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Showing papers by "University of Texas Health Science Center at Houston published in 1991"


Journal ArticleDOI
TL;DR: Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure, mean right atrial pressure, and cardiac index.
Abstract: Objective To characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival. Design Registry with prospective follow-up. Setting Thirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart, Lung, and Blood Institute. Patients Patients (194) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988. Measurements At diagnosis, measurements of hemodynamic variables, pulmonary function, and gas exchange variables were taken in addition to information on demographic variables, medical history, and life-style. Patients were followed for survival at 6-month intervals. Main results The estimated median survival of these patients was 2.8 years (95% Cl, 1.9 to 3.7 years). Estimated single-year survival rates were as follows: at 1 year, 68% (Cl, 61% to 75%); at 3 years, 48% (Cl, 41% to 55%); and at 5 years, 34% (Cl, 24% to 44%). Variables associated with poor survival included a New York Heart Association (NYHA) functional class of III or IV, presence of Raynaud phenomenon, elevated mean right atrial pressure, elevated mean pulmonary artery pressure, decreased cardiac index, and decreased diffusing capacity for carbon monoxide (DLCO). Drug therapy at entry or discharge was not associated with survival duration. Conclusions Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure, mean right atrial pressure, and cardiac index. Such an equation, once validated prospectively, could be used as an adjunct in planning treatment strategies and allocating medical resources.

3,301 citations


Journal ArticleDOI
TL;DR: Two new indexes are developed: the first quantitates rapid shallow breathing as the ratio of respiratory frequency to tidal volume (f/VT), and the second is termed CROP, because it integrates thoracic compliance, respiratory ṟate, arterial oxygenation, and P1max.
Abstract: Background. The traditional predictors of the outcome of weaning from mechanical ventilation — minute ventilation (VE) and maximal inspiratory pressure (P1max) — are frequently inaccurate. We developed two new indexes: the first quantitates rapid shallow breathing as the ratio of respiratory frequency to tidal volume (f/VT), and the second is termed CROP, because it integrates thoracic compliance, respiratory ṟate, arterial oxygenation, and P1max. Methods. The threshold values for each index that discriminated best between a successful and an unsuccessful outcome of weaning were determined in 36 patients, and the predictive accuracy of these values was then tested prospectively in an additional 64 patients. Sensitivity and specificity were calculated, and the data were also analyzed with receiver-operating-characteristic (ROC) curves, in which the proportions of true positive results and false positive results are plotted against each other for a number of threshold values of an index; the area...

1,093 citations


Journal ArticleDOI
TL;DR: Investigation of the ability of two depression scales to identify cases of DSM-III-R major depression and dysthymia in a large, community sample of high school students indicates that neither the BDI nor the CES-D should be used by themselves as methods for case ascertainment in either epidemiological or experimental studies.
Abstract: The ability of two depression scales, the Center for Epidemiologic Studies Depression Scale (CES-D) and the Beck Depression Inventory (BDI), to identify cases of DSM-III-R major depression and dysthymia was investigated in a large, community sample of high school students. Receiver operating characteristics analyses indicated that different caseness criteria should be used for boys and girls for both the CES-D and the BDI. Internal consistency-reliability and sensitivity and specificity for detecting current episodes of current depression and dysthymia were adequate and comparable to those found with adult samples, but both the CES-D and the BDI generated many false positives. Multiple screening using the "serial" strategy increased positive predictive power substantially for both the CES-D and the BDI, whereas using the "parallel" strategy had very little effect on the efficacy of the two screeners. The results indicate that neither the BDI nor the CES-D should be used by themselves as methods for case ascertainment in either epidemiological or experimental studies, although the BDI does function somewhat better than the CES-D as a screener.

863 citations


Journal ArticleDOI
TL;DR: Doctors pursue a less aggressive management approach to coronary disease in women than in men, despite greater cardiac disability in women, when differences were adjusted for important covariates.
Abstract: Background. Despite the fact that coronary artery disease is the leading cause of death among women, previous studies have suggested that physicians are less likely to pursue an aggressive approach to coronary artery disease in women than in men. To define this issue further, we compared the care previously received by men and women who were enrolled in a large postinfarction intervention trial. Methods. We assessed the nature and severity of anginal symptoms and the use of antianginal and anti-ischemic interventions before enrollment in the 1842 men and 389 women with left ventricular ejection fractions ≤40 percent after an acute myocardial infarction who were randomized in the Survival and Ventricular Enlargement trial. Results. Before their index infarction, women were as likely as men to have had angina and to have been treated with antianginal drugs. However, despite reports by women of symptoms consistent with greater functional disability from angina, fewer women had undergone cardiac catheterizati...

