20 NFLX-susceptible clinical isolates and 3 NFLX-resistant clinical isolates of Pseudomonas aeruginosa were transformed with the pNF111 plasmid, whose BamHI fragment is responsible for conferring susceptibility to NFLX, by complementing the nfxB mutation. The resulting patterns of MICs of NFLX, beta-lactams, aminoglycosides, and chloramphenicol and the observed increased accumulation of NFLX were consistent with the occurrence of the nfxB type mutation in these clinical isolates.


Development of a scale to measure the trait of food neophobia in humans.

Using standard test construction techniques, we developed a paper and pencil measure of the trait of food neophobia, which was defined as a reluctance to eat and/or avoidance of novel foods. The resulting 10-item test was found to have satisfactory test-retest reliability and internal consistency. Three behavioral validation studies demonstrated that test scores predicted behavior in laboratory food selection situations. Scores on the measure were found to be correlated with trait anxiety, age, the Experience Seeking subscale of the Sensation Seeking Scale, general neophobia, and general familiarity and experience with unusual foods. Scores were not related to gender or to finickiness.


Molecular basis of the efficacy of cefaclor against Haemophilus influenzae.

Cefaclor sustained its inhibitory activity against a beta-lactamase-producing strain of Haemophilus influenzae. Although a relatively high permeability coefficient was calculated for ampicillin compared with that calculated for cefaclor, the resulting periplasmic concentration of cefaclor was 5.7 times that of ampicillin. The efficacy of cefaclor may be due to its higher beta-lactamase resistance, which allows it to achieve a greater periplasmic concentration and adequate binding to crucial penicillin-binding proteins.


Selection of a diet by growing pigs given choices between foods differing in contents of protein and rapeseed meal.

The objective of the experiment was to test whether the rules that appear to underlie diet selection by pigs given choices between two foods of different crude protein (CP) content, persist when a rapeseed meal with possible goitrogenic effects is included in one or both foods. Forty-four pigs were given access to one food, or to two foods as a choice, from 12-30 kg liveweight. The foods were the combinations of two levels of CP (140 and 300 g CP/kg food) and two levels of inclusion (0 and 180 g/kg food) of a rapeseed meal, which resulted in foods L, H, LR, HR; in addition the equal parts mixture of foods L and H was also made (food M). The treatments were: access to a pair of foods as a choice, pairs LH, LR, H, LHR and LRHR (n = 6 per treatment) or access to a single food L, LR, M, H and HR (n = 4 per treatment). The inclusion of the rapeseed meal did not significantly affect the rates of food intake and liveweight gain of the pigs given access to one food. Pigs given a choice between a rapeseed-based food and another one (pairs LRH and LHR), showed a significant preference for the food without it. The rejection of the foods with rapeseed meal was such that it overpowered the physiological need of the pig to select a diet that would meet its CP requirement. When the two foods differed only in CP content (pairs LH and LRHR) pigs were able to select a diet whose composition changed systematically as they grew, and supported rapid growth. The diet selection of the choice-fed pigs is consistent with the idea that pigs, given a choice between a potentially harmful food and a non-harmful one, will favour the latter irrespective of its nutritional properties, only if it is assumed that the inclusion of rapeseed meal had a detrimental effect on the single fed pigs, which could not be seen in their performance as measured by the rates of food intake and liveweight gain.


Garlic: a sensory pleasure or a social nuisance?

A total of 100 female and male shoppers in Helsinki were interviewed to evaluate beliefs, attitudes and norms concerning the consumption of garlic. In a subsequent postal questionnaire, the annoyance related to the smell of garlic, compared with other social odors, was also measured. The most frequent beliefs about garlic pertained to its good taste, unpleasant smell, and healthiness. Users and non-users showed distinctly different belief patterns. Sweat and alcohol were considered the most annoying social odors, and garlic and perfume/aftershave the least so. The Fishbein-Ajzen model, in which individual beliefs and their evaluations as well as subjective norms were used as predictors, explained 35-36% of the variation of the reported consumption and intention to use garlic. The predictive power of the model rose to 56-62% when past behavior was included as a third independent variable. Although the predictive power of attitudes was greater than that of subjective norms, the latter were also significant predictors. Thus, use of garlic is a somewhat unusual form of food-related behavior in that it is controlled by both attitudes and normative factors.


The relationship between changes in body weight and changes in psychosocial functioning.

Previous studies have indicated that obesity is related to a variety of psychosocial problems. Unfortunately, the literature on the relationship between weight status and psychosocial functioning has primarily utilized clinical samples and cross-sectional designs. The current study prospectively explored the relationship between weight gain and changes in psychosocial functioning. Subjects were 195 women and 204 men recruited as part of a larger longitudinal study of cardiovascular risk factors, who attended assessment sessions once per year for 2 consecutive years. Psychosocial functioning was assessed using the Dyadic Adjustment Scale (DAS), the Family Environment Scale (FES) and the Family Adaptability and Cohesion Scale 3rd Edition (FACES-III). Subjects were categorized based on their weight status at each year so the effect of a change in weight status on changes in psychosocial functioning could be evaluated. Multivariate measures indicated no changes in psychosocial functioning as a result of change in weight status over a 1-year period for either men or women. It appears that shifts in body weight, at least in a sample of subjects with generally good levels of psychological functioning, are not associated with changes in the measured levels of psychosocial functioning.


Estimation of possible impact of non-caloric fat and carbohydrate substitutes on macronutrient intake in the human.

This paper addresses the expected impact of use of macronutrient substitutes by individuals without strong motivation to control macronutrient or energy intake when such modified foods serve as replacements of foods normally ingested rather than as "add-ons". A basic premise of the paper is that individuals are likely to replace a substantial part of the energy equivalent of the original substitution. It further assumes that the macronutrient composition of the additional foods consumed will reflect normal food selection behaviours. The paper derives a description of the expected selection behaviour from examination of the within subject variance in energy and macronutrient intake of 29 subjects followed for 365 consecutive days (the Beltsville One Year Dietary Intake Study). Patterns observed in these subjects were validated through examination of associations between macronutrient intake and energy intake in 600 women, each of whom contributed 6 days of dietary data (USDA CSFII-85). As presently proposed the model suggests that the use of non-caloric fat replacements, by subjects without strong motivation to control fat or energy intake, can be expected to result in a net decrease (less than original substitution) in fat intake and net increases in carbohydrate and protein intakes. Conversely, use of carbohydrate replacements in core foods can be expected to result in net increases in fat and protein intakes and a partial decrease in carbohydrate intake. The magnitude of these net changes is seen to be a function of the extent of replacement of energy.


Do maternal and intrauterine factors influence blood pressure in childhood?

