Showing papers by "University of Colorado Denver published in 1991"

Survival in Patients with Primary Pulmonary Hypertension: Results from a National Prospective Registry

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.

A Single Intravenous Infusion of Gamma Globulin as Compared with Four Infusions in the Treatment of Acute Kawasaki Syndrome

Abstract: Background. Treatment of acute Kawasaki syndrome with a four-day course of intravenous gamma globulin, together with aspirin, has been demonstrated to be safe and effective in preventing coronary-artery lesions and reducing systemic inflammation. We hypothesized that therapy with a single, very high dose of gamma globulin would be at least as effective as the standard regimen. Methods. We conducted a multicenter, randomized, controlled trial involving 549 children with acute Kawasaki syndrome. The children were assigned to receive gamma globulin either as a single infusion of 2 g per kilogram of body weight over 10 hours or as daily infusions of 400 mg per kilogram for four consecutive days. Both treatment groups received aspirin (100 mg per kilogram per day through the 14th day of illness, then 3 to 5 mg per kilogram per day). Results. The relative prevalence of coronary abnormalities, adjusted for age and sex, among patients treated with the four-day regimen, as compared with those treated with...

Programmed cell death in the immune system.

Abstract: Publisher Summary This chapter discusses the mechanisms of programmed cell death (PCD). In many different examples of PCD, regardless of the cell type involved and regardless of the stimulus, the cells undergo similar biochemical and morphological events, and PCD often follows a final common pathway. Evidence for the existence of programmed cell death and cell death program is discussed. Programmed cell death is an old phenomenon that has awakened new interest. It can be demonstrated in various systems.. They all have in common nuclear disintegration, the morphology of apoptosis, DNA damage, and early recognition by phagocytic cells. It is likely that there is a death program that all cells follow when they embark on this pathway, even if the specific (or nonspecific) triggers are very different. There are various stages in a B cell's life when it risks undergoing a programmed death.

A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder.

Abstract: Background. In carcinoma of the bladder, both intravesical chemotherapy and immunotherapy can induce tumor regression and reduce the rate of recurrence, but the relative merits of these two therapies are unclear. We conducted a multi-institutional study to address this question. Methods. Patients with rapidly recurrent (stage Ta or T1) or in situ transitional-cell carcinoma of the bladder were randomly assigned to receive either doxorubicin administered intravesically or bacille Calmette–Guerin (BCG) administered both intravesically and percutaneously. The 262 eligible patients were followed for a median of 65 months. Complete responses to treatment of carcinoma in situ were confirmed by biopsy and cytologic analysis of the urine. Results. For patients with Ta and T1 tumors without carcinoma in situ, the estimated probability of being disease free at five years was 17 percent after doxorubicin, as compared with 37 percent after immunotherapy with BCG (P = 0.015). The median times to treatment fai...

Prehospital hypertonic saline/dextran infusion for post-traumatic hypotension. The U.S.A. Multicenter Trial.

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.

HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions.

Abstract: The hepatitis B virus (HBV) X gene product trans-activates viral and cellular genes. The X protein (pX) does not bind independently to nucleic acids. The data presented here demonstrate that pX entered into a protein-protein complex with the cellular transcriptional factors CREB and ATF-2 and altered their DNA binding specificities. Although CREB and ATF-2 alone did not bind to the HBV enhancer element, a pX-CREB or pX-ATF-2 complex did bind to the HBV enhancer. Thus, the ability of pX to interact with cellular factors broadened the DNA binding specificity of these regulatory proteins and provides a mechanism for pX to participate in transcriptional regulation. This strategy of altered binding specificity may modify the repertoire of genes that can be regulated by transcriptional factors during viral infection.

Identification of mRNAs associated with programmed cell death in immature thymocytes.

Abstract: Programmed cell death is an essential cellular process that occurs in epithelial turnover, neural development, and regulation of cell populations of the immune system Thymocytes undergo programmed cell death in response to several inductive stimuli, including exposure to glucocorticoids or radiation This program can be blocked by inhibitors of RNA or protein synthesis; this implies that new proteins are required to execute the death programs To search for possible death-associated mRNAs, we directionally cloned cDNA representing mRNA from control and dexamethasone-treated thymocytes These libraries were used to produce ample amounts of DNA and RNA used in subtractive hybridization for the removal of sequences present in both control and induced cells The remaining unhybridized sequences were selectively amplified by polymerase chain reaction and cloned to produce a library enriched for sequences expressed in death-induced cells From this library we isolated cDNAs of death-associated mRNAs One of these mRNAs, RP-8, appears within 1 h after exposure to gamma radiation, and a second mRNA, RP-2, is observed within 2 h Both of these mRNAs accumulate during a period when a reference mRNA, actin, is declining RP-2 and RP-8 are no longer detectable after 6 h postinduction, when apoptosis and mRNA degradation are evident in the culture Sequence analysis of RP-8 cDNA indicates the presence of a zinc finger domain suggestive of a possible DNA regulatory role for the RP-8 protein cDNA sequence results on RP-2 classify the corresponding protein as an integral membrane protein We conclude that RP-2 and RP-8 are death-associated mRNAs that should be functionally evaluated in the context of the death process As previously suggested, it may be that a family of "death genes" is activated by various stimuli depending on the type of cell, in a manner somewhat analogous to the induction of heat shock (stress) protein genes

Concussion in sports. Guidelines for the prevention of catastrophic outcome.

