Showing papers by "University of Medicine and Dentistry of New Jersey published in 2004"

Interferons, interferon‐like cytokines, and their receptors

Abstract: Summary: Recombinant interferon-α (IFN-α) was approved by regulatory agencies in many countries in 1986. As the first biotherapeutic approved, IFN-α paved the way for the development of many other cytokines and growth factors. Nevertheless, understanding the functions of the multitude of human IFNs and IFN-like cytokines has just touched the surface. This review summarizes the history of the purification of human IFNs and the key aspects of our current state of knowledge of human IFN genes, proteins, and receptors. All the known IFNs and IFN-like cytokines are described [IFN-α, IFN-β, IFN-e, IFN-κ, IFN-ω, IFN-δ, IFN-τ, IFN-γ, limitin, interleukin-28A (IL-28A), IL-28B, and IL-29] as well as their receptors and signal transduction pathways. The biological activities and clinical applications of the proteins are discussed. An extensive section on the evolution of these molecules provides some new insights into the development of these proteins as major elements of innate immunity. The overall structure of the IFNs is put into perspective in relation to their receptors and functions.

Current Concepts in the Pathogenesis of Age-Related Macular Degeneration

Abstract: Objective To review and synthesize information concerning the pathogenesis ofage-related macular degeneration (AMD). Methods Review of the English-language literature. Results Five concepts relevant to the cell biology of AMD are as follows: (1)AMD involves aging changes plus additional pathological changes (ie, AMD isnot just an aging change); (2) in aging and AMD, oxidative stress causes retinalpigment epithelial (RPE) and, possibly, choriocapillaris injury; (3) in AMD(and perhaps in aging), RPE and, possibly, choriocapillaris injury resultsin a chronic inflammatory response within the Bruch membrane and the choroid;(4) in AMD, RPE and, possibly, choriocapillaris injury and inflammation leadto formation of an abnormal extracellular matrix (ECM), which causes altereddiffusion of nutrients to the retina and RPE, possibly precipitating furtherRPE and retinal damage; and (5) the abnormal ECM results in altered RPE-choriocapillarisbehavior leading ultimately to atrophy of the retina, RPE, and choriocapillarisand/or choroidal new vessel growth. In this sequence of events, both the environmentand multiple genes can alter a patient's susceptibility to AMD. Implicit inthis characterization of AMD pathogenesis is the concept that there is linearprogression from one stage of the disease to the next. This assumption maybe incorrect, and different biochemical pathways leading to geographic atrophyand/or choroidal new vessels may operate simultaneously. Conclusions Better knowledge of AMD cell biology will lead to better treatmentsfor AMD at all stages of the disease. Many unanswered questions regardingAMD pathogenesis remain. Multiple animal models and in vitro models of specificaspects of AMD are needed to make rapid progress in developing effective therapiesfor different stages of the disease.

A Multisite, Randomized Controlled Trial for Children With Sexual Abuse-Related PTSD Symptoms

Abstract: Objective To examine the differential efficacy of trauma-focused cognitive-behavioral therapy (TF-CBT) and child-centered therapy for treating posttraumatic stress disorder (PTSD) and related emotional and behavioral problems in children who have suffered sexual abuse. Method Two hundred twenty-nine 8- to 14-year-old children and their primary caretakers were randomly assigned to the above alternative treatments. These children had significant symptoms of PTSD, with 89% meeting full DSM-IV PTSD diagnostic criteria. More than 90% of these children had experienced traumatic events in addition to sexual abuse. Results A series analyses of covariance indicated that children assigned to TF-CBT, compared to those assigned to child-centered therapy, demonstrated significantly more improvement with regard to PTSD, depression, behavior problems, shame, and abuse-related attributions. Similarly, parents assigned to TF-CBT showed greater improvement with respect to their own self-reported levels of depression, abuse-specific distress, support of the child, and effective parenting practices. Conclusions This study adds to the growing evidence supporting the efficacy of TF-CBT with children suffering PTSD as a result of sexual abuse and suggests the efficacy of this treatment for children who have experienced multiple traumas.

