Morphological features of the entorhinal-hippocampal connection

The goal of this review in an overview of the structural elements of the entorhinal-hippocampal connection. The development of the dendrites of hippocampal neurons will be outlined in relation to afferent pathway specificity and the mature dendritic structure compared. Interneurons will be contrasted to pyramidal cells in terms of processing of physiological signals and convergence and divergence in control of hippocampal circuits. Mechanisms of axonal guidance and target recognition, target structures, the involvement of receptor distribution on hippocampal dendrites and the involvement of non-neuronal cellular elements in the establishment of specific connections will be presented. Mechanisms relevant for the maintenance of shape and morphological specializations of hippocampal dendrites will be reviewed. One of the significant contexts in which to view these structural elements is the degree of plasticity in which they participate, during development and origination of dendrites, mature synaptic plasticity and after lesions, when the cells must continue to maintain and reconstitute function, to remain part of the circuitry in the hippocampus. This review will be presented in four main sections: (1) interneurons-development, role in synchronizing influence and hippocampal network functioning; (2) principal cells in CA1, CA3 and dentate gyrus regions-their development, function in terms of synaptic integration, differentiating structure and alterations with lesions; (3) glia and glia/neuronal interactions-response to lesions and developmental guidance mechanisms; and (4) network and circuit aspects of hippocampal morphology and functioning. Finally, the interwoven role of these various elements participating in hippocampal network function will be discussed.     

Lymphoscintigraphic identification of sentinel lymph nodes: clinical evaluation of 0.22-micron filtration of Tc-99m sulfur colloid

PURPOSE: To evaluate the use of 0.22-micron filtration of technetium-99m sulfur colloid particles in the optimization of lymphoscintigraphy. MATERIALS AND METHODS: Forty-one consecutive lymphoscintigraphic studies obtained with 0.22-micron filtration of Tc-99m sulfur colloid in 41 patients (26 men, 15 women; average age, 55.4 years) and 41 consecutive studies obtained with 5.0-micron filtration in 41 patients (20 men, 21 women; average age, 54.5 years) were retrospectively, randomly reviewed. Studies were evaluated for lymphatic channel depiction and sentinel lymph node depiction. Studies included immediate flow images (obtained at 10 seconds per frame) and multiview static images obtained up to 2 hours after intradermal Tc-99m sulfur colloid injection. RESULTS: The number of drainage beds visualized was 52 with 5.0-micron filtration and 51 with 0.22-micron filtration (P = .570). The number of lymphatic channels visualized was 45 with 5.0-micron filtration and 75 with 0.22-micron filtration (P = .006). The number of lymph nodes visualized was 102 with 5.0-micron filtration and 123 with 0.22-micron filtration (P = .123). The number of studies judged as optimal (i.e., depicted lymphatic channels leading to sentinel nodes) was 10 with 5.0-micron filtration and 19 with 0.22-micron filtration (P = .038). The number of studies with depicted lymph nodes but no depicted lymphatic channel was 15 with 5.0-micron filtration and six with 0.22-micron filtration (P = .023). CONCLUSION: The use of 0.22-micron filtration in the preparation of Tc-99m sulfur colloid substantially improves study quality and increases the diagnostic certainty in the identification of sentinel lymph nodes.     

CD40 ligand/trimer DNA enhances both humoral and cellular immune responses and induces protective immunity to infectious and tumor challenge

CD40/CD40 ligand interactions have a central role in the induction of both humoral and cellular immunity. In this study, we examined whether a plasmid expressing CD40 ligand/trimer (CD40LT) could enhance immune responses in vivo. BALB/c mice were injected with plasmid expressing beta-galactosidase DNA with or without CD40LT DNA or IL-12 DNA, and immune responses were assessed. Mice vaccinated with beta-gal DNA plus CD40LT DNA or IL-12 DNA had a striking increase in Ag-specific production of IFN-gamma, cytolytic T cell activity, and IgG2a Ab. The mechanism by which CD40LT DNA enhanced these responses was further assessed by treating vaccinated mice with anti-IL-12 mAb or CTLA-4 Ig (CTLA4Ig). Production of IFN-gamma and CTL activity was abrogated by these treatments, suggesting that CD40LT DNA was mediating its effects on IFN-gamma and CTL activity through induction of IL-12 and enhancement of B7 expression, respectively. Physiologic relevance for the ability of CD40LT DNA to enhance immune responses by the aforementioned pathways was shown in two in vivo models. First, with regard to CTL activity, mice vaccinated with CD40LT DNA did not develop metastatic tumor following challenge with lethal dose of tumor. Moreover, in a mouse model requiring IL-12-dependent production of IFN-gamma, mice vaccinated with soluble Leishmania Ag and CD40LT DNA were able to control infection with Leishmania major. These data suggest that CD40LT DNA could be a useful vaccine adjuvant for diseases requiring cellular and/or humoral immunity.     

Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors

PURPOSE: A phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given by 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects. METHODS: In vitro and in vivo preclinical studies demonstrated increased activity with prolonged nolatrexed exposure. In 32 patients, nolatrexed was given as a 5-day infusion at 96 to 1,040 mg/m2/d for 5 days. Pharmacokinetics were determined from high-performance liquid chromatography (HPLC) analyses of plasma and urine. In addition to studying toxicity, plasma deoxyuridine (UdR) elevations were measured as a marker of TS inhibition. RESULTS: The MTD was 904 mg/m2/d for 5 days and the recommended phase II dose is 800 mg/m2/d for 5 days. The dose-limiting toxicity was neutropenia with clinically significant thrombocytopenia and mucositis. These antiproliferative toxicities of nolatrexed were predictable and reversible. A partial response that lasted 3 months occurred in a patient with metastatic colorectal cancer. Pharmacokinetics were nonlinear, with the median plasma clearance (CI) decreasing from 151 mL/min/m2 (range, 124 to 211) at 96 mg/m2/d for 5 days to 49 mL/min/m2 (range, 30 to 84) at 768 mg/ m2/d for 5 days. The half-life (t1/2) was 173 minutes (range, 43 to 784) and 18% (range, 9% to 35%) of the dose was excreted unchanged in the urine. Plasma UdR increased, but returned to pretreatment levels after the end of infusion. Hematologic toxicity was significantly related to nolatrexed plasma concentrations and dose. CONCLUSION: Nolatrexed can be safely administered to patients at a dose of 800 mg/m2/d over 5 days by continuous intravenous infusion and this schedule is associated with antitumor effects. The phase II evaluation of nolatrexed is ongoing.     

Effects of active immunization of sheep against an amino terminal peptide of the inhibin alpha C subunit on intrafollicular levels of activin A, inhibin A and follistatin

This article reviews issues involved in the diagnosis of insomnia and discusses treatment options, including pharmacologic treatment, which is indicated mainly in acute insomnia. Sleep hygiene is then discussed. Finally, the various behavioral treatments are reviewed, including light therapy, relaxation training, cognitive therapy, sleep curtailment, and stimulus control therapy.