Abstract: Concussion (defined as a traumatically induced alteration in mental status, not necessarily with loss of consciousness) is a common form of sports-related injury too often dismissed as trivial by physicians, athletic trainers, coaches, sports reporters, and athletes themselves. While head injuries can occur in virtually any form of athletic activity, they occur most frequently in contact sports, such as football, boxing, and martial arts competition, or from high-velocity collisions or falls in basketball, soccer, and ice hockey. The pathophysiology of concussion is less well understood than that of severe head injury, and it has received less attention as a result. We describe a high school football player who died of diffuse brain swelling after repeated concussions without loss of consciousness. Guidelines have been developed to reduce the risk of such serious catastrophic outcomes after concussion in sports. (JAMA. 1991;266:2867-2869)

A Controlled Trial of Acyclovir for Chickenpox in Normal Children

Abstract: Background. Chickenpox, the primary infection caused by the Varicella Zoster virus, affects more than 3 million children a year in the United States. Although usually self-limited, chickenpox can cause prolonged discomfort and is associated with infrequent but serious complications. Methods. To evaluate the effectiveness of acyclovir for the treatment of chickenpox, we conducted a multi-center, double-blind, placebo-controlled study involving 815 healthy children 2 to 12 years old who contracted chickenpox. Treatment with acyclovir was begun within the first 24 hours of rash and was administered orally in a dose of 20 mg per kilogram of body weight four times daily for five days. Results. The children treated with acyclovir had fewer varicella lesions than those given placebo (mean number, 294 vs. 347; P<0.001), and a smaller proportion of them had more than 500 lesions (21 percent, as compared with 38 percent with placebo; P<0.001). In over 95 percent of the recipients of acyclovir no new lesion...

Screening for colorectal cancer.

Abstract: GOLORECTAL cancer is a leading cause of death from cancer in the United States, with approximately 140,000 new cases and 60,000 deaths per year.1 A 50-year-old person has about a 5 percent risk of having colorectal cancer by the age of 80 and a 2.5 percent risk of dying from it.2 To reduce the morbidity and mortality due to colorectal cancer, some professional organizations have proposed that asymptomatic persons without known risk factors be screened to detect cancer at a curable stage.3 4 5 The rationale for screening is based on the widely held view6 that most colorectal cancers are the product . . .

Mechanisms of gallstone formation in women : effects of exogenous estrogen (premarin) and dietary cholesterol on hepatic lipid metabolism

Abstract: Our aim was to define mechanisms whereby conjugated estrogens (Premarin, exogenous estrogen; Ayerst Laboratories, New York) increase the risk of developing cholesterol gallstones and to determine the role, if any, of dietary cholesterol. We studied gallbladder motor function, biliary lipid composition and secretion, cholesterol absorption, cholesterol synthesis and esterification by peripheral blood mononuclear cells, the clearance of chylomicron remnants, and bile acid kinetics in 29 anovulatory women. 13 were studied on both a low (443 +/- 119 mumol/d) and high (2,021 +/- 262 mumol/d) cholesterol diet. Premarin increased the lithogenic index of bile (P less than 0.05), increased biliary cholesterol secretion (P less than 0.005), lowered chenodeoxycholate (CDCA) pool (P less than 0.001) and synthesis (P less than 0.05), altered biliary bile acid composition [( CA + DCA]/CDCA increases, P less than 0.005), stimulated cholesterol esterification (P less than 0.03), and enhanced the clearance of chylomicron remnants (P = 0.07). Increases in dietary cholesterol stimulated the biliary secretion of cholesterol (P = 0.07), bile acid (P less than 0.05), phospholipid (P = 0.07), and as a result, did not alter lithogenic index. The reduction in CDCA pool and synthesis by Premarin was reversed by increasing dietary cholesterol. Off Premarin, only 24% of the increase in cholesterol entering the body in the diet was recovered as biliary cholesterol or newly synthesized bile acid. On Premarin, 68% of this increase in cholesterol was recovered as these biliary lipids. We conclude that Premarin increases biliary cholesterol by enhancing hepatic lipoprotein uptake and inhibiting bile acid synthesis. These actions of Premarin divert dietary cholesterol into bile.

