Showing papers by "University of Colorado Denver published in 2000"

The Colorado Thyroid Disease Prevalence Study

Abstract: Context: The prevalence of abnormal thyroid function in the United States and the significance of thyroid dysfunction remain controversial. Systemic effects of abnormal thyroid function have not been fully delineated, particularly in cases of mild thyroid failure. Also, the relationship between traditional hypothyroid symptoms and biochemical thyroid function is unclear. Objective: To determine the prevalence of abnormal thyroid function and the relationship between (1) abnormal thyroid function and lipid levels and (2) abnormal thyroid function and symptoms using modern and sensitive thyroid tests. Design: Cross-sectional study.

A Stakeholder Approach to Organizational Identity

Abstract: We develop a model of organizational identity construction that reframes organizational identity within the broader context of manager-stakeholder relationships and more effectively integrates theory on organizational identity and organizational identification We describe organizational identity as emerging from complex, dynamic, and reciprocal interactions among managers, organizational members, and other stakeholders The model draws attention to organizational identity as negotiated cognitive images and to the embeddedness of organizational identity within different systems of organizational membership and meaning Viewing organizational identity from the perspective of manager-stakeholder relationships provides a more parsimonious but more complete theory of organizational identity management

Practice parameter: Screening and diagnosis of autism Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society

Abstract: Autism is a common disorder of childhood, affecting 1 in 500 children. Yet, it often remains unrecognized and undiagnosed until or after late preschool age because appropriate tools for routine developmental screening and screening specifically for autism have not been available. Early identification of children with autism and intensive, early intervention during the toddler and preschool years improves outcome for most young children with autism. This practice parameter reviews the available empirical evidence and gives specific recommendations for the identification of children with autism. This approach requires a dual process: 1) routine developmental surveillance and screening specifically for autism to be performed on all children to first identify those at risk for any type of atypical development, and to identify those specifically at risk for autism; and 2) to diagnose and evaluate autism, to differentiate autism from other developmental disorders.

Antiretroviral Therapy in Adults: Updated Recommendations of the International AIDS Society–USA Panel

Abstract: Objective To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. Participants A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society–USA in December 1995. Evidence Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. Consensus Process The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. Conclusions The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.

Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial.

Abstract: Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease

Regular Aerobic Exercise Prevents and Restores Age-Related Declines in Endothelium-Dependent Vasodilation in Healthy Men

Abstract: Background—In sedentary humans endothelium-dependent vasodilation is impaired with advancing age contributing to their increased cardiovascular risk, whereas endurance-trained adults demonstrate lower age-related risk. We determined the influence of regular aerobic exercise on the age-related decline in endothelium-dependent vasodilation. Methods and Results—In a cross-sectional study, 68 healthy men 22 to 35 or 50 to 76 years of age who were either sedentary or endurance exercise–trained were studied. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine and sodium nitroprusside were measured by strain-gauge plethysmography. Among the sedentary men, the maximum FBF response to acetylcholine was 25% lower in the middle aged and older compared with the young group (P<0.01). In contrast, there was no age-related difference in the vasodilatory response to acetylcholine among the endurance-trained men. FBF at the highest acetylcholine dose was almost identical in the middle aged and ...

Protein kinase C isozymes and the regulation of diverse cell responses

Abstract: Individual protein kinase C (PKC) isozymes have been implicated in many cellular responses important in lung health and disease, including permeability, contraction, migration, hypertrophy, proliferation, apoptosis, and secretion. New ideas on mechanisms that regulate PKC activity, including the identification of a novel PKC kinase, 3-phosphoinositide-dependent kinase-1 (PDK-1), that regulates phosphorylation of PKC, have been advanced. The importance of targeted translocation of PKC and isozyme-specific binding proteins (like receptors for activated C-kinase and caveolins) is well established. Phosphorylation state and localization are now thought to be key determinants of isozyme activity and specificity. New concepts on the role of individual PKC isozymes in proliferation and apoptosis are emerging. Opposing roles for selected isozymes in the same cell system have been defined. Coupling to the Wnt signaling pathway has been described. Phenotypes for PKC knockout mice have recently been reported. More specific approaches for studying PKC isozymes and their role in cell responses have been developed. Strengths and weaknesses of different experimental strategies are reviewed. Future directions for investigation are identified.

