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Central nervous system (CNS) drainage may occur via connections to the vasculature, but in animal models up to 50% occurs via perivascular, perineural and primitive lymphatic drainage to cervical lymph nodes. We evaluated efflux of particles from the brain to cervical lymph nodes in normal rats, using Combidex iron oxide-based magnetic resonance imaging (MRI) agent. After intracerebral, intraventricular, intracarotid or intravenous injection of Combidex in normal Long Evans rats, particle localization was assessed by MRI and histochemistry for iron and the dextran coat (n = 27). Intraventricular or intracerebral injection, but not intracarotid administration of Combidex (100 micro g), resulted in MRI signal changes in the deep cervical lymph nodes around the carotid artery, and, less strongly, in the superficial cervical nodes. Within 2 h of Combidex administration, iron was histologically localized in cervical lymph nodes, with patched staining of capsule and peripheral sinus consistent with delivery via multiple afferent lymphatic vessels. Lymph node staining in groups receiving CNS Combidex was significantly different from controls (P < 0.0001) and was significantly localized in the deep vs. superficial cervical lymph nodes (P = 0.0003). The trafficking of the superparamagnetic iron particles from the CNS in the rat could be visualized by MRI and histology. Combidex provides a powerful tool to rapidly assess drainage of virus-sized particles from the CNS.

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Modulation of glutathione has been proposed as a mechanism to alter the efficacy and toxicity of chemotherapeutic agents. We investigated in vitro cytoenhancement of chemotherapy toxicity by reducing cellular glutathione levels with L-buthionine-[S,R]-sulfoximine (BSO), and chemoprotection with small molecular weight sulfur-containing agents that mimic or replace glutathione. Cytotoxicity, caspase-2 enzymatic activity, and in situ DNA staining for apoptosis were assessed in cultured human small cell lung carcinoma cells and fibroblasts. BSO treatment reduced the half-maximal cytotoxic dose of the alkylating chemotherapeutics melphalan, carboplatin, and cisplatin, and increased the total magnitude of cell death. Melphalan was more sensitive than carboplatin or cisplatin to BSO. The chemoprotective agents sodium thiosulfate, N-acetylcysteine, and glutathione ethyl ester reduced the cytotoxicity of all three alkylating chemotherapeutics regardless of BSO treatment, but D-methionine was effective only against the platinum agents. N-Acetylcysteine was the most effective protectant tested. Chemoprotection against melphalan toxicity was maximally effective only if administered concurrent with chemotherapy, whereas chemoprotection for the platinum agents remained effective if delayed 4 h after chemotherapy. BSO enhancement and N-acetylcysteine chemoprotection for melphalan toxicity occurred at least partially through an apoptotic mechanism. Modulation of glutathione levels will be valuable in the clinical setting if chemotherapy and chemoprotectant can be physically and/or temporally separated. Cytoenhancement and chemoprotection may be particularly useful in the central nervous system where the blood-brain barrier of the cerebral vasculature creates two compartments, for cytoenhancement in brain tumors and systemic chemoprotection.

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INTRODUCTION: The Boston HAPPENS (HIV Adolescent Provider and Peer Education Network for Services) program is a collaborative network of care made up of 8 organizations that serve youth and provide coordinated care for human immunodeficiency virus (HIV)-positive, homeless, and at-risk youth aged 12 to 24 years. Learning youth perceptions about the program is essential to determine if the program is meeting their needs. METHODS: In this qualitative evaluation, 18 youth served by the network met in 4 focus groups to provide their view of the program. Services within 5 categories were assessed: (a) medical care, (b) mental health and substance abuse care, (c) HIV prevention and care, (d) case management, and (e) allocation of finances. RESULTS: Boston HAPPENS has achieved name recognition and provides many needed services for youth from a wide variety of backgrounds. The youth were comfortable receiving care and were appreciative of the comprehensive services available. They provided suggestions for how mental health services could be offered as one-on-one counseling as part of "wellness care." Young participants also requested more recreational and support opportunities for young people living with HIV. DISCUSSION: Qualitative evaluations such as this give a voice to youth to advocate for services they need. By including youth ideas and perspectives during program development and implementation, services can be more attractive to groups of at-risk youth who historically have been less likely to seek care.

