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PubMed2003

Enhanced immunogenicity to Mycobacterium tuberculosis by vaccination with an alphavirus plasmid replicon expressing antigen 85A.

The immunogenicity of a plasmid DNA vaccine incorporating Sindbis virus RNA replicase functions (pSINCP) and expressing antigen 85A (Ag85A) from Mycobacterium tuberculosis was compared with a conventional plasmid DNA vector encoding Ag85A. pSINCP-85A was highly immunogenic in mice and gave enhanced long-term protection against M. tuberculosis compared with the conventional vector.

Acyltransferases↗
PubMed2003

Coinjection with CpG-containing immunostimulatory oligodeoxynucleotides reduces the pathogenicity of a live vaccine against cutaneous Leishmaniasis but maintains its potency and durability.

The inoculation of live, nonattenuated Leishmania major to produce a lesion in a selected site that heals, referred to as leishmanization, is to date the only vaccine against leishmaniasis that has proven to be effective in humans. Its use has been restricted or abandoned entirely, however, due to safety concerns. In an attempt to develop a leishmanization protocol that minimizes pathology while maintaining long-term protection, live parasites were coinjected with CpG-containing immunostimulatory oligodeoxynucleotides (CpG ODNs) alone or in combination with whole-cell lysates of heat-killed L. major promastigotes bound to alum (ALM). C57BL/6 mice infected intradermally by using L. major plus CpG ODN with or without ALM developed few or no dermal lesions and showed an early containment of parasite growth, while mice infected with L. major with or without ALM developed sizable dermal lesions that required up to 10 weeks to heal. The CpG ODNs provoked a transient inflammation that included an early recruitment and accumulation of gamma interferon-producing CD4(+) lymphocytes in the site. Attenuation of the live vaccine did not compromise its ability to confer long-term immunity, as mice receiving L. major and CpG ODN plus ALM were totally protected against reinfection with L. major for up to 6 months. By comparison, the immunity elicited by two efficient nonlive vaccines began to wane by 6 months. Our results suggest that immune modulation using CpG ODNs might be a practical approach to improving the safety of a highly effective live vaccine that has already been widely applied.

Adjuvants, Immunologic↗
PubMed2005

Prevention and treatment of cutaneous leishmaniasis in primates by using synthetic type D/A oligodeoxynucleotides expressing CpG motifs.

Oligodeoxynucleotides (ODN) containing CpG motifs mimic microbial DNA and are recognized by toll-like receptor 9 on immune cells. The resulting response limits the early spread of infectious organisms and promotes the development of adaptive immunity. In this regard, CpG ODN show promise as immunoprotective agents and as vaccine adjuvants. Previous studies of nonhuman primates showed that administration of CpG ODN type D (also known as type A) at the site of infection 3 days before and after a challenge with Leishmania major enhanced host resistance and reduced the lesion's severity. In this study, we show that systemic administration of D/A ODN limits the size of lesions following an intradermal infection with L. major. Importantly, the reduced morbidity was not associated with a reduction in long-term immunity, as such treated macaques were still protected following a secondary challenge. Finally, administration of D/A ODN to macaques that had established cutaneous lesions reduced the severity of the lesions, suggesting a potential role for CpG ODN in L. major treatment. Together, these findings support the development of clinical studies to assess the use of CpG ODN types D/A as immunoprotective and therapeutic agents.

Animals↗
PubMed2000

DNA vaccines: immunology, application, and optimization*.

The development and widespread use of vaccines against infectious agents have been a great triumph of medical science. One reason for the success of currently available vaccines is that they are capable of inducing long-lived antibody responses, which are the principal agents of immune protection against most viruses and bacteria. Despite these successes, vaccination against intracellular organisms that require cell-mediated immunity, such as the agents of tuberculosis, malaria, leishmaniasis, and human immunodeficiency virus infection, are either not available or not uniformly effective. Owing to the substantial morbidity and mortality associated with these diseases worldwide, an understanding of the mechanisms involved in generating long-lived cellular immune responses has tremendous practical importance. For these reasons, a new form of vaccination, using DNA that contains the gene for the antigen of interest, is under intensive investigation, because it can engender both humoral and cellular immune responses. This review focuses on the mechanisms by which DNA vaccines elicit immune responses. In addition, a list of potential applications in a variety of preclinical models is provided.

Animals↗
PubMed1994

Acquisition of lymphokine-producing phenotype by CD4+ T cells.

