Biomedical subjects
Publications and source records attributed to A Brown.
Reports are presented demonstrating a technique for dissolving thrombus in coronary arteries and bypass grafts by using prolonged selective infusion of urokinase via an infusion wire. This allows one to pass a steerable guide wire through the culprit stenosis and perform angioplasty on a distal lesion which could not be previously seen.
UNLABELLED: During a 3-year period, intravenous streptokinase (IV STK) was given to 110 consecutive patients ages 34-78 in the course of acute myocardial infarction (AMI) in three community hospitals served by the same paramedic system. 1.5 million units of IV STK was given over 30 minutes. Half of the patients were brought to the hospital by paramedics. The average time from onset of pain to administration of IV STK was 107 minutes in the paramedic group and 182 minutes for the others. Of 110 patients, 98 (89%) showed clinical evidence of reperfusion and 94 of 106 patients (89%) showed angiographic reperfusion. Angiography was performed from 1 to 10 days post-AMI. Mean time to angiography was 6 days for the first 58 patients and 2 days for the last 52 patients. In-hospital mortality was 2 of 110 patients and there was 1 late death at 8 months for an overall 3-year mortality 2.7%. Of 86 patients, 83 (96%) working before their infarct are working now. Of 107 survivors, 96 (90%) are Functional Class I. CONCLUSIONS: (1) IV STK is safely administered in a high percentage of AMI patients. (2) IV STK is safely administered in community hospitals. (3) Paramedics act as an early warning system and allow for earlier treatment than patients presenting without paramedic involvement. (4) Successful coronary reperfusion with IV STK results in low mortality rates and minimizes functional disability. (5) A system-wide approach to reducing time to treatment in AMI may be the most influential factor in affecting morbidity and mortality.
Eighteen chemicals were tested for their mutagenic potential in the L5178Y tk+/- mouse lymphoma cell forward mutation assay by the use of procedures based upon those described by Clive and Spector [Mutat Res 44:269-278, 1975] and Clive et al [Mutat Res 59:61-108, 1979]. Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Significant responses were obtained with benzofuran, benzyl chloride, bromodichloromethane, butylated hydroxytoluene, chlorendic acid, o-chlorobenzalmalonitrile, 1,2,3,4-diepoxybutane, dimethyl formamide, dimethyl hydrogen phosphite, furfural, glutaraldehyde, hydroquinone, 8-hydroxyquinoline, and resorcinol. Apart from bromodichloromethane, butylated hydroxytoluene and dimethyl hydrogen phosphite, rat liver S9 mix was not a requirement for the activity of any of these compounds. Chemicals not identified as mutagens were water, tert-butyl alcohol, pyridine, and witch hazel.
Using the L5178Y mouse lymphoma cell thymidine kinase locus and the Salmonella his locus assays, the mutagenic potentials of several catecholamines and related compounds were examined. No supplementary metabolic activation systems were used. In the mouse lymphoma assay, the dihydroxybenzenes catechol and hydroquinone had similar and appreciable mutagenic potentials, whereas resorcinol was less active. Derivatives of catechol, such as dopamine and epinephrine, were mutagenic, whereas the related monohydroxylated compounds tyramine and synephrine were inactive. The primary amine, arterenol, and the corresponding secondary amine, epinephrine, induced similar mutagenic responses. Carboxylation of the side chain of dopamine, giving L-dopa, reduced the maximum mutagenic response. The introduction of charged groups directly on to the aromatic ring also reduced mutagenic activity, while an intervening methylene reversed this effect. Thus, 3,4-dihydroxyhydrocinnamic acid was more active than 3,4-dihydroxybenzoic acid. The compound active at the lowest doses was 4-tert-butyl catechol. The activities of these compounds are highly dependent upon substituent groups. Experiments with superoxide dismutase gave circumstantial evidence for some of the mutagenic activity being due to superoxide anion. Active oxygen species might be responsible for some of the observed effects, but this cannot be concluded from the superoxide dismutase experiments. Mutagenic responses in Salmonella were very low but were significant for L-dopa in three strains and for epinephrine and arterenol in one strain. Limited DNA association studies of 14C-dopamine suggest interactions in L5178Y and Salmonella cells and in mouse liver. The mutagenicity of dopamine in L5178Y is reduced by high serum concentrations during the exposure period, while the apparent association with DNA is unaffected.