858 citations


Journal ArticleDOI
TL;DR: The prevalence of epilepsy in Rochester, Minnesota has been determined for a specific date in each of 5 decennial census years since 1940, and was highest in the oldest age groups after 1950.
Abstract: Summary: : The prevalence of epilepsy in Rochester, Minnesota has been determined for a specific date in each of 5 decennial census years. Individuals with a diagnosis of epilepsy (recurrent unprovoked seizures) who were known to have experienced a seizure or who had received antiepileptic medication in the preceding 5 years were considered active prevalence cases. By this definition, the age-adjusted prevalence per 1,000 population, increased steadily from 2.7 in 1940 to 6.8 in 1980. At each of five prevalence dates, for all prevalence cases, 60% had epilepsy manifest by partial seizures, and 75% had no known etiology. Prevalence was higher for males than females for all except the last prevalence day. After 1950, prevalence tended to increase with advancing age and was highest in the oldest age groups. On the average, the 1980 prevalence cases had epilepsy 50% had their first diagnosis in the first 20 years of life. RESUME La prevalence de ľ epilepsie dans le Comtede Rochester, dans le Minnesota, a eteevaluee pour une date precise de chacune des 5 annees du recensement decennal. Les individus pour lesquels le diagnostic ďepilepsie avait ete pose (crises spontanees recurrentes) et qui avaient presente une crise ou recevaient un traitement antiepileptiques dans les 5 annees precedentes, ont ete consideres comme des cas de prevalence active. Selon cette definition, la prevalence ajustee pour Page pour 1000 habitants a agumente constamment de 2.7 en 1940 a 6.8 en 1980. A chacune des 5 dates de prevalence, pour tous les cas, 60% ont presente une epilepsie se manifestant par des crises partielles, et 75% n'avaient pas ďetiologie connue. La prevalence teAait plus elevee chez les hommes que chez les femmes, sauf lors du dernier jour de prevalence. Apres 1950, la prevalence tendait a augmenter avec ľâge, elle etait la plus forte dans les groupes ďâge eleve En moyenne, les cas de 1980 avaient une epilepsie evoluant depuis moins de 10 ans et plus de 50% avaient une epilepsie diagnos-tiquee au cours des 20 premieres annees de vie. RESUMEN Se ha determinado la prevalencia de epilepsyia en Rochester, Minnesota, para una fecha especifica en cada uno de los 5 dece-nios del censo. Individuos con diagnostico de epilepsia “ataques recurrentes sin provocacion” que habian tenido un ataque o recibido medicateon antiepileptica en los 5 anos precedentes, fueron considerados como casos activos de prevalencia. Segun esta definition la prevalencia ajustada a la edad por 1.000 habitantes se incremento continuadamente de 2.7 en 1940 a 6.8 en 1980. En cada una de las 5 fechas de prevalencia para todos los casos prevalentes, el 60% tenia epilepsyia manifestada por ataques parciales y el 75% de etiologia desconocida. La prevalencia fue mas elevada en varones que en hembras en todos los dias de prevalencia excepto el ultimo. Despues de 1950 la prevalencia mostro una tendencia al aumento con incremento de la edad y fue mas elevada en los grupos de mayor edad. Como promedio, los casos de prevalencia en 1980 habian padecido epilepsyia durante menos de 10 anos y mas del 50% tuvieron el primer diagnostico en los primeros 20 anos de su vida. ZUSAMMENFASSUNG Die Praevalenz der Epilepsie in Rochester, Minnesota wurde an einem bestimmten Datum in funf aufeinanderfolgenden Cen-sus-Decenien bestimmt. Personen mit der Diagnose Epilepsie (wiederholte nicht provozierte Anfalle), die einene Anfall erlitten hatten oder Antiepileptika eingenommen hatten wurden als ak-tive Praevalenz-Falle betrachtet. Demnach stieg die altersberei-nigte Praevalenz fur 1000 Einwohner kontinuierlich von 2,7 1940 auf 6,8 1980 an. Zu jedem der funf Praevalenz-Daten aller Praevalenz-Falle manifestierte sich die Epilepsie in 60% durch Partialanfalle, davon 75% ohne bekannte Atiologie. Die Praevalenz war fur Manner hoher als fur Frauen wahrend aller Stichtage, ausgenommen des letzten. Nach 1950 stieg die Praevalenz mit zunehmendem Alter leicht an und erreichte ihren hochsten Wert in der altesten Altersgruppe. Im Durchschnitt hatten 1980 die Praevalen-Falle eine Epilepsie fur weniger als 10 Jahre. Bei mehr als 50% wurde die Erstdiagnose Epilepsie in den ersten 20 Le-bensjahren gestellt.

784 citations


Journal ArticleDOI
TL;DR: The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk, and the dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocy topenia.
Abstract: A novel deoxycytidine analog, gemcitabine (2',2'-difluorodeoxycytidine [dFdC]), has been studied in a phase I clinical and pharmacology trial. Doses ranging from 10 to 1,000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose (MTD) was 790 mg/m2. The dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Nonhematologic toxicity was minimal. Two responses in patients with adenocarcinomas of the colon and lung were documented. The maximum dFdC plasma concentration, reached after 15 minutes of infusion, was proportional to the total dose administered. Elimination, due mainly to deamination, was rapid (terminal half-life [t1/2], 8.0 minutes) and dose independent. The deamination product 2',2'-difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2, 14 hours); it was the sole metabolite detected in urine. The concentration of dFdC 5'-triphosphate in circulating mononuclear cells increased in proportion to the dFdC dose at infusions between 35 and 250 mg/m2. No further increment in dFdC 5'-triphosphate (dFdCTP) was observed at higher doses, which resulted in plasma dFdC concentrations greater than 20 mumol/L (350 to 1,000 mg/m2), suggesting saturation of dFdC 5'-phosphate accumulation. The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk.

