[Drug-induced liver injury-significance of pathology]. / Drug-Induced Liver Injury ­ Stellenwert der Pathologie.

Many different medical agents, herbal products, and dietary supplements can induce drug-induced liver injury (DILI) as a clinically relevant complication. DILI, which is direct toxic or idiosyncratic, can have a broad spectrum of clinical appearances from elevation of liver enzymes to acute liver failure. DILI is categorized clinically according to the pattern of serum parameters or pathologically according to the pattern of histomorphology. Histopathological patterns can be described as hepatitic, granulomatous, cholestatic, ductopenic, fibrotic, steatotic, steatohepatitic, and vascular. Correlation to the corresponding drug can be carried out with the corresponding databases (US National Library of Medicine, Liver Tox; www.ncbi.nlm.nih.gov/books/NBK547852/ ). Liver biopsy, in contrast to a clinical/serological diagnostic, has the advantage of an exact resolution with evidence of pathophysiology, activity, regeneration, chronification, and prognosis. Co-occurrence of underlying liver disease can be excluded or confirmed. Histological patterns of DILI are described and illustrated. A diagnostic algorithm for the interpretation of liver biopsies is provided.

Contrasting phylogeographic pattern among Eudyptes penguins around the Southern Ocean.

Since at least the middle-Miocene, the Antarctic Polar Front (APF) and the Subtropical Front (STF) appear to have been the main drivers of diversification of marine biota in the Southern Ocean. However, highly migratory marine birds and mammals challenge this paradigm and the importance of oceanographic barriers. Eudyptes penguins range from the Antarctic Peninsula to subantarctic islands and some of the southernmost subtropical islands. Because of recent diversification, the number of species remains uncertain. Here we analyze two mtDNA (HVRI, COI) and two nuclear (ODC, AK1) markers from 13 locations of five putative Eudyptes species: rockhopper (E. filholi, E. chrysocome, and E. moseleyi), macaroni (E. chrysolophus) and royal penguins (E. schlegeli). Our results show a strong phylogeographic structure among rockhopper penguins from South America, subantarctic and subtropical islands supporting the recognition of three separated species of rockhopper penguins. Although genetic divergence was neither observed among macaroni penguins from the Antarctic Peninsula and sub-Antarctic islands nor between macaroni and royal penguins, population genetic analyses revealed population genetic structure in both cases. We suggest that the APF and STF can act as barriers for these species. While the geographic distance between colonies might play a role, their impact/incidence on gene flow may vary between species and colonies.

Cardiovascular risk and fitness in veteran football players.

Veteran football players above 40 years have rarely been subject to scientific investigations. This is worrisome because their number is considerable and their cardiovascular risk probably increased. Therefore, a cross-sectional study was conducted in 100 football players between 40 and 63 years of age. This included a medical history and physical examination, venous blood sampling, measurement of resting blood pressure, a resting electrocardiogram (ECG), an exhaustive cycle ergometry and a multistage field test. Also, measurements of heart rate and blood lactate concentration were carried out during one typical training session and one match. Participants trained 1.0 ± 0.6 sessions per week and played 27 ± 8 matches per season. Of them, 19% were smokers. Resting blood pressure was 138 ± 15/88 ± 8 mmHg. Hypertension prevalence (WHO definition) was 66%. Total cholesterol averaged 220 ± 41 mg . dl(-1), HDL 46 ± 13 mg . dl(-1) and LDL 134 ± 33 mg . dl(-1). The average 10-year risk for cardiovascular events (Framingham score) was 6%. Mean maximal power output on the cycle ergometer was 2.8 ± 0.6 W . kg(-1), mean VO2peak 40.0 ± 7.3 ml . min(-1) . kg(-1). Comparing training and competition, no significant differences in cardiovascular and metabolic load were found. In summary, their cardiovascular risk was similar to age-adjusted reference values. However, they showed slightly better ergometric performance. More frequent training stimuli might be necessary to reach more favourable risk factor profiles. Training and competition lead to similar cardiocirculatory and metabolic stress which is considerably high and might put players into danger who have pre-existing cardiac disease.

[Indications and limitations of fresh frozen sections in the pulmonary apparatus]. / Indikation und Grenzen des intraoperativen Schnellschnitts im Organbereich Lunge.

