Kevin P. High

Human cytomegalovirus gene expression during infection of primary hematopoietic progenitor cells: A model for latency

Human cytomegalovirus (HCMV) resides latently in hematopoietic cells of the bone marrow. Although viral genomes can be found in CD14+ monocytes and CD34+ progenitor cells, the primary reservoir for latent cytomegalovirus is unknown. We analyzed human hematopoietic subpopulations infected in vitro with a recombinant virus that expresses a green fluorescent protein marker gene. Although many hematopoietic cell subsets were infected in vitro, CD14+ monocytes and various CD34+ subpopulations were infected with the greatest efficiency. We have developed an in vitro system in which to study HCMV infection and latency in CD34+ cells cultured with irradiated stromal cells. Marker gene expression was substantially reduced by 4 days postinfection, and infectious virus was not made during the culture period. However, viral DNA sequences were maintained in infected CD34+ cells for >20 days in culture, and, importantly, virus replication could be reactivated by coculture with human fibroblasts. Using an HCMV gene array, we examined HCMV gene expression in CD34+ cells. The pattern of viral gene expression was distinct from that observed during productive or nonproductive infections. Some of these expressed viral genes may function in latency and are targets for further analysis. Altered gene expression in hematopoietic progenitors may be indicative of the nature and outcome of HCMV infection.

Practice guideline for evaluation of fever and infection in long-term care facilities

The elderly population (i.e., persons aged > or = 65 years) in the United States is rapidly expanding and will nearly double in number over the next 30 years. It is estimated that >40% of persons aged > or = 65 years will require care in a long-term care facility (LTCF), such as a skilled nursing facility (SNF), at some point during their lifetime. For the most part, residents of LTCFs are very old and have age-related immunologic changes, chronic cognitive and/or physical impairments, and diseases that alter host resistance; therefore, they are highly susceptible to infections and their complications. The diagnosis of infections in residents of LTCFs is often difficult because LTCFs differ from acute-care facilities in their goals of care, staffing ratios, types of primary care providers, availability of laboratory tests, and criteria for infections. Consequently, guidelines and standards of practice used for diagnosis of infections in patients in acute-care facilities may not be applicable nor appropriate for residents in LTCFs. Moreover, the clinical manifestations of diseases and infections are often subtle, atypical, or nonexistent in the very old. Fever may be low or absent in LTCF residents with infection. The initial evaluation of an LTCF resident suspected of an infection may not be done by a physician. Although nurses commonly perform initial assessments for infection in residents of LTCFs, further studies are needed to determine the appropriateness and validity of this practice. Provided there are no directives (advance or current by resident or caregiver) limiting diagnostic or therapeutic interventions, all residents of LTCFs with suspected symptomatic infection should have appropriate diagnostic laboratory studies done promptly, and the findings should be discussed with the primary care clinician (see Recommendations). The most common infections among LTCF residents are urinary tract infections, respiratory infections, skin or soft tissue infections, and gastroenteritis. Decisions concerning possible transfer of an LTCF resident to an acute-care facility are best expressed through an advance directive or, when not available, through transfer policies developed by the LTCF. In general, LTCF residents have been transferred to an acute-care facility when any of the following conditions exist: (1) the resident is clinically unstable and the resident or family goals indicate aggressive interventions should be initiated, (2) critical diagnostic tests are not available in the LTCF, (3) necessary therapy or the mode of administration of therapy (frequency or monitoring) are beyond the capacity of the LTCF, (4) comfort measures cannot be assured in the LTCF, and (5) specific infection-control measures are not available in the LTCF.

