Increased chitinase expression and fungal-specific antibodies in the bronchoalveolar lavage fluid of asthmatic children.

BACKGROUND: Increasing evidence highlights the contribution of chitinases and fungal infection to the development of asthma. OBJECTIVE: The purpose of this study was to characterize chitinase expression and serological markers of fungal infection in children with severe asthma. METHODS: Bronchoalveolar lavage fluid (BALF) was collected from children undergoing clinically indicated flexible bronchoscopy. A diagnosis of asthma was confirmed by pulmonary function testing. BALF was tested for chitinase activity and YKL-40 (an enzymatically inactive chitinase) concentrations. Specimens were cultured for fungal organisms and tested for cryptococcal antigen by ELISA. IgG and IgA reactivity to whole extract fungal (Aspergillus fumigatus, Alternaria alternata, Cryptococcus neoformans and Candida albicans) proteins were determined by immunoblot assay. RESULTS: Among the 37 patients studied, 30 were asthmatic and 7 were non-asthmatic. Asthmatics exhibited elevated serum IgE levels (median: 748 IU/mL, IQR: 219-1765 IU/mL). Chitinase activity was greater in the BALF of asthmatics (mean, 0.85 ± 1.2 U/mL) compared with non-asthmatics (mean: 0.23 ± 0.21 U/mL, P = 0.012). Likewise YKL-40 concentrations were higher in the BALF of asthmatics and correlated with chitinase activity. There was a trend towards increased fungal-specific IgG in the BALF of asthmatics compared with non-asthmatics and for C. albicans this difference reached statistical significance. IgA reactivity to C. neoformans and A. fumigatus was greater in the BALF of asthmatics compared with non-asthmatics. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with non-asthmatics, asthmatic children exhibited increased chitinase activity and increased YKL-40 levels in BALF. Increased IgG and IgA reactivity to fungal proteins in the BALF of asthmatics may reflect a local response to fungal infection. Our findings are consistent with and suggest a role for chitinases in asthma pathogenesis among Bronx children and provide serological evidence of an association between fungal infection and severe asthma.

Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function.

Combination chemotherapy with or without radiotherapy has had only modest efficacy in the treatment of primary CNS lymphoma. Median survival of these patients, treated primarily with radiotherapy, is 13 months; 5-year survival is less than 5%. Thirty consecutive non-acquired immune deficiency syndrome patients with primary CNS lymphoma were treated with barrier-dependent chemotherapy using intraarterial mannitol to open the blood-brain barrier (BBB). Follow-up included extensive neuropsychologic testing of all patients. Thirteen patients received cranial radiation 1 to 9 months before referral (group 1). Seventeen patients received initial BBB disruption chemotherapy with subsequent radiation only for tumor progression or recurrence (group 2). The difference in median survivals from diagnosis--17.8 months for group 1 and 44.5 months for group 2--was statistically significant (P = .039). Group 1 survival is comparable with the 20-month median survival of a historical series of patients (n = 208) treated with radiotherapy with or without chemotherapy. Group 2 patient survival represents an advance in the survival of CNS lymphoma and was associated with preservation of cognitive function in six of seven nonirradiated complete responders observed for 1 to 7 years. Patient toxicity was manageable in this intensive therapeutic regimen. In this series, a plateau in survival curves suggests that a major portion of these patients may be cured without the neuropsychologic sequelae associated with cranial radiation.

MR of primary CNS lymphoma in immunologically normal patients.

PURPOSE: To describe the MR findings of primary CNS lymphoma. METHODS: MR scans of 20 patients with histologically proved primary CNS lymphoma were reviewed. We evaluated the size, multiplicity, signal intensities, and enhancement characteristics of the lesions. We divided the lesions into an enhancing area referred to as Zone 1 and abnormal signal surrounding this, referred to as Zone 2. RESULTS: Primary CNS lymphoma presented as solitary enhancing lesions in 40% of the patients and multiple lesions in 40%. Thirty-three separate lesions were visible: 58% abutted the ventricular system, 76% showed a homogenous enhancement pattern, and 79% showed marked enhancement. In 64% of the lesions, Zone 1 and Zone 2 showed different signal intensities on T1-weighted images. CONCLUSIONS: Primary CNS lymphoma usually presents as solitary or multiple dense homogenous enhancing lesions that abut an ependymal surface. These lesions can be divided into an enhancing area and an area of surrounding abnormal signal. These two areas often have different signal intensities on unenhanced T2-weighted images. These findings are sufficiently suggestive of the diagnosis of primary CNS lymphoma that a needle biopsy be performed based on these findings and appropriate therapy can then be instituted.

Neuropsychological assessment outcomes of nonacquired immunodeficiency syndrome patients with primary central nervous system lymphoma before and after blood-brain barrier disruption chemotherapy.