Evidence for major gene transmission of developmental dyslexia

Abstract: Objective. —There is strong evidence that developmental dyslexia is both familial and heritable, but the mode of genetic transmission has remained unclear. In this article, we examine specific genetic hypotheses about the mode of transmission of developmental dyslexia by performing complex segregation analyses. Design. —A family study method was applied, whereby the relatives of dyslexic probands were examined for dyslexia. The families studied represent four independently ascertained samples. Setting. —The four samples of families were primarily from rural and suburban communities of Colorado, Washington State, and Iowa. Participants. — A total of 204 families and 1698 individuals in the four samples combined. Main Outcome Measures. —The complex segregation program, POINTER, was used to test competing genetic hypotheses of how a categorical trait (dyslexia) is transmitted in families. Results. —The results were consistent with major locus transmission in three of four samples and with polygenic transmission in the fourth. In these three samples, the estimates of penetrance for the AA, Aa , and aa genotypes (where A is the abnormal allele) were, respectively, 1.000, 1.000, and 0.001 to 0.039 in males, and 0.560 to 1.000, 0.550 to 0.897, and 0.000 in females. The estimated gene frequency of the major locus was between 3% and 5%. Conclusions. —Sex-influenced, additive, or dominant transmission occurs in a significant proportion of dyslexic families. Other evidence indicates, however, that dyslexia is etiologically heterogeneous and that there is genetic heterogeneity even among families selected for apparent dominant transmission. Thus, while no single major locus may account for all of dyslexia, it is important to pursue potential major loci for dyslexia using linkage techniques. (JAMA. 1991;266:1527-1534)

Role for cyclin A in the dependence of mitosis on completion of DNA replication.

Abstract: THE cyclins were first identified by their cell-cycle-dependent synthesis and destruction1–3 and have a key role in the control of mitosis in Xenopusembryonic cell cycles4–6. All higher eukaryotes have at least two types of cyclins, the A- and B-type, which can be distinguished by sequence motifs and the timing of their destruction in the cell cycle2,7–10. The degradation of both cyclins is required for exit from mitosis11, but the activation and destruction of cyclin A occur earlier in the cell cycle than with the B-type cyclins9–11. This suggests that cyclin A has a distinct role in cell-cycle progression. We have used an antisense oligodeoxy-nucleotide directed against cyclin A to investigate this role. Ablation of cyclin A messenger RNA in cytostatic factor/metaphase-arrested extracts of Xenopus eggs, followed by in vitro progression into interphase, resulted in the premature appearance of cyclin B/cdc2-associated H1 kinase activity and premature entry into mitosis. Although cyclin A-ablated extracts could initiate DNA synthesis during interphase, S phase was not completed before entry into mitosis. The effects of cyclin A ablation were reversed by the addition of cyclin A mRNA or cyclin A protein to the extracts.

The progression of erosion and joint space narrowing scores in rheumatoid arthritis during the first twenty-five years of disease.

Abstract: Erosions and cartilage destruction are nearly universal features in peripheral joints that have been chronically affected by rheumatoid arthritis. Scoring methods to measure the extent of these abnormalities in hands and wrists have been developed and have been thoroughly tested in several studies to establish their reproducibility. In this study, we utilized one of these scoring methods to examine the progression of radiologic damage as related to duration of disease. Two hundred ninety-two patients from 3 different participating centers in the Arthritis, Rheumatism, and Aging Medical Information System were included. Six hundred fifty films of the hands and wrists, obtained from 210 patients, were scored for erosions and joint space narrowing. The average annual rate of progression of the total radiologic score, which sums erosion and joint space abnormalities and has a maximum possible score of 314, was approximately 4 units per year over the first 25 years after onset; this progression was more rapid in the earlier years of disease and slightly slower in the later years. Data were insufficient to accurately determine the progression rate in disease of more than 25 years duration.

A review of cognitive teaching models

Abstract: The purpose of this article is to review from an instructional-design (ID) perspective nine teaching programs developed by cognitive psychologists over the last ten years. Among these models, Collins' cognitive apprenticeship model has the most explicit prescriptions for instructional design. In the article, the cognitive apprenticeship model is analyzed, then components of the model are used as an organizing framework for understanding the remaining models. Differences in approach are noted between traditional ID prescriptions and the cognitive teaching models. Surprisingly, no design strategies were found to be common to all the model programs. Key differences among programs included: (1) problem solving versus skill orientation, (2) detailed versus broad cognitive task analysis, (3) learner versus system control, and (4) error-restricted versus error-driven instruction. The article concludes with an argument for the utility of continuing dialogue between cognitive psychologists and instructional designers.

Cyclin B in Xenopus oocytes: implications for the mechanism of pre-MPF activation.

