Showing papers by "University of Texas Health Science Center at Houston published in 1982"

Patterns of Nucleotide Substitution in Pseudogenes and Functional Genes

Abstract: The pattern of point mutations is inferred from nucleotide substitutions in pseudogenes. The pattern obtained suggests that transition mutations occur somewhat more frequently than transversion mutations and that mutations result more often in A or T than in G or C. Our results are discussed with respect to the predictions from Topal and Fresco's model for the molecular basis of point (substitution) mutations (Nature 263:285–289, 1976). The pattern of nucleotide substitution at the first and second positions of codons in functional genes is quite similar to that in pseudogenes, but the relative frequency of the transition C→T in the sense strand is drastically reduced and those of the transversions C→G and G→C are doubled. The differences between the two patterns can be explained by the observation that in the protein evolution amino acid substitutions occur mainly between amino acids with similar biochemical properties (Grantham, Science 185:862–864, 1974). Our results for the patterns of nucleotide substitutions in pseudogenes and in functional genes lead to the prediction that both the coding and non-coding regions of protein coding genes should have high frequencies of A and T. Available data show that the non-coding regions are indeed high in A and T but the coding regions are low in T, though high in A.

The Effect of Treatment on Mortality in Mild Hypertension: Results of the Hypertension Detection and Follow-up Program

Abstract: In the Hypertension Detection and Follow-up Program, 7825 (71.5 per cent) of the 10,940 participants had diastolic blood pressures averaging between 90 and 104 mm Hg on entry into the study and were designated Stratum 1. Half were referred to their usual source of care in the community (the referred-care group), and half were treated intensively in special clinics (the stepped-care group). Five-year mortality in the Stratum 1 patients given stepped care was 20.3 per cent lower than in those given referred care (P less than 0.01). Particularly noteworthy was the beneficial effect of stepped-care treatment on persons with diastolic pressures of 90 to 104 mm Hg who had no evidence of end-organ damage and were not receiving antihypertensive medication when they entered the study. This subgroup had 28.6 per cent fewer deaths at five years among those treated with stepped care than among those treated with referred care (P less than 0.01). These findings support a recommendation that in patients with mild hypertension, treatment should be considered early, before damage to end organs occurs.

Experimental validation of quantitative coronary arteriography for determining pressure-flow characteristics of coronary stenosis.

Abstract: SUMMARY The applicability of classic fluid dynamic equations to tapering stenoses in vasoactive, flexible coronary arteries in vivo and the validity of quantitative coronary arteriography was tested by comparing experimentally measured and x-ray-predicted pressure gradients at equal flows for left circumflex stenoses in five dogs chronically instrumented with a balloon. occluder, flow probe, and proximal and distal catheters for.injection of contrast media or recording distal coronary pressure. Arterial borders on cut-film orthogonal arteriograms were digitized and computer processed into a three-dimensional reconstruction of the stenosis. The total pressure gradient was calculated from stenosis dimensions using classic fluid dynamic equations. Over the full range of flow, the correlation of x-ray-predicted and experimentally measured pressure gradient for 51 separate stenoses was y = 1.11x ± 0.75, r = 0.95, p < 0.001, with a standard deviation about the regression line of 9.4 mm Hg and with 95% of x-ray-predicted values falling within ± 18.5 mm Hg of the experimentally measured values (95.% confidence limits). Mean experimentally measured and x-ray-predicted pressure gradients were 10.1 7.7 mm Hg (± SD) and 10.9 ± 5.6 mmn Hg at low flow and 48.2 ± 23.1 mm Hg and 55.8 ± 28.8 mm Hg at high flow, respectively. The mean difference was 3.9 ± 4.3 mm Hg at rest flow and 11.9 ± 10.5 mm Hg at high flow. For all data over the entire range of flows, the frequency distribution of differences between x-ray-predicted and experimentally measured gradients was a bell-shaped curve with a peak, or mean difference, of ± 4 mm Hg, a standard deviation of ± 9.8 mm Hg and 95% confidence limits for individual values of ± 19.6 mm Hg. These data demonstrate the validity of applying classic fluid dynamic theory to tapering stenoses in vivo. Quantitative coronary arteriography on the average or in individual instances approximately predicts the pressure gradient-flow characteristics of coronary arterial stenoses in intact animals. However, as indicated by the above measures of variability, there is considerable scatter in x-ray predictions that limits its applicability to individual clinical cases. We believe that this scatter is a result of difficulties in visually tracing arterial borders on arteriograms and can most likely be reduced by automatic border recognition techniques.