730 citations


Journal ArticleDOI
TL;DR: Article de synthese sur l'adaptation cellulaire (assimilation du glucose), moleculaire (flux d'oxygene; enzymes glycolytiques) des muscles squelettiques en reponse a un exercice (aerobique, exercice de resistance).
Abstract: Article de synthese sur l'adaptation cellulaire (assimilation du glucose) et moleculaire (flux d'oxygene; enzymes glycolytiques) des muscles squelettiques en reponse a un exercice (aerobique, exercice de resistance). Utilisation de plusieurs modeles animaux (vertebres), de cultures cellulaires et comparaison avec l'activite physique humaine. Synthese sur les adaptations affectant le flux cardiaque, le flux sanguin peripherique et le petabolisme des myocytes cardiaques

708 citations


Journal ArticleDOI
Earl A. Palmer1, John T. Flynn2, Robert J. Hardy3, Dale L. Phelps4  +181 moreInstitutions (24)
TL;DR: The timing of retinal vascular events correlated more closely with postconceptional age than with postnatal age, implicating the level of maturity more than postnatal environmental influences in governing the timing of these vascular events.

613 citations


Journal Article
TL;DR: Comparison of the average excesses by a method of repeated sampling with random permutations revealed no significant difference in effects among populations, indicating that a given apo E allele acts in a relatively uniform manner in different populations despite differences in genetic background and environmental factors.
Abstract: Application of uniform methods for measuring the apolipoprotein (apo) E polymorphism and plasma cholesterol levels in nine populations (Tyrolean, Sudanese, Indian, Chinese, Japanese, Hungarian, Icelandic, Finnish, and Malay) revealed significant heterogeneity among them in apo E type frequencies and mean cholesterol levels The major apo E types in all populations were E3/2 (frequency range from 70% in Indians to 169% in Malays), E3/3 (frequency range from 398% in Sudanese to 721% in Japanese), and E3/4 (frequency range from 113% in Japanese to 359% in Sudanese) Mean cholesterol levels ranged from 1442 mg/dl in the Sudanese to 2285 mg/dl in the Icelandics Two-way analysis of variance of the effect of population and apo E type on cholesterol levels showed no significantly interaction effect, indicating that the effects of apo E type on cholesterol levels do not differ significantly among the populations The overall average excess for the epsilon 2 allele was -1412 mg/dl (range -3163 to -882 mg/dl); for the epsilon 3 allele, 004 mg/dl (range -187 to 158 mg/dl; and for the epsilon 4 allele, 814 mg/dl (range -171 to 1331 mg/dl) Despite the apparent heterogeneity in these values, especially for the epsilon 4 allele, comparison of the average excesses by a method of repeated sampling with random permutations revealed no significant difference in effects among populations These data indicate that a given apo E allele acts in a relatively uniform manner in different populations despite differences in genetic background and environmental factors

525 citations


Journal ArticleDOI
01 Oct 1991-Genetics
TL;DR: The nucleotide diversity in humans is very low, probably due to a relatively small long-term effective population size rather than any severe bottleneck during human evolution.
Abstract: The nucleotide diversity (pi) in humans is studied by using published cDNA and genomic sequences that have been carefully checked for sequencing accuracy. This measure of genetic variability is defined as the number of nucleotide differences per site between two randomly chosen sequences from a population. A total of more than 75,000 base pairs from 49 loci are compared. The DNA regions studied are the 5' and 3' untranslated regions and the amino acid coding regions. The coding regions are divided into nondegenerate sites (i.e., sites at which all possible changes are nonsynonymous), twofold degenerate sites (i.e., sites at each of which one of the three possible changes is synonymous) and fourfold degenerate sites (i.e., sites at which all three possible changes are synonymous). The pi values estimated are, respectively, 0.03 and 0.04% for the 5' and 3' UT regions, and 0.03, 0.06 and 0.11% for nondegenerate, twofold degenerate and fourfold degenerate sites. Since the highest pi value is only 0.11%, which is about one order of magnitude lower than those in Drosophila populations, the nucleotide diversity in humans is very low. The low diversity is probably due to a relatively small long-term effective population size rather than any severe bottleneck during human evolution.

481 citations


Journal ArticleDOI
TL;DR: Although this trial demonstrated trends supportive of HSD in hypotensive hemorrhagic shock patients requiring surgery, a larger sample size will be required to establish which subgroups of trauma patients might maximally benefit from the prehospital use of a small volume of hyperosmolar solution.
Abstract: The safety and efficacy of 7.5% sodium chloride in 6% dextran 70 (HSD) in posttraumatic hypotension was evaluated in Houston, Denver, and Milwaukee. Multicentered, blinded, prospective randomized studies were developed comparing 250 mL of HSD versus 250 mL of normal crystalloid solution administered before routine prehospital and emergency center resuscitation. During a 13-month period, 422 patients were enrolled, 211 of whom subsequently underwent operative procedures. Three hundred fifty-nine patients met criteria for efficacy analysis, 51% of whom were in the HSD group. Seventy-two per cent of all patients were victims of penetrating trauma. The mean injury severity score (19), Trauma Score plus Injury Severity Score (TRISS) probability of survival, revised trauma scores (5.9), age, ambulance times, preinfusion blood pressure, and etiology distribution were identical between groups. The total amount of fluid administered, white blood cell count, arterial blood gases, potassium, or bicarbonate also were identical between groups. The HSD group had an improved blood pressure (p = 0.024). Hematocrit, sodium chloride, and osmolality levels were significantly elevated in the Emergency Center. Although no difference in overall survival was demonstrated, the HSD group requiring surgery did have a better survival (p = 0.02), with some variance among centers. The HSD group had fewer complications that the standard treatment group (7 versus 24). A greater incidence of adult respiratory distress syndrome, renal failure, and coagulopathy occurred in the standard treatment group. No anaphylactoid nor Dextran-related coagulopathies occurred in the HSD group. Although this trial demonstrated trends supportive of HSD in hypotensive hemorrhagic shock patients requiring surgery, a larger sample size will be required to establish which subgroups of trauma patients might maximally benefit from the prehospital use of a small volume of hyperosmolar solution. This study demonstrates the safety of administering 250 mL 7.5% HDS to this group of patients.

