Showing papers by "University of Colorado Denver published in 1989"

A controlled trial of leuprolide with and without flutamide in prostatic carcinoma.

Abstract: To test the hypothesis that maximal androgen blockade improves the effectiveness of the treatment of prostatic cancer, we conducted a randomized, double-blind trial in patients with disseminated, previously untreated prostate cancer (stage D2). All 603 men received leuprolide, an analogue of gonadotropin-releasing hormone that inhibits the release of gonadotropins, in combination with either placebo or flutamide, a nonsteroidal antiandrogen that inhibits the binding of androgens to the cell nucleus. As compared with the 300 patients receiving leuprolide and placebo, the 303 patients randomly assigned to receive leuprolide and flutamide had a longer progression-free survival (16.5 vs. 13.9 months; P = 0.039) and an increase in the median length of survival (35.6 vs. 28.3 months; P = 0.035). The differences between the treatments were particularly evident for men with minimal disease and good performance status; however, further studies should be conducted in this subgroup. Symptomatic improvement was greatest during the first 12 weeks of the combined androgen blockade, when leuprolide alone often produces a painful flare in the disease. We conclude that in patients with advanced prostate cancer, treatment with leuprolide and flutamide is superior to treatment with leuprolide alone.

Abnormalities of the electron transport chain in idiopathic parkinson's disease

Abstract: Idiopathic Parkinson's disease may have a low-level familial association but does not follow mendelian patterns of inheritance Since inheritance of some components of the electron transport chain is nonmendelian and since inhibition of the electron transport chain with the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine models Parkinson's disease in humans and animals, we evaluated catalytic activities of the electron transport chain in platelet mitochondria purified from patients with idiopathic Parkinson's disease All 10 patients studied had significant reductions of complex I (NADH:ubiquinone oxidoreductase) activity Succinate:cytochrome c oxidoreductase activity was less strikingly reduced We hypothesize that the complex I abnormality may have an etiological role in the pathogenesis of Parkinson's disease and that this defect may be derived via the mitochondrial genome

Mechanics of stimulated neutrophils: cell stiffening induces retention in capillaries

Abstract: The effect of peptide chemoattractants on neutrophil mechanical properties was studied to test the hypothesis that stimulated neutrophils (diameter, 8 micrometers) are retained in pulmonary capillaries (5.5 micrometers) as a result of a decreased ability of the cell to deform within the capillary in response to the hydrodynamic forces of the bloodstream. Increased neutrophil stiffness, actin assembly, and retention in both 5-micrometer pores and the pulmonary vasculature were seen in response to N-formyl-methionyl-leucyl-phenylalanine. These changes were abolished in cells that had been incubated with 2 micromolar cytochalasin D, an agent that disrupts cellular actin organization. A monoclonal antibody directed at the CD11-CD18 adhesive glycoprotein complex did not inhibit the increase in stiffness or retention in pores. These data suggest that neutrophil stiffening may be both necessary and sufficient for the retention that is observed. Hence, neutrophil sequestration in lung and other capillaries in the acute inflammatory process may be the result of increased stiffness stimulated by chemoattractants.

Sulindac for polyposis of the colon.

Abstract: The effect of sulindac, a nonsteroid antiinflammatory drug, on colon polyposis has been evaluated in seven patients after subtotal colectomy and ileoproctostomy and in four patients with intact colons. The patients all had Gardner's syndrome or familial polyposis coli. All polyps were eliminated, except for a few that arose in the rectal mucosa and the anal canal. No cancers developed in these patients on follow-up.

Treatment of pulmonary hemangiomatosis with recombinant interferon alfa-2a.

Abstract: PULMONARY hemangiomatosis is a rare, fatal disorder characterized by diffuse microvascular proliferation within the lung. The disease most often affects children and young adults and usually progresses rapidly, causing death from pulmonary hypertension or bleeding. Most cases have been diagnosed at autopsy. Corticosteroids and cyclophosphamide have been used for this condition, but no successful therapy has been described. We describe a patient with pulmonary hemangiomatosis who presented with digital clubbing and bilateral interstitial pulmonary disease. After a decline in the patient's exercise tolerance, therapy with interferon alfa-2a was initiated and has been continued for 14 months at the time of . . .

