Cytokine production after intravenous or peritoneal gram-negative bacterial challenge in mice. Comparative protective efficacy of antibodies to tumor necrosis factor-alpha and to lipopolysaccharide.

The production of TNF-alpha, IL-1, and IL-6 was measured in mice after bolus i.v. Escherichia coli O111 LPS injections and during bacteremia induced either by bolus i.v. or by i.p. challenges of live E. coli O111. High but transient TNF-alpha peaks were observed after bolus i.v. LPS or bacterial challenges. In contrast, the levels during lethal peritonitis increased progressively to values 50- to 100-fold lower than the peak values observed after i.v. injections, and remained sustained until death. Whereas after i.v. challenge with 1000 LD50 of LPS, anti-TNF-alpha antibody fully protected mice from death and reduced serum IL-1 and IL-6 levels, anti-TNF-alpha antibody did not improve the survival of mice nor reduced serum IL-1 and IL-6 levels after i.p. bacterial challenge. In contrast to anti-TNF-alpha antibodies, anti-LPS antibodies were protective in the peritonitis model. Protection was accompanied by a striking reduction of bacterial numbers and of TNF-alpha, IL-1, and IL-6 levels in the serum, but the levels of these cytokines were only marginally affected in the peritoneal lavage fluid. This latter observation demonstrates that the local peritoneal cytokines did not diffuse readily into the circulation, thus suggesting that at least part of the circulating cytokines are produced systemically. In conclusion, the striking differences between cytokine profiles as well as the divergent efficacy of anti-TNF-alpha antibody after i.v. bolus and after i.p. challenges suggest that TNF-alpha may not be as important in the pathogenesis of lethal peritonitis than after lethal acute bacteremia.     

Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD)

BackgroundAcute liver failure (ALF) has been reported in ornithine transcarbamylase deficiency (OTCD) and other urea cycle disorders (UCD). The frequency of ALF in OTCD is not well-defined and the pathogenesis is not known.AimTo evaluate the prevalence of ALF in OTCD, we analyzed the Swiss patient cohort. Laboratory data from 37 individuals, 27 females and 10 males, diagnosed between 12/1991 and 03/2015, were reviewed for evidence of ALF. In parallel, we performed cell culture studies using human primary hepatocytes from a single patient treated with ammonium chloride in order to investigate the inhibitory potential of ammonia on hepatic protein synthesis.ResultsMore than 50% of Swiss patients with OTCD had liver involvement with ALF at least once in the course of disease. Elevated levels of ammonia often correlated with (laboratory) coagulopathy as reflected by increased values for international normalized ratio (INR) and low levels of hepatic coagulation factors which did not respond to vitamin K. In contrast, liver transaminases remained normal in several cases despite massive hyperammonemia and liver involvement as assessed by pathological INR values. In our in vitro studies, treatment of human primary hepatocytes with ammonium chloride for 48 hours resulted in a reduction of albumin synthesis and secretion by approximately 40%.ConclusionIn conclusion, ALF is a common complication of OTCD, which may not always lead to severe symptoms and may therefore be underdiagnosed. Cell culture experiments suggest an ammonia-induced inhibition of hepatic protein synthesis, thus providing a possible pathophysiological explanation for hyperammonemia-associated ALF.     

Die Spermatogenese bei Einer Grille Nemobius Fasciatus

Ohne Zusammenfassung Mit 3 Textabbildungen und Tafel IX–XI     

Étude clinique de phase I avec bénéfice individuel direct de radioimmunothérapie du myélome multiple utilisant l’anticorps anti-CD138 marqué à l’iode 131 (131I-B-B4)

PurposeThe objective of this study was to evaluate the toxicity, the absorbed dose to critical organs and tumour of B-B4 monoclonal antibody labeled with Iodine 131 in patients with multiple myeloma (MM) enrolled in a phase I study.Patients and methodFour patients with MM were enrolled and received for dosimetric study an injection of 20 mg/m² of B-B4 coupled with 370 MBq of Iodine 131. During the treatment phase, after viewing the target, three patients received a fixed dose of 20 mg/m² of ¹³¹I-B-B4 with an initial activity of 555 MBq/m², corresponding to level 1.ResultsImmunoscintigraphy showed an early and intensive uptake of the axial skeleton confirming the targeting of the disease by the antibody. Grade 3/4 haematological toxicity was observed in two patients with a trend to tally with the estimated average dose received by the bone marrow, calculated in the dosimetric study (blood method and imaging method). No other toxicity was observed. No complete or partial response was observed.ConclusionThe dose of 555 MBq/m² of ¹³¹I-B-B4 has shown encouraging results in terms of dosimetry and toxicity of RIT in MM. Other developments are possible with the use of humanized monoclonal antibody and the labeling with an alpha particle emitter.     

