Der Einfluss von Gebirge und See auf die 17-Ketosteroidausscheidung im Harn

Zusammenfassung Bei 11 Studenten aus Mainz wurde im September 1964 in Oberstdorf/Allgäu (843 m) und im September 1965 auf der Nordseeinsel Norderney täglich die Ausscheidung der 17-Ketosteroide untersucht, um den Adaptationsverlauf zu prüfen. Alle Versuchspersonen hatten eine erhöhte 17-KS-Ausscheidung,die an der Nordsee höher war als im Gebirge. Der Höhepunkt der Ausscheidung lag um den 10. Tag. Es bestanden individuelle Unterschiede in der 17-KS-Ausscheidung. Je niedriger diese vorher war, desto höher war die relative Steigerung im Gebirge und an der See.Während der Beobachtungsperiode waren wetterbedingte Abweichungen von den periodischen Schwankungen nachweisbar.

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The 17-ketosteroid excretion of 11 students from the University of Mainz was investigated during September 1964 in Oberstdorf (843 m) and in September 1965 on the North Sea island Norderney. All subjects had an increased 17-ketosteroid excretion which was higher at the sea than in the mountains.The maximum of the values was around the 10th day. There were individual differences; the lower the excretion at Mainz the higher was the relative increase at both locations. During the observation period deviations from the periodic changes were observed which were due to the effect of weather.

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Resume Afin d'examiner l'adaptation de 11 étudiants au milieu,on a analysé chaque jour leur excrétion de 17-kétostéroïde. Ces essais ont eu lieu en septembre 1964 à Oberstdorf/Allgäu (843 m d'altitude) et en septembre 1965 sur lïle de Norderney dans la Mer du Nord. On a pu déceler une augmentation de 17-kétostéroïde chez toutes les personnes examinées. Cette augmentation fut toutefois plus marquée au bord de la mer qu'en montagne. L'excrétion en fut maximum le 10ème jour.On a remarqué en outre des différences individuelle. Plus l'excrétion était faible au départ et plus l'augmentation relative était marquée ausi bien au bord de la mer qu'en montagne.Pendant la période des examens, on a pu prouver des divergences météorotropiques par rapport aux fluctuations périodiques.

     

Capillary blood perfusion during postischemic reperfusion in striated muscle.

Monitoring of nutritive blood flow in muscle is of particular importance to reconstructive surgeons, since ischemia/reperfusion in striated muscle is known to result in postischemic microvascular perfusion failure. Laser Doppler flowmetry has recently been introduced as an easy-to-use, noninvasive technique for continuous monitoring of microvascular tissue perfusion. Despite its popularity, there exists a great deal of controversy as to what actually generates the laser Doppler signal recorded from a given tissue. Intravital microscopy is a technique for direct visualization of the nutritional circulation in tissue. By using intravital microscopy, direct measurements of blood perfusion in individual segments of the nutritional microcirculation can be made. In 22 Syrian golden hamsters we performed laser Doppler flowmetry and intravital microscopy measurements in muscle tissue prior to and during reperfusion after 4 hours of tourniquet ischemia using the dorsal skinfold chamber model. Intravital microscopy (n = 10) revealed a heterogeneous capillary perfusion during the early reperfusion phase with a decrease (p less than 0.01) in functional capillary density to 49.4 +/- 17.0 percent of control. No recovery was observed after 24 hours of reperfusion. Laser Doppler flowmetry (n = 12) showed a parallel reduction of capillary red blood cell flux during the early perfusion phase to 43.9 +/- 22.6 percent of control values (p less than 0.01), and no recovery was observed after 24 hours of reperfusion. However, the laser Doppler flowmetry technique was not able to detect the capillary perfusion inhomogeneities shown by intravital microscopy. Postischemic reperfusion in striated muscle is characterized by a decrease in functional capillary density and a heterogeneous capillary perfusion. Laser Doppler flowmetry is a useful tool for monitoring microvascular tissue perfusion, although in striated muscle of the hamster it must be considered that accurate nutritional "capillary" flow readings can be grossly overestimated if larger vessels, such as arterioles and collecting venules, are contained in the measuring field of the laser Doppler probe.     

Curcumin Intake Affects miRNA Signature in Murine Melanoma with mmu-miR-205-5p Most Significantly Altered