Dephosphorylation and activation of Xenopus p34cdc2 protein kinase during the cell cycle.

Abstract: GENETIC studies in the fission yeast Schizosaccharomyces pombe have established that a critical element required for the G2-→ M-phase transition in the cell cycle is encoded by the cdc2+ gene1–5. The product of this gene is a serine/threonine protein kinase, designated p34cdc2, that is highly conserved functionally from yeast to man2 and has a relative molecular mass of 34,000 (34 K). Purified maturation-promoting factor (MPF) is a complex of p34cdc2 and a 45K substrate that appears in late G2 phase and is sufficient to drive cells into mitosis6–9. This factor has been identified in all eukaryotic cells10,11, and in vitro histone H1 is the preferred substrate for phosphorylation7,9,12. The increase in the activity of HI kinase in M-phase is associated with a large increase in total cell protein phosphorylation which is believed to be a consequence of MPF activation13–18. We show here that the HI kinase activity of p34cdc2 oscillates during the cell cycle in Xenopus, and maximal activity correlates with the dephosphorylated state of p34cdc2. Direct inactivation of MPF in vitro is accompanied by phosphorylation of p34cdc2 and reduction of its protein kinase activity.

Endotoxin pretreatment increases endogenous myocardial catalase activity and decreases ischemia-reperfusion injury of isolated rat hearts

Abstract: Hearts isolated from rats pretreated 24 hr before with endotoxin had increased myocardial catalase activity, but the same superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase activities, as hearts from untreated rats. Hearts isolated from rats pretreated with endotoxin 24 hr before also had increased myocardial function (decreased injury) after ischemia and reperfusion (Langendorff apparatus, 37 degrees C), as assessed by measurement of ventricular developed pressure, contractility (+dP/dt), and relaxation rate (-dP/dt), compared to control hearts. In contrast, hearts isolated from rats pretreated with endotoxin 1 hr before isolation or hearts perfused with endotoxin did not have increased catalase activity or decreased injury following ischemia and reperfusion. Aminotriazole pretreatment prevented increases in myocardial catalase activity and myocardial function after ischemia-reperfusion in hearts from endotoxin-pretreated rats. The results suggest that endotoxin pretreatment decreases cardiac ischemia-reperfusion injury and that increases in endogenous myocardial catalase activity contribute to protection.

Mammalian growth-associated H1 histone kinase: a homolog of cdc2+/CDC28 protein kinases controlling mitotic entry in yeast and frog cells.

Abstract: Mammalian growth-associated H1 histone kinase, an enzyme whose activity is sharply elevated at mitosis, is similar to cdc2+ protein kinase from Schizosaccharomyces pombe and CDC28 protein kinase from Saccharomyces cerevisiae with respect to immunoreactivity, molecular size, and specificity for phosphorylation sites in H1 histone. Phosphorylation of specific growth-associated sites in H1 histone is catalyzed by yeast cdc2+/CDC28 kinase, as shown by the in vitro thermal lability of this activity in extracts prepared from temperature-sensitive mutants. In addition, highly purified Xenopus maturation-promoting factor catalyzes phosphorylation of the same sites in H1 as do the mammalian and yeast kinases. The data indicate that growth-associated H1 kinase is encoded by a mammalian homolog of cdc2+/CDC28 protein kinase, which controls entry into mitosis in yeast and frog cells. Since H1 histone is known to be an in vivo substrate of the mammalian kinase, this suggests that phosphorylation of H1 histone or an H1 histone counterpart is an important component of the mechanism for entry of cells into mitosis.