It has been proposed that maternal health and nutrition may be important in the development of adult cardiovascular risk, and that blood pressure may be an important intermediate step in this process. To examine the relevance of this hypothesis in contemporary British children, the relationships of several maternal factors to blood pressure were studied in 3360 children of European origin aged 5-7 years. Maternal age, height, and body mass index were all positively related to blood pressure in childhood but these relationships were abolished once the child's body build was taken into account. Maternal social class, educational attainment, and history of smoking in pregnancy showed no relationship with blood pressure in childhood. Parity showed an inverse association with blood pressure, but this appeared to be due to an association between total sibship size and blood pressure, suggesting a postnatal rather than a prenatal origin. Blood pressure was higher in children whose mothers had a history of high blood pressure but this association was no stronger than that for paternal history. Both birth weight and gestational age were inversely related to blood pressure at 5-7 years. The association between birth weight and blood pressure was attenuated by standardisation for gestational age, and the relationships between birth weight and blood pressure were similar in preterm and full term infants. No specific association between blood pressure and the maternal factors studied have been observed in this population. Hypotheses relating maternal factors to cardiovascular risk need to specify the timing and nature of their effects more precisely. Although the relationship between birth weight and blood pressure is not fully understood, it appears to reflect size at birth rather than fetal growth rate.


Management and outcome of severe head injuries in the Trent region 1985-90.

In a five year period, 39 children (29 boys, 10 girls) aged 2 months to 13 years (mean 7.8 years) were studied who had suffered a major head injury (29 road traffic accidents, six falls, and four non-accidental injury). The injury had been assessed clinically and by cranial computed tomography or cranial ultrasound (in a single baby of 2 months). Initial Glasgow coma scores for all subjects ranged from 3-11 (mean 5.5), intact survivors 5-11 (7.4), minor handicap 4-11 (6.1), major handicap 3-6 (4.3), fatalities 3-6 (4.1). All were treated with sedation, paralysis, hyperventilation (arterial carbon dioxide tension 3.0-3.5 kPa), intracranial pressure monitoring and moderate body surface hypothermia to 32 degrees C. Nine children died and 30 survived (nine intact, 13 minor disability, and eight major disability). The worst cerebral perfusion pressure was over 40 mm Hg in all but one survivor, and less than 40 mm Hg in seven of nine fatalities. Severe hypocapnia both in the first 24 hours and overall was correlated with poor outcomes (dead or major disability), as were bilateral contusions or diffuse axonal injury.


Long term effects of periconceptional multivitamin supplements for prevention of neural tube defects: a seven to 10 year follow up.

Periconceptional supplementation with Pregnavite Forte F was offered to women who presented consecutively to the Oxford genetic counselling service in the early 1980s who had previously had one or more pregnancies complicated by a neural tube defect. The first 100 children born alive to these women are the subject of this study. Birth weight, gestation, and congenital abnormalities were recorded. At age 2-5 years all 96 children remaining in the United Kingdom were assessed clinically and developmentally and behavioural information was obtained by questionnaire. At age 7-10 years, follow up of 91 children by telephone and postal questionnaire yielded further information about growth, general health, vision, hearing, and educational and behavioural status. Entry criteria excluded single mothers but the social class distribution of the sample was otherwise representative of the Oxfordshire population. There were no recurrences of neural tube defects. One child had radiological evidence of spina bifida occulta affecting only the fifth lumbar vertebra. One had an autosomal recessive disorder. Eight had random minor congenital anomalies. Birth weight for gestational age was significantly greater than for the local population and at age 7-10 years the girls were considerably taller than expected. Health, auditory, visual, and developmental status were no different from the general population. None of the children had special educational needs. None showed a major behaviour disorder but worries, fussiness, and fearfulness were highly significantly over represented.


A randomised trial of low dose folic acid to prevent neural tube defects. The Irish Vitamin Study Group.

A randomised trial was initiated in Ireland in 1981 to determine if periconceptional supplementation with either folic acid alone or a multivitamin preparation alone could reduce the recurrence risk of neural tube defects (NTDs) in women with a previously affected pregnancy from 5.0% to 1.0% or less. The trial was concluded before the initial target number of study subjects was reached and without a clear treatment effect being observed. A total of 354 women were randomised to receive one of three treatments: folic acid, multivitamins without folic acid, and folic acid plus multivitamins. At the end of the trial 257 women had had a first trial pregnancy outcome (261 infants/fetuses) where the presence or absence of NTDs was ascertainable. There was one NTD recurrence in the 89 infants/fetuses of women in the multivitamin group and no recurrence in the 172 infants/fetuses of women in the folic acid groups, a non-significant difference. Otherwise eligible women who were pregnant when first contacted constituted a non-randomised control group; there were three recurrences among the 103 infants in this group. The difference in the recurrence rate between the folic acid groups and the non-randomised controls was statistically significant but we have reservations about the validity of this comparison. Although our findings do not provide clear evidence of a protective effect of folic acid supplementation they are consistent with those of the Medical Research Council (MRC) trial which demonstrated the efficacy of folic acid in preventing recurrence of NTDs and they raise the possibility that folic acid may be protective at a much lower dosage than that used in the MRC trial.


Bronchial responsiveness and lung function in infants with lower respiratory tract illness over the first six months of life.

The aim of this study was to determine whether increased bronchial responsiveness to histamine is associated with lower respiratory tract illness (one or more episodes of wheeze or cough, or both) in infancy. Fifty four normal newborn infants who had at least one atopic parent were recruited. At a median age of 6.5 months, 45 infants, 23 with a history of lower respiratory tract illness, and 22 without, underwent pulmonary function testing during a symptom free period. The maximum flow at functional residual capacity (VmaxFRC) was calculated from partial forced expiratory flow volume curves using the squeeze technique. Bronchial responsiveness to increasing doses of histamine was assessed by determining the provoking concentration which caused a 30% decrease in VmaxFRC (PC30). The length adjusted VmaxFRC was lower for symptomatic infants before the challenge (median 125 ml/s; 95% confidence intervals (CI) 85 to 164 ml/s) compared with control infants (median 215 ml/s; 95% CI 159 to 298 ml/s). There was no significant difference in PC30 between symptomatic infants (median 10.3 g/l; 95% CI 2.8 to 23.8 g/l) and control infants (median 16.5 g/l; 95% CI 2.4 to 27.9 g/l). Bronchial responsiveness to histamine can be shown in most infants early in life and is independent of lower respiratory tract symptoms including wheezing.


Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis.