Journal ArticleDOI
TL;DR: The results suggest that in the normal population, the level of plasma Lp(a), a cholesterol-rich lipoprotein that is distinguished by its content of a glycoprotein called apolipop protein, is largely determined by alleles at the apo(a) locus.
Abstract: Lipoprotein(a) [Lp(a)] is a cholesterol-rich lipoprotein that is distinguished by its content of a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) varies in size among individuals owing to different numbers of cysteine-rich sequences that are homologous to kringle 4 of plasminogen. The genetic basis for this variation is not understood at the genomic level. In this study we used pulsed-field gel electrophoresis and genomic blotting to identify a highly polymorphic restriction fragment from the apo(a) gene. The fragment contains multiple tandem repeats of a kringle 4-encoding sequence and varies in length from 48 to 190 kb depending on the number of kringle 4-encoding sequences. A total of 19 different alleles were identified among 102 unrelated Caucasian Americans. 94% of individuals studied had two different alleles which could be distinguished by size on pulsed-field gel electrophoresis. The degree of size heterogeneity was much greater than had been previously appreciated based on the analysis of the apparent molecular mass of the protein. The size of the apo(a) gene correlated directly with the size of the apo(a) protein, and inversely with the concentration of Lp(a) in plasma. Segregation analysis of the apo(a) gene was performed in families; siblings with identical apo(a) genotypes had similar plasma levels of Lp(a). These results suggest that in the normal population, the level of plasma Lp(a) is largely determined by alleles at the apo(a) locus.

Journal ArticleDOI
TL;DR: It is shown that there is considerable heterogeneity of the Lp(a) polymorphism among populations, that differences in apo( a) allele frequencies alone do not explain the differences in Lp (a) levels among populations and that in some populations, e.g. Sudanese Blacks, Lp-a levels are mainly determined by factors that are different from the apo-a) size polymorphism.
Abstract: Apolipoprotein(a) [apo(a)] exhibits a genetic size polymorphism explaining about 40% of the variability in lipoprotein(a) [Lp(a)] concentration in Tyroleans. Lp(a) concentrations and apo(a) phenotypes were determined in 7 ethnic groups (Tyrolean, Icelandic, Hungarian, Malay, Chinese, Indian, Black Sudanese) and the effects of the apo(a) size polymorphism on Lp(a) levels were estimated in each group. Average Lp(a) concentrations were highly significantly different among these populations, with the Chinese (7.0mg/dl) having the lowest and the Sudanese (46mg/dl) the highest levels. Apo(a) phenotype and derived apo(a) allele frequencies were also significantly different among the populations. Apo(a) isoform effects on Lp(a) levels were not significantly different among populations. Lp(a) levels were however roughly twice as high in the same phenotypes in the Indians, and several times as high in the Sudanese, compared with Caucasians. The size variation of apo(a) explains from 0.77 (Malays) to only 0.19 (Sudanese) of the total variability in Lp(a) levels. Together these data show (I) that there is considerable heterogeneity of the Lp(a) polymorphism among populations, (II) that differences in apo(a) allele frequencies alone do not explain the differences in Lp(a) levels among populations and (III) that in some populations, e.g. Sudanese Blacks, Lp(a) levels are mainly determined by factors that are different from the apo(a) size polymorphism.

Journal ArticleDOI
20 Jun 1991-Nature
TL;DR: The phylogenetic analyses of amino-acid sequence data imply that the guinea-pig diverged before the separation of the primates and the artiodactyls from the myomorph rodents (rats and mice), which would represent an early divergence in eutherian radiation.
Abstract: THE guinea-pig (Caviaporcellus), traditionally classified as a New World hystricomorph rodent, often shows anomalous morphological and molecular features in comparison with other eutherian mammals1–14. For example, its insulin differs from that of other mammals in anabolic and growth-promoting activities and in its capability to form hexamers5,6. Indeed, the literature about the molecular evolution of guinea-pigs abounds in references to 'convergent evolution', 'extremely rapid rates of substitution', and 'unique evolutionary mechanisms'. These claims are based on the assumption that the guinea-pig is a rodent. Our phylogenetic analyses of amino-acid sequence data, however, imply that the guinea-pig diverged before the separation of the primates and the artiodactyls from the myomorph rodents (rats and mice). If true, then the myomorphs and the caviomorphs do not constitute a natural clade, and the Caviomorpha (or the Histricomorpha) should be elevated in taxonomical rank and regarded as a separate mammalian order distinct from the Rodentia. If, as suggested by recent data15,16, the myomorphs branched off before the divergence among the carnivores, lagomorphs, artiodactyls and primates, then the new order would represent an early divergence in eutherian radiation.