Abstract: Using a polyclonal antibody raised against B2 cyclin from Xenopus laevis, we show that prophase-arrested Xenopus oocytes contain a stockpile of cyclin B2 protein. During progesterone-induced maturation, an increase in the synthesis of cyclin B2 is observed, although Western blotting experiments show that this new synthesis does not significantly increase the mass of cyclin over the maternal stockpile. In the oocyte cyclin B2 is already present in two forms which differ in the extent of phosphorylation, but the phosphorylated form becomes predominant as oocytes progress towards germinal vesicle breakdown (GVBD), coincident with cdc2 protein kinase activation. These two events do not depend upon formation of a new complex between cyclin and cdc2 protein kinase, since these two proteins are already found associated in resting oocytes, prior to activation of the kinase.

Efficacy of Statewide Neonatal Screening for Cystic Fibrosis by Assay of Trypsinogen Concentrations

Abstract: Background To evaluate the feasibility and efficacy of measuring immunoreactive trypsinogen in blood to screen for cystic fibrosis, we performed this test in 279,399 newborns in Colorado from 1982 to 1987 Methods Immunoreactive trypsinogen was measured in dried blood spots when the infants were 1 to 4 days old; if the level was elevated (≥140 μg per liter), the measurement was repeated (mean age, 38 days); if the level was again elevated, sweat testing was performed (mean age, 49 days) For the second test, two cutoff levels (120 and 80 μg per liter) were evaluated Results We found an incidence of cystic fibrosis of 1 in 3827 (026 per 1000), with 32 newborns per 1000 requiring repeat measurement When adjusted for race and compliance with testing, the incidence among the white infants (1 in 2521) was close to the expected incidence The false positive rate with the initial cutoff level (922 percent) was similar to the rate found in neonatal screening programs for other diseases False neg

Cytochrome Oxidase Deficiency in Alzheimer's Diseasea

Abstract: Alzheimer's disease (AD) is a degenerative neurologic disorder that may be familial but is usually sporadic and not easily analyzable in terms of conventional Mendelian genetics. The mitochondrial electron transport chain contains 13 proteins that are encoded by mitochondrial genes rather than nuclear (chromosomal) genes. Disorders resulting from heteroplasmic mutations of mitochondrial genes may appear to be sporadic rather than familial. We evaluated electron transport chain activity in platelet mitochondria prepared from patients with AD and found a specific defect in cytochrome oxidase in five of six patients studied. The mitochondrial genome may play a role in the pathogenesis of AD.

Dissociation and redistribution of Na+,K(+)-ATPase from its surface membrane actin cytoskeletal complex during cellular ATP depletion.

Abstract: Establishment and maintenance of a polar distribution of Na+,K(+)-ATPase is essential for efficient Na+ reabsorption by proximal tubule cells and is dependent upon the formation of a metabolically stable, detergent-insoluble complex of Na+,K(+)-ATPase with the actin membrane cytoskeleton. The present studies show that cellular ATP depletion results in a rapid duration-dependent dissociation of Na+,K(+)-ATPase from the actin cytoskeleton and redistribution of Na+,K(+)-ATPase to the apical membrane. During ATP depletion, total cellular Na+,K(+)-ATPase activity was unaltered, but the Triton-X-100-insoluble fraction (cytoskeleton associated) of Na+,K(+)-ATPase activity decreased (P less than 0.01), with a corresponding increase in the detergent-soluble fraction of Na+,K(+)-ATPase (P less than 0.01). Indirect immunofluorescent studies of cells with depleted ATP revealed a redistribution of Na+,K(+)-ATPase from the basolateral membrane into the apical membrane and throughout the cytoplasm. ATP depletion also resulted in the redistribution of F-actin from a primarily cortical concentration to a perinuclear location. There was also a rapid, duration-dependent conversion of monomeric G-actin to F-actin starting during the first 5 min of ATP depletion. Taken together, these data suggest that ATP depletion causes profound alterations in cell polarity by inducing major changes in the actin cytoskeletal architecture.

Hyperthermia Induces Apoptosis in Thymocytes

Abstract: Mild hyperthermia (43 degrees C for 1 h) induces extensive double-stranded DNA fragmentation and, at a later time, cell death in murine thymocytes. The cleavage of DNA into oligonucleosome-sized fragments resembles that observed in examples of apoptosis including radiation-induced death of thymocytes. Following hyperthermia, incubation at 37 degrees C is necessary to detect DNA fragmentation, although protein and RNA synthesis do not seem to be required. Two protein synthesis inhibitors, cycloheximide and emetine, and two RNA synthesis inhibitors, actinomycin D and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, do not inhibit DNA fragmentation or cell death in heated thymocytes at concentrations which significantly block these effects in irradiated thymocytes. We have used this difference in sensitivity to show that the DNA fragmentation induced in thymocytes which are irradiated and then heated seems to be caused only by the heating and not by the irradiation.