The portal tract mononuclear cell infiltrate has been characterised in 28 liver biopsy samples showing features of chronic aggressive hepatitis from 12 patients with autoimmune chronic active hepatitis, 12 with primary sclerosing cholangitis, and four with other chronic liver diseases (two with alpha 1-antitrypsin deficiency, one with Wilson's disease, and one with chronic hepatitis B infection). In all patients liver disease had started in childhood. The mononuclear cell infiltrate was investigated by a two step immunoperoxidase technique using monoclonal antibodies to: total, alpha/beta T cell receptor positive, helper/inducer, suppressor/cytotoxic T lymphocytes; B lymphocytes; killer/natural killer cells; monocyte/macrophages; and to the activation markers HLA-DR antigens, interleukin 2 receptor (IL-2R), transferrin receptor, and 4F2Ag. In all samples the infiltrate consisted of mainly alpha/beta T cell receptor T lymphocytes. Although T helper/inducer cells predominated in patients with autoimmune chronic active hepatitis, T suppressor/cytotoxic lymphocytes were preponderant in patients with primary sclerosing cholangitis and the other chronic liver diseases. Killer/natural killer cells accounted for up to 25% of the mononuclear cell infiltrate in patients with autoimmune chronic active hepatitis, being rare or absent in the other diseases. Monocytes/macrophages were always found, but they were more numerous in primary sclerosing cholangitis than in the other chronic liver diseases. B lymphocytes were rare or absent in all subjects. Activated mononuclear cells were present in all subjects, but although in patients with autoimmune chronic active hepatitis and primary sclerosing cholangitis most cells of the infiltrate expressed HLA-DR antigens and up to 75% IL-2R, in other forms of chronic liver diseases HLA-DR positive cells were less common and IL-2R positive cells ere rare or absent. These results show that the cells responsible for the histological characteristics of chronic aggressive hepatitis vary in their functional phenotype and state of activation according to the type of underlying liver disorder, confirming the involvement of different pathogenetic mechanisms.


Association of perinatal events, epilepsy, and central nervous system trauma with juvenile delinquency.

The association of perinatal events, childhood epilepsy, and central nervous system trauma with juvenile delinquency was studied prospectively in a geographically defined population of 5966 males in northern Finland. Those who had obtained a criminal record up to the age of 22 years, totalling 355, or 6.0%, were defined as delinquents. The incidence of delinquency was not increased in males with a birth weight less than 2500 g or greater than 4000 g, preterm births < 37 weeks' gestation, or those with perinatal brain damage or having epileptic seizures before 14 years of age. The incidence was increased by 6.8% in the group of males with birth weights less than 3500 g, but not significantly increased after standardisation for a number of social and demographic background variables. The incidence was increased by 10.3% among the males who had had a central nervous system trauma by the age of 14 years, however, and this factor remained significant when social and demographic factors were standardised by regression analysis, with an odds ratio of 1.9 for all males with a criminal record and an odds ratio of 3.15 for those who had committed a violent crime. Previous central nervous system trauma may be a cause of delinquency, or another possibility is that the type of behaviour pursued by males who are likely to commit a violent crime will expose them more often to accidents which can result in central nervous system trauma.


Teachers' perceptions of epilepsy.

A questionnaire survey undertaken among 142 schoolteachers in North Staffordshire revealed most of the respondents did not feel confident when teaching children who had epilepsy and a minority considered their knowledge of the subject to be adequate. Only four teachers had received recent specific instruction on childhood epilepsy and the majority requested training on epilepsy and other medical conditions. Despite this lack of confidence and specific training, the respondents demonstrated good general knowledge of epilepsy and adequate awareness of the difficulties encountered by epileptic schoolchildren. If optimal care is to be achieved for children with epilepsy, then teachers must feel confident with this subject. School health services have a clear role in ensuring that teachers have sufficient knowledge of childhood epilepsy, that they have adequate support, and that communication between teachers, parents, and paediatricians is encouraged.


Growth hormone deficiency during puberty reduces adult bone mineral density.

Bone mineral density (BMD) was evaluated by dual energy x ray absorptiometry in 60 adults (33 males, 27 females; aged 50, range 23-76 years) who were growth hormone deficient from various causes for 10.4 (1-31) years. Adult patients who had acquired growth hormone deficiency before completion of puberty had significantly reduced mean (SEM) BMD compared with age matched healthy controls at the lumbar spine: 0.87 (0.09) v 1.20 (0.03) g/cm2, femoral neck: 0.81 (0.06) v 1.08 (0.04) g/cm2, and Ward's triangle: 0.68 (0.07) v 1.04 (0.05) g/cm2. These values were also reduced compared with those of patients who had received human growth hormone during puberty. Untreated growth hormone deficiency when present during puberty results in reduced adult bone density.


Hazards of parenteral treatment: do particles count?

After prolonged parenteral nutrition a 12 month old infant died with pulmonary hypertension and granulomatous pulmonary arteritis. A review of necropsy findings in 41 infants who had been fed parenterally showed that two of these also had pulmonary artery granulomata, while none of 32 control patients who died from sudden infant death syndrome had similar findings. Particulate contaminants have been implicated in the pathogenesis of such lesions and these were quantified in amino acid/dextrose solutions and fat emulsions using automated particle counting and optical microscope counting respectively. Parenteral feed infusions compounded for a 3000 g infant according to standard nutritional regimens were found to include approximately 37,000 particles between 2 and 100 microns in size in one day's feed, of which 80% were derived from the fat emulsion. In-line end filtration of intravenous infusions may reduce the risk of particle associated complications. A suitable particle filter is required for use with lipid.


Thrombolysis with low dose tissue plasminogen activator.

Two cases of vena caval thrombosis in infants were successfully treated with low dose (0.01-0.05 mg/kg/hour) local infusions of tissue plasminogen activator after conventional anticoagulant treatment had been unsuccessful. This approach is useful for clots associated with indwelling intravascular catheters, and a low dose infusion of tissue plasminogen activator as a regional application is recommended to achieve clot lysis with minimal systemic effects.


Recovery of protein from urine specimens collected in cotton wool.

Cotton wool balls have been used to aid the collection of urine from infants. Concentrations of two urinary proteins, albumin and retinol binding protein, decreased by 40 and 80% respectively within 15 minutes of contact with the cotton wool. Cotton wool balls should not be used when investigating proteinuria.


The ethics of cardiopulmonary resuscitation. I. Background to decision making.

Futile cardiopulmonary resuscitation (CPR) may prevent humane care of the dying child and deprive parents of the opportunity to express their love, grief, and dedication at a critical moment, while appropriate and successful CPR may restore intact their child. Attempted resuscitation of corpses or children with terminal illness indicates inadequate knowledge, discrimination, and decision making. CPR is a medical procedure applicable to certain medical problems; weighing up the risks and benefits in each individual case is a medical function that is constrained by the law and must take full note of patient and family preferences, but cannot be governed by them and should not be over-ruled by laws based on complex but different cases. Time limits on occasions may curtail the full process of consultation and decision making. Applications of skills and resources in the right time and place requires understanding of the medical logistics and study of the potential for good outcome.


The ethics of cardiopulmonary resuscitation. II. Medical logistics and the potential for good response.