Journal ArticleDOI
TL;DR: This efficacy study demonstrates the feasibility of substantially modifying school lunches and school physical education to improve children's diet and physical activity behavior at school.
Abstract: BACKGROUND: National health objectives call for improved diet and more regular physical activity among children. We tested the effects of a school-based program to improve students' diet and physical activity behavior at school. METHODS: Two of the four elementary schools in one Texas school district were assigned to intervention and two to control conditions. The three intervention components were classroom health education, vigorous physical education, and lower fat, lower sodium school lunches. Nutrients from school lunches and the total day and the amount of physical activity students obtained during physical education were assessed as outcome. RESULTS: Analysis of school lunches showed declines from base line to posttest in the two intervention schools of 15.5% and 10.4% for total fat, 31.7% and 18.8% for saturated fat, and 40.2% and 53.6% for sodium; posttest values were lower in the intervention schools. Observation of physical activity during physical education classes indicated an increase in the...

Journal ArticleDOI
TL;DR: In general, low-dose antihypertensive drug therapy (with chlorthalidone or atenolol) improves rather than impairs the quality of life; however, chl Forthalidone with usual diet increases sexual problems in men.
Abstract: Objective: To evaluate treatment of mild hypertension using combinations of diet and low-dose pharmacologic therapies. Design: Multicenter, randomized, placebo-controlled clinical trial. Setting: T...

Journal ArticleDOI
TL;DR: It is demonstrated that BSP and osteocalcin are only expressed in differentiated osteoblasts and that most of the major non‐collagenous bone proteins associate with the bone mineral, however, some novel proteins together with some of the BSP are associated with the collagenous matrix where they can influence hydroxyapatite formation.
Abstract: The nature and tissue distribution of non-collagenous bone proteins synthesized by adult rat bone marrow cells, induced to differentiate in the presence of dexamethasone (DEX) and β-glycerophosphate (β-GP), was studied in vitro to determine the potential role of these proteins in bone formation. Northern hybridization analysis revealed a strong induction of bone sialoprotein (BSP) and osteocalcin in DEX-treated cultures, whereas the constitutive expression of secreted phosphoprotein I (SPP-1), type I collagen, SPARC, and alkaline phos-phatase was stirnulated 6-, 5-, 3-, and 2.5- fold, respectively. Metabolic labeling of proteins showed that the sialoproteins (SPP-1 and BSP) were mostly secreted into the culture medium in the non-mineralizing (-β-GP) cultures, but were the predominant non-collagenous proteins associated with the hydroxyapatite of the bone nodules in mineralizing cultures (+β-GP). Extraction of the tissue matrix with 4 M GuHCI and digestion of the demineralized tissue matrix with bacterial collagenase revealed that some BSP was also associated non-covalently and covalently with the collagenous matrix. SPP-1 was present in two distinct, 44 kDa and 55 kDa, forms in the conditioned medium of all cultures and was preferentially associated with the hydroxyapatite in the mineralizing cultures. In comparison, SPARC was abundant in culture media but could not be detected in de-mineralizing extracts of the mineralized tissue. Radiolabeling with [35SO4] demonstrated that both SPP-1 and BSP synthesized by bone cells are sulfated, and that a 35 kDa protein and some proteoglycan were covalently associated with the collagenous matrix in +DEX cultures. Labeling with [32PO4] was essentially confined to the sialoproteins; the 44 kDa SPP-1 incorporating significantly more [32PO4] than the 55 kDa SPP-1 and the BSP. These studies demonstrate that BSP and osteocalcin are only expressed in differentiated osteoblasts and that most of the major non-collagenous bone proteins associate with the bone mineral. However, some novel proteins together with some of the BSP are associated with the collagenous matrix where they can influence hydroxyapatite formation.

Journal Article
TL;DR: To improve carrier detection and prenatal diagnosis for Duchenne and Becker muscular dystrophy families, allele frequencies and measures of variation for four (dC-dA)n.(dG-dT)n loci identified within a deletion-prone region of the human dystrophin gene are determined.
Abstract: To improve carrier detection and prenatal diagnosis for Duchenne and Becker muscular dystrophy families, we determined allele frequencies and measures of variation for four (dC-dA)n.(dG-dT)n loci identified within a deletion-prone region of the human dystrophin gene. The loci are highly polymorphic, with predicted heterozygosities of 71.6%-93.3%. Direct DNA sequence analysis of the (dC-dA)n.(dG-dT)n locus in intron 49 revealed an additional length polymorphism which varies by single-basepair increments, is adjacent to the dinucleotide repeat block, and enhances the polymorphic content of this marker. The four (dC-dA)n.(dG-dT)n loci are each easily amplified by PCR in two diplex reactions. The variability of allele lengths at these loci makes them ideal for carrier detection and prenatal diagnosis, often providing diagnostic information when RFLP analysis is uninformative. These markers have aided in identification of deletion mutations, exclusion of maternal cell contamination of chorionic villus samples, confirmation of paternity, and mapping of gene recombinations. The allele identification of these loci can be performed either with a radiolabel or with an automated, nonradioactive, fluorescent gel detection system.

Journal ArticleDOI
TL;DR: It is hypothesized that light phototoxicity may be playing an expressive role in this point mutation of the rhodopsin gene, the first report in which a type of retinitis pigmentosa has been associated with a specific molecular gene defect, although the actual pathophysiologic mechanism currently is unknown.
Abstract: • A cytosine-to-adenine transversion in codon 23 of rhodopsin, the rod visual pigment gene, was reported recently by Dryja et al in 17 of 148 unrelated patients with autosomal dominant retinitis pigmentosa, but the clinical findings associated with this deletion have not been reported in detail. In screening our patients with autosomal dominant retinitis pigmentosa for the codon 23 transversion, we found positive results in four affected individuals from two families with sectoral retinitis pigmentosa, while 12 patients with sectoral retinitis pigmentosa from different families had negative results, suggesting that other gene sites or locations may give this same phenotypic change. From our patients' history of light exposure and the location of degeneration in the retina, we hypothesize that light phototoxicity may be playing an expressive role in this point mutation of the rhodopsin gene. This is the first report in which a type of retinitis pigmentosa has been associated with a specific molecular gene defect, although the actual pathophysiologic mechanism currently is unknown.