Methods and prevalence of non-insulin-dependent diabetes mellitus in a biethnic colorado population the san luis valley diabetes study

Abstract: The San Luis Valley Diabetes Study was undertaken to determine the prevalence, risk factors, and complications of non-insulin-dependent diabetes mellitus in Hispanics and Anglos (non-Hispanic whites), using a geographically based case-control design. The study was conducted in two southern Colorado counties that include 43.6% Hispanic and 54.9% Anglo persons. Medical practice records were reviewed to identify medically diagnosed diabetics. Controls without diabetes were identified by a two-stage random sample of households. Diabetics (n = 343) and controls (n = 607) attended a clinic where an oral glucose tolerance test or current hypoglycemic therapy confirmed or diagnosed non-insulin-dependent diabetes mellitus. The age-adjusted prevalence of confirmed non-insulin-dependent diabetes mellitus was 21/1,000 in Anglo males and 44/1,000 in Hispanic males, accounting for non-response. For Anglo females, the prevalence was 13/1,000 compared with 62/1,000 for Hispanic females, accounting for nonresponse. Previously undiagnosed non-insulin-dependent diabetes mellitus was also higher among Hispanics. There was a 2.1-fold excess of confirmed non-insulin-dependent diabetes mellitus among Hispanic males and a 4.8-fold excess among Hispanic females, consistent with the excess non-insulin-dependent diabetes mellitus among Hispanics reported from comparable studies. Non-insulin-dependent diabetes mellitus is a major chronic disease problem for persons of Hispanic ethnicity.

Nonoperative management of blunt splenic trauma: a multicenter experience.

Abstract: The experience of six referral trauma centers with 832 blunt splenic injuries was reviewed to determine the indications, methods, and outcome of nonoperative management. During this 5-year period, 112 splenic injuries were intentionally managed by observation. There were 40 (36%) patients less than 16 years old and 72 adults. The diagnosis was established by computed tomography in 89 (79%) patients, nuclear scan in 23 (21%), ultrasound in four (4%), and arteriography in two (2%). There were 28 Class I, 51 Class II, 31 Class III, two Class IV, and no Class V splenic injuries. Nonoperative management was unsuccessful in one (2%) child and 12 (17%) adults (p less than 0.05). Failure was due to ongoing hemorrhage in 12 patients and delayed recognition of pancreatic injury in one patient. Of the 12 patients ultimately requiring laparotomy for control of hemorrhage, seven (58%) were successfully treated with splenic salvage techniques. Overall mortality was 3%; none of the four deaths was due to splenic or associated abdominal injury. This contemporary multicenter experience suggests that patients with Class I, II, or III splenic injuries after blunt trauma are candidates for nonoperative management if there is: 1) no hemodynamic instability after initial fluid resuscitation; 2) no serious associated abdominal organ injury; and 3) no extra-abdominal condition which precludes assessment of the abdomen. Strict adherence to these principles yielded initial nonoperative success in 98% of children and 83% of adults. Application of standard splenic salvage techniques to treat the patients with persistent hemorrhage resulted in ultimate splenic preservation in 100% of children and 93% of adults.

Pseudoangiomatous hyperplasia of mammary stroma. Some observations regarding its clinicopathologic spectrum.

Abstract: Pseudoangiomatous hyperplasia of mammary stroma (PHMS) is a benign proliferation of keloid-like fibrosis, containing slit-like pseudovascular spaces. Its main importance is its distinction from angiosarcoma; however, the clinicopathologic spectrum of PHMS remains incompletely described. We report two new cases and describe our findings in 200 consecutive breast specimens evaluated for the presence of PHMS. The first patient presented with peau-de-orange change in the overlying breast skin, thus mimicking inflammatory breast carcinoma. Furthermore, this patient's PHMS lesion had been diagnosed and treated inappropriately as a low-grade angiosarcoma. The second case showed the more typical, fibroadenoma-like presentation of PHMS. In addition, PHMS changes occur commonly in routine breast biopsy specimens. In fact, our review of 200 consecutive breast specimens showed PHMS in at least one microscopic focus in 23% of cases. The PHMS changes occurred in younger patients than the control population and were associated with fibrocystic changes, in fibroadenomas, in gynecomastia, in normal breast tissue, and in sclerosing lobular hyperplasia. Ultrastructural and immunohistochemical studies of one case showed that the capillary-like spaces were either acellular or lined by fibroblasts. Pseudoangiomatous hyperplasia of mammary stroma represents a clinicopathologic spectrum, extending from focal, insignificant microscopic changes to cases where PHMS produces a breast mass. Increased awareness of PHMS and its clinicopathologic spectrum will allow its differentiation from other vascular tumors of the breast, especially low-grade angiosarcoma.