Naive CD4+ T cells when stimulated produce IL-2 as their major lymphokine. Upon priming, these cells develop into cells that produce either IFN gamma, TNF beta, and IL-2 or IL-4 and its congeners. The former cells are designated TH1-like, and the latter TH2-like. Here we review the regulation of the differentiation of naive CD4 cells into IFN gamma- or IL-4-producers. The dominant factors that determine such differentiation are lymphokines and other cytokines. IL-2 itself appears to be required for naive cells to develop into TH1- or TH2-like cells but is not deterministic of their differentiation fate. If IL-4 is also present during the priming period, the resultant CD4+ T cells produce IL-4 upon restimulation; the development of IFN gamma-producing cells is strikingly inhibited by IL-4. In the absence of IL-4, priming for IFN gamma-production occurs, but this is markedly enhanced by IL-12. The role of IFN gamma in enhancing priming for IFN gamma-production is not fully resolved. In some in vitro systems, it appears to act together with IL-12 to enhance such production. Anti-IFN gamma diminishes priming for IFN gamma production in vivo. Lymphokines also exert a "cross-regulatory" or inhibitory effect. As noted above, IL-4 strikingly diminishes priming for IFN gamma production, although this inhibitory effect is blunted in the presence of IL-12. IFN gamma similarly diminishes priming for IL-4 production; this effect is principally observed when low concentrations of IL-4 are used in the priming culture. Although other factors may play a role in the determination of lymphokine-producing phenotype, such as antigen dose, type of antigen-presenting cell, and expression of accessory molecules and hormones, these effects appear to be secondary to the dominant role of the lymphokines and cytokines.

Animals↗
PubMed1991

Production of interleukin-4 and other cytokines following stimulation of mast cell lines and in vivo mast cells/basophils.

Interleukin-3 (IL-3)-dependent mast cell lines, upon stimulation by calcium ionophores or by Fc epsilon RI cross-linking, express mRNA for, and secrete, a distinct pattern of cytokines, similar to those secreted by cloned mouse T cells of the TH2 type. The mast-cell-derived cytokines include IL-3, IL-4, IL-5 and IL-6. Not only in vitro mast cell lines, but also in vivo derived peritoneal mast cells secrete cytokines. An in vivo derived cell, in mouse spleen and bone marrow, secretes IL-4 and other cytokines upon stimulation with calcium ionophores or by Fc epsilon RI cross-linking or Fc gamma RII cross-linking. The IL-4-producing cells are highly enriched in the Fc epsilon R+ subset of spleen and bone marrow cells. These Fc epsilon R+ cells produce large amounts of IL-4, and they have characteristics similar to those of immature mast cells and/or basophils. It is possible that cytokines produced by mast cells and/or basophils participate in allergic inflammatory diseases.

Animals↗
PubMedDate not supplied

Are differentiated human T helper cells reversible?

Cytokines and cytokine antagonists have important roles in controlling the type of immune response generated. These mediators have the most profound effects if used at the initiation of an immune response. For example, IL-4 and IL-12 are important determinants in the generation of Th1 and Th2 cells, respectively, in both murine and human systems. One critical question that relates to human pathogenesis is whether Th1- and Th2-type cells can be altered after disease is initiated. Data will be presented showing how cytokines can change the types of cytokines produced from established Th1 and Th2 cells. Moreover, intracellular staining of cytokines was done to more accurately define whether cytokine production was altered on a single cell basis. These studies may have implications for immune manipulation for established allergic or autoimmune diseases.

Animals↗
PubMed1996

IL-12 in conjunction with dendritic cells enhances antiviral CD8+ CTL responses in vitro.

CD8+ cytolytic T lymphocytes (CTLs) are important mediators for resistance to infections and malignant diseases. IL-12 enhances proliferative and cytolytic responses by killer cells, but its function in the generation of human antiviral CD8+ T cell responses has not been defined. We therefore evaluated the role of IL-12 in the generation of CTLs to influenza-infected dendritic cells. IL-12 was not detectable in supernatants of infected-dendritic cells, or during CTL generation. Furthermore, anti-IL-12 antibody did not block CTL generation. However, exogenous IL-12 (30-300 pg/ml) enhanced CD8+ T cell proliferative and cytolytic responses. The effect was greatest in individuals with weak reactivity to influenza virus or at antigen-presenting cell (APC):T cell ratios of 1:100 or less. IL-12 augmented interferon-gamma production during CTL generation. The CTL enhancing effects of the cytokine, however, could not be blocked by neutralizing anti-interferon-gamma antibody. Together with IL-12, antigen-pulsed dendritic cells may be a useful approach for boosting CTL responses against infectious agents and malignancies.

Dendritic Cells↗
PubMed1975

Psychotherapy patient transfer: secondhand rose.

The author uses the analogy of the marketplace to examine the dynamics of the transfer of psychotherapy patients in university clinic settings. The outgoing therapist is the seller, the prospective therapist the buyer, and the patient the commodity--the secondhand Rose. Marketing techniques that are used in this buyers' market allow no active patient participation and are therefore antithetical to the tenets of psychotherapy. The author suggests early clarification of therapeutic goals, assignment of therapists on the basis of patient choice, and explanation of time frames and limits as means for ameliorating the problems he describes.

Education, Medical, Graduate↗
PubMed1977

Moral therapy and the problem of morale.

