Electrophysiological and pharmacological evidence in favor of amino acid neurotransmission in fimbria-fornix fibers innervating the lateral septal complex of rats

Summary Electrical stimulation of fimbria-fornix (fifx) fibers monosynaptically activated many of the neurons tested in the lateral septal complex (LSC) of the rat. The orthodromically activated LSC neurons were classified as strongly orthodromically activated (SOA) or weakly orthodromically activated (WOA) cells according to their threshold for eliciting a response, stability of the response latency, frequency following and the stimulus-response ratio.Microiontophoretically applied glutamate (GLU) could excite both SOA and WOA neurons. However, the expelling currents needed to activate the SOA cells were often considerably lower than those necessary to excite the WOA cells suggesting higher sensitivity to GLU of those cells which receive a strong fi-fx innervation. Iontophoretically administered glutamic acid diethylester (GDEE) in general reversibly attenuated excitatory responses of LSC cells to GLU but not to acetylcholine. GDEE was also effective in blocking the synaptic responses of SOA septal cells to fi-fx stimuli. In addition, GDEE administered topically reversibly suppressed the field potential induced in the LSC by fi-fx stimulation.These electrophysiological and pharmacological results support recent biochemical observations suggesting that the excitatory innervation of LSC neurons by fi-fx fibers is mediated by GLU or a closely related excitatory amino acid.The investigations were supported by the Foundation for Medical Research FUNGO which is subsidized by the Netherlands Organization for Advancement of Pure Research (Z.W.O.), grant 13-31-045 awarded to I.J. A. Urban     

Unterschiedliche Reaktion von Lymphocyten auf Phythämagglutinin (PHA) bei Lebererkrankungen

Zusammenfassung Lymphocyten aus peripherem Blut von Patienten mit akuter infektiöser Hepatitis und aggressiv chronischer Hepatitis konnten in der Kultur nicht durch PHA stimuliert werden. Die RNS-Synthese unterschied sich nicht von der unstimulierter Lymphocyten. Die DNS-Synthese lag signifikant niedriger als die stimulierter Lymphocyten von Gesunden. Die Blutlymphocyten von Patienten mit Alkoholhepatitis und Arzneimittelikterus wiesen dagegen eine normale PHA-Reaktion auf. Diesen Befunden könnte eine klinisch-differentialdiagnostische Bedeutung für die Abgrenzung der akuten infektiösen Hepatitis vom Arzneimittelikterus und der Alkoholhepatitis zukommen. Die gleichartige Hemmung der PHA-Reaktion bei chronisch aggressiver Hepatitis und akuter infektiöser Hepatitis läßt auf eine gleichartige Veränderung der peripheren Lymphocyten bei beiden Erkrankungen schließen. Der Nachweis dieser Funktionsstörung könnte die Hypothese stützen, daß es sich bei der aggressiv chronischen Hepatitis um eine persistierende Virusinfektion handelt.

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Summary Peripheral lymphocytes from patients with acute infectious hepatitis and aggressive chronic hepatitis could not be stimulated by PHA in culture. The RNA synthesis was not increased above control levels. The DNA synthesis was significantly lower than in stimulated lymphocytes from healthy persons. Lymphocytes from patients with alcohol hepatitis and from patients with drug jaundice showed a normal response to PHA. These findings might be helpful in differentiating acute infectious hepatitis from alcohol hepatitis and drug jaundice. The suppression of the response to PHA in aggressive chronic hepatitis and acute infectious hepatitis suggests a similar functional lesion in peripheral lymphocytes in both diseases. This could support the hypothesis of a persisting viral infection in aggressive chronic hepatitis.

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Die Untersuchungen wurden mit Unterstützung der Deutschen Forschungsgemeinschaft durchgeführt.     

Impaired responses to toll-like receptor 4 and toll-like receptor 3 ligands in human cord blood

Toll-like receptor (TLR)-4 signaling pathway plays an essential role in host defense against gram-negative bacteria while TLR-3-mediated signaling is critically involved in anti-viral immunity. To gain insight into the defects responsible for impaired Th1 responses in human newborns, we investigated the responses of human cord blood cells to lipopolysaccharide, LPS, and to polyinosinic-polycytidylic acid, Poly (I:C), ligands of TLR-4 and TLR-3, respectively. Measurement of cytokine levels revealed a profound defect in IL-12 (p70) synthesis and an increased release of IL-10 in cord blood exposed to LPS or Poly (I:C), as compared to adult blood. Moreover, Poly (I:C)-induced IFN-alpha production was found to be significantly impaired in cord blood. Phenotypic maturation of myeloid DC in response to LPS or Poly (I:C) was next compared in cord and adult blood. We observed that neonatal myeloid DC displayed decreased upregulation of CD40, CD80 whereas CD86 and HLA-DR upregulation did not differ significantly between adults and neonates. Taken together, these findings might be relevant to the increased vulnerability of human newborns to intracellular pathogens and to their inability to develop efficient Th1-type responses.     

