Alexander disease: putative mechanisms of an astrocytic encephalopathy

Alexander disease (AXD) is the first primary astrocytic disorder. This encephalopathy is caused by dominant mutations in the glial fibrillary acidic protein (GFAP) gene, encoding the main intermediate filament of astrocyte. Pathologically, this neurodegenerative disease is characterised by dystrophic astrocytes containing intermediate filament aggregates associated with myelin abnormalities.More than 20 GFAP mutations have been reported. Many of them cluster in highly conserved regions between several intermediate filaments. Contrary to other intermediate filament-related diseases, AXD seems to be the consequence of a toxic gain of function induced by aggregates. This is supported by the phenotype of mice overexpressing human GFAP. Nevertheless, GFAP null mice display myelin abnormalities and blood-brain barrier dysfunction that are present in AXD.Given the pivotal role of astrocytes in brain physiology, there are many possibilities for astrocytes to dysfunction and to impair the functions of other cells. Physiopathological hypotheses are discussed in the frame of AXD.Received 11 April 2003; received after revision 22 July 2003; accepted 31 July 2003Both authors contributed equally to this work.     

What’s new in the renin-angiotensin system?

The angiotensin AT(4) receptor was originally defined as the specific, high-affinity binding site for the hexapeptide angiotensin IV (Ang IV). Subsequently, the peptide LVV-hemorphin 7 was also demonstrated to be a bioactive ligand of the AT(4) receptor. Central administration of Ang IV, its analogues or LVV-hemorphin 7 markedly enhance learning and memory in normal rodents and reverse memory deficits observed in animal models of amnesia. The AT(4) receptor has a broad distribution and is found in a range of tissues, including the adrenal gland, kidney, lung and heart. In the kidney Ang IV increases renal cortical blood flow and decreases Na(+) transport in isolated renal proximal tubules. The AT(4) receptor has recently been identified as the transmembrane enzyme, insulin-regulated membrane aminopeptidase (IRAP). IRAP is a type II integral membrane spanning protein belonging to the M1 family of aminopeptidases and is predominantly found in GLUT4 vesicles in insulin-responsive cells. Three hypotheses for the memory-potentiating effects of the AT(4) receptor/IRAP ligands, Ang IV and LVV-hemorphin 7, are proposed: (i) acting as potent inhibitors of IRAP, they may prolong the action of endogenous promnestic peptides; (ii) they may modulate glucose uptake by modulating trafficking of GLUT4; (iii) IRAP may act as a receptor, transducing the signal initiated by ligand binding to its C-terminal domain to the intracellular domain that interacts with several cytoplasmic proteins.     

An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice

Inflammation influences iron balance in the whole organism. A common clinical manifestation of these changes is anemia of chronic disease (ACD; also called anemia of inflammation). Inflammation reduces duodenal iron absorption and increases macrophage iron retention, resulting in low serum iron concentrations (hyposideremia). Despite the protection hyposideremia provides against proliferating microorganisms, this 'iron withholding' reduces the iron available to maturing red blood cells and eventually contributes to the development of anemia. Hepcidin antimicrobial peptide (Hamp) is a hepatic defensin-like peptide hormone that inhibits duodenal iron absorption and macrophage iron release. Hamp is part of the type II acute phase response and is thought to have a crucial regulatory role in sequestering iron in the context of ACD. Mice with deficiencies in the hemochromatosis gene product, Hfe, mounted a general inflammatory response after injection of lipopolysaccharide but lacked appropriate Hamp expression and did not develop hyposideremia. These data suggest a previously unidentified role for Hfe in innate immunity and ACD.     

The central dusty torus in the active nucleus of NGC 1068

Active galactic nuclei (AGNs) display many energetic phenomena--broad emission lines, X-rays, relativistic jets, radio lobes--originating from matter falling onto a supermassive black hole. It is widely accepted that orientation effects play a major role in explaining the observational appearance of AGNs. Seen from certain directions, circum-nuclear dust clouds would block our view of the central powerhouse. Indirect evidence suggests that the dust clouds form a parsec-sized torus-shaped distribution. This explanation, however, remains unproved, as even the largest telescopes have not been able to resolve the dust structures. Here we report interferometric mid-infrared observations that spatially resolve these structures in the galaxy NGC 1068. The observations reveal warm (320 K) dust in a structure 2.1 parsec thick and 3.4 parsec in diameter, surrounding a smaller hot structure. As such a configuration of dust clouds would collapse in a time much shorter than the active phase of the AGN, this observation requires a continual input of kinetic energy to the cloud system from a source coexistent with the AGN.     

Allogeneic effect on induction of thyroglobulin antibodies and thyroid lesions in mice

Summary All previous attempts failed to induce thyroglobulin antibodies or thyroid infiltrates in mice immunized with homologous thyroglobulin without adjuvants. However, an allogeneic effect obviated the need of adjuvants for triggering thyroglobulin-reactive lymphocytes to produce thyroglobulin antibodies or thyroid lesions.This work was supported by a grant from the Margaret Duffy and Robert Cameron C. Troup Fund. I thank Ellen Kenney for technical assistance and Dr Pei-nan Tsung for the X-ray irradiation.     

EEG synchronization produced by peripheral nerve stimulation

Riassunto La stimolazione a 3–8/sec di nervi cutanei e muscolari, eseguita in gatti integri non anestetizzati, produce una sincronizzazione dell'attività elettrica cerebrale. La soglia per questa risposta corrisponde in media a 0,4–0,9 volte l'intensità minima di corrente che applicata allo stesso nervo e in analoghe condizioni sperimentali produce la reazione di risveglio.

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This investigation was supported by PHS research grant B-2990 from the National Institute of Neurological Diseases and Blindness, N.I.H., Public Health Services, U.S.A.     

The importance of autoplastically transplanted pituitaries for survival and for regeneration of adultTriturus

Résumé Une hypophyse greffée autoplastiquement dans la chambre antérieure de l'il, dans lemanus ou dans letarsus s'est avérée capable de remplacer l'hypophysein situ dans son action sur la régénération et la survie chez le Triton, à condition que s'établisse une vascularisation satisfaisante du greffon et que la durée de l'expérience ne dépasse pas plusieurs mois.