Melanoma is the most aggressive form of skin cancer with estimated 48,000 deaths per year worldwide. The polyphenol curcumin derived from the plant Curcuma longa is well known for its anti-inflammatory and anti-cancerogenic properties. Accordingly, dietary intake of this compound may be suitable for melanoma prevention. However, how this compound affects basic cellular mechanisms in developing melanoma still remains elusive. Therefore, the aim of this study was to investigate for the first time the impact of oral curcumin administration on the miRNA signature of engrafting melanoma. For this purpose, the effects of a 4% curcumin diet were tested on melanoma, which were established by injection of murine B78H1 cells in the flank of C57BL/6 mice. Curcumin diet or standard chow (control) was administered two weeks prior to injection of tumor cells until termination of the experiment. High throughput chip-based array analysis was deployed to detect alterations in the miRNA signature of the tumors. Curcumin treatment significantly reduced the growth of the flank tumors. Furthermore the miRNA expression signature in tumors was substantially altered by curcumin intake with mmu-miR-205-5p over 100 times higher expressed when compared to controls. The expression levels of identified key miRNAs in the tumor samples were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). A comparable expression pattern of these miRNAs was also detected in other curcumin-treated melanoma cell lines under in vitro conditions. Putative targets of curcumin-induced up-regulated miRNAs were enriched in ‘o-glycan biosynthesis’, ‘endoplasmatic reticulum protein processing’ and different cancer-related pathways. Western Blot analyses revealed that of these targets anti-apoptotic B-cell CLL/lymphoma 2 (Bcl-2) and proliferating cell nuclear antigen (PCNA) were significantly down-regulated in curcumin-treated tumors. These findings demonstrate a profound alteration of the miRNA expression signature in engrafting curcumin-treated melanoma with mmu-miR-205-5p being up-regulated most significantly.     

Multiple conformational states of the hammerhead ribozyme, broad time range of relaxation and topology of dynamics

The dynamics of a hammerhead ribozyme was analyzed by measurements of fluorescence-detected temperature jump relaxation. The ribozyme was substituted at different positions by 2-aminopurine (2-AP) as fluorescence indicator; these substitutions do not inhibit catalysis. The general shape of relaxation curves reported from different positions of the ribozyme is very similar: a fast decrease of fluorescence, mainly due to physical quenching, is followed by a slower increase of fluorescence due to conformational relaxation. In most cases at least three relaxation time constants in the time range from a few microseconds to ~200 ms are required for fitting. Although the relaxation at different positions of the ribozyme is similar in general, suggesting a global type of ribozyme dynamics, a close examination reveals differences, indicating an individual local response. For example, 2-AP in a tetraloop reports mainly the local loop dynamics known from isolated loops, whereas 2-AP located at the core, e.g. at the cleavage site or its vicinity, also reports relatively large amplitudes of slower components of the ribozyme dynamics. A variant with an A→G substitution in domain II, resulting in an inactive form, leads to the appearance of a particularly slow relaxation process (τ ≈200 ms). Addition of Mg²⁺ ions induces a reduction of amplitudes and in most cases a general increase of time constants. Differences between the hammerhead variants are clearly demonstrated by subtraction of relaxation curves recorded under corresponding conditions. The changes induced in the relaxation response by Mg²⁺ are very similar to those induced by Ca²⁺. The relaxation data do not provide any evidence for formation of Mg²⁺-inner sphere complexes in hammerhead ribozymes, because a Mg²⁺-specific relaxation effect was not visible. However, a Mg²⁺-specific effect was found for a dodeca-riboadenylate substituted with 2-AP, showing that the fluorescence of 2-AP is able to indicate inner sphere complexation. Amplitudes and time constants show that the equilibrium constant of inner sphere complexation is 1.2, corresponding to 55% inner sphere state of the Mg²⁺ complexes; the rate constant 6.6 × 10³ s^–1 for inner sphere complexation is relatively low and shows the existence of some barrier(s) on the way to inner sphere complexes.     

Vasomotion in critically perfused muscle protects adjacent tissues from capillary perfusion failure

We analyzed the incidence and interaction of arteriolar vasomotion and capillary flow motion during critical perfusion conditions in neighboring peripheral tissues using intravital fluorescence microscopy. The gracilis and semitendinosus muscles and adjacent periosteum, subcutis, and skin of the left hindlimb of Sprague-Dawley rats were isolated at the femoral vessels. Critical perfusion conditions, achieved by stepwise reduction of femoral artery blood flow, induced capillary flow motion in muscle, but not in the periosteum, subcutis, and skin. Strikingly, blood flow within individual capillaries was decreased (P < 0.05) in muscle but was not affected in the periosteum, subcutis, and skin. However, despite the flow motion-induced reduction of muscle capillary blood flow during the critical perfusion conditions, functional capillary density remained preserved in all tissues analyzed, including the skeletal muscle. Abrogation of vasomotion in the muscle arterioles by the calcium channel blocker felodipine resulted in a redistribution of blood flow within individual capillaries from cutaneous, subcutaneous, and periosteal tissues toward skeletal muscle. As a consequence, shutdown of perfusion of individual capillaries was observed that resulted in a significant reduction (P < 0.05) of capillary density not only in the neighboring tissues but also in the muscle itself. We conclude that during critical perfusion conditions, vasomotion and flow motion in skeletal muscle preserve nutritive perfusion (functional capillary density) not only in the muscle itself but also in the neighboring tissues, which are not capable of developing this protective regulatory mechanism by themselves.     