Mismatches between provision of paediatric cardiopulmonary resuscitation (CPR) and potential to benefit are examined. Deficiencies are most likely to occur in peripheral maternity units but futile CPR is more common in emergency departments where the child is unknown. Decision making in individual cases is best retained by the medical profession for the sake of the child and family. American style intervention by the legislature is likely to dissipate scarce resources and perhaps harm infants not capable of benefiting.


Factitious illness: recognition and management.

An analysis of Munchausen syndrome by proxy is proposed, which involves a categorisation of parental behaviour in terms of desire to consult and ability to distinguish the child's needs from parents' own needs. The Munchausen syndrome by proxy case is proposed as one extreme of a much broader and commoner group for which the term factitious illness is used. An outline of assessment and investigation is given, applicable to all degrees of factitious illness, together with a model of collaboration between paediatrician and child psychiatrist. The role of the child psychiatrist is described. Collaboration results in a broader analysis of the situation which facilitates understanding and points the way to appropriate intervention.


Pelvic inflammatory disease: a clinical syndrome with social causes.

Prevalence of pelvic inflammatory disease (PID) reflects community and individual risk factors. Cultural and behavioural factors influence community prevalence of sexually transmitted disease (STD), illegal abortion, puerperal sepsis and contraceptive usage--all of which influence risk of PID. The relative importance of these factors will vary by region. Individual risk factors for the ascent of a lower genital tract infection are still poorly understood but are thought to be behavioural and immunological. Prevention of PID must be undertaken at several levels. At primary level, it requires a reduction in community risk. At secondary level, individual risk can be modified by ensuring diagnosis and treatment of STD before damage of the upper genital tract occurs. More attention to cultural factors should increase the potential for prevention at both levels.


Raising awareness about reproductive morbidity.

Lack of awareness of the extent and effect of reproductive morbidity on the health and quality of life of women in developing countries is evident at national, community and individual levels. Raising awareness at national level requires population-based, epidemiological information which must be validated. At community level, public opinion mediates women's actions when they are sick and fear of social consequences provides a barrier to treatment. Individually, women find it difficult to talk about sexual reproductive health and its management. Methodologies currently being developed for raising awareness at all levels are described.


Gender-planned health services.

Gender-planned health services are planned on the basis that women and men play different roles in society and have different medical needs. The feminist movement has provided a broad charter of rights for women, reflecting women's needs, but these have yet to be translated into operational programmes. National programmes for women would allow co-ordination of broad-based programmes to improve women's health and social position. To change social norms discriminating against women will require changing male attitudes. Health programmes for males have received little attention, except from family planning organizations, although in most countries, males have a high rate of accidents, infections and parasitic disease. Controlled studies are required to evaluate the benefits of gender-planned health services.


Prevention of PID: a challenge for the health service.

The control of sexually transmitted diseases (STD) will reduce the prevalence of pelvic inflammatory disease (PID). In most developing countries, treatment services are limited, coverage of the infected female population is inadequate and women seeking treatment are likely to be mismanaged. Family planning clinics do not usually provide routine screening for non-pregnant women. Screening only at family planning clinics would result in failure to treat some high-risk individuals, especially unmarried adolescents. The use of simplified protocols in the community has been recommended, but these may underestimate the problems of contact tracing, provide no systematic screening and induce passivity in the patient. For pregnant women, STD control has targetted syphilis, which does not cause PID. An integrated service for the management of reproductive health is required, and the development of women's clinics is suggested, using well-trained nurses and affordable technologies.


Responses of visual single cells in the superior colliculus of the albino rat to bright bars.

We studied the responses of 57 visual cells of the superior colliculus of the albino rat to bright sweeping and stationary flashing bright bars to determine the properties of their receptive fields. We observed that 9% (8% in superficial and 11% in deep layers) of the studied cells presented orientation preference and 16% showed direction selectivity (13% in superficial and 22% in deep layers). According to their responses to a flashed bright bar they were classified in OFF-type (19%) and ON-OFF-type (81%). No ON-type cells were found. All cells were driven by the contralateral eye, and only in three cases was single cell activation from the ipsilateral eye possible. Twenty-one per cent (22% in superficial and 18% in deep layers) showed end-stopping when they were tested with bright bars of several lengths.


Cholinergic microstimulation of the peribrachial nucleus in the cat. I. Immediate and prolonged increases in ponto-geniculo-occipital waves.

The cholinergic agonist carbachol was injected into the pontine Pb area where PGO bursting cells have been recorded. When microinjections were localized to the ventrolateral aspect of the caudal Pb nucleus near aggregates of ChAT immunolabeled cholinergic neurons, carbachol produced an immediate onset of state-independent PGO waves in the ipsilateral LGB. These state-independent PGO waves persisted for 3-4 days. After the first 24 hrs PGO wave activity increasingly became associated with REM sleep and with REM transitional SP sleep as both of these PGO-related states increased in amount to 3-4 times baseline levels. The increase in amount of PGO-related states peaked on days 2-4 following one carbachol injection and persisted for 10-12 days. These results suggest a two stage process: stage one, PGO enhancement, is the direct consequence of the membrane activation of cholinoceptive PGO burst neurons by carbachol; stage two, REM enhancement, is the consequence of metabolic activation of endogenous cholinergic neurons. This experimental preparation is a useful model for the study of the electrophysiology and functional significance of PGO wave and REM sleep generation.


[Cytotoxicity of ferric chloride used as an adjuvant of organic acid precipitation].

The objective of this study was the amelioration of the organic acid precipitation technique currently used as a secondary stage for viruses concentration using ferric chloride (FeCl3) as an adjuvant. To carry out this work successfully, we have studied the cytotoxicity effect of FeCl3 towards cell lines usually used for the investigation of enteric viruses. Two kinds of african green monkey kidney cells, MA104 and BGM, were used as a cellular model. The results showed that optimum concentration of FeCl3 for either BGM or MA104 cell survival and organic acid precipitation varies from 0.5 to 1 mM. The cytotoxicity test used in this work was simple, easy to realize and gives an appreciable information about the cytotoxicity dose of a given biological and chemical product.


Cholinergic microstimulation of the peribrachial nucleus in the cat. II. Delayed and prolonged increases in REM sleep.

The hypothesis that REM sleep is cholinergically mediated is supported by the identification of a cholinoceptive trigger zone in the FTG. Since this trigger zone is devoid of cholinergic neurons, the aim of the present study was to test the hypothesis that a cholinergic drive for REM sleep may come from the cholinergic cells of the PBL region. Chronically implanted freely moving cats with electrodes for sleep and PGO wave recordings were used. Guide tubes were implanted for carbachol microinjections (4 micrograms/250 nl) in the PBL and FTG. All microinjections were delivered in close vicinity of ChAT+ cholinergic cells in the PBL region. Results showed that a single unilateral carbachol microinjection into the PBL induced sustained (24 hr) state-independent ipsilateral PGO wave activity. This PGO wave activity was followed by a prolonged enhancement of REM sleep lasting for more than six days. We also observed that REM enhancement was followed by a delayed but marked enhancement of S sleep episodes with PGO waves (SP), which are normally brief transitions from S to REM sleep. Our findings strongly support the hypothesis that cholinergic drive for REM sleep comes from the lateral pontine tegmentum and we suggest that the PBL region plays a major role in both PGO wave generation and long-term regulation of REM sleep induction.