Seventy-two chemicals were tested for their mutagenic potential in the L5178Y tk+/- mouse lymphoma cell forward mutation assay, using procedures based upon those described by Clive and Spector (Mutat Res 44:269-278, 1975) and Clive et al. (Mutat Res 59:61-108, 1979). Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Significant responses were obtained with allyl isothiocyanate, p-benzoquinone dioxime, benzyl acetate, 2-biphenylamine HCl, bis(2-chloro-1-methylethyl)ether, cadmium chloride, chlordane, chlorobenzene, chlorobenzilate, 2-chloroethanol, chlorothalonil, cytarabine.HCl, p,p'-DDE, diazinon, 2,6-dichloro-p-phenylenediamine, N,N-diethylthiourea, diglycidylresorcinol ether, 2,4-dimethoxy aniline.HCl, disperse yellow 3, endosulfan, 1,2-epoxyhexadecane, ethyl acrylate, ethyl benzene, ethylene thiourea, F D and C yellow Number 6, furan, heptachlor, isophorone, mercuric chloride, 4,4'-methylenedianiline.2 HCl, methyl viologen, nickel sulfate.6H2O, 4,4'-oxydianiline, pentachloroethane, piperonyl butoxide, propyl gallate, quinoline, rotenone, 2,4,5,6-tetrachloro-4-nitro-anisole, 1,1,1,2-tetrachloroethane, trichlorfon, 2,4,6-trichlorophenol, 2,4,5-trimethoxybenzaldehyde, 1,1,3-trimethyl-2-thiourea, 1-vinyl-3-cyclopetene dioxide, vinyl toluene, and ziram. Apart from 2-biphenylamine.HCl, 2-chloroethanol, disperse yellow 3, ethylene thiourea, FD and C yellow number 6, phenol, and 1,1,2-tetrachloroethane, rat liver S9 mix was not a requirement for these compounds. Chemicals not identified as mutagens were acid red, 11-aminoudecanoic acid, boric acid, 5-chloro-o-toluidine, coumaphos, cyclohexanone, decabromodiphenyl oxide, di(2-ethylhexyl)adipate, ferric chloride, fluometuron, melamine, monuron, phenesterin, phthalimide, reserpine, sodium dodecyl sulfate, 4,4-sulfonyldianiline, tetrachloroethylene, and zearalenone. The assay was incapable of providing a clear indication of whether some chemicals were mutagens; these were benzyl alcohol, 1,4-dichlorobenzene, phenol, succinic acid-2,2-dimethyl hydrazide, and toluene.
Sixty-three families with multiple instances of leprosy were identified through a major leprosy treatment center in northern Thailand. Complex segregation analyses for single major genes or polygenic inheritance were performed using the maximum-likelihood routine POINTER to determine the most likely etiologic model of genetic susceptibility. Liability differences between men and women were considered in these models. When individuals were considered to be affected because they had any form of leprosy, a generalized major gene model with nearly dominant parameters on the liability scale, but additive penetrances, was found to be the most likely. When only those individuals who had tuberculoid forms of leprosy were considered to be affected, a recessive model was found to be the most likely; however, the discrimination between various models was poor. Further analyses are necessary to delineate genetic mechanisms to explain these apparently divergent results. In particular, methods of testing two locus models should be considered.
Two patients are reported with Mycoplasma pneumoniae-related cervical myelitis. Magnetic resonance imaging in each case demonstrated clinically silent lesions suggesting more extensive neurological involvement. This supports the concept of widespread immunologically mediated disease occurring as a remote effect of initial M. pneumoniae respiratory infection. Differences from the MRI appearances of a patient with mycoplasma-related Guillian-Barré syndrome imply that more than one antigenic determinant is involved.
Infection of the human leukemia hematopoietic stem cell line, K-562, with Semliki Forest virus (SFV) can be characterized by three stages: (1) an early virus-proliferating stage lasting 1 to 4 days post-infection (pi) in which infectious virus is produced in high titers (10(3)pfu/cell) but in which there is minimal cytopathic effect. All cells appear viable by trypan blue dye exclusion, although they do not proliferate, and DNA and cell protein synthesis decrease to less than 3% of uninfected controls within 24 hours; (2) an intermediate stage extending from day 5 to about day 24-30 pi in which the amount of infectious virus declines to low levels. During this stage, viral protein synthesis decreases to undetectable levels, although viral gylcoproteins are readily demonstrated by immunofluorescence and by immunoblot; however, capsid protein appears to degrade within 21 days pi. Cell numbers remain constant but the viability of the non-proliferating cells determined by trypan blue exclusion could not be determined with confidence; (3) a final long-term stage in which viral glycoproteins, E1 and E2, are detectable by immunoblots and immunofluorescence for many months but the cells are metabolically inactive and do not synthesize viral proteins. These non-viable cells do not lyse for as long as 2 years.