Field Evaluation of a Push-Pull System to Reduce Malaria Transmission

Malaria continues to place a disease burden on millions of people throughout the tropics, especially in sub-Saharan Africa. Although efforts to control mosquito populations and reduce human-vector contact, such as long-lasting insecticidal nets and indoor residual spraying, have led to significant decreases in malaria incidence, further progress is now threatened by the widespread development of physiological and behavioural insecticide-resistance as well as changes in the composition of vector populations. A mosquito-directed push-pull system based on the simultaneous use of attractive and repellent volatiles offers a complementary tool to existing vector-control methods. In this study, the combination of a trap baited with a five-compound attractant and a strip of net-fabric impregnated with micro-encapsulated repellent and placed in the eaves of houses, was tested in a malaria-endemic village in western Kenya. Using the repellent delta-undecalactone, mosquito house entry was reduced by more than 50%, while the traps caught high numbers of outdoor flying mosquitoes. Model simulations predict that, assuming area-wide coverage, the addition of such a push-pull system to existing prevention efforts will result in up to 20-fold reductions in the entomological inoculation rate. Reductions of such magnitude are also predicted when mosquitoes exhibit a high resistance against insecticides. We conclude that a push-pull system based on non-toxic volatiles provides an important addition to existing strategies for malaria prevention.     

Increased exercise after stable closed fracture fixation does not affect fracture healing in mice

PurposeThe aim of the present study was to evaluate the systemic biological effect of increased exercise on bone repair after stable fracture fixation.MethodsTwo groups of SKH-1 h mice were studied. Animals of the first group (n=36) were housed in cages supplied with a running wheel, while mice of the second group (n=37) were housed in standard cages for control. Using a closed femur fracture model, bone repair was analysed by histomorphometry and biomechanical testing at 2 and 5 weeks. At 2 weeks, we additionally evaluated the expression of the proliferation marker PCNA (proliferating cell nuclear antigen) and the angiogenic and osteogenic growth factor VEGF (vascular endothelial growth factor). To standardise the mechanical conditions in the fracture gap, we used an intramedullary compression screw for stable fracture fixation.ResultsEach mouse of the exercise group run a mean total distance of 23.5 km after 2 weeks and 104.3 km after 5 weeks. Histomorphometric analysis of the size and tissue composition of the callus could not reveal significant differences between mice undergoing exercise and controls. Accordingly, biomechanical testing showed a comparable torsional stiffness, peak rotation angle, and load at failure of the healing bones in the two groups. The expression of PCNA and VEGF did also not differ between mice of the exercise group and controls.ConclusionWe conclude that increased exercise does not affect bone repair after stable fracture fixation.     

Structure-activity relationship of synthetic branched-chain distearoylglycerol (distearin) as protein kinase C activators

Several representative branched-chain analogues of distearin (DS) were synthesized and tested for their abilities to activate protein kinase C (PKC) and to compete for the binding of [3H]phorbol 12,13-dibutyrate (PDBu) to the enzyme. Substitutions of stearoyl moieties at sn-1 and sn-2 with 8-methylstearate decreased activities on these parameters, relative to those of the parental diacylglycerol DS, a weak PKC activator. Substitutions with 8-butyl, 4-butyl, or 8-phenyl derivatives, on the other hand, increased activities of the resulting analogues to levels comparable to those seen for diolein (DO), a diacylglycerol prototype shown to be a potent PKC activator. Kinetic analysis indicated that 8-methyldistearin (8-MeDS) acted by decreasing, whereas 8-butyldistearin (8-BuDS) and 8-phenyldistearin (8-PhDS) acted by increasing, the affinities of PKC for phosphatidylserine (PS, a phospholipid cofactor) and Ca2+ compared to the values seen in the absence or presence of DS. The stimulatory effect of 8-BuDS and 8-PhDS on PKC, as DO, was additive to that of 1,2-(8-butyl)distearoylphosphatidylcholine [1,2(8-Bu)DSPC] and, moreover, they abolished the marked inhibition of the enzyme activity caused by high concentrations of 1,2(8-Bu)DSPC. The present findings demonstrated a structure-activity relationship of the branched-chain DS analogues in the regulation of PKC, perhaps related to their abilities to specifically modify interactions of PKC with PS and/or Ca2+ critically involved in enzyme activation/inactivation.     

Hepatocellular apoptosis is mediated by TNFα-dependent Fas/FasLigand cytotoxicity in a murine model of acute liver failure

There is increasing evidence that the active contribution of hepatocytes to liver disease is strongly dependent on local cytokine environment. It has been shown in vitro that TNFα can enhance hepatocyte FasLigand (FasL)-mediated cytotoxicity. Here, we demonstrate that TNFα-induced apoptosis was associated with Fas and FasL upregulation and that a FasL-neutralizing antibody prevented TNFα-induced apoptosis. We further examined in vivo the relevance of the Fas/FasL pathway to hepatocellular apoptosis in a TNFα-driven model of acute liver failure. Livers of galactosamine/lipopolysaccharide (Gal/LPS)-exposed Fas wild-type mice highly expressed both Fas and FasL and revealed marked hepatocellular apoptosis that was almost completely blocked by soluble TNFα-receptor; this was also almost absent in Gal/LPS-exposed Fas lymphoproliferation mutant mice. Our data provide evidence for a direct link between TNFα and Fas/FasL in mediating hepatocyte apoptosis. Fratricidal death by Fas–FasL interactions of neighbouring hepatocytes may actively contribute to acute liver failure.