Phagocytosis of neuronal or glial debris by microglial cells: upregulation of MHC class II expression and multinuclear giant cell formation in vitro

Most CNS pathologies are accompanied by the occurrence of activated, phagocytic microglial cells. We intended to investigate whether (1) isolated microglial cells removed from the CNS cytokine network sustain their capacity to acquire an activated phenotype when challenged with cellular or noncellular debris; and (2) different substrates lead to different patterns of microglial activation. It was observed that although removed from their usual surroundings microglial cells preserve their ability to transform to an amoeboid morphology, form multinucleated giant cells, and enhance their expression of MHC class II when exposed to membranes of neuronal or glial origin. Furthermore, cellular substrates derived from primary hippocampal neuronal cultures, neuroblastic cells (B50), or glial cells were all able to induce similar morphological changes and enhanced expression of MHC class II. In contrast, phagocytosis of Latex beads induced an amoeboid morphology but no increase in the expression of immunologically relevant molecules. Interferon-beta (IFN-beta), a substance clinically used in the treatment of the relapsing-remitting form of multiple sclerosis, was shown to inhibit the phagocytosis-induced upregulation of MHC-class II. In summary, phagocytic microglial cells are independent from the CNS cytokine network in their transition from a resting to an activated phenotype; and different cellular substrates, regardless whether they are of neuronal, glial, or even malignant origin, result in similar morphological and functional changes.     

Der Verlauf herzsynchroner Volumenänderungen des Thoraxraumes und deren Auswirkung auf die Ventilation

Zusammenfassung Bei bronchoskopischer und bronchospirometrischer Versuchsanordnung wurden bei durch Muskelrelaxation aufgehobener Atmung die Atemwege nach außen luftdicht abgeschlossen und mit Elektromanometern der Druckablauf im Thoraxraum verfolgt.Es lassen sich herzsynchrone Druckschwankungen registrieren, die meist in vier Wellen ablaufen. Diese vier Sekundärwellen sind häufig bestimmten zeitlichen Abschnitten der Herzaktion zuzuordnen.Diese Druckwellen werden vor allem als in ihrem Vorzeichen wechselnde Differenz zwischen zuströmender und abströmender Blutmenge aufgefaßt. Die Druckwellen laufen in der linken und in der rechten Lunge prinzipiell gleichsinnig ab, wobei aber kleinere Unterschiede sicher vorhanden sind.Solange der Normbereich dieser variablen Druckwellen nicht übersehen werden kann, sollten keine pathophysiologischen Deutungen versucht werden. Bei länger dauerndem Atemstillstand und unter Narkose mit Anstieg des Kohlensäuredruckes ändert sich der Ablauf der Druckwellen deutlich, aber nicht systematisch. Das Ausmaß der aus den Druckwellen zu erwartenden und errechneten herzsynchronen Verschiebungen der Atemgase wird für die Durchmischung von Totraum- und Alveolarluft von Bedeutung sein.Mit 6 Textabbildungen     

Infection of mice with Nematospiroides dubius: demonstration of neutrophil-mediated immunity in vivo in the presence of antibodies

The ability of murine neutrophils to confer resistance to mice against infection by the helminth parasite Nematospiroides dubius has been investigated. Mice whose neutrophils had been 'altered' by an immunizing infection with third-stage larvae (L3) of N. dubius exhibited resistance to a challenge dose of L3 given 4 days after the immunizing infection, provided greater than 0.1 ml of immune mouse serum was passively transferred within 0-24 hr of challenge. Normal mouse serum was ineffective, as was immune serum given at the time of challenge to naive (unimmunized) mice. Neutrophils purified from the blood of mice infected 4 days previously were able to reduce the infectivity of exsheathed L3 when incubated with the latter in vitro in the presence of fresh immune serum. In contrast, peritoneal exudate cells collected at the same time were inactive in this test, indicating that activated macrophages capable of damaging L3 were not yet present and that the immunity of 4-day infected mice given immune serum was probably attributable to the presence of 'altered' neutrophils. The capacity of neutrophils to confer resistance to infection in vivo was unambiguously demonstrated by the passive transfer of 98 +/- 4% pure neutrophils, isolated from the blood of 4-day infected (C57Bl X BALB/c)F1 mice, to uninfected F1 mice. Only those mice which received both neutrophils and immune serum exhibited resistance to a challenge infection. In contrast, mice injected with an eosinophil-enriched cell preparation and immune serum were not resistant. These results indicate for the first time that neutrophils have the capacity to damage nematode parasites in vivo and that they are active against N. dubius in mice infected with this parasite.     