Elevated levels of FMR1 mRNA in carrier males : A new mechanism of involvement in the fragile-X syndrome

Abstract: Summary Fragile-X syndrome is a trinucleotide-repeat–expansion disorder in which the clinical phenotype is believed to result from transcriptional silencing of the fragile-X mental retardation 1 ( FMR1 ) gene as the number of CGG repeats exceeds ∼200. For premutation alleles (∼55–200 repeats), no abnormalities in FMR1 -gene expression have been described, despite growing evidence of clinical involvement in premutation carriers. To address this (apparent) paradox, we have determined, for 16 carrier males (55–192 repeats), the relative levels of leukocyte FMR1 mRNA, by use of automated fluorescence-detection reverse transcriptase–PCR, and the percent of lymphocytes that are immunoreactive for FMR1 protein (FMRP). For some alleles with >100 repeats, there was a reduction in the number of FMRP-positive cells. Unexpectedly, FMR1 mRNA levels were elevated at least fivefold within this same range. No significant increase in FMR1 mRNA stability was observed in a lymphoblastoid cell line (160 repeats) derived from one of the carrier males, suggesting that the increased message levels are due to an increased rate of transcription. Current results support a mechanism of involvement in premutation carriers, in which reduced translational efficiency is at least partially compensated through increased transcriptional activity. Thus, diminished translational efficiency may be important throughout much of the premutation range, with a mechanistic switch occurring in the full-mutation range as the FMR1 gene is silenced.

Antiretroviral drug resistance testing in adult HIV-1 infection: Recommendations of an international AIDS society-USA panel

Abstract: ObjectiveAssays for drug resistance testing in human immunodeficiency virus type 1 (HIV-1) infection are now available and clinical studies suggest that viral drug resistance is correlated with poor virologic response to new therapy. The International AIDS Society–USA sought to update prior recommendations to provide guidance for clinicians regarding indications for HIV-1 resistance testing.ParticipantsAn International AIDS Society–USA 13-member physician panel with expertise in basic science, clinical research, and patient care involving HIV resistance to antiretroviral drugs was reconvened to provide recommendations for the clinical use of drug resistance testing.Evidence and Consensus ProcessThe full panel met regularly between January and October 1999. Resistance and resistance testing data appearing in the last decade through April 2000 and presentations at national and international research conferences were reviewed. Recommendations and considerations were developed by 100% group consensus, acknowledging that definitive data to support final recommendations are not yet available.ConclusionsEmerging data indicate that despite limitations, resistance testing should be incorporated into patient management in some settings. Resistance testing is recommended to help guide the choice of new regimens after treatment failure and for guiding therapy for pregnant women. It should be considered in treatment-naive patients with established infection, but cannot be firmly recommended in this setting. Testing also should be considered prior to initiating therapy in patients with acute HIV infection, although therapy should not be delayed pending the results. Expert interpretation is recommended given the complexity of results and assay limitations.

Inhibition of angiogenesis decreases alveolarization in the developing rat lung.

Abstract: To determine whether angiogenesis is necessary for normal alveolarization, we studied the effects of two antiangiogenic agents, thalidomide and fumagillin, on alveolarization during a critical period of lung growth in infant rats. Newborn rats were treated with daily injections of fumagillin, thalidomide, or vehicle during the first 2 wk of life. Compared with control treatment, fumagillin and thalidomide treatment reduced lung weight-to-body weight ratio and pulmonary arterial density by 20 and 36%, respectively, and reduced alveolarization by 22%. Because these drugs potentially have nonspecific effects on lung growth, we also studied the effects of Su-5416, an inhibitor of the vascular endothelial growth factor receptor known as kinase insert domain-containing receptor/fetal liver kinase (KDR/flk)-1. As observed with the other antiangiogenic agents, Su-5416 treatment decreased alveolarization and arterial density. We conclude that treatment with three different antiangiogenic agents attenuated lung vascular growth and reduced alveolarization in the infant rat. We speculate that angiogenesis is necessary for alveolarization during normal lung development and that injury to the developing pulmonary circulation during a critical period of lung growth can contribute to lung hypoplasia.