Is HIV a Model of Accelerated or Accentuated Aging

BACKGROUND Antiretroviral therapy has reduced the incidence of adverse events and early mortality in HIV-infected persons. Despite these benefits, important comorbidities that increase with age (eg, diabetes, cardiovascular disease, cancer, liver disease, and neurocognitive impairment) are more prevalent in HIV-infected persons than in HIV-uninfected persons at every age, and geriatric syndromes such as falls and frailty occur earlier in HIV-infected persons. This raises a critical research question: Does HIV accelerate aging through pathways and mechanisms common to the aging process or is HIV simply an additional risk factor for a wide number of chronic conditions, thus accentuating aging? METHODS Extensive literature review. RESULTS The purpose of this review is to briefly outline the evidence that age-related clinical syndromes are exacerbated by HIV, examine the ways in which HIV is similar, and dissimilar from natural aging, and assess the validity of HIV as a model of premature aging. Specific biomarkers of aging are limited in HIV-infected hosts and impacted by antiretroviral therapy, and a high rate of modifiable life style confounders (eg, smoking, substance abuse, alcohol) and coinfections (eg, hepatitis) in HIV-infected participants. CONCLUSIONS There is a need for validated biomarkers of aging in the context of HIV. Despite these differences, welldesigned studies of HIV-infected participants are likely to provide new opportunities to better understand the mechanisms that lead to aging and age-related diseases.

Infectious Disease Outbreaks in Nursing Homes: An Unappreciated Hazard for Frail Elderly Persons

The common occurrence and dire consequences of infectious disease outbreaks in nursing homes often go unrecognized and unappreciated. Nevertheless, these facilities provide an ideal environment for acquisition and spread of infection: susceptible residents who share sources of air, food, water, and health care in a crowded institutional setting. Moreover, visitors, staff, and residents constantly come and go, bringing in pathogens from both the hospital and the community. Outbreaks of respiratory and gastrointestinal infection predominate in this setting, but outbreaks of skin and soft-tissue infection and infections caused by antimicrobial-resistant bacteria also occur with some frequency.

A New Paradigm for Clinical Investigation of Infectious Syndromes in Older Adults: Assessment of Functional Status as a Risk Factor and Outcome Measure

Adults aged >or=65 years comprise the fastest-growing segment of the United States population, and older adults experience greater morbidity and mortality due to infection than do young adults. Although age is well established as a risk factor for infection, most clinical investigations of infectious diseases in older adults focus on microbiology and on crude end points of clinical success, such as cure rates or death; however, they often fail to assess functional status, which is a critical variable in geriatric care. Functional status can be evaluated either as a risk factor for infectious disease or as an outcome of interest after specific interventions using well-validated instruments. This article outlines the currently available data that suggest an association between infection, immunity, and impaired functional status in elderly individuals, summarizes the instruments commonly used to determine specific aspects of functional status, and provides recommendations for a new paradigm in which clinical trials that involve older adults include assessment of functional status.

HIV Infection and Dementia in Older Adults

Human immunodeficiency virus (HIV) infection in older patients is becoming increasingly common as seropositive individuals live longer because of long-term antiretroviral treatment. Simultaneously, the development and expression of dementia among HIV-infected patients is evolving in the era of highly active antiretroviral therapy (HAART) and immune reconstitution. How long-term HAART interacts with chronic HIV infection and advanced age with regard to cognition is not fully understood. This article provides an overview of HIV cognitive impairment as it relates to aging and presents some emerging issues in the field. Particular emphasis is placed on describing the changing landscape of HIV-related cognitive impairment and discussing possible concerns regarding the long-term effects of antiretroviral treatment. A brief discussion of potential adjunctive therapies to reduce cognitive symptoms associated with HIV infection in older individuals is provided.

Nutritional Strategies to Boost Immunity and Prevent Infection in Elderly Individuals

Older adults are at risk for malnutrition, which may contribute to their increased risk of infection. Nutritional supplementation strategies can reduce this risk and reverse some of the immune dysfunction associated with advanced age. This review discusses nutritional interventions that have been examined in clinical trials of older adults. The data support use of a daily multivitamin or trace-mineral supplement that includes zinc (elemental zinc, >20 mg/day) and selenium (100 microg/day), with additional vitamin E, to achieve a daily dosage of 200 mg/day. Specific syndromes may also be addressed by nutritional interventions (for example, cranberry juice consumption to reduce urinary tract infections) and may reduce antibiotic use in older adults, particularly those living in long-term care facilities. Drug-nutrient interactions are common in elderly individuals, and care providers should be aware of these interactions. Future research should evaluate important clinical end points rather than merely surrogate markers of immunity.

