Biomedical subjects
Publications and source records attributed to W R Wilson.
This report describes the first well-documented reported case of the recovery of Blastomyces dermatitidis from the blood of a patient with disseminated blastomycosis. The isolate was recovered by using a lysis-centrifugation method and inhibitory mold agar after 6 days of incubation at 30 degrees C. One of six blood samples collected yielded a positive culture.
Auditory brainstem response (ABR) wave V detection levels, latency, and amplitude were studied in a group of 15 young adults with Down syndrome for whom behavioral measures of hearing sensitivity were also obtained. Comparisons were made to a group of nonretarded control subjects matched by age and sex. Auditory brainstem response detection levels were elevated, response amplitude was reduced, and latency-intensity functions were significantly steeper for the subjects with Down syndrome than for the control group. These findings were associated with a high frequency (8000 Hz) hearing loss prevalent in the otherwise normal-hearing experimental group.
An established in vitro cell line (LLTC), originally derived from the Lewis lung carcinoma (LL), was found to have lost sensitivity to the C-nucleoside antitumor agent tiazofurin (NSC-286193; 2-beta-D-ribofuranosylthiazole-4-carboxamide) both in vitro and in vivo. A new in vitro cell line (LLAK) was derived from LL and compared to LLTC in its growth properties and sensitivity to tiazofurin. LLAK resembled the in vivo tumor in having both a high S-phase fraction and a high rate of cell death at high cell density. In continuous drug exposure growth inhibition assays, the concentration of tiazofurin required to reduce the number of cells in a culture by 50% with respect to control cultures was 0.51 microM for LLAK, 2.6 microM for LLTC, and greater than 10 microM for a range of human cancer cell lines. In cytotoxicity assays involving a 2-hour drug exposure followed by clonogenic assay, tiazofurin was more toxic to LLAK cells than to LLTC cells or L1210 murine leukemia cells, consistent with its high in vivo activity against LL. MM-96 human melanoma cells were highly resistant. Flow cytometry studies indicated that tiazofurin selectively depleted the LLAK cell population of S- and G2-phase cells. In one experiment involving 16 consecutive in vitro passages of LLAK in the absence of tiazofurin, a new line emerged that was resistant to tiazofurin in the clonogenic assay. The results demonstrate the spontaneous emergence of resistance from a tiazofurin-sensitive cell line. If similar processes occur during adaptation of human tumor cells to culture, this may explain the finding of low activity of tiazofurin toward a range of human tumor cell lines.
Intraocular lenses are known to be efficacious in the correction of aphakia, but their suitability and durability in Army aviators has not been previously evaluated. Eight experienced pilots (preoperative flight time average: 7,660 hours), who had intraocular lens implants following removal of cataractus lenses, were studied. All had returned to flight duty, seven as pilots, with a total of 2,700 hours postoperative flight time accumulated. All were very pleased with the surgery and with the effectiveness of their lenses. Minor problems included: halos around lights in low illumination (5/8 pilots), erythropsia (2/8), and difficulties with a fixed focal length (2/8). Two aviators reported significant visual problems: complications associated with a platinum loop iris supported intraocular lens, and discomfort and glare stemming from traumatic corneal scarring. A detailed ophthalmological examination revealed abnormalities (5/8 pilots), but none which would be directly attributed to flying. Modern intraocular lenses appear to be an acceptable means of correcting aphakia in Army aviators.
In order to examine possible selectivity of amine uptake by synaptic vesicles, the ATP-stimulated accumulation of 3H-5-hydroxytryptamine (5HT) by synaptic vesicles from rat whole brain was examined in a medium comprised largely of membrane-impermeant anions (d-tartrate). Such media have previously been shown to stabilize vesicular accumulation of several neurotransmitters. Accumulation of 3H-5HT did not occur in tartrate medium alone, but was increased biphasically with increasing concentrations of both potassium phosphate and potassium bicarbonate. At optimal concentrations of each anion (10 mM), stable accumulation of 3H-5HT was observed at 37 degrees (26.1 +/- 1.2 pmol/mg protein; Km 6 X 10(-7) M), which was reduced by greater than 95% in the absence of K2ATP, at 4 degrees C, in the presence of 10(-6) M reserpine, or in the presence of the proton ionophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP). Uptake was significantly antagonized by millimolar concentrations of Na+, Mg++ or Cl-, but was unaffected by ouabain (10(-5) M). Pretreatment of animals with 5,7-dihydroxytryptamine (5,7-DHT) (200 micrograms, intraventricular) 10 days prior to sacrifice reduced endogenous 5HT levels by 70%, while levels of endogenous norepinephrine (NE) and dopamine (DA) were unaffected. Accumulation of 3H-5HT, examined in the presence of 10(-6) M NE to block 3H-5HT accumulation by vesicles from noradrenergic nerve endings, was reduced by 40% in vesicles from treated animals. Vesicular accumulation of 3H-(-)-NE and 3H-DA was unaffected by 5,7-DHT treatment. The data suggest the possibility of preferential accumulation of 3H-5HT by vesicles arising from serotonergic nerve endings.