Importance of ascospore ornamentation in the taxonomy of Daldinia

Representative specimens of fifteen Daldinia spp. were studied for ultrastructural characteristics of their ascospores by scanning electron microscopy (SEM). The ornamentation of their outermost spore layers was found to be species-consistent, confirming the results of concurrent studies on the morphology of their teleomorphs and anamorphs, secondary metabolite profiles and PCR-based genetic fingerprints. Daldinia spp. may either show smooth or transversally striated ascospores. The spores of the species within the latter group are always ellipsoid-equilateral to ellipsoid-inequilateral with narrowly rounded ends. Smooth, broadly ellipsoid to cylindrical ascospores were observed in all species (D. caldariorum, D. fissa and D. loculata) that are known to produce their stromata on substrates damaged by fire. The ascospores of D. concentrica differed from those of D. childiae (i.e., the cosmopolitan taxon previously regarded as D. concentrica ss. auct.) and other Daldinia spp. in showing a very faint ornamentation, which only became visible at 10000× magnification by SEM. A specimen collected on the isle of Jersey (Channel Islands, UK) showed morphological similarities to the pantropical D. eschscholzii, but its ascospores appeared smooth by SEM, and it may therefore represent a previously undescribed species. Dedicated to Professor Yoshinori Asakawa, Tokushima, Japan, on the occasion of his 60^th birthday PH-R Life Science Center Natural Products     

Exploring movement patterns and changing distributions of baleen whales in the western North Atlantic using a decade of passive acoustic data

Six baleen whale species are found in the temperate western North Atlantic Ocean, with limited information existing on the distribution and movement patterns for most. There is mounting evidence of distributional shifts in many species, including marine mammals, likely because of climate‐driven changes in ocean temperature and circulation. Previous acoustic studies examined the occurrence of minke (Balaenoptera acutorostrata) and North Atlantic right whales (NARW; Eubalaena glacialis). This study assesses the acoustic presence of humpback (Megaptera novaeangliae), sei (B. borealis), fin (B. physalus), and blue whales (B. musculus) over a decade, based on daily detections of their vocalizations. Data collected from 2004 to 2014 on 281 bottom‐mounted recorders, totaling 35,033 days, were processed using automated detection software and screened for each species' presence. A published study on NARW acoustics revealed significant changes in occurrence patterns between the periods of 2004–2010 and 2011–2014; therefore, these same time periods were examined here. All four species were present from the Southeast United States to Greenland; humpback whales were also present in the Caribbean. All species occurred throughout all regions in the winter, suggesting that baleen whales are widely distributed during these months. Each of the species showed significant changes in acoustic occurrence after 2010. Similar to NARWs, sei whales had higher acoustic occurrence in mid‐Atlantic regions after 2010. Fin, blue, and sei whales were more frequently detected in the northern latitudes of the study area after 2010. Despite this general northward shift, all four species were detected less on the Scotian Shelf area after 2010, matching documented shifts in prey availability in this region. A decade of acoustic observations have shown important distributional changes over the range of baleen whales, mirroring known climatic shifts and identifying new habitats that will require further protection from anthropogenic threats like fixed fishing gear, shipping, and noise pollution.     

Intracellular Theileria annulata Promote Invasive Cell Motility through Kinase Regulation of the Host Actin Cytoskeleton

The intracellular, protozoan Theileria species parasites are the only eukaryotes known to transform another eukaryotic cell. One consequence of this parasite-dependent transformation is the acquisition of motile and invasive properties of parasitized cells in vitro and their metastatic dissemination in the animal, which causes East Coast Fever (T. parva) or Tropical Theileriosis (T. annulata). These motile and invasive properties of infected host cells are enabled by parasite-dependent, poorly understood F-actin dynamics that control host cell membrane protrusions. Herein, we dissected functional and structural alterations that cause acquired motility and invasiveness of T. annulata-infected cells, to understand the molecular basis driving cell dissemination in Tropical Theileriosis. We found that chronic induction of TNFα by the parasite contributes to motility and invasiveness of parasitized host cells. We show that TNFα does so by specifically targeting expression and function of the host proto-oncogenic ser/thr kinase MAP4K4. Blocking either TNFα secretion or MAP4K4 expression dampens the formation of polar, F-actin-rich invasion structures and impairs cell motility in 3D. We identified the F-actin binding ERM family proteins as MAP4K4 downstream effectors in this process because TNFα-induced ERM activation and cell invasiveness are sensitive to MAP4K4 depletion. MAP4K4 expression in infected cells is induced by TNFα-JNK signalling and maintained by the inhibition of translational repression, whereby both effects are parasite dependent. Thus, parasite-induced TNFα promotes invasive motility of infected cells through the activation of MAP4K4, an evolutionary conserved kinase that controls cytoskeleton dynamics and cell motility. Hence, MAP4K4 couples inflammatory signaling to morphodynamic processes and cell motility, a process exploited by the intracellular Theileria parasite to increase its host cell''s dissemination capabilities.     

Flugunfähigmachen von Vögeln – Für und Wider

The techniques and biological functions of avian flight are briefly presented. The reasons for rendering zoo birds flightless are explained taking into account the tasks and obligations of modern zoos, and the various deflighting procedures are described. The legal situation regarding deflighting as it currently exists in Germany and other countries is clarified. It is discussed in detail under which circumstances it would be justifiable to render a bird flightless, to what extent keeping the birds in aviaries would be an alternative and whether reversible or irreversible methods should be preferred. A legal opinion has been sought which came to the conclusion that even under the restrictive Animal Welfare Law of Germany interventions to render a bird flightless were admissible if based on veterinary indication on a case-by-case basis. Such indication may be justified by the anticipation that a bird may be injured or die from an accident in future if not deflighted. Contrary to the views of some legal experts commenting on the German Animal Welfare Law the authors consider feather clipping not to be an intervention prohibited under the law. In the interest of the good functioning of european and international breeding programmes the authors suggest that the German legislation should be modified with a view of containing a general derogation for rendering flightless at least certain species of zoo birds.