Recommendations for the diagnosis of lung tumors almost limit the use of fresh frozen sections to the evaluation of resection margins. In pathology pretherapeutic methods for assessment of clinically suspected lung cancer are favored over intraoperative frozen section diagnosis. For the interdisciplinary management of uncertain lung findings diagnostic methods, such as cytopathology and examination of biopsy material are available. The use of rapid on-site evaluation (ROSE) in cytopathology is limited due to the lack of necessary personnel. Diagnosis of unclear pulmonary lesions or distinction of metastases from primary lung tumors by intraoperative frozen sections is therefore limited to exceptional cases that were not resolved by preoperative biopsies. Such rare cases require a common consensus strategy between thoracic surgeons and pathologists in a preoperative tumor board.

Disruption of intracerebral progression of C6 rat glioblastoma by in vivo treatment with anti-CD44 monoclonal antibody.

OBJECT: Glioblastoma multiforme (GBM) invasiveness is a complex process that involves recognition and attachment of GBM cells to particular extracellular matrix (ECM) molecules before migrating into proteolytically modified matrix and inducing angiogenesis. The CD44 molecule, which is a transmembrane adhesion molecule found on a wide variety of cells including GBM, has been suggested as the principal mediator of migration and invasion. The aim of the present study was to demonstrate whether an antibody specific to the standard form of CD44 (CD44s, 85-90 kD) might prevent invasion and thus disrupt progression of C6 GBM in vivo. METHODS: Immunostaining demonstrated homogeneous expression of CD44s on the surface of C6 GBM cells and tumors. Flow cytometric analysis demonstrated binding saturation of anti-CD44s monoclonal antibody (mAb) to the receptor at 1 microg/5 x 10(5) cells. Blocking of CD44s in vitro resulted in a dose-dependent progressive (up to 94+/-2.7%; mean +/- standard deviation [SD]) detachment of C6 cells from ECM-coated culture. Blocking of CD44s in vivo resulted in significantly reduced C6 brain tumors (3.6+/-0.4% [SD])--measured as the quotient: tumor surface (mm2)/brain surface (mm2) x 100--compared with untreated (19.9+/-0.9%) or sham-treated (19.2+/-1.1 to 19.3+/-2.5% [SD]) rats. Disruption of C6 GBM progression correlated with an improved food intake; treated rats were significantly less cachectic (166.6+/-16.4 g [SD]) than those that were untreated (83+/-2.7 g [SD]) or sham-treated (83.4+/-1.1 to 83+/-2.2 g [SD]) rats. CONCLUSIONS: The authors conclude that CD44s-targeted treatment with specific mAb may represent an effective means for preventing progression of highly invasive GBMs.

CD44s-targeted treatment with monoclonal antibody blocks intracerebral invasion and growth of 9L gliosarcoma.

Glioma invasiveness is a complex process involving recognition and attachment of tumor cells to particular extracellular matrix (ECM) molecules prior to migrating into proteolytically modified matrix and inducing angiogenesis. CD44 is a group of transmembrane adhesion molecules found on a wide variety of cells including gliomas that has been suggested as the principal mediator of migration/invasion. The aim of the present study was to demonstrate whether antibody specific for the standard form of CD44 (CD44s, 85-90 kDa) might prevent invasion, thus blocking growth of the 9L gliosarcoma in vivo. High expression of CD44s on the surface of 9L cells and brain tumors was demonstrated by immunochemistry. Fluorescence-activated cell sorting (FACS) demonstrated binding saturation of anti-CD44s monoclonal antibody (mAb) to the receptor at 1 microg/5 x 10(5) cells. Blocking of CD44s in vitro resulted in a dose-dependent progressive, up to 95%+/-2.5% detachment of 9L cells from ECM-coated culture surfaces. Blocking of CD44s in vivo resulted in significantly reduced 9L brain tumors (2.5%+/-0.4%)--measured as the quotient: tumor surface (mm2)/brain surface (mm2) x 100--as compared to untreated (16.1%+/-2.2%) or sham-treated rats (16%+/-3.7% to 16.1%+/-3%). We conclude that CD44s-targeted treatment with specific mAb may be an effective means for preventing glioma progression.

Foraging strategies of incubating and brooding king penguins Aptenodytes patagonicus.

