Genetic determinants: is there an "atherosclerosis gene"?

It is now clear that atherosclerotic disease is a chronic inflammatory disease triggered by a sequence of events initiated at sites with turbulent flow under normal conditions such as in the coronary arteries or at bifurcations or where normal laminar flow is replaced by turbulent flow because of vessel pathologies. Normally, laminar flow is protected by generation of NO by endothelial NO synthase (eNOS), which becomes activated via stretch activated channels. When the flow turns turbulent, such protective NO generation ceases, leading to endothelial cell activation and lipid deposition into the extra-cellular space. There, lipoproteins and specifically phospholipids become oxidized by cells of the monocytic-macrophage lineage. Only when the LDL-cholesterol level is high enough lipid peroxidation products are generated in sufficient amounts to perpetuate the disease by generating a feed forward loop of endothelial cell activation leading to an inflammatory response. That inflammatory response might also be added by bacterial or viral infections such as Chlamydia pneumoniae or viruses. The disease then progresses to a chronic inflammatory state, whereby the immune system seems to contribute significantly and markers of chronic inflammation such as fibrinogen, leukocytes, PAI-1 and CRP are found increased.     

Prostaglandin E2 synthesis in human monocyte-derived dendritic cells

Prostaglandin E2 (PGE2), which is generated by the enzymatic activity of cyclooxygenase-1 and -2 (COX-1/2), plays a central role in the maturation process of dendritic cells (DC). Since regulation of COX-1/2 expression in human DC is only partially understood, we addressed the expression and activity of COX-1/2 in these cells. Here we show that lipopolysaccharide (lps) induces COX-2 mRNA and protein synthesis as well as the release of PGE2 in human interleukin-4 and granulocyte/macrophage colony-stimulating factor-differentiated monocyte-derived DC cultivated in the presence of 1% human plasma. Moreover, we found that lps induces p38 stress-activated protein kinase (p38) in these cells and inhibitors of p38 blocked lps-induced COX-2 expression and activity. Our data indicate that during lps-induced maturation p38 regulates COX-2 expression and PGE2 synthesis in DC.     

Low sialic acid-bearing mouse thymocytes do not express helper T cell properties in vitro

Immature, presumably cortical, mouse thymocytes were isolated by removing mature thymocytes by agglutination with the sialic acid-specific lectin, lobster agglutinin 1 (LAg1). These immature cells do not respond to the mitogenic effects of concanavalin A (Con A), even in the presence of interleukin 2. Moreover, they do not exhibit two properties of helper T cells; they do not secrete interleukin 2 when stimulated with Con A, nor do they provide T help for an in vitro immune response by spleen B cells to the T-dependent antigen, sheep erythrocytes. LAg1-negative thymocytes fail to provide T help even though Con A is added to the cultures, regardless of the number of LAg1-negative thymocytes added per culture, and even in the presence of exogenous macrophages. Unseparated thymocytes, LAg1-positive thymocytes and cortisone-resistant thymocytes all provide T cell help under these conditions. These experiments indicate that immature, presumably cortical mouse thymocytes, isolated by virtue of their low levels of surface sialic acid, are inherently unable to provide T cell help in vitro.     

Localization of a highly specific neuronal protein,serotonin binding protein,in thyroid parafollicular cells

A highly specific serotonin binding protein (SBP) has been found in serotonergic neurons in both brain and gut. This protein has an extremely high affinity for serotonin and may be a storage protein. Serotonin is found in many endocrine cells, including parafollicular cells of the sheep thyroid, as well as in neurons. SBP is also present in sheep thyroid. The present study was done to localize the protein in the gland. Thyroid glands were divided into five segments. Concentrations of serotonin and SBP, as well as parafollicular cell volume were measured in each. Serotonin was assayed by enzymatic conversion to melatonin using tritiated S-adenosylmethionine. SBP was assayed by molecular sieve chromatography on sephadex G-50. The relative volume of parafollicular cells was obtained by stereological analysis of electron micrographs. Experiments were also done to demonstrate these cells by histofluorescence and radioautography following incubation with tritiated 5-hydroxytryptophan. Good correlations were found between serotonin and SBP concentrations, and parafollicular cell volume. These peaked in the rostro-central portion of the gland and were minimal at the poles. We conclude that thyroid SBP is probably localized in parafollicular cells.     

Dielectric properties of a combined main-chain/side-chain liquid-crystalline polymer

The dielectric relaxation properties of a combined main-chain/side-chain liquid-crystalline polymer were investigated. It was found that the rotation of the side chain about the main chain (δ-process) is not as strongly restricted as in side-chain liquid-crystalline polymers. This is attributed to the facts that the side chain is attached to the flexible spacer within the chain backbone and that the concentration of the side chains is comparatively small. Two low-temperature relaxation processes were observed to occur in the glassy smectic and the crystalline state. They are attributed to intramolecular motions with in the mesogenic groups.     