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BACKGROUND: Overexpression of the 70 kDa heat shock protein (Hsp70) protects myocytes and neural cells from hypoxic injury. In contrast, Hsp70 induction in the kidney after ischemic or thermal preconditioning does not correlate well with protection from hypoxic injury. Herein, we directly tested if Hsp70 overexpression protects LLC-PK1 porcine tubular epithelial cells from hypoxic or thermal injury. METHODS: LLC-PK1 cells were either cotransfected with an Hsp70 and a luciferase expression vector or singly transfected with the luciferase expression vector. Loss of intracellular luciferase activity was used to assess injury after exposure to hypoxia or hyperthermia and after recovery under normal growth conditions. RESULTS: Overexpression of Hsp70 decreased loss of and improved restoration of intracellular luciferase activity in LLC-PK1 cells exposed to hyperthermia. In contrast, Hsp70 overexpression did not decrease the loss of or improve restoration of luciferase activity in cells exposed to hypoxia. CONCLUSIONS: These results suggest that Hsp70 overexpression is sufficient to protect LLC-PK1 proximal tubular cells from hyperthermia but is not sufficient for protection from hypoxia.

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In animal models of cardiac or cerebral ischemic preconditioning, induction of heat shock proteins (HSPs), especially HSP70, correlates with protection from subsequent injury. The extent of HSP70 induction after stress correlates inversely with initial HSP70 levels. Primate cells, unlike nonprimate cells, express high basal levels of HSP70; thus, primate cells may respond differently to preconditioning than nonprimate cells. We have demonstrated that exposing cultured human proximal tubular epithelial cells (PTEC) to 12 h of hypoxia followed by a 24-h recovery period (hypoxic preconditioning) induces resistance to subsequent hypoxic injury. Herein, we characterize the expression of HSP70, HSP90, and heat shock cognate-70 (HSC70) in PTEC under basal conditions and after hypoxic preconditioning. By Northern blot analysis, we demonstrate that hypoxic preconditioning of PTEC increases mRNA for HSP70 > HSP90 > HSC70. With reverse transcription and polymerase chain reaction, mRNA transcripts from three different HSP70 genes (HSP70 A, B, and C) were detected in unstressed PTEC. Transcripts from these genes were also detected in freshly isolated human renal cortex, indicating that all three genes are expressed in vivo. By Western blot analysis, we demonstrate that PTEC express high basal levels of HSP70, HSC70, and HSP90. Hypoxic preconditioning did not lead to a significant increase in protein content of any of these HSPs, despite increased mRNA levels. This suggests that HSP accumulation cannot account for the development of cytoresistance after hypoxic preconditioning in PTEC. However, high basal expression of HSP70 in human PTEC may contribute to their innate resistance for hypoxia.

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There are few qualitative studies that assess the experiences and preferences of urban youth with regard to use of primary care. The purpose of this pilot survey was to identify positive and negative influences and underlying issues for adolescents leading to seeking and returning for primary health care. Four focus groups totaling 20 diverse adolescents ranging in age from 13 to 21 years were conducted between April 1994 and June 1994. Participants were recruited through existing peer leadership groups that meet regularly at community health centers or afterschool programs. Urban adolescents are most concerned with being respected and treated well by primary care providers. They want to be listened to, to have their problems taken seriously, and to be treated with dignity and respect. Participants expressed strong preferences regarding sex, sexual orientation, and language of providers, but not for race or ethnicity. Qualitative methods such as focus groups give a voice to youth to advocate for access to adolescent-specific health services. Further research is needed to corroborate the results of this study, to expand our understanding of existing problems, and to investigate the predictors of health care use by vulnerable youth.

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