The herpesvirus family is associated with sudden hearing loss syndrome and the evidence includes clinical findings (HV-Z), temporal bone studies (CMV and HV-Z), and serologic studies. The data presented demonstrate that herpes infections, in association with sudden viral hearing loss, occur as part of a multiple viral infection in 70% of instances. This feature is unique to the herpesvirus infections when compared to other neurotropic viral agents. The study also demonstrates that the variables of viral hearing loss, such as degree of hearing loss, percentage of recovery, or the incidence of vertigo are unaffected by the presence of herpesvirus infection. Mechanisms for inner ear injury may be influenced by temporary alterations in cellular immunity secondary to simultaneous viral infections as well as the native virulence of the infecting herpesvirus.
Eight human haematopoietic cell lines and four human carcinoma lines were used to compare the activity of a number of cytotoxic drugs including amsacrine, the amsacrine analogue CI-921, methotrexate, nitracrine, doxorubicin, daunorubicin and 5-fluorouracil. Activity was assessed by means of semiautomated microculture growth inhibition assays. Cell density of the non-adherent cell lines was measured using the technique of Mosmann (J Immunol Methods 1983, 65, 55-63), in which the dye thiazolyl blue (MTT) is metabolised to a dark blue formazan product. This technique gives similar results to those obtained by direct cell counting in an electronic cell counter, and when applied to some adherent cell lines gives similar results to those obtained by the methylene blue staining technique previously developed (Anal Biochem 1984, 139, 272-277). Both methylene blue and MTT methods were used to investigate cytotoxicity in conjunction with semi-automated 96-well microculture plate techniques. The results show that the three T-cell leukaemia lines (CCRF-CEM, Jurkat and MOLT-4) are more sensitive to DNA-binding drugs (excluding nitracrine) than are the colon carcinoma lines (HCT-8, HT-29, SW480 and SW620). The more resistant haematopoietic lines are intermediate in drug sensitivity between the T cell leukaemia and carcinoma lines. The DNA binding drugs show remarkably similar patterns of differential activity against the different cell lines.
The 1-nitroacridine nitracrine [NC,1-nitro-9-(dimethylaminopropyl-amino)acridine] is a potent hypoxia-selective cytotoxic agent in culture, but lacks activity against hypoxic tumor cells in vivo at therapeutically accessible doses. To clarify reasons for this failure in vivo the metabolism of NC was investigated in stirred suspension cultures of Chinese hamster ovary cells, in EMT-6 spheroids, and in mice. One major low molecular weight metabolite (identical to that generated by NaBH4/Pd/C reduction) was observed in hypoxic (less than 10 ppm O2) single cell suspensions, while [G-3H-acridinyl]NC formed trichloroacetic acid- and acetonitrile-insoluble macromolecular adducts (MA) at a rate seven-fold higher than in aerobic (20% O2) cultures. Formation of these adducts correlated with cytotoxicity under air or nitrogen, and hence may provide a dosimeter for NC-induced damage. Autoradiographic investigation of the distribution of MA in spheroids equilibrated with 5% O2 showed that the label was restricted to the outer cell layers rather than being localized in the hypoxic central region. Thus metabolic activation is probably too rapid, even in well-oxygenated cells, to allow adequate distribution to hypoxic microenvironments in tumors. In mice, levels of MA were higher in liver, kidney, spleen and lung than in Lewis lung tumors, indicating that oxygen concentration does not exert a dominant influence on relative rates of metabolic activation in vivo. The development of nitroacridines with useful hypoxic selectivity in vivo will require identification of analogs for which reductive metabolism is more completely inhibited at oxygen concentrations found in normal tissues.