The dependence of the twitch course of medial gastrocnemius muscle of the rat and its motor units on stretching of the muscle.

The relationship between the force of a single twitch of the medial gastrocnemius muscle of the rat and contraction and half-relaxation times, on one hand, and the load of the muscle on the other, was studied. Twitches of the whole muscle and its individual motor units were induced. The optimal load, at which the majority of motor units reached the greatest twitch force, was 10 G. Mean optimal loads for twitches of different types of motor units were very similar. Slow motor units reached a slightly greater twitch force at greater loads (12.5 G) than at 10 G. However, the optimal load for the twitch of the whole muscle was much greater. It was 47 G on the average. The contraction and half-relaxation times of motor units, as well as of the whole muscle, became longer as the force stretching the muscle increased. Half-relaxation time changed more rapidly than contraction time. Both parameters were undergoing the greatest changes in slow motor units.


Effects of sleep deprivation on fos-like immunoreactivity in the rat brain.

The molecular mechanisms involved in sleep regulation and function are largely unknown, and our understanding of the localization of such mechanisms within specific brain structures is still incomplete. In this work, we explored the consequences of sleep deprivation by the immunocytochemical mapping of the induction of the protein product of the immediate early gene c-fos in the brain of sleep-deprived rats. The expression of Fos protein is an indicator of neuronal activity. In addition, since immediate early genes can function as "third messengers" and regulate the transcription of a number of target genes, their induction could be directly relevant to the homeostasis and functions of sleep. The present results show that, as a result of 24 hours of manual sleep deprivation, Fos-like immunoreactive cells are found in specific brain areas. These areas include the medial preoptic area of the hypothalamus, the nucleus accumbens, the lateral septum, several regions of the dorsal pontine tegmentum (central gray, dorsal raphe, locus coeruleus, pedunculopontine and laterodorsal tegmental nuclei, parabrachial nuclei) and an area medial to the parabigeminal nucleus at the ponto-mesencephalic junction. Some of these areas had already been implicated in slow-wave sleep and desynchronized sleep regulation.


Synthesis and inhibitory activities against enkephalin degrading aminopeptidase of H-Trp(Nps)-Lys-OMe analogues bearing chelating groups.

With the aim of increasing the inhibitory potency of the analgesic dipeptide H-Trp(Nps)-Lys-OMe against enkephalin-degrading aminopeptidases, the following derivatives bearing chelating groups at the N-terminus have been synthesized: Ac-Trp(Nps)-Lys-OMe (3), HS(CH2)nCO-Trp(Nps)-Lys-OMe [n = 1 (4), n = 2 (5)], MeOCO(CH2)n-Trp(Nps)-Lys-OMe [n = 1 (6), n = 2 (7)] and analogues in which the N alpha-amino group has been replaced by a methoxycarbonyl group (8) and a bidentate hydroxamate function (9), respectively. The inhibitory activities of all these compounds and the S-protected derivatives EtNHCOS(CH2)nCO-Trp(Nps)-Lys-OMe [n = 1 (16), n = (17)] against the mentioned enzyme, isolated from rat striatum, are compared with those of the parent dipeptide 2 and bestatin. All the new derivatives showed, in general, inhibitory potencies of the same order of magnitude as compound 2.


Preparation and diuretic properties of novel amiloride analogues.

Fifteen novel amiloride analogues were synthesized and their diuretic properties compared to amiloride and triamterene in white wistar rats. Whereas none of the 6-substituted derivatives exhibited significant natriuretic and antikaliuretic effects, five of the compounds modified in the 2-position were found equal or better than standards. The results are discussed with respect to chemical structure and physiochemical properties.


Synthesis of some guanylhydrazones and imidazolinylhydrazones as thromboxane-synthase and platelet aggregation inhibitors.

The imidazolinylhydrazones of (3-pyridinyloxy)-acetaldehyde and of 6-[3-(2-formyl-pyridinyl)oxy]hexanoic acid were synthesized as cyclic analogues of the corresponding guanylhydrazones which were found to be selective inhibitors of human thromboxane-synthase. The benzene isosters were also prepared in order to define the importance of the ring nitrogen for the activity. Moreover, the guanyl- and imidazolinyl-hydrazones of two 6-[(3-pyridinyl)oxy]hexanoic acids showing in the 2 position an alkyl chain with an alpha, beta-unsaturated ketonic function were prepared. Imidazolinylhydrazones 7 and 18 are selective inhibitors of thromboxane-synthase, while the two guanylhydrazones 14 and 15 which do not affect prostanoid biosynthesis seemed to be antagonists at the thromboxane receptor.


[Thiophene as a structural element of physiologically active substances. 20. Thiophene analogs of the leukotriene D4 antagonist Ro 23-3544].

The synthesis of 6-Acetyl-7-[[5-(5-acetyl-4-hydroxy-3-propyl-2-thienyl- oxy)pentyl]oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (1), a thiophene analogue of the leukotriene antagonist Ro 23-3544, is described. Compound 1 shows almost no effect on leukotriene D4 induced broncho-constriction on anesthesized guinea pigs.


[The lecture in the system of teaching pathology].

The material of lectures on pathology in 75 higher medical schools of the country is analyzed. The types of lectures, their optimal planning are indicated. Recommendations to enhance their efficiency taking into consideration the motivation of their learning are given. Optimal form for the lecture is considered a problem lecture.


[Practical games--one of the forms of independent student work].

The games imitating a clinical pathology conference and a session of the therapeutical-control commission are an efficient method of student learning during the biopsy-sectional course. They favour activation of perception, form clinico-anatomical thinking, facilitate the learning of the diagnosis concept and the role of physicians of various profile (therapeutist, surgeon, pathologist, gynecologist, etc.).


[Methodologic approaches to creating an automated test on pathology].

The designers of the topical computer test on pathological anatomy based it on the test method of the control of student knowledge. First, computer standard topical tests covering all the sections of the program are developed. The stages of each test development involve working out of various tasks, the test trial and statistical processing of the test results. The statistical analysis permits assessment of individual and group student knowledge, of quality of the test itself as well as correction of the test drawbacks. Finally, the appropriate tests form a bank of computer knowledge control after putting them in as a special computer program.


[Organization and methods of teaching a course on biopsy and dissection].