The risk of neurotoxicity was evaluated in eight consecutive patients with non-acquired immunodeficiency syndrome (AIDS) primary central nervous system lymphoma who had survived disease free for more than 1 year after completion of treatment with osmotic opening of the blood-brain barrier and chemotherapy (methotrexate, cytoxan, procarbazine, and decadron). Trends in neuropsychological assessment results between baseline and follow-up (1 to 7 years) were analyzed for all eight nonradiated survivors. This serial assessment design addressed the specific issue of neurotoxic risk potential of treatment, when confounding factors of tumor persistence/recurrence and cranial irradiation were ruled out. Follow-up results of an extensive battery of tests to assess higher cortical function provided evidence of the safety of chemotherapy protocol with the blood-brain barrier disruption. These findings stand in contrast to well-known cognitive risks associated with cranial radiotherapy. Long-term follow-up suggests that chemotherapy can be given in conjunction with osmotic opening of the blood-brain barrier in nonradiated patients without cognitive manifestations of neurotoxicity.

The puzzle of noncompliance in the manic patient.

Patients with affective disorders may be seriously compromised by failure to comply with prescribed medication regimens. At the time of his hospitalization, the patient discussed here had a severe bipolar disorder characterized by disruptive and repetitive manic episodes that were generated by medication noncompliance and substance abuse. Through an understanding of the longitudinal and progressive development of this rapidly cycling disorder, the consultant emphasizes the importance of long-term maintenance pharmacotherapy in the context of environmental restructuring to attempt to reverse the malignant nature of the patient's affective disorder.

Transplacental transmission of Cryptococcus neoformans to an HIV-exposed premature neonate.

Cryptococcosis during pregnancy is well documented, but transmission of infection to the fetus is rare. We describe a premature neonate born to a mother with congenitally acquired human immunodeficiency virus (HIV) and active cryptococcosis. Histological examination of the placenta revealed Cryptococcus neoformans within the maternal intervillous space with focal invasion into the chorionic villi. A positive serum cryptococcal antigen (1:2) was detected on days 1 and 5 of life. The neonate had no evidence of central nervous system disease and was treated with fluconazole with resolution of antigenemia. This case highlights both the potential for transplacental transmission of C. neoformans infection and the complexities of caring for pregnant mothers who themselves are congenitally infected with HIV.

Serologic evidence for reactivation of cryptococcosis in solid-organ transplant recipients.

Cryptococcosis is a significant infection with a high mortality in solid-organ transplant recipients. Nonetheless, the pathogenesis of this disease is poorly understood. It has been hypothesized that cryptococcosis may result from either primary infection or reactivation of a latent infection. Sera were obtained from transplant recipients prior to transplantation and at the time they developed cryptococcosis. Control sera were obtained before and after transplant from patients who did not develop cryptococcosis. Sera were tested for antibodies against Cryptococcus neoformans by using an immunoblot assay. Antibody responses were also compared with those observed in sera from rats with experimental pulmonary cryptococcosis. In all, 52% of the transplant recipients who developed cryptococcosis exhibited serologic evidence of cryptococcal infection before transplantation. These patients developed cryptococcosis significantly earlier after transplant than patients without preexisting reactivity did (5.6 +/- 3.4 months compared to 40.6 +/- 63.8 months, respectively [P = 0.0011]). The results from our study suggest that a substantial proportion of transplant-associated cryptococcosis cases result from the reactivation of a latent infection. These findings also highlight the potential utility of serologic studies in identifying patients at risk for the development of cryptococcosis after transplantation.

Phenotypic switching in Cryptococcus neoformans.

Phenotypic switching has been described in serotype A and D strains of Cryptococcus neoformans. It occurs in vivo during chronic infection and is associated with differential gene expression and changes in virulence. The switch involves changes in the polysaccharide capsule and cell wall that affect the yeast's ability to resist phagocytosis. In addition, the phenotypic switch variants elicit qualitatively different inflammatory responses in the host. In animal models of chronic cryptococosis, the immune response of the host ultimately determines which of the switch variants are selected and maintained. The importance of phenotypic switching is further underscored by several findings that are relevant in the setting of human disease. These include the ability of the mucoid colony variant of RC-2 (RC-2 MC) but not the smooth variant (RC-2 SM) to promote increased intracerebral pressure in a rat model of cryptococcal meningitis. Furthermore, chemotherapeutic and immunological antifungal interventions can promote the selection of the RC-2 MC variant during chronic murine infection.

Phenotypic switching of Cryptococcus neoformans can produce variants that elicit increased intracranial pressure in a rat model of cryptococcal meningoencephalitis.

Increased intracranial pressure (ICP) plays an important role in the morbidity and mortality of cryptococcal meningoencephalitis. The microbial and host factors that contribute to the development of increased ICP are poorly understood. We found that phenotypic switch variants of Cryptococcus neoformans (smooth and mucoid) differed in their abilities to promote increased ICP in a rat model of cryptococcal meningitis. Rats infected with the mucoid variant developed increased ICP, whereas rats infected with the smooth parent did not. This trend correlated with a shorter survival time and a higher cerebrospinal fluid (CSF) fungal burden for mucoid variant-infected rats, although brain fungal burdens were comparable between mucoid variant- and smooth parent-infected rats. Magnetic resonance imaging revealed enhanced T2 signal intensity over the surfaces of the brains of mucoid variant-infected rats. In addition, more polysaccharide accumulated in the CSF and brains of mucoid variant-infected rats. The accumulation of glucorunoxylomannan was associated with elevated levels of MCP-1 (CCL2) and, accordingly, a more pronounced but ineffective monocytic inflammatory response in the meninges of mucoid variant-infected rats. In summary, these findings suggest that strain-specific characteristics can influence the development of increased ICP and indicate a manner in which phenotypic switching could influence the outcome of a central nervous system infection.