Indications for the administration of vancomycin in the perioperative period have expanded in recent years. Used in this situation, vancomycin has caused adverse reactions, the most serious of which is hypotension. We describe five patients who had adverse reactions to vancomycin perioperatively. Vancomycin-induced hypotension usually results from a negative inotropic and vasodilator effect produced in part by a histamine-release phenomenon, which occurs most commonly with rapid intravenous infusion of the drug. Such a release of histamine may also produce an acute urticarial flushing of the upper torso (the "red neck syndrome") and symptoms of pain and muscle spasm in the chest or paraspinal muscles, which may mimic myocardial infarction. These effects usually abate promptly when the infusion of vancomycin is discontinued, and their resolution may be expedited by administration of an antihistamine.
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Group B streptococci were less susceptible in vitro to penicillin and to aminoglycosides with an inoculum size of 10(7)-10(8) cfu/ml than with an inoculum size of 5.5 X 10(5)-10(6) cfu/ml. With a rabbit model of experimental group B streptococcal endocarditis, after one or three days of therapy with procaine penicillin alone, the mean log10 cfu/g of valve vegetation was significantly lower (P less than 0.01) than that of the control groups. After one day of therapy, procaine penicillin combined with streptomycin was significantly more effective (P less than 0.01) than was treatment with procaine penicillin alone. There was no significant difference (P greater than 0.05) in the results of treatment of animals for one day with procaine penicillin combined with streptomycin compared with those of animals treated for three days with procaine penicillin alone.
Sixty-five women with uncomplicated urinary tract infection were evaluated in a prospective, randomized, double blind study comparing ciprofloxacin (250 mg twice daily for ten days) with co-trimoxazole (160 mg trimethoprim and 800 mg sulphamethoxazole twice daily for ten days). Results were analysed with respect to eradication of the urinary tract pathogen, resolution of clinical symptoms, incidence of relapse, and incidence of adverse effects. Among the 31 women who received ciprofloxacin, there was eradication of the micro-organism and complete resolution of clinical symptoms in 100% five to nine days after completion of therapy. Among the 34 patients who received co-trimoxazole, there was eradication in 94% and clinical resolution in 91%. Of the ciprofloxacin-treated women 6.5% (2/31) relapsed compared with 18% (6/34) of co-trimoxazole-treated women. Overall cure rates for 65 patients were 93.5% and 82.3% for ciprofloxacin and co-trimoxazole (difference not statistically significant), respectively. A statistically significant (P less than 0.05) increase in adverse side effects was noted in patients treated with co-trimoxazole. Based upon preliminary data it appears that ciprofloxacin is as effective and less toxic than co-trimoxazole for treatment of uncomplicated urinary tract infection in women.
Rabbits with nutritionally variant viridans group streptococcal experimental endocarditis were treated three times daily for 3 days with procaine penicillin (1.2 X 10(6) U) alone or together with low-dose streptomycin (2 mg/kg), high-dose streptomycin (8 mg/kg), low-dose gentamicin (0.32 mg/kg), or high-dose gentamicin (1.05 mg/kg). The mean 0.5-h serum concentrations of streptomycin were 5.3 and 22.5 micrograms/ml in the low- and high-dose group, respectively, and the concentrations of gentamicin were 0.7 and 2.5 micrograms in the low- and high-dose groups, respectively. The combination of procaine penicillin with each dose of aminoglycoside was significantly more effective (P less than 0.001) than was procaine penicillin alone. In combination with procaine penicillin, the higher dose of streptomycin was significantly more effective (P less than 0.02) than the lower dose of streptomycin. The higher dose of streptomycin was not significantly more effective than either dose of gentamicin. The results of treatment with the high or low dose of gentamicin were virtually identical.
We used two strains of streptomycin-susceptible enterococci (MIC, 64 and 128 micrograms of streptomycin per ml, respectively) isolated from patients with infective endocarditis. When combined with penicillin, 20 micrograms of streptomycin per ml killed both strains synergistically in vitro whereas combinations of 5 and 10 micrograms of streptomycin per ml did not act synergistically against either strain. By using the rabbit model of enterococcal experimental endocarditis, animals were treated for 3 days with procaine penicillin (1.2 X 10(6) U intramuscularly three times daily) together with low-dose streptomycin (3.5 mg/kg) or high-dose streptomycin (10 mg/kg) intramuscularly three times daily. The peak concentrations of streptomycin in serum at 0.5 h were 9.2 and 26.8 micrograms/ml in the low- or high-dose group, respectively. When combined with procaine penicillin, both dosages of streptomycin were more effective (P less than 0.01) than procaine penicillin alone for the treatment of enterococcal experimental endocarditis. There was no significant difference in the efficacy of procaine penicillin plus low-dose streptomycin versus procaine penicillin plus high-dose streptomycin therapy of enterococcal experimental endocarditis.