This course is to be organized during the last year of the Institute, the student group should have at least 18 lectures lasting for not more than 2-3 hours. The course should be integrated with other medical disciplines and chairs. The teaching of hospital pathology should be based on unified modern concepts of diagnosis, clinico-anatomical correlations, student independent work, etc.


[Experience in teaching a course on biopsy and dissection].

Basic aspects of the biopsy-sectional course are listed: knowledge of the structure, tasks, juridical status of the pathology service; clinico-anatomical analysis during necropsy; principles of the pathology diagnosis and clinico-anatomical epicrisis; visual presentation of the biopsy and operation material, including urgent biopsies; participation of students in the city clinico-anatomical conferences; lectures about medical deontology and physician errors.


[Analysis of training pathologists on the basis of an educational-research-practicum complex].

The experience of the work of the educational-research-practical association (chair of pathology-pathologo-anatomical bureau) is analyzed. It is believed that organization of such complexes aimed at integration of educational, scientific and practical activity is one of the most effective ways of reorganization of the system of higher medical education and health service. Working within the complex permits a rapid improvement in the quality of education, effectiveness of scientific work and practical activity in pathological anatomy. A conclusion is made that one of the priorities of reorganization of the system of health care is realization of the principle of centralized management and technical supply of these complexes.


[Teaching pathology in European countries].

Similarities and differences of pathology teaching in various European universities are described concerning mainly the number of academic hours assigned to different sections of pathology. General problems in the organization of higher, including medical, education are discussed. Rules and statuses of the European universities are considered in the light of the forthcoming reforms in Russian universities.


[Current tasks of institutional pathology departments in training physicians in the system of postgraduate education].

The difficulties in the postgraduate training of pathologists are analyzed and the leading role of the pathology chairs of the institutes for postgraduate medical training is outlined. Measures for retaining and improving the existing system for the training of pathologists are discussed. The importance of the physician's attestation in their qualification categories, and other possibilities in improving the postgraduate pathologist training are considered.


[Postgraduate training of pathologists].

Specialization of institutions engaged in training of pathologists is a key condition of skilled specialists turn out. Medical colleges should be responsible for training hospital and junior physicians. Institutes for postgraduate medical education must ensure updating of the practicing pathologists knowledge and prepare them for getting special degrees and diplomas including "European Pathologist". The system of continuous training of pathologists should rest on fundamental legal base which should be warranted by the Russian Federation Ministry of Public Health.


[An attempt to analyze lethal outcomes].

The results of the analysis of 2675 autopsy protocols for 1987-1990 in the Moscow City Pathology Centre and 18246 cases of surgery of patients with urgent abdominal pathology in the Ostroumov's Hospital N 33 for 1980-1989 (with 870 lethal issues) are presented. Over 62% of the total are patients over 75 years of age. The advanced age, the presence of multiple diseases (polypathies) considerably influenced the course, diagnosis, therapy and issues of diseases, particularly in the urgent surgical pathology. This is considered particularly in the urgent surgical pathology. This is considered in details on the example of the gallbladder stones. The frequency of different variants of ischemic cardiac disease, vascular brain damage, malignant tumours, respiratory diseases, diseases of the digestive and urinary tract is presented. Clinical diagnosis in cases of death at home is discussed.


[Primary retroperitoneal adenocarcinoma].

A rare case is reported of retroperitoneal papillary adenocarcinoma in a 25-year-old female. Two recurrences were observed after surgical and radiation treatment. The tumour became inoperable after the second recurrence. The duration of the disease was somewhat more than 5 years. The attention is drawn to the difficulty of differential diagnosis with a metastasis. The young age and histological structure allow one to regard the tumour disembryogenetic and originating from the embryonal germs of urinary-genital organs or from the intestinal tube.


[Teaching of pathology in medical education].

The representatives from 90 departments of pathological anatomy at medical colleges participated in the 3d National Education and Methodology Conference held in December of 1991. The conference discussed the problems of teaching students and postgraduate specialists pathologic anatomy. The conference approved recommendations on further improvement of the system of clinical pathologists training. The International Association of Pathologic Anatomy Teachers has been established. The principal task of the association is coordination of the efforts in advancing the skill of the teachers and development of new guidelines, text books, etc.


[Basic principles in the integration of pathology with medico-biologic disciplines].

Five principles should be used for the student knowledge integration at chairs of medico-biological profile and pathology: 1) wide professional orientation, 2) justified sequence of teaching, 3) teaching synchronization, 4) feedback mechanism, 5) reasonable sufficiency of the material. This may become realistic if the teachers of the highest qualification are employed and if health care officials pay due attention to the student teaching.


[Pathology of acute radiation sickness induced by relatively proportional combined radiation damage].

Materials are presented on six cases of fatal acute radiation disease consequent to relatively proportional beta- and gamma-irradiation after accident in the nuclear submarine. The comparison is performed of this material with the data published on the radiation sequelae of the Chernobyl nuclear catastrophe.


[Comparative study of the changes in structural parameters of collagen fibers during natural aging and pneumosclerosis formation].

Changes in diameter of the collagen fibers and their number in fascicles of the rat lung in the process of natural ageing and formation of radiation-induced pneumo-sclerosis were studied electron microscopically. The decrease of the fibril thickness and the increase of their number in fascicles progressed during the postirradiation period and reached the values absent in the control animals.


[Morphohistochemical characteristics of heart myocardiocytes under profound donor hypothermia].

Hearts of 52 pups were studied histochemically and electron-microscopically at various stages of total-body hypothermia. The dependence of the myocardiocyte metabolic alterations on the factors acting in the myocardium during different stages of hypothermia and during subsequent warming is shown. The vitality of the cooled heart is largely determined by retaining not only of its function, but by its anatomo-physiological links with the organism. The method of the profound hypothermia of the donor organism is, according to the authors, one of the ways to sustain the donor heart vitality before transplantation.


[Inhibition of tumor induction by methylnitrosourea in resected urinary bladder].

In the present experiments the dependence of tumour induction upon the different phases of the cell cycle in the proliferating urinary bladder was examined. For stimulation of urothelial proliferation, a one-third resection of the bladder was performed in female Wistar rats. To synchronize the proliferating urothelial cells, hydroxyurea was given. The direct-acting urothelial carcinogen N-methyl-N-nitrosourea (MNU) was administered as a single intravesical dose during different cell cycle phases. The incidence of urothelial bladder tumors was 32.6% in the controls. By comparison, the tumour incidences were 18.9, 9.3, 21.7, 26.3, 25.0 and 30.0%, respectively, when MNU was instilled during the late Gi-, early and late S-, G2+M-, and early and late postmitotic phase. The results obtained from a total of 283 rats clearly document a cell cycle specific inhibition of tumour development in the proliferating urinary bladder particularly when the carcinogen was administered during the early S-phase. MNU has also been shown to produce mesenchymal tumours in the bladder (overall incidence: 4.9%) as well as urothelial tumours in the renal pelvis (3.2%) and ureters (1.4%).