Magnitude of Peroxisome Proliferator-Activated Receptor-γ Activation is Associated With Important and Seemingly Opposite Biological Responses in Breast Cancer Cells

Background The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) has become a potential target for the prevention and treatment of breast cancer. However, recent in vitro and in vivo studies have raised the question of whether activation of PPARγ leads to the promotion or reduction of tumor formation. Studies using several cancer cell lines, animal models, and a variety of PPARγ agonists have shown discordant results, including changes in cellular proliferation, differentiation, and apoptosis of cancer cells and tumors. Methods We studied the effects of low-, moderate-, and high-dose treatment of the PPARγ ligands 15-deoxy-Δ12,14 prostaglandin J2 (15dPGJ2) and troglitazone (TGZ) on parameters of cell growth, differentiation, and apoptosis in the epithelial breast cancer cell line MDA-MB-231. Results The biologic effects of these compounds depend largely on ligand concentration and the degree of PPARγ activation. For example, low concentrations of 15dPGJ2 (<2.5 μM) and TGZ (<5 μM) increased cellular proliferation, but concentrations of 15dPGJ2 >10 μM and of TGZ at 100 μM blocked cell growth. TGZ (100 μM) slowed cell cycle progression, and 15dPGJ2 (10 μM) caused an S-phase arrest in the cell cycle and induced morphological characteristics consistent with apoptosis. Expression of CD36, a marker of differentiation in these cells, was induced by 2.5 μM 15dPGJ2 or 5 to 100 μM TGZ. However, higher concentrations of 15dPGJ2 did not alter CD36 expression. Transcriptional activation studies demonstrated that 15dPGJ2 is a more potent PPARγ ligand than TGZ. Regardless of the ligand used, though, low transcriptional activation correlated with an increased cellular proliferation, whereas higher levels of activation correlated with cell cycle arrest and apoptosis. Conclusions PPARγ activation induces several important and seemingly opposite changes in neoplastic cells, depending on the magnitude of PPARγ activation. These data may explain, at least in part, some of the discordant results previously reported.

A framework for crafting clinical practice guidelines that are relevant to the care and management of people with multimorbidity.

ABSTRACTMany patients of all ages have multiple conditions, yet clinicians often lack explicit guidance on how to approach clinical decision-making for such people. Most recommendations from clinical practice guidelines (CPGs) focus on the management of single diseases, and may be harmful or impractical for patients with multimorbidity. A major barrier to the development of guidance for people with multimorbidity stems from the fact that the evidence underlying CPGs derives from studies predominantly focused on the management of a single disease. In this paper, the investigators from the Improving Guidelines for Multimorbid Patients Study Group present consensus-based recommendations for guideline developers to make guidelines more useful for the care of people with multimorbidity. In an iterative process informed by review of key literature and experience, we drafted a list of issues and possible approaches for addressing important coexisting conditions in each step of the guideline development process, with a focus on considering relevant interactions between the conditions, their treatments and their outcomes. The recommended approaches address consideration of coexisting conditions at all major steps in CPG development, from nominating and scoping the topic, commissioning the work group, refining key questions, ranking importance of outcomes, conducting systematic reviews, assessing quality of evidence and applicability, summarizing benefits and harms, to formulating recommendations and grading their strength. The list of issues and recommendations was reviewed and refined iteratively by stakeholders. This framework acknowledges the challenges faced by CPG developers who must make complex judgments in the absence of high-quality or direct evidence. These recommendations require validation through implementation, evaluation and refinement.

Diabetes and cardiovascular disease in older adults: Current status and future directions

The prevalence of diabetes increases with age, driven in part by an absolute increase in incidence among adults aged 65 years and older. Individuals with diabetes are at higher risk for cardiovascular disease, and age strongly predicts cardiovascular complications. Inflammation and oxidative stress appear to play some role in the mechanisms underlying aging, diabetes, cardiovascular disease, and other complications of diabetes. However, the mechanisms underlying the age-associated increase in risk for diabetes and diabetes-related cardiovascular disease remain poorly understood. Moreover, because of the heterogeneity of the older population, a lack of understanding of the biology of aging, and inadequate study of the effects of treatments on traditional complications and geriatric conditions associated with diabetes, no consensus exists on the optimal interventions for older diabetic adults. The Association of Specialty Professors, along with the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and the American Diabetes Association, held a workshop, summarized in this Perspective, to discuss current knowledge regarding diabetes and cardiovascular disease in older adults, identify gaps, and propose questions to guide future research.