Journal ArticleDOI
TL;DR: Electrophoretic analysis of triplex formation indicates that specific TFOs bind to their target sites with apparent dissociation constants in the 10(-7)-10(-9) M range, which is consistent with a structure in which the TFO binds in the major groove of double-stranded DNA to form a three-Stranded complex that is superficially similar to previously described triplexes.
Abstract: A class of triplex-forming oligodeoxyribonucleotides (TFOs) is described that can bind to naturally occurring sites in duplex DNA at physiological pH in the presence of magnesium. The data are consistent with a structure in which the TFO binds in the major groove of double-stranded DNA to form a three-stranded complex that is superficially similar to previously described triplexes. The distinguishing features of this class of triplex are that TFO binding apparently involves the formation of hydrogen-bonded G.GC and T.AT triplets and the TFO is bound antiparallel with respect to the more purine-rich strand of the underlying duplex. Triplex formation is described for targets in the promoter regions of three different genes: the human c-myc and epidermal growth factor receptor genes and the mouse insulin receptor gene. All three sites are relatively GC rich and have a high percentage of purine residues on one strand. DNase I footprinting shows that individual TFOs bind selectively to their target sites at pH 7.4-7.8 in the presence of millimolar concentrations of magnesium. Electrophoretic analysis of triplex formation indicates that specific TFOs bind to their target sites with apparent dissociation constants in the 10(-7)-10(-9) M range. Strand orientation of the bound TFOs was confirmed by attaching eosin or an iron-chelating group to one end of the TFO and monitoring the pattern of damage to the bound duplex DNA. Possible hydrogen-bonding patterns and triplex structures are discussed.

Journal ArticleDOI
TL;DR: Factors other than mitotic activity may influence tumor radiosensitivity, and one of these may be susceptibility to induction of apoptosis (programmed cell death), because this was a prominent early radiation response by the radiosensitive OCaI tumors.
Abstract: Early radiation responses of transplantable murine ovarian (OCaI) and hepatocellular (HCaI) carcinomas were examined at 6, 24, 48, 96, and 144 h after single photon doses of 25, 35, or 45 Gy. Previous studies using tumor growth delay and tumor radiocurability assays had shown OCaI tumors to be relatively radiosensitive and HCaI tumors to be radioresistant. At 6 h, approximately 20% of nuclei in OCaI tumors showed aberrations characteristic of cell death by apoptosis. This contrasted to an incidence of 3% in HCaI tumors. Mitotic activity was eliminated in OCaI tumors but was only transiently suppressed in HCaI tumors. At 24-96 h, OCaI tumors continued to display apoptosis and progressive necrosis, whereas HCaI tumors responded by exhibiting marked pleomorphism. Factors other than mitotic activity may influence tumor radiosensitivity, and one of these may be susceptibility to induction of apoptosis (programmed cell death), because this was a prominent early radiation response by the radiosensitive OCaI tumors.

Journal ArticleDOI
TL;DR: The high frequency of Native American-derived genes in the contemporary Hispanic population predict a higher frequency of non-insulin-dependent diabetes mellitus (NIDDM) under the assumption that genes are important in NIDDM etiology.
Abstract: The purpose of this article was to characterize the origins of the United States Hispanic population and discuss the implications of these origins in the context of diabetes risk. Particular attention was focused on the genetic origins of the three major U.S. Hispanic groups, i.e., Mexican Americans, Puerto Ricans, and Cubans. The U.S. Census figures provided basic demographic information. Genetic marker data for ancestral populations were taken from a review of the literature and compendia. Genetic marker data for the Puerto Rican and Cuban populations were extracted from the literature. Genetic markers determined on ∼ 1000 randomly selected Mexican Americans from Starr County, Texas, were taken as representative of the Mexican-American population. The Hispanic population is the second largest and fastest growing minority in the U.S. Estimates of the Hispanic population in 1988 indicated some 19.4 million residents, of whom 62% were classified as Mexican, 13% as Puerto Rican, and the remaining 25% as Cubans and others. Various lines of evidence can be used to characterize the Hispanic population and its origins. These include ethnohistory, self-assessment of ancestry, surname distributions, speech and cultural characteristics, quantitative traits, and genetic structure. Genetic data were used to estimate the contribution of putative ancestral populations to the contemporary gene pool. For Mexican Americans, 31% of the contemporary gene pool is estimated to be Native American derived, whereas 61 and 8% are Spanish and African derived, respectively. In Puerto Rico, the percentage of contributions of Spanish, Native American, and African admixture to the population are 45, 18, and 37%, respectively. For Cuba, the parallel estimates are 62, 18, and 20%. The high frequency of Native American-derived genes in the contemporary Hispanic population predict a higher frequency of non-insulin-dependent diabetes mellitus (NIDDM) under the assumption that genes are important in NIDDM etiology. Our results are consistent with the finding of the significant role of genes in determining risk.