Granulomatous Infectious Diseases Associated with Tumor Necrosis Factor Antagonists

Abstract: The relationship between the use of tumor necrosis factor antagonists and onset of granulomatous infection was examined using data collected through the Adverse Event Reporting System of the US Food and Drug Administration for January 1998-September 2002. Granulomatous infections were reported at rates of approximately 239 per 100,000 patients who received infliximab and approximately 74 per 100,000 patients who received etanercept (P<.001). Tuberculosis was the most frequently reported disease, occurring in approximately 144 and approximately 35 per 100,000 infliximab-treated and etanercept-treated patients, respectively (P<.001). Candidiasis, coccidioidomycosis, histoplasmosis, listeriosis, nocardiosis, and infections due to nontuberculous mycobacteria were reported with significantly greater frequency among infliximab-treated patients. Seventy-two percent of these infection occurred < or =90 days after starting infliximab treatment, and 28% occurred after starting etanercept treatment (P<.001). These data indicate a risk of granulomatous infection that was 3.25-fold greater among patients who received infliximab than among those who received etanercept. The clustering of reports shortly after initiation of treatment with infliximab is consistent with reactivation of latent infection.

Epigenetic dynamics of imprinted X inactivation during early mouse development.

Abstract: The initiation of X-chromosome inactivation is thought to be tightly correlated with early differentiation events during mouse development. Here, we show that although initially active, the paternal X chromosome undergoes imprinted inactivation from the cleavage stages, well before cellular differentiation. A reversal of the inactive state, with a loss of epigenetic marks such as histone modifications and polycomb proteins, subsequently occurs in cells of the inner cell mass (ICM), which give rise to the embryo-proper in which random X inactivation is known to occur. This reveals the remarkable plasticity of the X-inactivation process during preimplantation development and underlines the importance of the ICM in global reprogramming of epigenetic marks in the early embryo.

The Future of Family Medicine: a collaborative project of the family medicine community.

Abstract: BACKGROUND Recognizing fundamental fl aws in the fragmented US health care systems and the potential of an

Considering context, place and culture: the National Latino and Asian American Study

Abstract: This paper provides a rationale for, and overview of, procedures used to develop the National Latino and Asian American Study (NLAAS). The NLAAS is nationally representative community household survey that estimates the prevalence of mental disorders and rates of mental health service utilization by Latinos and Asian Americans in the US. The central aims of the NLAAS are to: 1) describe the lifetime and 12-month prevalence of psychiatric disorders and the rates of mental health services use for Latino and Asian American populations using nationwide representative samples of Latinos and Asian Americans, 2) assess the associations among social position, environmental context, and psychosocial factors with the prevalence of psychiatric disorders and utilization rates of mental health services, and 3) compare the lifetime and 12-month prevalence of psychiatric disorders, and utilization of mental health services of Latinos and Asian Americans with national representative samples of non-Latino whites (from the National Comorbidity Study-Replication) (NCS-R) and African Americans (from the National Survey of American Life) (NSAL). This paper presents new concepts and methods utilized in the development of the NLAAS to capture and investigate ethnic, cultural and environmental considerations that are often ignored in mental health research.

Spatial Epidemiology: Current Approaches and Future Challenges

Abstract: Spatial epidemiology is the description and analysis of geographic variations in disease with respect to demographic, environmental, behavioral, socioeconomic, genetic, and infectious risk factors. We focus on small-area analyses, encompassing disease mapping, geographic correlation studies, disease clusters, and clustering. Advances in geographic information systems, statistical methodology, and availability of high-resolution, geographically referenced health and environmental quality data have created unprecedented new opportunities to investigate environmental and other factors in explaining local geographic variations in disease. They also present new challenges. Problems include the large random component that may predominate disease rates across small areas. Though this can be dealt with appropriately using Bayesian statistics to provide smooth estimates of disease risks, sensitivity to detect areas at high risk is limited when expected numbers of cases are small. Potential biases and confounding, particularly due to socioeconomic factors, and a detailed understanding of data quality are important. Data errors can result in large apparent disease excess in a locality. Disease cluster reports often arise nonsystematically because of media, physician, or public concern. One ready means of investigating such concerns is the replication of analyses in different areas based on routine data, as is done in the United Kingdom through the Small Area Health Statistics Unit (and increasingly in other European countries, e.g., through the European Health and Environment Information System collaboration). In the future, developments in exposure modeling and mapping, enhanced study designs, and new methods of surveillance of large health databases promise to improve our ability to understand the complex relationships of environment to health.

Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2009 Update by the HIV Medicine Association of the Infectious Diseases Society of America

Abstract: Evidence-based guidelines for the management of persons infected with human immunodeficiency virus (HIV) were prepared by an expert panel of the HIV Medicine Association of the Infectious Diseases Society of America. These updated guidelines replace those published in 2004. The guidelines are intended for use by health care providers who care for HIV-infected patients or patients who may be at risk for acquiring HIV infection. Since 2004, new antiretroviral drugs and classes have become available, and the prognosis of persons with HIV infection continues to improve. However, with fewer complications and increased survival, HIVinfected persons are increasingly developing common health problems that also affect the general population. Some of these conditions may be related to HIV infection itself and its treatment. HIV-infected persons should be managed and monitored for all relevant age- and gender-specific health problems. New information based on publications from the period 2003‐2008 has been incorporated into this document.

Rhinosinusitis: Establishing definitions for clinical research and patient care

Abstract: Objectives: to develop consensus definitions for rhinosinusitis and outline strategies useful in clinical trials

Infliximab induction therapy for patients with severe plaque-type psoriasis: A randomized, double-blind, placebo-controlled trial

Abstract: Background Tumor necrosis factor–α is a key mediator in the pathogenesis of psoriasis. Infliximab is a monoclonal antibody that specifically binds to tumor necrosis factor-α, blocking its biologic activity. Objective The purpose of this study was to access the efficacy and safety of infliximab induction therapy for patients with severe plaque psoriasis. Methods In this multicenter, double-blind, placebo-controlled trial, 249 patients with severe plaque psoriasis were randomly assigned to receive intravenous infusions of either 3 or 5 mg/kg of infliximab or placebo given at weeks 0, 2, and 6. The primary end point was the proportion of patients who achieved at least 75% improvement in Psoriasis Area and Severity Index score from baseline at week 10. At week 26, patients whose Physician Global Assessment indicated moderate or severe disease were eligible for a single intravenous infusion of their assigned treatment to assess the safety of retreatment after a 20-week, treatment-free interval. Results At week 10, 72% of patients treated with infliximab (3 mg/kg) and 88% of patients treated with infliximab (5 mg/kg) achieved a 75% or greater improvement from baseline in Psoriasis Area and Severity Index score compared with 6% of patients treated with placebo ( P Conclusions Infliximab treatment resulted in a rapid and significant improvement in the signs and symptoms of psoriasis. Infliximab was generally well tolerated.

Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial.

Abstract: Studies examining the effect of postmenopausal hormone therapy on concentrations of glucose, insulin and diabetes incidence have been inconclusive, in part because many of the studies were too small. We examined the effect of oestrogen plus progestin on diabetes incidence and insulin resistance. The study was a randomised, double-blind trial comparing the effect of daily 0.625 mg conjugated equine oestrogens plus 2.5 mg medroxyprogesterone acetate with that of placebo during 5.6 years of follow-up. The participants were 15,641 postmenopausal women enrolled in the Women’s Health Initiative Hormone Trial. These women were aged 50 to 79 and all had an intact uterus. Diabetes incidence was ascertained by self-report of treatment with insulin or oral hypoglycaemic medication. Fasting glucose, insulin, and lipoproteins were measured in a random sample at baseline and at 1 and 3 years. The cumulative incidence of treated diabetes was 3.5% in the hormone therapy group and 4.2% in the placebo group (hazard ratio 0.79, 95% CI 0.67–0.93, p=0.004). There was little change in the hazard ratio after adjustment for changes in BMI and waist circumference. During the first year of follow-up, changes in fasting glucose and insulin indicated a significant fall in insulin resistance in actively treated women compared to the control subjects (Year 1 to baseline between-group difference −0.22±0.10, p=0.03). These data suggest that combined therapy with oestrogen and progestin reduces the incidence of diabetes, possibly mediated by a decrease in insulin resistance unrelated to body size. Future studies of alternative postmenopausal hormone therapy regimens and selective oestrogen agonists and/or antagonists should consider the effects of these regimens on insulin resistance and diabetes.