Experimentelle Untersuchungen an Hör- und Gleichgewichtsapparat unter Alkohol

Ohne ZusammenfassungMit 6 Textabbildungen.Herrn Prof. Dr.A. Seiffert zum 70. Geburtstag. — Für die Anregung und Unterstützung der Arbeit dürfen wir Herrn Prof. Dr.B. Mueller (Gerichtsmedizinisches Institut der Universität Heidelberg) herzlich danken. Den Herren cand. med.Schmidtmann undBührer, die unsere Ergebnisse in ihren Dissertationen mitverwerten, danken wir für die Mitarbeit.     

Rhabdomyolysis associated with gemfibrozil-colchicine therapy

OBJECTIVE: To report a case of rhabdomyolysis possibly due to combination therapy with colchicine and gemfibrozil. CASE SUMMARY: A 40-year-old man with amyloidosis and hepatitis B virus-related chronic liver disease was admitted to the university hospital because of fatigue, lack of appetite, dark brownish urine, and myalgia for 2 weeks. The patient was receiving colchicine and gemfibrozil. Elevations of serum creatine kinase, lactate dehydrogenase, and aspartate aminotransferase concentrations with myalgia were compatible with the diagnosis of rhabdomyolysis. DISCUSSION: To our knowledge, myopathy and rhabdomyolysis due to a combination of colchicine and gemfibrozil therapy have not been previously reported. Preexisting mild renal failure, hepatitis B-related chronic liver disease, and amyloidosis may be contributing risk factors for the development of rhabdomyolysis in this patient. An objective causality assessment revealed that the adverse drug event was possible. CONCLUSIONS: Patients receiving combination therapy with colchicine and gemfibrozil, especially those with renal and hepatic dysfunction, should be monitored for rhabdomyolysis, and concomitant colchicine and gemfibrozil therapy should be considered in the differential diagnosis of rhabdomyolysis.     

Childhood attention deficit/hyperactivity disorder and alcohol dependence: a 1-year follow-up

AIMS: To investigate the onset and outcome of alcohol dependence in subjects with childhood attention deficit/hyperactivity disorder (ADHD) in a Turkish sample. METHODS: Among patients being treated for alcohol dependence, 15 had a history of childhood ADHD [ADHD (+)] and 45 did not [ADHD (-)]. ADHD history was assessed according to DSM-IV criteria by a child and adolescent psychiatrist who interviewed the subjects and their close relatives. Severity of dependence was measured by the Michigan Alcoholism Screening Test. Subjects were followed up for 1 year for the assessment of relapse. RESULTS: The age of onset for alcohol drinking, alcohol abuse and alcohol dependence were significantly lower in the ADHD (+) group than in the ADHD (-) group. Comorbid substance use was more prevalent in the ADHD (+) group. The study found no significant difference in the severity of alcohol dependence between ADHD (+) and ADHD (-) groups. During follow-up, 80% of the ADHD (+) subjects relapsed, compared with 55.6% in the ADHD (-) group. Relapse occurred on average 2.74 months earlier in the ADHD (+) group than in the ADHD (-) group. CONCLUSIONS: As found in other countries, alcohol dependence in Turkish subjects with childhood ADHD starts early and is relatively resistant to treatment. Early diagnosis and treatment of ADHD might help prevent alcohol- and substance-related disorders.     

Identification of neuronal cell death in a model of degeneration in the hippocampus

Neuronal cell death and microglial changes are both hallmarks of neurodegenerative disorders. Therefore, analysis of degenerating neurons related to microglial changes are addressed in many studies of neurosciences. Here we compared different lesion models and two markers for neurodegeneration (Fluoro-Jade and propidium iodide) in an in vivo as well as an in vitro approach. Fluoro-Jade is a specific and selective marker to identify neurons undergoing degeneration. We also tested this marker to analyze neurodegeneration in organotypic hippocampal slice cultures. We could show that activation of microglia is followed by neuronal cell death. Most degeneration markers, such as propidium iodide, only stain the neuronal cell body excluding the axonal and dendritic processes. Fluoro-Jade is able to stain the distal portion as well as the proximal portion of the dissected axon including the axotomized neuron, as so called anterograde and retrograde degeneration after axotomy. To analyze the specificity of Fluoro-Jade, we used primary microglial and BV-2 cells, a well-described murine microglial cell line. Treatment of microglial and BV-2 cells with an excess of L-glutamate induces cell death which could be detected by propidium iodide staining, but not by Fluoro-Jade, demonstrating its specificity to monitor neuronal cell death.