Fatal PML associated with efalizumab therapy: insights into integrin αLß2 in JC virus control.

OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders. METHODS: We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLß2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients. RESULTS: Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE. CONCLUSIONS: From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control.

CD8+ T-cell immunity in chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: Chronic inflammatory demyelinating polyradiculopathy (CIDP) is a common, but often misdiagnosed disease of the peripheral nervous system with assumed autoimmune pathogenesis. While current concepts of CIDP postulate a pathogenetic role of B cells and (auto)antibodies, the relevance of CD8 T cells present in the biopsies is still elusive. Thus, we asked whether nervous tissue infiltrating and blood-derived lymphocytes in CIDP are clonally expanded to evaluate the involvement of T cells in the pathogenesis of the disease. METHODS: We characterized the clonal composition of the T-cell receptor repertoire in sural nerve biopsies (n = 25) and matching peripheral blood (n = 12) of patients with CIDP using PCR-based CDR3 spectratyping and subsequent DNA sequencing. As controls we used inflammatory myopathies (dermatomyositis, inclusion body myositis) and nonpathologic control biopsies. Immunohistochemistry was employed to visualize expanded CD8+ T-cell populations in sural nerve biopsies. RESULTS: In contrast to controls, T cells in CIDP biopsies showed strong monoclonal and oligoclonal restrictions in their T-cell receptor repertoire. Strikingly, clonal expansions found in the biopsies were reflected in the CD8+ T-cell pool of patients' peripheral blood. Clones overlapping between blood and biopsy could be confirmed by CDR3 sequencing. Finally, the predominance of expanded nerve-infiltrating CD8+ T-cell clones was visualized by immunohistochemistry. CONCLUSIONS: Together, these data provide strong evidence for an antigen-driven, major histocompatibility complex class I restricted, CD8+ T-cell-mediated attack against peripheral nerve tissue components contributing to the pathogenesis of CIDP.

Clonal expansions of pathogenic CD8+ effector cells in the CNS of myelin mutant mice.

Tissue damage in the CNS is critically influenced by the adaptive immune system. Primary oligodendrocyte damage (by overexpression of PLP) leads to low-grade inflammation of high pathological impact, which is mediated by CD8+ T cells. To yield further insight into pathogenesis and nature of immune responses in myelin mutated mice, we here apply a detailed immunological characterization of CD8+ T cells in PLP-transgenic and aged wild type mice. We provide evidence that T effector cells accumulate in the CNS of PLP-transgenic and wild-type mice and show a higher level of activation in mutant mice, indicated by surface markers and clonal expansions, as demonstrated by T cell receptor CDR3-spectratype analysis. Vbeta-Jbeta similarities suggest specificity against a common antigen, albeit we could not find specific responses against myelin-antigen-derived peptides. The association of primary oligodendrocyte damage with secondary expansions of pathogenic cells underlines the role of adaptive immune reactions in neurodegenerative and neuroinflammatory diseases.

[Extended outcome assessment in endonasal sinus surgery]. / Erweiterte Ergebnisanalyse der endonasalen Nasennebenhöhlenchirurgie.

BACKGROUND: Endonasal optically guided surgery has gained wide acceptance for treatment of chronic sinusitis. However, irrespective to the advent of minimally-invasive techniques, standard outcome assessment has not always reflected the increased technical and conceptual efforts. "Psychometric" instruments offer additional information on patients' perceptions of health. We analyzed the practical value of an extended outcome assessment. METHODS: Standardized interviews were carried out with 103 patients pre- and postoperatively applying several psychometrical instruments ("SF-36" and other valid general health-status instruments besides disease-specific questionnaires, providing 124 items/questions altogether). RESULTS: The diverse changes of subtle health status subscores as a rule paralleled each other and were concordant with traditional self-estimated global ratings of the surgical success by the patient. Significant postoperative changes of the "SF-36" questionnaire were especially seen in the subscale "bodily pain" and "level of energy". With few exceptions only, items reflecting any indirect burden of chronic sinusitis revealed less pronounced improvements postoperatively. CONCLUSION: It appears legitimate to question the special benefits of extended psychometric outcome research in comparison to traditional global ratings for daily surgical practice.