Alkyl sulfhydryl drugs protect against acute gastric hemorrhagic mucosal lesions. We tested the protective effect of cyclic drugs containing oxidized (KT1-32, KT1-39, KT1-94), or reduced (KT1-66, KT1-109, KT1-293, KT1-720, KT1-756) sulfhydryls. The most potent protective agents (KT1-32, KT1-109, KT1-720, KT1-756) were investigated in detail. Drugs were administered intragastrically to fasted rats 30 min before 100% ethanol (1 ml) or acidified aspirin (10 mg/100 g), and mucosal lesions were measured planimetrically 1 hr later. Control rats receiving only ethanol had lesions involving 14.5% of the glandular mucosa. KT1-32, KT1-109, KT1-720, or KT1-756 (10 mg/100 g) reduced lesions to 0.7, 2.7, 1.8, or 0.7% of glandular stomach respectively. Aspirin-induced lesions involved 1.52% of the glandular mucosa and 10 mg/100 g of KT1-32, KT1-109, or KT1-720, or 2 mg/100 g of KT1-756 diminished the damage to 0.13, 0.02, or 0.04, or 0.00%, respectively. Indomethacin interfered with protection against ethanol by KT1-109, while the sulfhydryl alkylator N-ethylmaleimide abolished protection by both KT1-32 and KT1-109. Among the drugs investigated in detail, KT1-756 increased gastric acid output, while KT1-720 and KT1-756 significantly enhanced pepsin secretion. All four compounds studied in detail (ie, KT1-32, KT1-109, KT1-720, KT1-756) decreased the extent of vascular lesions in the gastric mucosa as revealed by monastral blue 1 min after ethanol. Thus, the mechanism of gastric mucosal protection by these novel aryl sulfhydryl compounds cannot be ascribed to an antisecretory effect, but may be related to prevention of vascular injury.
Octopine and nopaline Ti-plasmids confer upon Agrobacterium tumefaciens C58C1 the ability to respond chemotactically to the vir-inducing phenolic wound exudate, acetosyringone. A. tumefaciens C58C1 containing Ti-plasmids with Tn5 insertions in virB, C, D or E exhibited marked chemotaxis towards acetosyringone. However, Ti-plasmids with mutations in virA or virG were unable to confer the responsive phenotype. Of the cosmid clones pVK219 (virAB) pVK221 (virBGC) pVK225 (virGCDE) and pVK257 (virABGC) mobilized to cured A. tumefaciens C58C1, only pVK257 bestowed acetosyringone chemotaxis. virA and virG are thus required for chemotaxis of A. tumefaciens towards acetosyringone. This suggests a multifunctional role for virA and virG: at low concentrations of acetosyringone they mediate chemotaxis and at higher concentrations they effect vir-induction.
Neurophysiological measurements comprising surface electromyography (EMG) of the urethral and anal sphincters, measurement of the sensory thresholds of the dorsal nerve (DN) of the clitoris and the urethra and sacral reflex latencies from the dorsal nerve to urethra and anus and from the urethra to anus were performed in 44 females with genuine stress incontinence, in order to detect any relationship between the clinical disorder and a neurogenic defect in the innervation of the muscles involved in maintaining continence. Plain X-rays of the renal tracts (KUB films) were also studied to establish whether the prevalence of spina bifida occulta was increased in this group of patients and was a likely explanation for the nerve defects. Forty-three patients were found to have abnormal neurophysiological responses and the prevalence of spina bifida occulta was 50%, which compares with a prevalence of 17% in normal female controls. Genuine stress incontinence appears to be at least partly associated with defective innervation of the lower urinary tract and it is likely that in some cases the defect may be related to the presence of spina bifida occulta.
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The rates of adverse reproductive outcomes in 40 women with rheumatoid arthritis (RA) were compared with 67 of their unaffected female relatives. All women were aged between 35 and 65 years at the time of inquiry. Seven of the women with RA reported a perinatal death (six stillbirths, one early neonatal death) compared with one women in the unaffected group: estimated age adjusted relative risk (R) = 12.4, 95% confidence interval (95% CI) 1.6-91.1. The rate of spontaneous abortions was, however, not significantly different between the two groups (R = 1.2, 95% CI 0.5-2.9). All the perinatal deaths occurred before clinical disease onset in the women with RA. It is possible that in these two groups of women with a similar genetic background perinatal loss may be related, at least in part, to disease expression.
The heat-shock response of Legionella pneumophila was examined by radiolabelling bacterial cell proteins with [35S]methionine following a temperature shift from 30 to 42 degrees C. Five heat-shock proteins were identified as having molecular masses of 17, 60, 70, 78, and 85 kilodaltons (kDa). The 85- and 60-kDa proteins were equally distributed between supernatant and pellet fractions following ultracentrifugation at 100,000 x g, the 70- and 78-kDa proteins were found primarily in the supernatant, and the 17-kDa protein was found primarily in the pellet. Synthesis of subsets of the heat-shock proteins could be stimulated by novobiocin, patulin, or puromycin. Ethanol, an effector of the heat-shock response in other microorganisms, had little effect on L. pneumophila, even at the highest concentration tolerated by the bacterial cells (1.9%). Finally, the 60-kDa heat-shock protein of L. pneumophila was immunologically cross-reactive with a polyclonal antibody prepared to the Escherichia coli groEL protein. However, a mouse monoclonal antibody reactive with the 60-kDa protein of all legionellae tested did not cross-react with the E. coli groEL protein, suggesting that the Legionella 60-kDa protein contains common and unique epitopes.