Autoantibodies directed against the amino-terminal domain I of human calpastatin (ACAST-DI Ab) in connective tissue diseases. High levels of ACAST-DI Ab are associated with vasculitis in lupus

To identify new autoantibody populations in patients with rheumatic diseases, a cDNA expression library was immunoscreened with a rheumatoid arthritis (RA) patient's serum which contains autoantibodies binding to uncharacterized polypeptides by Western-blotting. One clone encoding the amino-terminal region (Nt) [domain L and half of domain I] of human calpastatin was selected. Different fragments of the selected cDNA were prepared and the corresponding recombinant polypeptides were produced by in vitro translation and analysed by Western blotting. Most RA sera bound to recombinant amino-terminal region and domain I but not to domain L. This prompted us to use a recombinant polypeptide corresponding to the domain I of calpastatin as the antigen in a solid-phase ELISA to test sera from patients with various systemic rheumatic diseases and healthy controls.Anti-calpastatin domain I antibodies (ACAST-DI Ab), were detected by ELISA in RA, systemic lupus erythematosus (SLE), Sj?gren's syndrome and control sera at respective frequencies of 10, 9, 0 and 1%. These Ab did not have prognostic value in early RA; high levels were significantly associated with vasculitis in SLE. Antibodies reacting with the calpastatin amino-terminal region are produced during systemic rheumatic diseases and are predominantly directed against domain I. High levels of these Ab may constitute a marker of vasculitis in SLE.     

Impact of a patient education program on adherence to HIV medication: a randomized clinical trial

Patients' knowledge of their HIV condition and its treatment, which has been recognized as a factor that influences adherence to antiretroviral therapy, can be improved through educational programs. This prospective, randomized, controlled trial compared an experimental group that participated in an educational program and a control group with standard care. The study evaluated the impact of an educational intervention on adherence to antiretroviral therapy, patients' knowledge, quality of life, and therapeutic response in patients treated with highly active antiretroviral therapy. Three hundred twenty-six patients were analyzed at inclusion. A higher level of adherence was associated with patients who were older, had higher incomes, and did not smoke. CD4 cell count and plasma viral load were correlated with adherence at entry. The educational intervention had an impact on adherence and knowledge in the experimental group at 6 months, which was maintained at 12 and 18 months. A delayed increase in adherence was observed in the control group at 12 months. No significant impact on quality of life was observed over time. The patients' health status improved in 56% of the experimental group subjects and 50% of the control subjects. However, no significant impact was shown on CD4 cell count and plasma viral load. This study shows that an educational intervention improves adherence to antiretroviral regimens and health status and suggests that it should be initiated early in therapy.     

Pre- and postnatal depression and coping: a comparative approach

BACKGROUND: The assessment of perinatal depressions and coping style. Methods: With depression scales (EPDS, GHQ.12) and Carver's BriefCope, the authors compared the prevalence rates of pre and postnatal depression in a cohort of 277 French women. RESULTS: Their work revealed very high levels of prenatal depression (almost 20%) and less important but nonetheless sizeable rates (11%) of postnatal depression, making such perinatal depressions a major public health concern. The coping styles proposed in Carver's public health BriefCope questionnaire make it possible to significantly differentiate during these two periods between depressive women and their non-depressed counterparts. CONCLUSIONS: This enables us to underline factors of risk and protection suggesting the importance of setting up compensatory and preventive systems and evaluating their pertinence in the framework of future research.     

Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage

ATP-binding cassette (ABC) transporters facilitate unidirectional translocation of chemically diverse substances, ranging from peptides to lipids, across cell or organelle membranes. In peroxisomes, a subfamily of four ABC transporters (ABCD1 to ABCD4) has been related to fatty acid transport, because patients with mutations in ABCD1 (ALD gene) suffer from X-linked adrenoleukodystrophy (X-ALD), a disease characterized by an accumulation of very-long-chain fatty acids (VLCFAs). Inactivation in the mouse of the abcd1 gene leads to a late-onset neurodegenerative condition, comparable to the late-onset form of X-ALD [Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M. and Mandel, J.L. (2002) Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum. Mol. Genet., 11, 499-505.]. In the present work, we have generated and characterized a mouse deficient for abcd2, the closest paralog to abcd1. The main pathological feature in abcd2-/- mice is a late-onset cerebellar and sensory ataxia, with loss of cerebellar Purkinje cells and dorsal root ganglia cell degeneration, correlating with accumulation of VLCFAs in the latter cellular population. Axonal degeneration was present in dorsal and ventral columns in spinal cord. We have identified mitochondrial, Golgi and endoplasmic reticulum damage as the underlying pathological mechanism, thus providing evidence of a disturbed organelle cross-talk, which may be at the origin of the pathological cascade.