[Public, decentralized and community health networks in Bolivia]. / Redes públicas, descentralizadas y comunitarias de salud en Bolivia.

Health sector reform in Bolivia is based primarily on the principles of decentralization and equity, and with the objectives of improving quality and of expanding health services coverage in rural and low-income areas of the country. As an experiment in reform, the Bolivian Ministry of Health and Social Welfare, the department of La Paz, and the municipality of El Alto signed an agreement with a nongovernmental organization (NGO), transferring to the NGO the overall management of one of the health services networks in El Alto. The transfer was based on a management contract that had process and outcome indicators for the network. A year after implementation began, the preliminary results suggest that through the agreement the quality of management and services has improved, health services coverage has expanded, and the network's primary care services have been strengthened. Bed occupancy rates are generally very low in secondary hospitals in Bolivia, with that figure being just 43% in the department of La Paz in 1999. However, in the second 6 months of operation of the El Alto network the occupancy rate for the network's hospital reached 84%. Between the first 6 months of 1999 and the same period in 2000, outpatient consultations increased by 55% in the network (83% in the hospital and 18% in the network's primary care centers). Over that same period, institutional deliveries increased by 41% and the percentage of deliveries in the primary care centers grew from 5% of the total to 9%. A recent user survey found that 87% of the people receiving care in the network felt highly satisfied with the service they had received, and 75% of the persons surveyed said they would recommend the service to others. These are not typical data for health services in Bolivia. This pilot effort suggests that a change in the organization and management of a health services network, with a separation of the roles of purchaser and provider, combined with management based on results and with community participation in the process, can improve the quality and efficiency of those health services, stimulate demand for them, and increase user satisfaction.

Professional liability insurance.

The American Association of Nurse Attorneys recommends that all nurses engaged in the practice of nursing insure themselves against liability to third parties arising out of that practice. To make an informed decision whether to purchase individual insurance and how much to purchase, each school nurse must personally evaluate a multitude of factors. Each school nurse should also understand the various types of insurance policies available and how an individual policy is affected by coverage provided through the school district policy or self-insurance program. In certain states, school nurses also may be protected by the legal doctrine of sovereign immunity. This article provides answers to some of the questions frequently posed by school nurses about individual professional liability insurance.

Consent and release.

Because school nursing practice by definition involves delivering services to minors, school nurses often find themselves with questions about consent. Because school districts, much like other health care providers, occasionally face liability for the undesired health care outcomes of their clients (i.e., students), another question that surfaces frequently deals with release from liability. Each question must be answered based on analysis of the specific facts and applicable laws. This article provides an overview of the principles that provide school nurses with general guidance on consent issues and release of liability and, by way of example, applies them in the answers to four specific questions forwarded by practicing school nurses.

Risk of coronary heart disease, dietary fat modification, stages of change, and self-efficacy in surgically and naturally postmenopausal women.

This nonexperimental two-by-two study was designed to determine whether a difference existed between postmenopausal women who underwent surgical menopause and those who experienced natural menopause and between those who were and those who were not taking hormone replacement therapy (HRT) on four dependent variables. Bandura's self-efficacy theory and Prochaska and DiClemente's transtheoretical model of change provided the framework. Subjects (n = 77) were recruited from one physician's practice at a metropolitan multi-specialty outpatient clinic. Instruments were the Demographic Data Form, Risk of Coronary Heart Disease Table, Food Habits Questionnaire, Stage of Change to Dietary Fat Reduction, and Self-Efficacy for Health-Related Diet Behaviors. The independent variables, type of menopause and hormone status, had two levels. The dependent variables were coronary heart disease (CHD) risk, dietary fat modification, stages of change, and self-efficacy. Two-way ANOVA were used to determine differences between the two independent variables on the dependent variables. Findings indicated that women who experienced natural menopause and were not on HRT were at greater risk for CHD than women who underwent surgical menopause, the majority of whom were on HRT. Those women with natural menopause had a greater risk of developing CHD over time than their counterparts. Significant findings indicated that women who experience natural menopause should receive education on the risks and benefits of HRT. Hopefully, this education will enhance their ability to make their choice wisely.