Estimation of average number of nucleotide substitutions when the rate of substitution varies with nucleotide.

Abstract: A formal mathematical analysis of Kimura's (1981) six-parameter model of nucleotide substitution for the case of unequal substitution rates among different pairs of nucleotides is conducted, and new formulae for estimating the number of nucleotide substitutions and its standard error are obtained. By using computer simulation, the validities and utilities of Jukes and Cantor's (1969) one-parameter formula, Takahata and Kimura's (1981) four-parameter formula, and our sixparameter formula for estimating the number of nucleotide substitutions are examined under three different schemes of nucleotide substitution. It is shown that the one-parameter and four-parameter formulae often give underestimates when the number of nucleotide substitutions is large, whereas the six-parameter formula generally gives a good estimate for all the three substitution schemes examined. However, when the number of nucleotide substitutions is large, the six-parameter and four-parameter formulae are often inapplicable unless the number of nucleotides compared is extremely large. It is also shown that as long as the mean number of nucleotide substitutions is smaller than one per nucleotide site the three formulae give more or less the same estimate regardless of the substitution scheme used.

Familial renal cell carcinoma with a 3 ; 11 chromosome translocation limited to tumor cells

Abstract: Cytogenic studies were performed on the direct chromosome preparations of the renal cell carcinoma cells and the cultured peripheral blood lymphocytes of a patient with familial renal cell carcinoma. The results revealed a specific, acquired translocations (3p;11p) present in the majority of metaphases of the tumor, indicating that the development of renal cell carcinoma is associated with a deletion in the proximal end of 3p. Renal cell carcinoma is thus the third example--the first two being retinoblastoma and Wilms' tumor--of a chromosomal deletion occurring germinally or somatically in association with a specific tumor. This finding adds further support to the existence of specific human cancer genes.

Emergence of high-level trimethoprim resistance in fecal Escherichia coli during oral administration of trimethoprim or trimethoprim-sulfamethoxazole.

Abstract: The effect of daily administration of trimethoprim (TMP), trimethoprim–sulfamethoxazole (TMP-SMX), or placebo on aerobically grown fecal gram-negative bacteria was monitored in 136 students from the United States during a two-week diarrhea-prevention study in Mexico. Unlike patients in other studies with these agents, who had urinary-tract infection or granulocytopenia, most persons in this study had no change in total fecal Enterobacteriaceae and had high-level TMP and SMX resistance in virtually all these strains. Escherichia coli was the predominant TMP-resistant organism isolated; 96 per cent of 165 TMP-resistant Esch. coli isolates were resistant to at least four antimicrobial agents, and 25 per cent were resistant to seven. TMP resistance was transferable in 40 of 100 strains tested. Despite the lack of TMP resistance in other studies of prophylaxis, our results clearly demonstrate the remarkable capacity for emergence and dissemination of resistance to this agent. (N Engl J Med. 1982; 306:...

Human central nervous system distribution of cis-diamminedichloroplatinum and use as a radiosensitizer in malignant brain tumors

Abstract: The human central nervous system pharmacology of cis -diamminedichloroplatinum (CDDP) was studied, and trials were initiated of CDDP as a radiosensitizer in the treatment of malignant primary brain tumors. Samples were assayed for platinum using X-ray-dispersive fluorescence spectrometry. Platinum was barely detectable in cerebrospinal fluid from two patients and was not detectable ( Fifteen patients with malignant brain tumors received CDDP, 40 mg/sq m/week i.v., during cranial irradiation, and some received 105 to 120 mg/sq m every 3 weeks after cranial irradiation. Close follow-up was necessary, and some weekly treatments needed to be omitted in individual patients. During the weekly CDDP, gastrointestinal, scalp, and renal toxicities and hypomagnesemia were noted but were tolerable. Only one patient developed myelosuppression. Ototoxicity may have been enhanced. Postirradiation CDDP, 105 to 120 mg/sq m every 3 weeks, caused substantially more gastrointestinal toxicity and may have caused central nervous system toxicity in four patients, although other factors probably contributed. It is too early to evaluate effect on survival.