For oceanic birds like king penguins, a major constraint is the separation of foraging areas from the breeding colony, largely because swimming increases foraging costs. However, the relationship between foraging strategy and breeding stage has been poorly investigated. Using time-depth recorders, we studied the diving behaviour of two groups of king penguins that were either incubating or brooding chicks at Crozet Islands (Southern Indian Ocean) at the same period of the year. Although birds with chicks had the highest predicted energy demand, they made foraging trips half as long as incubating birds (6 vs. 14 days) and modified their time and depth utilisation. Birds with chicks dived deeper during daylight (mean maximum depth of 280 m vs. 205 m for those incubating). At night, birds with chicks spent twice as much time diving as those incubating, but birds at both stages never dived beyond 30 m. Movements to greater depths by brooding birds are consistent with the vertical distribution of myctophid fish which are the main prey. As chick provisioning limits trip duration, it is suggested that it is more efficient for parents to change their diving patterns rather than to restrict their foraging range.

Diving energetics in king penguins (Aptenodytes patagonicus).

Dive duration in wild king penguins and the energetic cost of swimming in a 30m long swim channel were determined at Ile de la Possession, Crozet Archipelago, using external data loggers and respirometry, respectively. Calibrated electronic data loggers equipped with a pressure sensor were used to determine dive durations: 95% of dives were less than 6 min long and 66% of dives were less than 4 min long. Dive patterns show that king penguins may intersperse long dive durations (4-6.3 min) with short ones (1.5-3 min) and make surface pauses of variable duration between them (0.5-3.5 min), or dive regularly (for up to 5 h) with long dive durations (5 min) and constant interdive surface intervals (1.5 min). The latter indicates that the aerobic dive limits (ADL) of this species could be higher and oxygen consumption lower than previously reported. Assuming that king penguins dive within their aerobic limit, different approaches to the analysis of the data obtained in the swim channel are discussed to derive the ADL. Swimming speeds observed in the channel ranged from 0.9 to 3.4 m s-1. Transport costs were lowest between 1.8 and 2.2 m s-1. Although at 2.2 m s-1 king penguins used only 10.3 Wkg-1 over a dive+surface cycle (minimal transport costs of 4.7 J kg-1 m-1), we speculate that tisse oxygen consumption during submergence may be as low as 0.23 ml O2 kg-1 s-1 (2.1 times standard metabolic rate, SMR) or perhaps lower (which gives an ADL of 4.2 min). During surface phases, oxygen uptake would be increased to at least 1 ml O2kg-1 s-1 (9.3 times SMR). This implies that at least 70% of all dives are aerobic. Potential physiological mechanisms allowing king penguins to partition O2 consumption between submergence and surface periods remain, however, unclear.

[Inhibition of angiogenesis and growth of malignant gliomas in the athymic nude rat model: immunotherapy against "basic fibroblast growth factor"]. / Hemmung von Angiogenese und Wachstum maligner Gliome am Modell der Athymischen Nacktratte: Immuntherapie gegen "Basic Fibroblast Growth Factor".

An important feature of malignant progression in human gliomas is increased polymorphism of tumor cells associated with karyotypic heterogenity and a variety of secondary changes, one of which is increased angiogenesis. The capability of brain tumors for angiogenesis most probably is the earliest sign for malignancy in 95% of cases and occurs before typical changes of histology appear. Malignant brain tumors are known to produce several angiogenic growth factors. One of the most potent of these factors is the basic fibroblast growth factor (bFGF). In an experimental study human U87 MG glioma cells (2.10(5) cells/50 microliters) were implanted through a burrhole into the cerebral cortex in a group of 25 nude rats. After 3 weeks we found a reproducible extensive tumor growth with extensive neovascularization. Immunohistochemical evaluations proved a high expression of bFGF in the tumor. A parallel group of xenotransplanted rats were treated with 33 micrograms of rabbit anti-bFGF antibodies during tumor cell implantation. Thereafter, the same dosages of antibodies were administrated intracranially twice a week for 3 weeks. We found a significant inhibition of tumor vascularization and growth compared to other groups who had no treatment or who received irrelevant immunoglobulins or saline as a control. Our results indicate that inhibition of tumor angiogenesis might contribute to inhibition of tumor growth in malignant gliomas.