Managing risks in professional and clinical performance dilemmas: Part II.

The primary purpose of the second article in this 2-part series is to describe and illustrate the use of an analytical framework that may assist school nurses to approach and resolve the dilemmas they may face in practice. Part I of the article was published in the April issue of this journal. It defined the terms "professional performance issue" and "clinical performance issue" and described a 5-step framework for analyzing practice dilemmas related to clinical and performance issues. In this article, the framework will be applied to a specific case scenario involving unsafe staffing and delegation.

School health services after Cedar Rapids Independent School District v. Garret F.

In 1999, the U.S. Supreme Court ruled that "school health services" include nursing services that are required for students needing one-on-one ("private-duty") nursing care to attend school. This ruling settled opposing federal court interpretations of the Individuals with Disabilities Education Act, clarifying the rights of students with complex medical needs and the responsibility of school districts to provide them with an appropriate educational program. In responding to the challenges and opportunities raised by this decision, school nurses must understand the implications for school nursing practice and for school districts, educate their school leaders and communities, and provide leadership for creative and collaborative problem solving.

Effectiveness of RSVIG prophylaxis and therapy of respiratory syncytial virus in an immunosuppressed animal model.

Respiratory syncytial virus (RSV) has emerged as a leading cause of pneumonia, with high mortality, in bone marrow transplant (BMT) recipients, as well as in other profoundly immunocompromised patients, such as myelosuppressed adults with leukemia. We tested the efficacy of immunoglobulin with high anti-RSV neutralizing antibody levels (RSVIG) for prophylaxis and therapy of RSV infection in cotton rats undergoing prolonged immunosuppression with cyclophosphamide. These animals experience persistent infection, a model which is similar to the disease seen in post-BMT humans. Both prophylaxis and therapy reduced pulmonary viral replication over 500-fold to nearly undetectable levels. In animals receiving continual immunosuppression, the use of multiple therapeutic doses of RSVIG was able to prevent rebound viral replication, though virus was not completely eliminated.

Delegation and supervision in school settings. Standards, issues and guidelines for practice (Part 1)

Part one of this article reviews nursing standards and practice issues related to the delegation of nursing activities to, and the supervision of, unlicensed assistive personnel. Part two, which will be published in a future issue, provides specific strategies, practices and resources to assist school nurses to apply these standards and concepts in their everyday school nursing practice.

Effects of somatostatin and captopril on glomerular prostaglandin E2 production in normal and diabetic rats.

Somatostatin (SRIH) has recently been shown to be effective in reversing many of the early changes of diabetic nephropathy. It is unknown whether SRIH exerts its protective effects via its ability to suppress growth hormone (GH) or via other direct renal effects. Since changes in glomerular prostaglandin (PG) E2 production are thought to be an important part of the underlying pathophysiology of diabetic nephropathy, we sought to determine if SRIH altered glomerular PG E2 production in the rat. Whole glomeruli isolated from streptozotocin-diabetic rats and from controls were incubated with either saline, captopril, or varying concentrations of SRIH, and PG E2 production was determined by direct radioimmunoassay of media. Incubation with captopril (10(-4) M) resulted in equivalent increases in PG E2 production in glomeruli from both control and diabetic rats (140.8 +/- 12.8% and 150.2 +/- 18.9% respectively). Incubation with high concentrations of SRIH (10(-6) M) also resulted in significant increases in glomerular PG E2 production in both diabetic and control rats. However, at low SRIH concentrations (10(-10) M), glomerular PG E2 production was increased only in the diabetic rats (167.0 +/- 11.4% vs 95.3 +/- 9.2% in normals). We conclude that SRIH increases glomerular PG E2 production, and that glomeruli from diabetic rats appear to be more sensitive to lower concentrations of SRIH when compared to normal rats. It is possible that this effect on PG E2 production may underlie the favorable effects of SRIH on the glomerulus in diabetes.