Treatment of travelers' diarrhea with trimethoprim/sulfamethoxazole and with trimethoprim alone.

Abstract: We conducted a double-blind treatment study of 110 adults from the United States who were attending summer classes in Guadalajara, Mexico, and had diarrhea (four or more unformed stools in 24 hours, or three or more unformed stools per eight-hour period plus one or more additional clinical indicators of enteric infection). Thirty-seven patients received trimethoprim/sulfamethoxazole (TMP/SMX) (160 mg of TMP and 800 mg of SMX), 38 were given TMP alone (200 mg), and 35 took a placebo twice daily for five days. By the end of the first 24 hours of treatment, patients taking either TMP/SMX or TMP alone passed fewer unformed stools than did patients given placebo (P = 0.0002 and P = 0.01, respectively). Abdominal pain and nausea were reduced in both treatment groups. The beneficial effect was seen in treatment of Escherichia coli-induced diarrhea, shigellosis, and diarrhea not associated with an enteropathogen. Five per cent of patients given TMP/SMX, 8 per cent of those given TMP, and 49 per cent of those given placebo were considered treatment failures (P less than 0.001 for both active drugs as compared with placebo). Early treatment with TMP/SMX or TMP is an alternative to prophylactic use of drugs for travelers' diarrhea.

Dopaminergic dysfunction in tourette syndrome

Abstract: A prospective clinical and biochemical study on the effects of treatment with haloperidol has been performed in seven patients with Tourette syndrome. Pretreatment cerebrospinal fluid levels of homovanillic acid (CSF HVA) were significantly reduce in all patients, whereas 5-hydroxyindoleacetic acid was reduced in only two. With haloperidol treatment, symptoms decreased in all cases (21 to 88%) and clinical improvement was associated with an increased level of CSF HVA, often returning to the normal range. Optimal therapeutic response was found with serum levels of haloperidol between 1 and 4 ng/ml; however, disturbing side effects also occurred within this range. These results support the hypothesis that Tourette syndrome may result from a supersensitivity of dopaminergic receptors.

Familial cavernous angiomas: Natural history and genetic study over a 5‐year period

Abstract: In a kindred of 122 individuals we found 5 individuals with cerebral vascular malformation, 3 representing typical cavernous angiomas. The condition was inherited as an autosomal dominant trait with variable expressivity. Forty-three relatives were examined prospectively by cranial computed tomography (CCT) and lesions were found in 15; 7 were followed prospectively with CCT scans for 5 years. Angiography in 5 of these cases failed to demonstrate the lesion. In 3 patients with previously normal CCT scans a change in blood volume or membrane permeability allowed visualization of the lesion on contrast scans. In 2 individuals, both parents of affected children, a normal CCT scan was found. This emphasizes the limitations of CCT in detecting this disorder. Biochemical and red blood cell immunological genetic linkage studies were done in 36 persons. No linkage was found with any of the markers. The natural history of this disorder, characterized by marked clinical and radiographic variation in site of lesion, and the timing and severity of intracranial hemorrhage, make it a useful model for investigating contributing factors and consequences of intracranial hemorrhage in general. For at-risk and affected patients early and sequential CCTs are necessary. Familial cavernous angioma should be included in the differential diagnosis of all young persons presenting with cerebrovascular impairment, seizures, intracranial calcifications or hemorrhage.

Risk of handling injectable antineoplastic agents

Abstract: Uptake of mutagenic substances by persons handling injectable antineoplastic agents was studied, and various methods of preventing such exposure were evaluated. Six persons who prepared i.v. admixtures individually collected their urine in 24-hour batches during several eight-day study periods; each prepared from 12 to 90 admixtures per working day during each period. I.V. personnel prepared admixtures in both horizontal laminar-flow hoods and vertical-flow biological-safety cabinets, and using gloves and masks. Three pharmacy personnel who did not handle any drugs served as controls. Urine was concentrated (each 24-hour sample was concentrated to about 1 ml), and the Salmonella/mammalian microsome mutagenicity test (Ames test) was used to detect mutagenic activity in the urine concentrates. Mutagenicity was observed in the urine of all personnel during periods when they prepared antineoplastic admixtures in horizontal laminar-flow hoods, both when using no protection and while wearing gloves or masks. When admixtures were prepared in the vertical-flow biological safety cabinet by personnel wearing gloves, no urine mutagenicity was detected. The control group showed no urine mutagenicity. Protective intervention methods should be used by all persons handling antineoplastic agents. Guidelines for handling these drugs are presented.