Journal ArticleDOI
01 Dec 1991-Genomics
TL;DR: Linkage mapping in a large, seven-generation family with type 2 autosomal dominant retinitis pigmentosa (ADRP) demonstrates linkage between the disease locus (RP1) and DNA markers on the short arm of human chromosome 8, and mutations at two different loci, at least, have been shown to cause ADRP.

Journal ArticleDOI
TL;DR: The findings illustrate the value of pulsed-field gel electrophoresis for epidemiologic analyses and support the importance of identifying and containing organisms with new resistance properties in an effort to decrease their transmission to and from, as well as within, hospitals.
Abstract: Beta-lactamase-producing (Bla+) enterococci have been reported in three state and two countries. Pulsed-field gel electrophoresis was used to compare 14 Bla+ Enterococcus (Streptococcus) faecalis isolated from hospitalized patients in seven states and three continents. The restriction endonuclease digestion patterns of isolates from Connecticut, Massachusetts, Lebanon, and Argentina were all markedly different, indicating that these were different strains. However, isolates from Delaware, Texas, Pennsylvania (Philadelphia and Pittsburgh), Florida, and Virginia were similar, indicating that these isolates were derivatives of a single strain. This conclusion was supported by hybridization using individual fragments as probes. Spread of Bla+ enterococci within the hospital setting was also demonstrated. These findings illustrate the value of pulsed-field gel electrophoresis for epidemiologic analyses and support the importance of identifying and containing organisms with new resistance properties in an effort to decrease their transmission to and from, as well as within, hospitals.

Journal ArticleDOI
TL;DR: There appears to be a relationship between the time of prenatal drug exposure and the type of cerebral anomaly, evoking malformations, disruptions, or fetal strokes.
Abstract: • We describe 10 infants with developmental delay and congenital cerebral anomalies who were found to have had in utero exposure to vasoactive drugs. Nine infants had ophthalmological abnormalities; these included strabismus, nystagmus, and/or hypoplastic optic discs. Six mothers used cocaine, one used cocaine and heroin, one used only heroin, one used amphetamine, and one used phenylpropanolamine. Each of these cerebral anomalies (agenesis of the corpus callosum, septo-optic dysplasia, schizencephaly, hydranencephaly, congenital hydrocephalus, porencephaly, and cerebral infarctions) can be attributed to insults at different stages of development. There appears to be a relationship between the time of prenatal drug exposure and the type of cerebral anomaly, evoking malformations, disruptions, or fetal strokes. Since many or possibly all of these anomalies are thought to have a vascular origin, it seems appropriate to implicate prenatal exposure to vasoactive drugs. ( AJDC . 1991;145:688-695)

Journal ArticleDOI
TL;DR: The results suggest that CBCDA given at 400 mg/m2 or 450 mg/ m2 every 4 weeks is marginally active in patients with recurrent malignant gliomas and since hematologic toxicity is mild, a higher dose could possibly be given, and may increase the response rate.
Abstract: Thirty patients with recurrent malignant glioma were treated with intravenous (IV) carboplatin (CBDCA) every 4 weeks at a starting dose of 400 mg/m2 escalating to 450 mg/m2. All patients had documented recurrent tumor after prior radiotherapy but had not received prior chemotherapy. Of 29 assessable patients, four (14%) responded to the treatment for 44, 51+, 72, and 91 weeks; 10 (34%) achieved stable disease (S); while 15 (52%) had progressive disease (P). The total response (responses plus S) rate was 48%, with a median time to progression (MTP) of 26 weeks in these patients; the MTP for all 29 patients was 11 weeks. The toxic effects were mainly hematologic, with thrombocytopenia and granulocytopenia being mild at 400 mg/m2 and 450 mg/m2 doses. NO neurotoxicity or renal toxicity was encountered. These results suggest that CBCDA given at 400 mg/m2 or 450 mg/m2 every 4 weeks is marginally active in patients with recurrent malignant gliomas. Since hematologic toxicity is mild, a higher dose could possibly be given, and may increase the response rate.

Journal Article
TL;DR: DNA from both normal and tumor tissue from WT patients is analyzed and a patient with bilateral WT who is heterozygous for a small germinal deletion within this candidate gene is reported, supporting the identification of this locus as an 11p13 WT gene (WT1) and providing direct molecular data supporting the two-hit mutational model for WT.
Abstract: The inactivation of two alleles at a locus on the short arm of chromosome 11 (band 11p13) has been suggested to be critical steps in the development of Wilms tumor (WT), a childhood kidney tumor. Two similar candidate WT cDNA clones (WT33 and LK15) have recently been identified on the basis of both their expression in fetal kidney and their location within the smallest region of overlap of somatic 11p13 deletions in some tumors. These homozygous deletions, however, are large and potentially affect more than one gene. Using a cDNA probe to the candidate gene, we have analyzed DNA from both normal and tumor tissue from WT patients, in an effort to detect rearrangements at this locus. We report here a patient with bilateral WT who is heterozygous for a small (less than 11 kb) germinal deletion within this candidate gene. DNA from both tumors is homozygous for this intragenic deletion allele, which, by RNA-PRC sequence analysis, is predicted to encode a protein truncated by 180 amino acids. These data support the identification of this locus as an 11p13 WT gene (WT1) and provide direct molecular data supporting the two-hit mutational model for WT.