School health records: nursing practice and the law.

School nurses are increasingly faced with professional-legal dilemmas related to student health records and documentation. This article provides guidance in an often extremely confusing area, as well as recommendations for policy and practice changes that might help simplify the search for resolutions.

Antihypertensive effect of the GABA receptor agonist muscimol in spontaneously hypertensive rats. Role of the sympathoadrenal axis.

The antihypertensive action of central GABA-ergic stimulation was investigated in conscious stroke prone spontaneously hypertensive rats. Injection of the potent GABA agonist muscimol (0.01-1 microgram) into the lateral brain ventricle (icv) lowered mean arterial blood pressure (192.1 +/- 8.4 mm Hg) dose-dependently in stroke prone spontaneously hypertensive rats with a maximal fall of -52.7 +/- 5 mm Hg lasting for about 90 minutes. This was accompanied by bradycardia and sedation. Pretreatment with atropine (2 mg/kg, ip, or 15 micrograms/kg, icv) did not significantly influence the muscimol-induced fall in mean arterial pressure. In normotensive (109.3 +/- 1.9 mm Hg) Wistar-Kyoto controls, the maximal decrease in mean arterial pressure was -12.1 +/- 1.6 mm Hg from 109.3 +/- 1.9 mm Hg, and the duration of the effect was much less than in stroke prone spontaneously hypertensive rats, Following 1 microgram muscimol, icv, plasma noradrenaline did not fall significantly in stroke prone spontaneously hypertensive and Wistar-Kyoto rats, but in stroke prone spontaneously hypertensive rats, plasma adrenaline was fully suppressed (from 118.1 +/- 24.2 to 22.8 +/- 5.7 pg/ml) throughout the depressor response. The efferent sympathetic nervous activity as directly recorded from the n. splanchnicus was similar in conscious stroke prone spontaneously hypertensive and Wistar-Kyoto rats, and was moderately reduced in both strains by 1 microgram muscimol, icv.(ABSTRACT TRUNCATED AT 250 WORDS)

Gabaergic stimulation inhibits central actions of angiotensin II: pressor responses, drinking and release of vasopressin.

In conscious rats, intracerebroventricular (i.c.v.) treatment with the GABA agonist muscimol (1-100 ng) suppressed the pressor responses to ANG II (100 ng i.c.v.) in a dose-dependent and reversible fashion. Treatment i.c.v. with GABA (1-500 micrograms) produced a similar but shorter inhibition. Inhibition of endogenous GABA degradation with amino-oxyacetic acid (AOAA, 30 mg/kg i.p.) markedly reduced the pressor responses to ANG II (10-1000 ng i.c.v.) with a recovery period of 24 h. This inhibition was reversed by the GABA antagonist bicuculline (1 microgram i.c.v.). Muscimol (100 ng i.c.v.) did not significantly attenuate the pressor responses to i.c.v. histamine (10 micrograms). Pretreatment with muscimol (100 ng i.c.v.) drastically reduced the drinking responses to i.c.v. ANG II (500 ng) and increased the latency to drink. Muscimol also suppressed drinking induced by carbachol (50 ng i.c.v.). Muscimol (10-1000 ng i.c.v.) inhibited the ANG II (100 ng i.c.v.)-induced release of AVP from the pituitary gland with complete suppression of the response at the highest dose. Our results demonstrate that the GABAergic system exerts an inhibitory control on pathways mediating the various central actions of ANG II, which appears to be most specific for the ANG II-induced pressor responses.