Human tissue distribution of platinum after cis-diamminedichloroplatinum.

Abstract: Using X-ray fluorescence spectrometry, platinum concentrations were determined in autopsy tissue samples from 12 patients who had received cis-diamminedichloroplatinum (DDP) 20-120 mg/m2 up to 6 months antemortem. Tissue platinum concentrations were highest in liver (0.5-3.7 micrograms/g wet weight), prostate (1.6-3.6 micrograms/g), and kidney (0.4-2.9 micrograms/g), somewhat lower in bladder, muscle, testicle, pancreas, and spleen, and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum, Platinum concentrations in tumors were generally somewhat lower than the concentration in the organ in which the tumor was located, with the exception of intracerebral tumors. Different metastatic sites in the same patient had substantially different platinum concentrations and hepatic metastases had the highest concentrations. Intra-arterial administration of drug may augment tissue concentrations of platinum. In a patient undergoing therapeutic abortion 4 days after treatment, the platinum concentration was 0.5 micrograms/g in the placenta and 0.3 micrograms/g in the fetus. The data suggest that for in vitro sensitivity testing, DDP concentrations of less than or equal to 7 micrograms/ml should be used.

The influence of sex hormones on antidepressant-induced alterations in neurotransmitter receptor binding

Abstract: Long term (21-day) treatment with antidepressants induces a decrease in beta-adrenergic and serotonin 2 (5-HT2) receptor binding in rat brain frontal cortex. Since hormone imbalances are known to be associated with affective illness, the present study was undertaken to determine whether sex hormones influence these alterations in neurotransmitter receptor binding. Using receptor binding assays, we found that castration abolishes the decline in the concentration of 5-HT2, but not beta-adrenergic, receptors brought on by chronic imipramine or iprindole treatment in both male and female rats. In contrast, the receptor responses to trazodone, mianserin, and pargyline were not influenced by surgery. Furthermore, mianserin was found to reduce beta-adrenergic binding in intact females, but not males, suggesting a sex-related specificity with regard to the response to this agent. Testosterone and estrogen, but not dihydrotestosterone, reversed the effects of castration in males, suggesting that the interaction between the steroids and antidepressants is mediated through estrogenic, rather than androgenic, receptors. The results indicate that the receptor responses to some antidepressant drugs is dependent, at least in part, on the hormonal state of the animals.

Physiological significance of coronary flow velocity and changing stenosis geometry during coronary vasodilation in awake dogs.

Abstract: In order to describe the mechanisms and significance of coronary flow velocity and increased stenosis severity during coronary vasodilation, we determined stenosis geometry by quantitative coronary arteriography in conscious dogs at resting and high coronary flows. The circumflex coronary artery was instrumented with a Doppler flow velocity transducer, periarterial balloon constrictor, and small implanted arterial catheters proximal and distal to the constrictor for contrast injection and pressure measurements. Biplane, orthogonal x-rays of coronary stenosis were taken in mid-diastole at resting and high coronary blood flow after intracoronary papaverine. Arterial borders on x-ray prints were outlined on a digitizing tablet and stenoses reconstructed in three dimensions by computer. Dimensions for each of 51 stenoses ranging from 45% to 78% diameter narrowing were compared before and after papaverine with three important findings: (1) There was no significant change in the minimum cross-sectional area or in exit outflow angle of the stenosis from resting to high coronary flow. Cross-sectional area of the normal artery proximal and distal to the stenosis increased significantly during high flow by 16% and 12%, respectively (P < 0.001), thereby causing diameter stenosis to increase from 68% to 71% (P < 0.001) associated with a 16% increase in the pressure gradient across the stenosis due solely to changes in stenosis geometry. These observations raise basic questions about how stenosis severity should be defined. (2) The cross-sectional area of the artery within the chronically implanted Doppler transducer increased by 32% with vasodilation despite perivascular scarring within the transducer observed at postmortem. Consequently, relative changes in coronary flow velocity were 30–40% less than changes in volume flow, thereby introducing a significant error in measuring relative coronary flow responses unless changes in arterial diameter were also determined.