[Transplantation of embryonal brain tissue].

Analysis of the experimental results on the embryonal nervous tissue transplantation into the various parts of the nervous system of animals and man is made in the review. Transplants in many experiments survive and differentiate even in transplantation between different species. Main problem is isolation of specific groups of donor cells, ensuring their survival and differentiation into a given direction in the host brain. The most favourable results are anticipated in the xenotransplantation when the donor cells are those of neural germs of insects and amphibia.


[Problem of the relationship of probable and real ecologic pathology].

Ecology plays more and more important role as an etiological factor of human diseases: congenital defects, tumours, immunodyzergies, hematopoietic and endocrine disorders. Two directions should be taken into consideration in establishing the role of ecology in human disease: pathology itself and ecogenic factor. The first one consists of the complex "populations at risk-pattern of mortality-ecogenic diseases, the second direction is "geography of potentially ecogenic diseases-correlation with geography of environmental pollution-eco-etiological factor". The analysis of death causes may form an alternative to generalized ecomedical analysis having a low informative value. Additional problem of ecological pathology is an ecogenically induced weakness, premorbid and latent states.


Stria vascularis in Ménière's disease: a quantitative histopathological study.

To investigate the role of pathology of the stria vascularis in Ménière's disease, the vascularity and the cross-sectional area of the stria vascularis in a midmodiolar section of the cochlea were examined by histological observation and a computer-aided planimetric, respectively, in eight temporal bones from individuals with Ménière's disease and eight age-matched normal temporal bones. The number of vessels in the stria vascularis was significantly smaller in most of the cochlear turns in ears with Ménière's disease than in control ears, and the cross-sectional area of the stria vascularis in the same sections was significantly smaller in all the cochlear turns in ears with Ménière's disease than in controls. Furthermore, vascularity correlated significantly with the cross-sectional area of the stria vascularis in all the temporal bones examined. From these results it appears that poor vascularity of the stria vascularis is closely related to strial atrophy, and that these pathological findings might be important factors in the pathophysiology of Ménière's disease.


Recording eye movement during stepping in place with a CCD (charge-coupled device) imagesensor.

A new system for recording eye movements using a charge-coupled device (CCD) imagesensor in a video camera, in which less than 0.5 degree of horizontal and vertical eye movements can be recorded, was applied in 7 subjects. Eye movements were recorded while they stepped in place. We observed 5 normal subjects, a patient with horizontal and vertical oscillopsia during walking, and one with a chronic limp. In the normal adults, the amplitude of vertical eye movement was less than 0.5 degree, and the horizontal eye movement was less than 2 degrees. The mean amplitude of horizontal and vertical eye movements in the subject who limped was larger than that of normal subjects. The patient who complained of vertical oscillopsia during walking showed the largest amplitude of vertical eye movement among any subject tested. The vertical oscillopsia in the patient was due to the largest amplitude of vertical eye movement. This system for recording eye movements will be useful in analyzing the mechanism of gaze fixation during walking.


Academic success of integrated hearing-impaired pupils who had enrolled in the early written-oral language program.

Data on academic success were analyzed for 37 hearing-impaired pupils who had been trained by the Written-Oral Language Method before school age. Seventy-one percent of pupils whose average hearing level was less than 89 dB and 77% of pupils whose hearing was 90 to 120 dB succeeded academically. Degree of hearing impairment, speech intelligibility, and gender were not important to their success. Linguistic competence evaluated just before enrollment in a normal educational setting at 6 years of age was the only factor significant to their academic success. However, we propose that the investigation of other factors, IQ and age at the start of preschool training program, must be analyzed in more detail in the future.


Evaluation of the Pharmacia CAP System, a new test for allergic diagnosis (cedar pollinosis).

For the diagnosis of allergic rhinitis we measured the specific IgE and the total serum IgE in the blood. Although we had measured them by the conventional Phadebas RAST and the Pharmacia IgE RIA before, we now adopted the new Pharmacia CAP System (CAP RAST FEIA and CAP IgE FEIA). To compare these methods, we measured the specific IgE to the cedar pollen and total serum IgE in the same blood of 224 hospital staff at the regular physical examination. As a result the new Pharmacia CAP System proved to be simpler, safer, faster, easier, more specific, and more sensitive than the Phadebas RAST and the Pharmacia IgE RIA. And also these methods correlated well with each other.


Electron microscopic observation of killer cells induced by mixed culture of lymphocytes with autologous cancer cells and further culture with recombinant interleukin-2.

Peripheral blood lymphocytes obtained from 2 patients with hypopharyngeal cancer were cultured with mitomycin C treated autologous tumor cells (autologous MLTC) for 10 days and further cultured with recombinant interleukin 2 (rIL-2). In one case 10-day MLTC induced increase of CD25-positive lymphocyte count, indicating that IL-2 receptors were expressed dominantly by the autologous tumor stimulation, and further culture with rIL-2 differentiated killing activity against autologous tumor cells. In the other case, however, MLTC alone induced killing activity against autologous tumor cells, indicating that the tumor cells from this patient might possess stimulatory activity sufficient to induce mature killer cells. Electron microscopic observation of the morphological features of lymphocytes cultured for 10 days revealed mostly small lymphocytes with low incidence of cytoplasmic granules. Further culture with rIL-2, however, induced slightly larger lymphocytes with well-developed microvilli, and cytoplasmic granules were found in many of the cells. Lymphokine activated killer (LAK) cells induced by culture of lymphocytes with rIL-2 alone were much larger and had long microvilli and abundant cytoplasmic granules, and were apparently morphologically different from the killer cells initiated by MLTC. The small lymphocytes induced by autologous MLTC alone might be autologous tumor specific cytotoxic T lymphocytes (CTL) and/or CTL precursors. Further culture with rIL-2 induced maturation of the CTL. However, the nature of the cytoplasmic granules remains obscure.


Tuberculoma of the nasopharynx.

A 67-year-old female patient with tuberculosis of the nasopharynx is reported. The diagnosis was confirmed on histological and bacteriological examination of a biopsy from her postnasal space. There was no evidence of any other active foci of tuberculosis but she had had a right nephrectomy 45 years previously for renal tuberculosis. A review of the literature on nasopharyngeal tuberculosis shows this to be a very rare disease in the absence of active pulmonary involvement.


Migration of fishbone following penetration of the cervical esophagus presenting as a thyroid mass.

Fishbones are among the commonest foreign bodies lodged in the cervical esophagus. A small percentage of them will penetrate the esophageal wall and will be found either intra- or extraluminally. Migration of esophageal foreign bodies to the thyroid gland, and presentation as a mass, is extremely rare. We present such a case and review the relevant literature.