Community patterns of posttraumatic stress disorders.

Abstract: This paper reports lifetime rates for posttraumatic stress disorder (PTSD) in two rural northwest communities. One community was affected by a major natural disaster, the eruption of Mt. St. Helens. Following an epidemiology study of this disaster, community-wide patterns of PTSD were identified. Disaster-related, combat, sexual assault, and all other types of PTSD are presented for men and women. Symptom patterns from these distinct PTSD stressors are compared along with concurrent psychiatric disorders. The findings are discussed with other studies that use a broader definition of disaster stress response syndromes. This comparison identifies a limitation of PTSD diagnostic criteria that may significantly underestimate community rates. Language: en

Increased platelet intracellular calcium concentration in patients with bipolar affective disorders.

Abstract: • Using the fluorescent indicator Fura 2, we measured the free intracellular calcium ion concentration in blood platelets of patients with untreated mania, bipolar depression, and unipolar depression; patients who had recovered from bipolar depression or mania; and age- and sex-matched controls. The baseline intracellular calcium ion concentration was significantly increased in platelets from patients with mania compared with controls. The free intracellular calcium ion concentration after stimulation with platelet-activating factor and thrombin was significantly higher in platelets of manic and bipolar depressed patients than in all other groups. The degree to which intracellular calcium ion concentration increased over baseline after stimulation was significantly lower in unipolar than in bipolar patients. These findings suggest that platelets of manic and depressed bipolar patients have a similar enhancement of intracellular calcium ion activity that is distinctly different from the decreased ability of platelets of unipolar patients to mobilize intracellular calcium in response to stimulation.

Failure of postnatal adaptation of the pulmonary circulation after chronic intrauterine pulmonary hypertension in fetal lambs.

Abstract: To determine the effects of chronic intrauterine pulmonary hypertension on the perinatal pulmonary circulation, we induced chronic elevations of pulmonary artery pressure in 24 late-gestation fetal lambs by maintaining partial compression of the ductus arteriosus with an inflatable vascular occluder. Pulmonary artery pressure was increased from 44 +/- 1 to 62 +/- 3 mmHg for 3-14 d. Although left pulmonary artery blood flow initially increased during acute partial ductus compression, the increase in flow was not sustained during chronic ductus compression despite persistent elevations of pulmonary artery pressure (P less than 0.01). Chronic hypertension decreased the slope of the pressure-flow relationship from 3.4 +/- 0.3 (initial) to 0.9 +/- 0.1 ml/min per mmHg, and blunted the fetal pulmonary vascular response to small increases in PO2 (P less than 0.0001). Pulmonary hypertension for greater than 8 d increased the wall thickness of small pulmonary arteries (P less than 0.001). Compared with controls, hypertensive animals had higher pulmonary artery pressure, lower pulmonary blood flow, and predominant right-to-left ductus shunting after cesarean-section delivery (P less than 0.0001). We conclude that chronic pulmonary hypertension in utero, in the absence of hypoxemia or sustained increases in blood flow, causes abnormal fetal pulmonary vasoreactivity, structural remodeling, and the failure to achieve the normal decline in pulmonary resistance at birth.

Purified perforin induces target cell lysis but not DNA fragmentation.