Boundary lubrication imparted by pleural surfactants and their identification

Abstract: Phospholipids have been identified in pleural washings from live dogs and were found to include phosphatidylethanolamines, sphingomyelin, and, predominantly, phosphatidylcholines. The extracts were...

The natural history of resectable metastatic melanoma (Stage IVA melanoma).

Abstract: One-hundred-two patients with malignant melanoma who had distant metastases surgically resected and were judged to be clinically free of disease (M. D. Anderson Stage IVA melanoma) were studied. The median survival for all the patients from time of diagnosis of stage IVA disease was 18 months. The site of the resected metastases did not appear to influence survival, being approximately the same for the brain (15 months), lung (16 months), intraabdominal (18 months), and skin and/or lymph nodes (23 months). The site of the resected metastases also did not influence the median disease-free interval. Patients who had metastases resected from several organs at the same time had a median survival of 15 months, which was similar to that of patients with one resected site. Patients who were rendered Stage IVA on several occasions by surgical excisions had a median survival of 36 months. Thirty-five patients received surgery only and 67 patients received adjuvant chemotherapy, immunotherapy, or combined chemoimmunotherapy after surgery. For the group treated with surgery only, the median disease-free interval and survival from diagnosis of stage IVA disease were 6 months and 16 months, respectively, and for the adjuvant group 6 months and 21 months, respectively. Specifically, by the type of adjuvant therapy, the median disease-free interval and survival from stage IVA for 23 patients receiving Corynebacterium parvum were 6.9 and 19 months; for 39 patients receiving BCG, eight months and 26 months; for 24 patients receiving BCG + DTIC, eight and 17.4 months; and for all 51 DTIC treated patients 6.3 and 17.8 months, respectively. Patients receiving BCG had a median survival superior to the surgery only group (P = 0.02). An increase in survival was seen predominantly in patients who achieved IVA status more than once and received BCG. Patients with recurrent soft-tissue metastases appeared to benefit most from BCG in prolonging the disease-free interval. Only 1/10 treated by surgery alone had a disease-free interval longer than 1 year, compared with 9/16 who received BCG (P = 0.01). Stage IVA melanoma appears to be distinctly different in prognosis from Stage IVB melanoma and should be classified separately. Patients with recurrent soft-tissue disease may benefit significantly from treatment with BCG.

Genetic differentiation of quantitative characters between populations or species: I. Mutation and random genetic drift

Abstract: Introducing a new genetic model called the discrete allelic-state model, the evolutionary change of genetic variation of quantitative characters within and between populations is studied under the assumption of no selection. This model allows us to study the effects of mutation and random genetic drift in detail. It is shown that when the allelic effects on phenotype are additive, the rate of approach of the genetic variance within populations to the equilibrium value depends only on the effective population size. It is also shown that the distribution of genotypic value often deviates from normality particularly when the effective population size and the number of loci concerned are small. On the other hand, the interpopulational variance increases linearly with time, if the intrapopu-lational variance remains constant. Therefore, the ratio of interpopulational variance to intrapopulational variance can be used for testing the hypothesis of neutral evolution of quantitative characters.

Immunopharmacological monitoring of cyclosporin A-treated recipients of cadaveric kidney allografts.