Immediate and long-term results of percutaneous balloon aortic valvuloplasty: a report of 33 procedures.

The purpose of this study was to evaluate the immediate and long-term clinical and haemodynamic effects of Percutaneous Balloon Aortic Valvuloplasty (PBAV). Thirty-three procedures were performed in 27 patients, 11 males and 16 females with a mean age of 72 years. The peak to peak systolic gradient across the aortic valve decreased by 52%, from 67 +/- 24 mmHg to 31 +/- 15 mmHg (p < 0.0001) and the aortic valve area increased by 35%, from 0.48 +/- 0.16 to 0.67 +/- 0.21 cm2 (p < 0.001) after PBAV. There were no procedural deaths. Minor complications occurred in seven patients. Eighty-one per cent of patients (27 procedures) showed immediate symptomatic improvement, five remained symptomatic and one died in hospital before discharge. In a mean follow-up of 17 +/- 12 months (range six to 38 months), eight patients died due to congestive cardiac failure, six underwent repeat PBAV, three died due to noncardiac causes and three had recurrent symptoms controlled on medical therapy. Event free survival at 15 months was 43%. In conclusion PBAV produces a satisfactory immediate clinical and haemodynamic result, however, considering the high rate of symptom recurrence, this procedure has a beneficial role only in short-term palliation of severely symptomatic patients who are unable to undergo aortic valve replacement.


Autoantibodies to neutrophil cytoplasmic (ANCA) and endothelial cell surface antigens (AECA) in chronic inflammatory bowel disease.

Sera from 103 patients with chronic inflammatory bowel disease (IBD) were tested prospectively for antibodies against neutrophil cytoplasmic antigens (anti-neutrophil cytoplasm antibodies, ANCA) and endothelial cell surface antigens (anti-endothelial cell antibodies, AECA) by indirect immunofluorescence (IIF) and assays based on whole fixed neutrophils, purified neutrophil enzyme substrates and human umbilical vein endothelial cells. Using IIF, ANCA were found in 26 IBD sera (25%) and in none of 51 controls. Twenty-two positive sera (85%) were from patients with ulcerative colitis (UC). The pattern of distribution of immunofluorescence was always perinuclear (P-ANCA). A majority of UC patients positive for these autoantibodies (68%) had active colitis, but none had evidence of vasculitis. Using a whole neutrophil ELISA, binding was demonstrable in 73% of UC sera compared to 27% of Crohn's (CD) sera and only 4% of controls. Unlike vasculitis sera, UC sera with P-ANCA did not bind strongly to myeloperoxidase (MPO). Forty-five per cent of IBD sera tested positive for IgG AECA in an endothelial cell ELISA, compared to seven of 51 (14%) controls. Binding correlated with both active and extensive colitis. A type of P-ANCA, in most cases distinct from MPO-specific P-ANCA observed in vasculitis, is detected in a significant proportion of patients with UC, but rarely Crohn's colitis and therefore may be of differential diagnostic value. IgG AECA are also frequent in CIBD sera but are less disease specific than ANCA.


A comparison of peripheral blood stem cell mobilisation after chemotherapy with cyclophosphamide as a single agent in doses of 4 g/m2 or 7 g/m2 in patients with advanced cancer.

We used cyclophosphamide at a dose of 7 g/m2 in patients with advanced cancer and compared the efficacy of this treatment to generate peripheral blood stem cells (PBSC) with the previously reported regimen of cyclophosphamide 4 g/m2 in a similar group of patients. None of these patients received haemopoietic growth factors. Twenty-two patients received 7 g/m2 and 37 received 4 g/m2. PBSC were collected by apheresis after the leukocyte count recovered to 1.0 x 10(9)/L. The yield of colony forming unit-granulocyte macrophage (CFU-GM) was higher for the 7 g/m2 group with a median of 35 x 10(4)/kg versus 15 x 10(4)/kg body weight (BW) (p < 0.05) and higher mononuclear cell yield with medians of 4.2 x 10(8)/kg compared with 3.1 x 10(8)/kg BW (p < 0.001). The percentage of patients achieving the minimum safe level of > 15 x 10(4) CFU-GM/kg BW was higher in the 7 g/m2 cyclophosphamide group (82%) than the 4 g/m2 cyclophosphamide group (51%). The duration of significant neutropaenia was a median of 11 compared with nine days (p < 0.004) and all patients receiving 7 g/m2 required admission to hospital and intravenous antibiotic therapy compared with 44% in the 4 g/m2 group. There was one death during the period of neutropaenia after cyclophosphamide in each group. Nineteen per cent of patients required platelet transfusions after cyclophosphamide 7 g/m2 compared with 18% after 4 g/m2. We conclude that the 7 g/m2 cyclophosphamide gives a higher yield of haemopoietic progenitor cells than the 4 g/m2 but at increased clinical toxicity.


New approaches to the management of poor prognosis non-seminomatous germ cell tumours.

While most patients with disseminated non-seminomatous germ cell tumours (NSGCT) are cured by treatment with cisplatinum-based chemotherapy, a subset die from refractory or relapsing disease. Poor prognostic factors at diagnosis include bulky disease, visceral involvement, high serum marker levels and an inadequate rate of fall in these markers in response to treatment. There are a number of approaches to poorer risk patients. One is to use conventional induction chemotherapy followed by second-line salvage regimens in those who fail induction. Results with this approach have been disappointing. A second approach is to use more intensive induction regimens, in some cases with growth factor support; whether these are superior to standard treatment has yet to be established by randomised studies. A third approach, based on the chemotherapy-dose responsiveness of NSGCT, consists of the administration of very high dose chemotherapy followed by haematological rescue with autologous marrow to patients failing initial therapy. Review of autograft studies suggest that durable remissions can be obtained in most patients with responsive disease, but not if the disease is chemotherapy-refractory. A new approach may be elective early autografting in patients identified at diagnosis to have very poor prognosis disease.


The role of dipyridamole in addition to low dose aspirin in the prevention of occlusion of coronary artery bypass grafts.

One hundred and one subjects were randomised to receive either aspirin 100 mg or aspirin 100 mg + dipyridamole 300 mg daily before undergoing coronary bypass surgery. The drugs were commenced at least 36 hours before operation and patients were followed for one year. There were three perioperative deaths and 37 withdrawals, of which 14 were drug related (aspirin four, aspirin + dipyridamole ten). Cineangiocardiograms at nine weeks and one year showed vein graft patency rates of 93% and 87% for subjects treated with aspirin alone; and 90% and 89% in those who received aspirin+dipyridamole. During the follow-up period 14% of 232 coronary lesions in the aspirin treated group advanced by more than two grades compared with 15% of 315 lesions in the aspirin+dipyridamole group. The study did not establish superiority of one regimen over another in terms of graft patency or progress of lesions in native vessels. However, low dose aspirin was better tolerated than combination therapy.