The author reviews the history of moral therapy and the lessons and warnings it holds for modern psychiatry. Custodial management replaced moral therapy in this country in the late 1800s because of inadequate manpower and fiscal resources, a lack of charismatic leaders, the increasing lack of control over admissions and discharge, and other factors. One "solution" to the unacceptable conditions of custodial care was an increased faith in science and technology; humanistic medical science became scientism, and patients suffered. Morale is essential to the provision of moral therapy, and the increasing emphasis on somatic therapies has strained the union of morale and moral treatment. The author believes that the profession can reaffirm its identity and distinguish itself through the appropriate provision of humane, psychosocial care--the essence of moral therapy.

Attitude of Health Personnel↗
PubMed1987

Bringing psychiatric patients into the Medicare prospective payment system: alternatives to DRGs.

The basis of Medicare's prospective payment for alcohol, drug abuse, and mental illness hospital admissions has been the patient classification system known as diagnosis-related groups (DRGs). This paper describes two alternative patient classification systems, disease staging and clinically related groups, and reports how well each system predicts resource use compared to the DRG system. Medicare data from four states were used to test the comparative strength of these patient classification systems. Although disease staging and clinically related groups performed better than DRGs, they were still poor predictors of resource use.

Alcoholism↗
PubMed1989

Managed health care and the Massachusetts experience.

Managed health care, through prepaid health delivery systems and utilization review organizations, is perhaps the greatest trend in modern health care. The authors examine the remarkable growth of managed care and outline its clinical, economic, ethical, and practical implications. They then review examples of how organized psychiatry has been involved in managed care and describe the efforts to date of the Massachusetts Psychiatric Society in this area. Managed care is here to stay. The future climate of psychiatric practice and the care available to psychiatric patients are dependent on informed and organized activities by psychiatrists and their local and national representatives.

Delivery of Health Care↗
PubMed1990

Transfers of hospitalized psychiatric patients under Medicare's prospective payment system.

Medicare's reimbursement policy provides payment incentives for hospitals to transfer psychiatric patients to another acute-care facility, especially when the destination facility is exempt from Medicare's prospective payment system. The authors found, however, that transfers were relatively infrequent in 1985, accounting for only approximately 3.4% of all psychiatric hospitalizations under Medicare. The most common type of transfer was from a nonspecialized general hospital bed to a Medicare-exempt psychiatric unit within the same hospital. Given that increasing financial pressures may result in a rise in the number of transfers, the authors discuss potential reforms of Medicare reimbursement for these cases.

Centers for Medicare and Medicaid Services, U.S.↗
PubMed1992

Judicial and legislative responses to cost containment.

Cost containment through reduction of insurance benefits and aggressive utilization review is increasingly risking the sacrifice of good clinical care in the pursuit of financial objectives. This article provides examples of judicial and legislative responses to perceived fiscal intrusions into clinical practice. Principles for asserting clinical goals in the cost containment process are also provided to assist in the inevitable negotiations and battles ahead.

Adult↗
PubMed2000

A self-report symptom and problem rating scale to increase inpatients' involvement in treatment.

OBJECTIVE: The study sought to determine whether psychiatric inpatients who completed a self-report symptom and problem rating scale on admission and reviewed the results with a clinician would perceive at discharge that they had been more involved in their treatment than patients who did not complete the scale. METHODS: In a quasiexperimental design, 109 inpatients were assigned to one of three groups. Patients in one group met individually with a psychiatric resident to review their responses to the Behavior and Symptom Identification Scale (BASIS-32), a self-report outcome assessment tool. Patients' views of their difficulties were then used by the treatment team to build a therapeutic alliance and to inform treatment planning. The remaining two groups received treatment as usual by either a psychiatric resident or an attending psychiatrist. Patients' perceived involvement in decisions about their treatment, perceptions of other aspects of care, and treatment outcome were compared. RESULTS: Patients in the intervention group rated their involvement in decisions about their treatment significantly higher than patients in either of the comparison groups. Patients in the intervention group more frequently reported that they were treated with respect and dignity by the staff than did patients in the comparison group treated by attending psychiatrists. Compared with patients treated by attending psychiatrists, patients treated by residents, whether they received the intervention or not, were more likely to say that they would recommend the hospital to others. Treatment outcome did not differ among the groups. CONCLUSIONS: The results suggest that an outcome assessment tool can be used to engage patients in the treatment process.

Adult↗
PubMed2001

Factors affecting psychiatric nurses' intention to leave their current job.

Using the National Institute for Occupational Safety and Health job stress questionnaire, the authors examined psychiatric nurses' intention to leave their job in relation to their perceived risk of assault, their job satisfaction, and their supervisory support. Respondents were 1,494 nurses (response rate, 76.5 percent) employed in 27 psychiatric hospitals in Japan. Forty-four percent reported intention to leave their job, and 89 percent of those perceived a risk of assault. Younger age, fewer previous job changes, less supervisory support, lower job satisfaction, and more perceived risk of assault were significant predictors of intention to leave. Organizational efforts are necessary to retain frontline professional staff.

Adult↗