The 40 year evolution of the first modern day hospital.

The first modern psychiatric day hospital founded over 40 years ago has gone through a number of re-organizations which reflect utilization patterns representative of day hospitals in general. The author traces chronologically the dynamic movement from self-contained settings emphasizing group integration to expanded structures providing individualized treatment approaches. The day hospital's unique location at the interface of the institution and the community has important implications for today's mental health policy.

The uses of a medication group in a day hospital.

This paper explores the multiple uses of a psychiatrist-conducted educational group for patients on psychopharmacotherapy. The advantages of such an approach are considered from the viewpoint of the psychiatrist, the patients, and the nonmedical staff. Model answers to questions of particular concern to group members are examined.

Understanding partial hospitalization through organizational models.

This paper discusses three interrelated organizational models relevant to partial hospitalization. Such a management perspective can play an important role in the planning of effective mental health-care delivery structures.

Two pioneers of today's partial hospital and their ideas.

Inspiration for the modern-day hospital comes from two sources, the hospital-based work of D. Ewen Cameron and the community-oriented approach of Joshua Bierer. Examination of their respective viewpoints sheds light on the baffling diversity which partial hospitalization, at the interface of hospital and community, has manifested over the last four decades. Such an intellectual history offers insights into the provision of more rational day programming.

Historical notes on partial hospitalization.

The author addresses the historical antecedents of three important aspects of partial hospitalization: (1) therapeutic use of the milieu, (2) decentralization of hospital-based care, and (3) a pluralistic view of the human organism. In the process, a tour d'horizon of Western psychiatry from the period of Phillipe Pinel to that of Adolf Meyer is provided. Such an excursion into history permits a greater appreciation of the partial hospital setting and the relevance of history in the evolution of psychiatric thinking.

Dorothea Dix and her two missions of mercy in Nova Scotia.

Dorothea Lynde Dix, 19th century defender of the rights of the mentally ill to hospital care, holds a significant place in the history of Nova Scotia. Her two major accomplishments in this province include laying the groundwork for its first psychiatric hospital and the outfitting of treacherous Sable Island with rescue equipment to aid ships stranded off its shore. The techniques that Miss Dix employed in these missions parallel those she successfully used in the establishment of psychiatric hospitals in a number of American states. It will be argued that her influence has been a positive one on the treatment of the mentally ill particularly in light of the failures of the deinstitutionalization movement.

Partial-hospital treatment of potentially violent patients, or who's afraid of Tatiana Tarasoff?

Partial hospitalization has taken on an increasingly important role in the treatment of violence-prone patients. In response to the 1976 Tarasoff decision in California and its progeny widening the scope in many jurisdictions of a therapist's duty to protect endangered third parties from the violent acts of such individuals, strategies relevant to the day hospital need to be formulated. Treaters can provide beneficial containment through the use of informed consent, the therapeutic contract, and reality-based work which involves the patient and significant others. Nevertheless, the partial-hospital team must not lose sight of the limits of such interventions and should consider inpatient care as a serious option.

Anatomy of a second generation Tarasoff case.

Few medicolegal doctrines have spread so widely and wildly as the Tarasoff duty of professionals to protect potential victims of violence perpetrated by psychiatric patients. Post-Tarasoff decisions have not been limited to identifiable third parties in danger, but in some circumstances have been extended to the community at large. Lipari v. Sears, Roebuck and U.S. is the first of such court rulings to invoke the concept of strict liability for the violent acts of a patient who, in the case presented, randomly fired at club patrons, killing one and wounding many others. A detailed examination of this pivotal and troubling case will facilitate recognition of the inherent complexity associated with subjecting human problems to the legal process.

The psychiatric certification examination in Canada and the United States: views of two recent candidates.

The psychiatry certification process in both Canada and the United States is compared. Three important and interrelated areas are delineated: 1) the role of mandatory certification in Canada versus voluntary certification in the United States; 2) the differing emphasis of neurology and the medical model in the two exam procedures; and 3) the effect of the speciality exam on professional development. Compulsory certification in Canada has the potential to steer candidates in a direction that may not be immediately consonant with career plans and population needs. On the other hand, the American Board examination by its optional character does not seem to reach a large percentage of psychiatrists, an issue that has implications for the education of medical professionals. The ambiguity of the American Board's quasi-public position is portrayed. Competence in neurology appears as a distinct area for evaluation in the American Board of Psychiatry and Neurology examination. The emphasis on neurology in the Canadian Royal College exam is less marked. These issues lead to a discussion of psychiatry in Canada as a discipline in its own right as contrasted to the mixed loyalties to neurology and psychotherapy perceived in the American system. Finally, this paper sheds light on how the certification examination of both countries plays an important role in the passage to full professional status.