spa Typing Method for Discriminating among Staphylococcus aureus Isolates: Implications for Use of A Single Marker to Detect Genetic Micro- and Macrovariation

Abstract: Strain typing of microbial pathogens has two major aims: (i) to index genetic microvariation for use in outbreak investigations and (ii) to index genetic macrovariation for use in phylogenetic and population-based analyses. Until now, there has been no clear indication that one genetic marker can efficiently be used for both purposes. Previously, we had shown that DNA sequence analysis of the protein A gene variable repeat region (spa typing) provides a rapid and accurate method to discriminate Staphylococcus aureus outbreak isolates from those deemed epidemiologically unrelated. Here, using the hypothesis that the genetic macrovariation within a low-level recombinogenic species would accurately be characterized by a single-locus marker, we tested whether spa typing could congruently index the extensive genetic variation detected by a whole-genome DNA microarray in a collection of 36 isolates, which was recovered from 10 countries on four continents over a period of four decades, that is representative of the breadth of diversity within S. aureus. Using spa and coa typing, pulsed-field gel electrophoresis (PFGE), and microarray and multilocus enzyme electrophoresis (MLEE) data in molecular epidemiologic and evolutionary analyses, we determined that S. aureus likely has a primarily clonal population structure and that spa typing can singly index genetic variation with 88% direct concordance with the microarray and can correctly assign isolates to phylogenetic lineages. spa typing performed better than MLEE, PFGE, and coa typing in discriminatory power and in the degree of agreement with the microarray at various phylogenetic depths. This study showed that genetic analysis of the repeat region of protein A comprehensively characterizes both micro- and macrovariation in the primarily clonal population structure of S. aureus.

Clinical calibration of DSM-IV diagnoses in the World Mental Health (WMH) version of the World Health Organization (WHO) Composite International Diagnostic Interview (WMH-CIDI)

Abstract: An overview is presented of the rationale, design, and analysis plan for the WMH-CIDI clinical calibration studies. As no clinical gold standard assessment is available for the DSM-IV disorders assessed in the WMH-CIDI, we adopted the goal of calibration rather than validation; that is, we asked whether WMH-CIDI diagnoses are 'consistent' with diagnoses based on a state-of-the-art clinical research diagnostic interview (SCID; Structured Clinical Interview for DSM-IV) rather than whether they are 'correct'. Consistency is evaluated both at the aggregate level (consistency of WMH-CIDI and SCID prevalence estimates) and at the individual level (consistency of WMH-CIDI and SCID diagnostic classifications). Although conventional statistics (sensitivity, specificity, Cohen's kappa) are used to describe diagnostic consistency, an argument is made for considering the area under the receiver operator curve (AUC) to be a more useful general-purpose measure of consistency. In addition, more detailed analyses are used to evaluate consistency on a substantive level. These analyses begin by estimating prediction equations in a clinical calibration subsample, with WMH-CIDI symptom-level data used to predict SCID diagnoses, and using the coefficients from these equations to assign predicted probabilities of SCID diagnoses to each respondent in the remainder of the sample. Substantive analyses then investigate whether estimates of prevalence and associations when based on WMH-CIDI diagnoses are consistent with those based on predicted SCID diagnoses. Multiple imputation is used to adjust estimated standard errors for the imprecision introduced by SCID diagnoses being imputed under a model rather than measured directly. A brief illustration of this approach is presented in comparing the precision of SCID and predicted SCID estimates of prevalence and correlates under varying sample designs.

T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation

Abstract: T cell receptor (TCR) stimulation induces rapid generation of reactive oxygen species, although the mechanisms for this are unclear. Here we found that T cells expressed a functional phagocyte-type nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. TCR crosslinking induced oxidase activation through the recruitment of preformed Fas ligand and Fas. TCR stimulation induced three separable events generating reactive oxygen species: rapid hydrogen peroxide production independent of Fas or NADPH oxidase; sustained hydrogen peroxide production dependent on both Fas and NADPH oxidase; and delayed superoxide production that was dependent on Fas ligand and Fas yet independent of NADPH oxidase. NADPH oxidase-deficient T cells showed enhanced activation of the kinase Erk and a relative increase in T helper type 1 cytokine secretion. Thus, mature T cells express a phagocyte-type NADPH oxidase that regulates elements of TCR signaling.