Abstract: Rapid and extensive target cell DNA fragmentation is a unique characteristic of CTL-mediated killing. We studied the role of the granule pore-forming protein (PFP/perforin/cytolysin) of CTL in mediating lysis and DNA fragmentation of target cells. Perforin was isolated from murine CTL by sequential application of perforin-enriched granule fractions to four chromatographic columns: DEAE-Sepharose, Q-Sepharose, Polyanion SI, and Superose 12. Purified perforin was eluted as a single band of 70 kD in SDS-PAGE. While purified perforin produced potent lysis of a variety of target cells tested, it did not induce any measurable amount of DNA fragmentation. In parallel experiments, intact CTL produced marked DNA fragmentation of the same target cell populations. Our results suggest that perforin alone is not responsible for the DNA fragmentation observed during CTL-mediated killing and that other, as yet unknown, mediators or mechanisms are likely to be involved in the induction of target cell nuclear damage.

The G-protein family and their interaction with receptors.

Abstract: Introduction THE FAMILY of GTP-binding proteins, called Gproteins, provides a signal transduction coupling mechanism for many cell surface receptors. The receptors act catalytically to mediate guanine nucleotide exchange at the GDP-GTP binding site of G-proteins. This process is referred to as activation and results in the displacement of bound GDP for GTP. The GTP-bound form of the G-protein then initiates a cellular response by altering the activity of specific enzymes. Examples of such signal transduction systems include the receptor regulation of adenylyl cyclase activity and the photoreceptor regulation of cyclic (c)GMP phosphodiesterase. Recent evidence also suggests that specific ion channels may be regulated by G-proteins. As detailed in this review, recent elucidation of both receptor and G-protein primary sequence has allowed structural predictions and new experimental approaches to study the mechanism of receptor-catalyzed G-protein regulation of effector systems and the control of cell function.

School District Leave Policies, Teacher Absenteeism, and Student Achievement

Abstract: In an effort to reduce salary costs, many school districts have begun to offer teachers financial incentives to retire early Often, however, these districts have limits on the number of cumulated unused sick leave days that teachers may receive cash payments, credits toward future health insurance, or retirement credits for, at retirement Thus, one might expect that in addition to stimulating early retirement, early retirement incentive programs may interact with sick leave provisions and provide an unintended incentive for increased teacher absenteeism To the extent that less learning occurs when regular teachers are absent and student motivation to attend school is also reduced, student academic performance may suffer This surely would be an unintended side effect of these policies To address these issues, this paper, which is based on an extensive data collection effort by the authors, presents an econometric analyses of variations in teacher and student absenteeism across the over 700 school districts in New York State in 1986-87 and of how such variations influence student test score performance

Carnitine and acylcarnitine metabolism during exercise in humans. Dependence on skeletal muscle metabolic state

Abstract: Carnitine metabolism has been previously shown to change with exercise in normal subjects, and in patients with ischemic muscle diseases. To characterize carnitine metabolism further during exercise, six normal male subjects performed constant-load exercise on a bicycle ergometer on two separate occasions. Low-intensity exercise was performed for 60 min at a work load equal to 50% of the lactate threshold, and high-intensity exercise was performed for 30 min at a work load between the lactate threshold and maximal work capacity for the individual. Low-intensity exercise was not associated with a change in muscle (vastus lateralis) carnitine metabolism. In contrast, from rest to 10 min of high-intensity exercise, muscle short-chain acylcarnitine content increased 5.5-fold while free carnitine content decreased 66%, and muscle total carnitine content decreased by 19% (all P less than 0.01). These changes in skeletal muscle carnitine metabolism were present at the completion of 30 min of high-intensity exercise, and persisted through a 60-min recovery period. With 30 min of high-intensity exercise, plasma short-chain and long-chain acylcarnitine concentrations increased by 46% and 23%, respectively. Neither exercise state was associated with a change in the urine excretion rates of free carnitine or acylcarnitines. Thus, alterations in skeletal muscle carnitine metabolism, characterized by an increase in acylcarnitines and a decrease in free and total carnitine, are dependent on the work load and, therefore, the metabolic state associated with the exercise, and are poorly reflected in the plasma and urine carnitine pools.

Hyponatremia and seizures in young children given DDAVP.