A number of new anilino ring variants of the anti-tumour drug amsacrine have been synthesised and their anti-tumour activity evaluated. In vitro selectivity, as measured by the logarithmic ratio of IC50 growth inhibition assays against P388 leukaemia and Lewis lung carcinoma cells, was significantly correlated with the increase in life span in vivo with the P388 leukaemia and Lewis lung lines, whereas the growth inhibition IC50 values alone correlated with the dose potency in mice. It was thus possible to predict both in vivo anti-tumour activity and dose potency, identifying compounds with high therapeutic activity, using a combination of two in vitro assays. Two new compounds have been identified which provide, along with an acridine-substituted analogue of amsacrine which is at present in clinical trial (CI-921), a high proportion of cures against the Lewis lung tumour in vivo. Since amsacrine is thought to interact with the enzyme topoisomerase II, and because the anilino group of 9-anilinoacridine derivatives is thought to project from the DNA intercalation site of the drug-DNA complex, these compounds may be of particular interest in mode of action studies.
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Strict criteria were used to identify all definite, probable, and possible cases of endocarditis in residents of Olmsted County, Minnesota, from 1950 through 1981. The mean annual age- and sex-adjusted incidence rates per 100,000 person-years were 3.8 for total cases and 3.2 for definite and probable cases only. Total rates were 4.3 for 1950 through 1959, 3.3 for 1960 through 1969, and 3.9 for 1970 through 1981. Rheumatic heart disease was the underlying disorder in 26% of cases, with a shift noted during 1970 through 1981 to involvement of prosthetic rather than natural valves in these patients. Mitral valve prolapse was identified in 17% of cases. No source of infection could be identified in 41% of cases, including half of those cases with rheumatic or congenital heart disease. In cases diagnosed prior to autopsy, the 60-day fatality fell from 46% during 1950 through 1959 to 22% and 26% during 1960 through 1969 and 1970 through 1981, respectively.
Patients with infective endocarditis caused by penicillin-sensitive streptococci (minimal inhibitory concentration for penicillin of 0.1 microgram/ml or less) may be treated successfully with one of the following regimens: aqueous penicillin G administered intravenously for four weeks, intravenous aqueous penicillin G for four weeks combined with streptomycin for the first two weeks of therapy, or parenterally administered penicillin plus streptomycin for two weeks. A cure rate of at least 98 percent may be anticipated with each of these regimens. During a 12-year period among 142 patients treated for two weeks with penicillin and streptomycin, one (0.7 percent) had relapse and four (3 percent) had vestibular toxicity. The major advantage of the two-week regimen is that it is more cost-effective than the four-week regimens. The major disadvantage of the use of streptomycin is the relatively low risk of vestibular toxicity. Patients with enterococcal endocarditis were treated initially for four weeks with aqueous penicillin G together with either streptomycin (streptomycin-susceptible enterococci, 36 patients) or gentamicin (streptomycin-resistant enterococci, 20 patients). Compared with patients who had symptoms for less than three months, patients with symptoms for longer than three months had a higher relapse rate (0 percent versus 44 percent; p less than 0.001) and mortality (2.5 percent versus 25 percent; p less than 0.001). Patients with mitral valve endocarditis had a significantly higher relapse rate (25 percent) than patients with aortic valve infection (0 percent; p less than 0.01]. Gentamicin-associated nephrotoxicity was more frequent (p less than 0.001) among patients treated with more than 3 mg/kg per day of gentamicin than among those treated with 3 mg/kg per day or less (100 percent versus 20 percent). Relapse and mortality rates did not differ significantly between patients treated with low-dose or high-dose gentamicin regimens. Patients who have had symptoms of enterococcal endocarditis for longer than three months or perhaps patients with mitral valve infection should receive at least six weeks of penicillin therapy together with an aminoglycoside; patients without either high-risk factor may be treated successfully for four weeks.