Progesterone Receptor Isoform A But Not B Is Expressed in Endometriosis

Abstract: We previously demonstrated that 17beta hydroxysteroid dehydrogenase type 2, the enzyme that inactivates estradiol to estrone, is expressed in luteal eutopic endometrium in response to progesterone but not in simultaneously biopsied peritoneal endometriotic tissue. This molecular evidence of progesterone resistance, together with the clinical observation of resistance of endometriosis to treatment with progestins, led us to determine the levels of progesterone receptor (PR) isoforms PR-A and PR-B in eutopic endometrial and extra-ovarian endometriotic tissues. It was proposed that progesterone action on target genes is mediated primarily by homodimers of PR-B, whereas the truncated variant PR-A acts as a repressor of PR-B function. Immunoprecipitation, followed by Western blot analysis, was performed to detect bands specific for PR-A and PR-B in paired samples of endometriotic and eutopic endometrial tissues simultaneously biopsed from 18 women undergoing laparoscopy during various phases of the menstrual cycle. PR-B was present in 17 of 18 eutopic endometrial samples, and its level increased in the preovulatory phase, as expected, whereas PR-A was detected in all samples (n = 18) with a similar, but less prominent, cyclic variation in its levels. In endometriotic samples, however, no detectable PR-B could be demonstrated, whereas PR-A was detected in all samples (n = 18), albeit in much lower levels and without any cyclic variation in contrast with the eutopic endometrium. Levels of PR-A and PR-B in endometriotic and eutopic endometrial tissues were determined and compared after normalization to total protein and estrogen receptor-alpha levels. Using RNase protection assay, we also demonstrated indirectly that only PR-A transcripts were present in endometriotic tissue samples (n = 8), whereas both PR-A and PR-B transcripts were readily detectable in all eutopic endometrial samples (n = 8). This was indicative that failure to detect PR-B protein in endometriotic tissues is due to the absence of PR-B transcripts. We conclude that progesterone resistance in endometriotic tissue from laboratory and clinical observations may be accounted for by the presence of the inhibitory PR isoform PR-A and the absence of the stimulatory isoform PR-B.

Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation

Abstract: A 5-week-old male infant presented with severe bacterial infections and poor wound healing, suggesting a neutrophil defect. Neutrophils from this patient exhibited decreased chemotaxis, polarization, azurophilic granule secretion, and superoxide anion (O2−) production but had normal expression and up-regulation of CD11b. Rac2, which constitutes >96% of the Rac in neutrophils, is a member of the Rho family of GTPases that regulates the actin cytoskeleton and O2− production. Western blot analysis of lysates from patient neutrophils demonstrated decreased levels of Rac2 protein. Addition of recombinant Rac to extracts of the patient neutrophils reconstituted O2− production in an in vitro assay system. Molecular analysis identified a point mutation in one allele of the Rac2 gene resulting in the substitution of Asp57 by an Asn (Rac2D57N). Asp57 is invariant in all defined GTP-binding proteins. Rac2D57N binds GDP but not GTP and inhibits oxidase activation and O2− production in vitro. These data represent the description of an inhibitory mutation in a member of the Rho family of GTPases associated with a human immunodeficiency syndrome.

Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes

Abstract: With the development of an insulin autoantibody (IAA) assay performed in 96-well filtration plates, we have evaluated prospectively the development of IAA in NOD mice (from 4 weeks of age) and children (from 7 to 10 months of age) at genetic risk for the development of type 1 diabetes. NOD mice had heterogeneous expression of IAA despite being inbred. IAA reached a peak between 8 and 16 weeks and then declined. IAA expression by NOD mice at 8 weeks of age was strongly associated with early development of diabetes, which occurred at 16–18 weeks of age (NOD mice IAA+ at 8 weeks: 83% (5/6) diabetic by 18 weeks versus 11% (1/9) of IAA negative at 8 weeks; P < .01). In man, IAA was frequently present as early as 9 months of age, the first sampling time. Of five children found to have persistent IAA before 1 year of age, four have progressed to diabetes (all before 3.5 years of age) and the fifth is currently less than age 2. Of the 929 children not expressing persistent IAA before age 1, only one has progressed to diabetes to date (age onset 3), and this child expressed IAA at his second visit (age 1.1). In new onset patients, the highest levels of IAA correlated with an earlier age of diabetes onset. Our data suggest that the program for developing diabetes of NOD mice and humans is relatively “fixed” early in life and, for NOD mice, a high risk of early development of diabetes is often determined by 8 weeks of age. With such early determination of high risk of progression to diabetes, immunologic therapies in humans may need to be tested in children before the development of IAA for maximal efficacy.

Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study.

Abstract: Treatment for Hodgkin's disease (HD) is associated with a variety of thyroid abnormalities, including hypothyroidism, hyperthyroidism, and thyroid neoplasms. Due to the small sample size and short follow-up time of most published studies, it has been difficult to appreciate the full extent of the problem and to characterize the interaction between various patient and treatment variables. To overcome these limitations we have assessed thyroid status in 1,791 (959 males) HD survivors from among 13,674 participants in the Childhood Cancer Survivor Study, a cohort of 5-yr survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. Thyroid abnormalities were ascertained as part of a 22-page questionnaire sent to participants. Survivors were a median of 14 yr (range, 2-20 yr) at diagnosis of HD and a median of 30 yr (range, 12-47 yr) at follow-up. Seventy-nine percent of subjects were treated with radiation (median dose of radiation to the thyroid, 3,500 cGy; range, 0.37-5,500 cGy). Control data were available from 2,808 (1,346 males) sibling controls. Thirty-four percent of the entire cohort has been diagnosed with at least one thyroid abnormality. Hypothyroidism was the most common disturbance, with a relative risk of 17.1 (P < 0.0001) compared to sibling controls. Increasing dose of radiation, older age at diagnosis of HD, and female sex were all independently associated with an increased risk of hypothyroidism. Actuarial risk of hypothyroidism for subjects treated with 4,500 cGy or more is 50% at 20 yr from diagnosis. Hyperthyroidism was reported by 5% of survivors, which was 8-fold greater (P < 0.0001) than the incidence reported by the controls. Thyroid dose of 3,500 cGy or more was the only risk factor identified for hyperthyroidism. The risk of thyroid nodules was 27 times (P < 0.0001) that in sibling controls. Female sex and radiation dose to the thyroid of 2,500 cGy or more were independent risk factors for thyroid nodules. The actuarial risk of a female survivor developing a thyroid nodule is 20% at 20 yr from diagnosis. Thyroid cancer was diagnosed in 20 survivors, which is 18 times the expected rate for the general population. After taking into account the possibility that some of the relative risk estimates may be exaggerated due to ascertainment bias, abnormalities of the thyroid are still extremely common in young adult survivors of childhood HD, particularly among females treated with high doses of radiation to the neck.

Association of mammographically defined percent breast density with epidemiologic risk factors for breast cancer (United States)

Abstract: Objective: Mammographically defined percent breast density is an important risk factor for breast cancer, but the epidemiology of this trait is poorly understood. Although several studies have investigated the associations between reproductive factors and density, few data are available on the associations of breast density and waist-to-hip ratio (WHR), physical activity, education, alcohol and smoking. Methods: We investigated the associations of known and suspected breast cancer risk factors with breast density in a large breast cancer family study. Information was collected on members of 426 families through telephone interviews, mailed questionnaires and mammography. Mammographic films on 1900 women were digitized and breast density was estimated in discrete five-unit increments by one radiologist. Analysis of covariance techniques were used and all analyses were performed stratified by menopausal status. Results: Similar to other reports, nulliparity, late age at first birth, younger age and lower body mass index were associated with increased percent density in both premenopausal and postmenopausal women, and hormone replacement therapy among postmenopausal women. Higher levels of alcohol consumption and low WHR were associated with increased percent density among both premenopausal and postmenopausal women (differences of 3–11% between high and low categories). However, smoking and education were inversely associated with percent density among premenopausal (p = 0.004 and p = 0.003, respectively) but not postmenopausal women (p = 0.52 and p = 0.90). Physical activity was not associated with percent density in either stratum (p values > 0.25). Combined, these factors explained approximately 37% of the variability in the percent density measure in premenopausal women and 19% in postmenopausal women. Conclusions: Many of these factors may potentially affect breast cancer risk through their effect on percent breast density.