Abstract: Desmopressin (DDAVP), a synthetic vasopressin, temporarily corrects bleeding abnormalities associated with mild hemophilia A, von Willebrand disease, and disorders of platelet function. The side effects of DDAVP are considered benign although most of its use has been in adults and older children. We report four children under the age of 2 years who became hyponatremic after intravenous DDAVP administration (0.3 microgram/kg). Three of them developed grand mal seizures. A review of the literature and these cases indicate that associated risk factors for hyponatremia after DDAVP administration include stress, surgery, anesthesia and narcotics (endogenous release of antidiuretic hormone), vomiting (loss of Na+), liver disease (hindered metabolism of DDAVP), renal tubular acidosis (chronically low serum Na+), multiple doses of DDAVP, and overhydration with hyponatremic fluids. DDAVP is not a benign drug in this age group and shows a serious potential for hyponatremia and seizures. Fluid restriction, avoidance of hyponatremic solutions, and close monitoring of serum electrolytes and urine output for at least 15-20 hr after the administration of DDAVP, when used in children under the age of 2 years, is warranted.

Pattern of cutaneous immunoglobulin G deposition in subacute cutaneous lupus erythematosus is reproduced by infusing purified anti-Ro (SSA) autoantibodies into human skin-grafted mice.

Abstract: Subacute cutaneous lupus and neonatal lupus are closely associated with the presence of anti-Ro (SSA) autoantibodies, but there is no direct evidence establishing a role for anti-Ro (SSA) in these diseases. After parental injection into mice, IgG from sera containing anti-Ro (SSA) will bind human skin grafted onto the mice. To determine whether the antibody binding is due to anti-Ro (SSA), affinity-purified anti-Ro (SSA) and serum depleted of anti-Ro (SSA) were prepared. After injection into human skin-grafted mice, purified anti-Ro (SSA) antibodies bound an antigen in the human skin graft, while preabsorbing anti-Ro (SSA) serum with Ro (SSA) virtually abolished binding to the human skin graft. Moreover, the pattern of IgG deposition was primarily epidermal and was identical in the human skin-grafted mice injected with purified anti-Ro (SSA) when compared with that found in five patients with subacute lupus (four adults, one neonate). These data directly show that anti-Ro (SSA) antibodies bind to the skin, and support the hypothesis that anti-Ro (SSA) autoantibodies are involved in the disease process that produces subacute cutaneous lupus and neonatal lupus.

Further studies of the helix dipole model: Effects of a free α‐NH3+ or α‐COO− group on helix stability

Abstract: Interactions between the α-helix peptide dipoles and charged groups close to the ends of the helix were found to be an important determinant of α-helix stability in a previous study.1 The charge on the N-terminal residue of the C-peptide from ribonuclease A was varied chiefly by changing the α-NH2 blocking group, and the correlation of helix stability with N-terminal charge was demonstrated. An alternative explanation for some of those results is that the succinyl and acetyl blocking groups stabilize the helix by hydrogen bonding to an unsatisfied main-chain NH group. The helix dipole model is tested here with peptides that contain either a free α-NH α-COO− groups, and no other charged groups that would titrate with similar pKa's. This model predicts that α-NH3α-COO- groups are helix-destabilizingand that the destabilizing interactions are electrostatic in origin. The hydrogen bonding model predicts that α-NH3 and α-COO- groups are not themselves helix-destabilizing, but that an acetyl or amide blocking group at the N- or C- terminus, respectively, stabilizes the helix by hydrogen bonding to an unsatisfied main-chain NH or CO group. The results are as follows: (1) Removal of the charge from α-NH3 and α-COO- groups by pH titration stabilizes an α-helix. (2) The increase in helix stability on pH titration of these groups is close to the increase produced by adding an acetyl or amide blocking group. (3) The helix-stabilizing effect of removing the charge from α-NH3 and α-COO- groups by pH titration is screened by increasing the NaCl concentration, and therefore the effect is electrostatic in origin. (4) Replacing the C-terminal amide blocking group with a methylester blocking group, which cannot donate a hydrogen bond, causes little change in helix stability.