Abstract: Twelve cadaveric kidney allograft recipients, who were established preoperatively to be strong responders, were treated with cyclosporin A (Cy A) and subjected to postoperative monitoring of drug levels and immune performances. The Cy A-treated recipients were compared with 72 historical (36 strong and 36 weak immune responders) and 18 current, strong responder, azathioprine-treated control patients. Estimation of Cy A levels in plasma and whole blood revealed that 75% of the drug at trough and 44% at peak was cell bound. Concomitant radioimmunoassay (RIA) and high performance liquid chromatography (HPLC) determinations on whole blood yielded concordant values. Trough levels above 200 ng/ ml in plasma and 600 ng/ml in whole blood were associated with toxic manifestations. Although absolute peak levels were not helpful, calculation of peak to trough ratios yielded values which when less than 3.0 predicted toxicity. Post-transplant immune monitoring showed administration of Cy A to be associated with fewer (1) rejection episodes; (2) nonspecific immune events; and (3) donor-specific in vitro reactions than were observed after treatment with azathioprine. Although the activity of peripheral blood mononuclear cells as natural killers of K562 target cells was not affected by Cy A treatment, their capacity to suppress the generation of a third-party mixed lymphocyte culture was enhanced to the same degree as cells from azathioprine-treated patients. Enumeration of peripheral blood lymphocyte T cell subpopulations using monoclonal xeonoantisera revealed (1) the total number of T cells to be unaffected by administration of either Cy A or azathioprine and (2) a reduction in the ratio of helper-inducer to suppressor-cytotoxic cells specificially in Cy A-treated recipients compared with normal individuals, hemodialysis patients, or azathioprine-treated recipients. Although pharmacological monitoring of blood levels may be useful to discern patients at high risk for toxic complications, the achievement of maximal therapeutic efficacy may depend upon identifying and quantitating the cellular target responsible for the disruption of immune homeostasis observed during Cy A administration.

A tonic gamma-aminobutyric acid-mediated inhibition of cholinergic amacrine cells in rabbit retina

Abstract: Using the in vivo rabbit eyecup, we have studied the light-evoked release of acetylcholine (ACh) which is presumed to indicate the activity of cholinergic amacrine cells. Gamma-Aminobutyric acid (GABA) inhibited the light-evoked release of ACh (IC50 congruent to 1 mM), but the GABA antagonists bicuculline (5 micro M) and picrotoxin (20 micro M) potentiated the light-evoked release and markedly increased the resting release of ACh. This bicuculline/picrotoxin-evoked release was calcium dependent and the effects of bicuculline, but not picrotoxin, were blocked by muscimol, a potent GABA agonist. Muscimol also inhibited the light-evoked release of ACh (IC50 less than 1 micro M) and was at least 1000 times more potent than GABA. Nipecotic acid (1 mM), a GABA transport blocker, also inhibited the light-evoked release of ACh, but the effect was slow in onset and recovery was prompt. We conclude that the cholinergic amacrine cells of rabbit retina are inhibited by GABA. The relatively weak action of GABA, compared to muscimol, may be due to the presence of avid GABA transport systems. We ascribe the excitatory effects of bicuculline and picrotoxin to the antagonism of endogenous GABA, suggesting that the cholinergic cells are influenced by a tonic release of GABA. This is consistent with the effects of nipecotic acid. Although we are unable to specify the synaptic arrangements involved, we suggest that the most likely interaction is directly between GABA amacrine cells and the cholinergic amacrine cells and/or their presumed bipolar cell inputs.

Bioaccumulation of lead and cadmium in the Royal Tern and Sandwich Tern.

Abstract: Lead and cadmium concentrations were measured in eggs and tissues of downy young, prefledgling, and adult Royal and Sandwich Terns collected from Galveston Bay, Texas. These species do not differ significantly in the amount of heavy metals they accumulate; however, they differed from other species of the same trophic level from Galveston Bay in degree and pattern of temporal accumulations of these metals. Lead levels were lower in terns, but cadmium levels in adult terns were higher than those of other species. The pre-fledglings of other species at this trophic level have lead and cadmium concentrations which are similar to those found in adults. In contrast, the concentrations of the metals in adult terns are markedly higher than those found in prefledgling terns. This suggests that accumulation of metals continues as the birds age.

Age dependent changes in retention in rats I

Abstract: These experiments examined the retention of newly acquired responses in 70-day-, 1-year-, and 2-year-old (Fischer 344) rats. In the first experiment, the rats were trained in a one-trial inhibitory (passive) avoidance task and retention performance was tested after training-test intervals ranging from 2 hrs to 6 weeks. When tested 2 hrs after training, 2-year-old rats performed significantly better than did 70-day-old rats. However, at longer intervals, the decline in retention performance (i.e., rate of forgetting) varied directly with age. Two-year-old rats exhibited more rapid loss of the avoidance response than did 70-day-old rats. One-year-old rats exhibited intermediate rates of forgetting. A second experiment examined retention performance tested 1, 7, or 21 days after training in a discriminated avoidance task. In this task as well, the rate of decline in retention performance varied directly with age. Thus, these findings suggest that aged Fischer 344 rats forget recently acquired inform...