Distinct effects of surfactant protein A or D deficiency during bacterial infection on the lung.

Abstract: Mice lacking surfactant protein (SP)-A (SP-A-/-) or SP-D (SP-D-/-) and wild-type mice were infected with group B streptococcus or Haemophilus influenzae by intratracheal instillation. Although decreased killing of group B streptococcus and H. influenzae was observed in SP-A-/- mice but not in SP-D-/- mice, deficiency of either SP-A or SP-D was associated with increased inflammation and inflammatory cell recruitment in the lung after infection. Deficient uptake of bacteria by alveolar macrophages was observed in both SP-A- and SP-D-deficient mice. Isolated alveolar macrophages from SP-A-/- mice generated significantly less, whereas those from SP-D-/- mice generated significantly greater superoxide and hydrogen peroxide compared with wild-type alveolar macrophages. In SP-D-/- mice, bacterial killing was associated with increased lung inflammation, increased oxidant production, and decreased macrophage phagocytosis. In contrast, in the absence of SP-A, bacterial killing was decreased and associated with increased lung inflammation, decreased oxidant production, and decreased macrophage phagocytosis. Increased oxidant production likely contributes to effective bacterial killing in the lungs of SP-D-/- mice. The collectins, SP-A and SP-D, play distinct roles during bacterial infection of the lung.

Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18

Abstract: A novel, constitutively expressed and secreted IL-18 binding protein (IL-18BP) neutralizes IL-18 and thereby suppresses the production of IFN-γ, resulting in reduced T-helper type 1 immune responses. In the present study, four human and two mouse isoforms, resulting from mRNA splicing and found in various cDNA libraries, were expressed, purified, and assessed for binding and neutralization of IL-18 biological activities. Human IL-18BP isoform a (IL-18BPa) exhibited the greatest affinity for IL-18 with a rapid on-rate, a slow off-rate, and a dissociation constant (Kd) of 399 pM. IL-18BPc shares the Ig domain of IL-18BPa except for the 29 C-terminal amino acids; the Kd of IL-18BPc is 10-fold less (2.94 nM). Nevertheless, IL-18BPa and IL-18BPc neutralize IL-18 >95% at a molar excess of two. IL-18BPb and IL-18BPd isoforms lack a complete Ig domain and lack the ability to bind or neutralize IL-18. Murine IL-18BPc and IL-18BPd isoforms, possessing the identical Ig domain, also neutralize >95% murine IL-18 at a molar excess of two. However, murine IL-18BPd, which shares a common C-terminal motif with human IL-18BPa, also neutralizes human IL-18. Molecular modeling identified a large mixed electrostatic and hydrophobic binding site in the Ig domain of IL-18BP, which could account for its high affinity binding to the ligand. It is likely that preferential secretion of functional and nonfunctional isoforms of IL-18BP affect the immune response.

The devastating potential of blunt vertebral arterial injuries.

Abstract: Blunt vertebral arterial injury (BVI) has historically been considered an uncommon event of relative insignificance. There have been many case reports describing BVI-associated cerebrovascular accidents, both ischemic and hemorrhagic, but clinical series of vertebral artery injuries have been composed primarily of penetrating injuries. In the seven largest reports, only 8 (4%) of 195 total reported patients had sustained blunt mechanisms; these 8 patients as a group had reasonably good outcomes, leading to the belief that BVI is relatively innocuous. 1–7 This concept was further supported in small series dealing specifically with blunt injuries. 8–14 In 1996 we adopted an aggressive screening protocol for blunt carotid arterial injuries. 15 Using four-vessel cerebral arteriography, we began identifying a significant number of BVIs in addition to blunt carotid injury. Fabian et al 16 previously demonstrated the benefits of systemic heparin therapy in treating patients with blunt carotid injury; our experience with asymptomatic patients affirmed the Memphis data. 15 Extrapolation of blunt carotid injury treatment principles to BVI, however, has not been supported. Collectively, the consensus in the literature to date is that asymptomatic patients with narrowing, irregularity, or occlusion of the vertebral artery do not require treatment. 1–7,11,12 The purpose of this study was to analyze our experience and formulate a rational diagnostic and therapeutic approach to BVI.