The chronic and acute effects of different types of dietary fat on postprandial lipoprotein metabolism were studied in eight normolipidemic subjects. Each person was placed for 25 d on each of three isocaloric diets: a saturated fat (SFA), a w-6 polyunsaturated fat (w-6 PUFA) and a w-3 polyunsaturated fat (w-3 PUFA) diet. Two vitamin A-fat loading tests were done on each diet. The concentrations in total plasma and chylomicron (Sf greater than 1,000) and nonchylomicron (Sf less than 1,000) fractions of retinyl palmitate (RP) were measured for 12 h postprandially. Compared with the SFA diet, the w-6 PUFA diet reduced chylomicron and nonchylomicron RP levels 56 and 38%, respectively, and the w-3 PUFA diet reduced these levels 67 and 53%, respectively. On further analysis, the main determinant of postprandial lipoprotein levels was the type of fat that was chronically fed, which appeared to mediate its effect by changing the concentration of the endogenous competitor for the system that catabolizes triglyeride-rich lipoproteins. However, there was a significant effect of the acute dietary fat load, which appeared to be due to a differential susceptibility to lipolysis of chylomicrons produced by SFA as opposed to PUFA fat loads. The levels of postprandial lipoproteins are determined by the interaction of these chronic and acute effects.
The access of the homeless mentally ill to the benefits of psychiatric hospitalization has been excessively limited by deinstitutionalization, the devaluation of the benefits of inpatient evaluation and treatment, a shortage of public-sector psychiatric beds, and a tendency to regard the homeless mentally ill as untreatable. A pilot program was devised to increase the access of the homeless mentally ill to short-term hospital-based treatment within a public mental health system in which beds are in short supply. The program's usefulness demonstrates the value of hospital-based treatment for this population and suggests that hospital-based treatment is currently underutilized.
This study was designed to assess potential differences in ventilation homogeneity related to growth. One hundred thirty-three healthy subjects representing four stages of growth were studied: group 1, preschool, ages 34-74 months; group 2, preadolescent, ages 8-10 yr; group 3, postpubertal, ages 15-17 yr; group 4, young adult, ages 26-40 yr. Ventilation homogeneity was assessed by moment analysis of multibreath nitrogen washout with functional residual capacity, the ratio of the 1st to 0th moment (MR 1/0), and the ratio of the 2nd to 0th moment (MR 2/0) being the outcome variables of interest. Across the four groups functional residual capacity increased as a curvilinear function of height. At all heights functional residual capacity was larger in males than females and the slope of the regression was steeper in males than females (p less than 0.001). Both MRs 1/0 and 2/0 were significantly higher in group 1 than the other groups, indicating that ventilation washout was less homogeneous in the preschool subjects than in older children or adults. Males of group 1 had significantly higher values for both moment ratios (more ventilation nonuniformity) than females. In the other groups there were no significant sex based differences although there was a trend for males to have a lower MR 1/0 than females in the young adults, p = 0.08. The results indicate that both age and sex are important determinants of the growth of distribution of ventilation.
Insulin-like growth factor-I (IGF-I) is produced in multiple tissues and is believed to exert its action in a paracrine or autocrine fashion. We have investigated the GH dependency of tissue IGF-I gene expression in rats harboring implanted somatomammotropic tumors. Circulating GH and radioimmunoassayable IGF-I levels were markedly elevated in these animals. Hepatic IGF-I messenger RNA (mRNA) transcripts were induced about 5-fold in the tumor-bearing rats relative to control animals, and about 50-fold relative to the hypophysectomized liver IGF-I mRNA. IGF-I mRNA content was also modestly induced in the heart, muscle, and kidney of the tumor-bearing animals. IGF-I mRNA transcripts of 8.0, 6.2, 3.8, 2.4, 1.3, and 1.0 kilobases were markedly stimulated in the pituitaries of the GH-tumor bearing rats relative to control pituitaries. Pituitary IGF-I mRNA induction was maximal between 2 and 6 weeks after tumor implantation, a time at which circulating GH levels were also increasing sharply. As previously reported, pituitary GH mRNA was inhibited in tumor-bearing rats. The stimulation of pituitary IGF-I gene expression in these animals, therefore, appears to be dependent on circulating, and not local, pituitary GH concentrations. These data support the GH dependency of pituitary IGF-I gene expression. IGF-I is known to decrease GH production in vitro. High circulating levels of IGF-I present in these animals may account for the observed inhibition of GH gene expression. These data raise the alternative possibility that induction of locally produced IGF-I may contribute to this phenomenon.