Protein synthesis is required for the enhancement of long-term potentiation and long-term memory by spaced training

Spaced training is generally more effective than massed training for learning and memory, but the molecular mechanisms underlying this trial spacing effect remain poorly characterized. One potential molecular basis for the trial spacing effect is the differential modulation, by distinct temporal patterns of neuronal activity, of protein synthesis-dependent processes that contribute to the expression of specific forms of synaptic plasticity in the mammalian brain. Long-term potentiation (LTP) is a type of synaptic modification that may be important for certain forms of memory storage in the mammalian brain. To explore the role of protein synthesis in the trial spacing effect, we assessed the protein synthesis dependence of hippocampal LTP induced by 100-Hz tetraburst stimulation delivered to mouse hippocampal slices in either a temporally massed (20-s interburst interval) or spaced (5-min interburst interval) fashion. To extend our studies to the behavioral level, we trained mice in fear conditioning using either a massed or spaced training protocol and examined the sensitivity of long-term memory to protein synthesis inhibition. Larger LTP was induced by spaced stimulation in hippocampal slices. This improvement of synaptic potentiation following temporally spaced synaptic stimulation in slices was attenuated by bath application of an inhibitor of protein synthesis. Further, the maintenance of LTP induced by spaced synaptic stimulation was more sensitive to disruption by anisomycin than the maintenance of LTP elicited following massed stimulation. Temporally spaced behavioral training improved long-term memory for contextual but not for cued fear conditioning, and this enhancement of memory for contextual fear was also protein synthesis dependent. Our data reveal that altering the temporal spacing of synaptic stimulation and behavioral training improved hippocampal LTP and enhanced contextual long-term memory. From a broad perspective, these results suggest that the recruitment of protein synthesis-dependent processes important for long-term memory and for long-lasting forms of LTP can be modulated by the temporal profiles of behavioral training and synaptic stimulation.     

Pathologische Myophosphorylasereaktion bei der malignen Hyperthermie

Zusammenfassung Die Myophosphorylasereaktion (MPR) zeigt bei der malignen Hyperthermie (MH) charakteristische Veränderungen, die in Minutenschnelle entstehen: 1.) eine allgemein stark abgeschwächte Reaktion, 2.) zahlreiche negativ reagierende Fasern, 3.) häufig fleck- und/oder streifenförmig abgeschwächt oder negativ reagierende und streifenförmig verstärkt reagierende Faserabschnitte mit relativ engen Sarkomerenabständen (Zeichen der Hyperkontraktion). Diese morphologischen Befunde mit den kennzeichnenden Streifenfasern sind offenbar für das MH-Syndrom spezifisch! Wichtig ist, daß die derart veränderten Muskelfasern in der Regel bei den anderen Färbungen und Reaktionen unauffällig sind.Wir sahen diese pathologische MPR bei 5 verstorbenen Patienten, einmal unabhängig von einer Anästhesie nach einem Marsch, und bei 19 Schweinen, davon 18mal nach dem Halothantest und einmal bei einem Versuchstier mit gesicherter MH. Sie fehlte bei Schweinen mit negativer Halothanreaktivität und vor dem Halothantest und bei vielen, sehr verschiedenen gesunden und kranken Kontroll- und Vergleichsfällen aus dem bioptischen und autoptischen Untersuchungsgut. Die MPR erlaubt den sicheren Nachweis einer inszenierten oder abgelaufenen MH und damit eine Aufklärung rätselhafter oder scheinbar klarer Todesfälle während oder nach der Narkose oder allgemein nach Streß (human stress syndrome), von denen sicher viele der klinischen Aufmerksamkeit und den üblichen morphologischen Untersuchungsmethoden entgehen. Sie ist nicht geeignet, potentielle Opfer zu erkennen.Mit Unterstützung des Ministeriums f. Gesundheitswesen (HFR Schwangerschaft und frühkindliche Entwicklung, FR Genetische Defekte). Auszugsweise vorgetragen auf dem IV. Internationalen Myologie-Kolloquium in Jena 1984     

Hyperactive vestibulo-ocular reflex in cerebellar degeneration: pathogenesis and treatment

We studied a patient with a cerebellar degeneration and hyperactive vestibulo-ocular reflex (VOR). He complained of oscillopsia and blurred vision with head movement. A twofold increase in VOR gain (peak eye velocity/peak head velocity) at high frequencies was associated with a VOR time constant of 6 seconds (low normal). Visual cancellation ("suppression") of the VOR and smooth pursuit were also abnormal. We hypothesized that his high VOR gain was due to dysfunction of olivocerebellar projections. Physostigmine reduced his VOR gain, consistent with the hypothesis that these projections are cholinergic.