Journal ArticleDOI
TL;DR: Patellar complications following total knee arthroplasty (TKA) systems should include instrumentation that allows precise restoration of overall patellar thickness while maintaining a bony patella thickness of at least 15 mm.
Abstract: Patellar complications following total knee arthroplasty (TKA) have begun to emerge as a major cause of failure. In an effort to understand some of the mechanical factors that might contribute to patellar component failure, a biomechanical study was performed. Quadriceps force and anterior patellar strain were measured during dynamic flexion in 10 fresh, paired human cadaver knee joints. First, tests were performed in the intact knee, followed by either posterior cruciate ligament (PCL) retention or sacrifice of TKA without patellar resurfacing. Tests were then performed following patellar resurfacing with an overly thick, optimum and thin, bony patella. Patellar strain increased in each specimen (with flexion angles of up to 80°), was most pronounced as the bony patella became thinner, was closest to the intact knee when the patella was not resurfaced, and was unaffected by PCL retention or sacrifice. Patellar osteotomy, resulting in a bony patellar thickness of less than 15 mm, resulted in significantly increased strain. TKA systems should include instrumentation that allows precise restoration of overall patellar thickness while maintaining a bony patellar thickness of at least 15 mm.

Journal ArticleDOI
TL;DR: Seven mongrel dogs were chronically instrumented for the measurement of aortic and left ventricular blood pressures, cardiac output,left ventricular wall thickening, left Ventricular dP/dt, and circumflex coronary, renal, hepatic and portal blood flows under the influence of desflurane and isoflurane.
Abstract: Seven mongrel dogs were chronically instrumented for the measurement of aortic and left ventricular blood pressures, cardiac output, left ventricular wall thickening, left ventricular dP/dt, and circumflex coronary, renal, hepatic and portal blood flows under the influence of desflurane (D) and isoflurane (I). Administration of the two anesthetics, was randomized, as was the order of the concentrations administered. Each dog was studied awake and at 1.2, 1.4, 1.75, and 2.0 MAC of each anesthetic on different days. Both anesthetics decreased mean arterial pressure, stroke volume, systemic vascular resistance, left ventricular dP/dt, and wall thickness. The decreases were dose-dependent for mean arterial pressure (percent of awake values: D 78, I 85 at 1.2 MAC, and D 67, I 69 at 2.0 MAC); stroke volume (D 66, I 72 at 1.2 MAC, and D 52, I 57 at 2.0 MAC); dP/dt (D 61, I 64 at 1.2 MAC, and D 46, I 49 at 2.0 MAC); and WT (D 68, I 70 at 1.2 MAC, and D 47, I 60 at 2.0 MAC). Systemic vascular resistance decreased approximately the same at 1.2 MAC (D 71, I 87%) as at 2.0 MAC (D 71, I 79%). Heart rate increased but also not in a dose-dependent fashion (percent of awake values: D 177, I 145 at 1.2 MAC, and D 176, I 155 at 2.0 MAC). Coronary blood flow was increased by both anesthetics at all concentrations (percent of awake values: I 136 at 1.2 MAC and 161 at 2.0 MAC of awake, and D 131 at 1.2 MAC and 138 at 2.0 MAC.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal ArticleDOI
TL;DR: SPP-1 and BSP are the major osteoblast-derived bone proteins to bind to the bone mineral, demonstrating that these proteins associate with preformed mineral crystals.
Abstract: To determine the relationship between the expression of bone proteins and the formation of mineralized-tissue matrix, the biosynthesis of non-collagenous bone proteins was studied in cultures of fetal-rat calvarial cells, which form mineralized nodules of bone-like tissue in the presence of beta-glycerophosphate. The temporal pattern of protein synthesis in both mineralizing and non-mineralizing cultures was studied by metabolic labelling with [35S]methionine, 35SO4(2-) or 32PO4(3-) over a 5-day period. After a 24 h labelling period, the culture media were harvested and the cell layers extracted sequentially with aq. 0.5 M-NH3, followed by 4 M-guanidinium chloride (GdmCl), 0.5 M-EDTA and a second extraction with 4 M-GdmCl. Protein associated with collagenous bone matrix was analysed after digestion with bacterial collagenase. On the basis of [35S]methionine labelling, the major proteins extracted from the mineralizing matrix were secreted phosphoprotein-1 (SPP-1; osteopontin), bone sialoprotein (BSP) and a 14 kDa phosphoprotein. The presence of SPP-1 and BSP in the conditioned media of both mineralizing and non-mineralizing cultures and their incorporation into the mineralizing nodules indicated that these proteins associate with preformed mineral crystals. However, some BSP was also present in GdmCl extracts and, together with a 35 kDa sulphated protein, was released from a bacterial-collagenase digestion of the tissue residue in both non-mineralizing and mineralizing cultures. Two forms of sulphated SPP-1 were identified, a highly phosphorylated 44 kDa species being the predominant form in the mineralized matrix. The BSP was more highly sulphated but less phosphorylated than SPP-1. Bone SPARC (secreted protein, acid and rich in cysteine) protein (osteonectin) was present almost entirely in the conditioned media and did not incorporate 32PO4(3-) or 35SO4(2-). The SPP-1 and the 14 kDa protein were susceptible to thrombin digestion, the 44 kDa SPP-1 being specifically cleaved into 28 and 26 kDa fragments. The fragments were labelled uniformly with [35S]methionine, but the 28 kDa fragment incorporated more 35SO4(2-), but less 32PO4(3-), than the 26 kDa fragment. These studies demonstrate that SPP-1 and BSP are the major osteoblast-derived bone proteins to bind to the bone mineral. That BSP also binds to the collagenous bone matrix indicates a potential role for this protein in linking the hydroxyapatite with collagen.