Ausdauersport und kardiale Adaptation (Sportherz)

One essential function of the cardiovascular system is to provide an adequate blood supply to all organs, including the skeletal muscles at rest and during exercise. Adaptation to chronic exercise proceeds mainly via the autonomic nervous system. On the one hand, peripheral muscles influence the autonomic reactions through "feedback" control via ergoreceptors, in particular, mechano- and chemoreceptors. On the other hand, there is central control in the sense of a "feed forward" regulation, e. g., the reaction of an athlete before competition. Along with other influential factors, such as circulatory presso-, chemo-, and volume receptors, the incoming impulses are processed in vegetative centers.A cardiovascular reaction, then, is the result of nerval and humoral sympathetic and parasympathetic activity. At rest, the parasympathetic tone dominates. It reduces heart frequency and conduction velocity. The high vagal tone is initially reduced with increasing physical exertion and switches at higher intensity to increasingly sympathetic activation. This mechanism of reaction to exercise is supported by inverse central and peripheral transmissions.Chronic endurance training leads to an improved local aerobic capacity of the exercised musculature. At rest, it augments parasympathetic activity when the muscle mass is sufficiently large, i. e., 20-30% of the skeletal musculature. The extent of the adaptation depends on individual factors, such as scope, intensity of training, and type of muscle fiber. A higher vagal tone delays the increase in the sympathetic tone during physical exertion. The regulatory range of heart rate, contractility, diastolic function, and blood pressure is increased. In addition, adaptation results in functional and structural changes in the vascular system. Cardiocirculatory work is economized, and maximum performance and oxygen uptake are improved. Endurance training exceeding an individual limit causes harmonic enlargement and hypertrophy of the heart. The thickness of both, the septum and posterior wall increases to the same extent as the interior volume. The mass/volume ratio, and therefore the maximum systolic wall stress, remains constant in contrast to pathologic forms of hypertrophy. Adaptations, including function and size of the heart, show a regression in healthy inactive persons without any structural heart disease.     

Treatment of acquired hemophilia by the Bonn-Malmo Protocol: documentation of an in vivo immunomodulating concept

Acquired hemophilia (AH) is an extremely rare condition in which autoantibodies (inhibitors) against clotting factor VIII induce acute and life-threatening hemorrhagic diathesis because of abnormal blood clotting. The mortality rate of AH is as high as 16%, and current treatment options are associated with adverse side effects. We investigated a therapeutic approach for AH called the modified Bonn-Malmo Protocol (MBMP). The aims of MBMP include suppression of bleeding, permanent elimination of inhibitors, and development of immune tolerance, thereby avoiding long-term reliance on coagulation products. The protocol included immunoadsorption for inhibitor elimination, factor VIII substitution, intravenous immunoglobulin, and immunosuppression. Thirty-five high-titer patients with critical bleeding who underwent MBMP were evaluated. Bleeding was rapidly controlled during 1 or 2 apheresis sessions, and no subsequent bleeding episodes occurred. Inhibitor levels decreased to undetectable levels within a median of 3 days (95% confidence interval [95% CI], 2-4 days), factor substitution was stopped within a median of 12 days (95% CI, 11-17 days), and treatment was completed within a median of 14 days (95% CI, 12-17 days). Long-term follow-up (7 months-7 years) showed an overall response rate of 88% for complete remission (CR). When cancer patients were excluded, the CR rate was 97%.     

Experimentelle Studien zur Physiologie des ersten Atemzuges

Archives of Gynecology and Obstetrics -     

Animal cells connected by nanotubes can be electrically coupled through interposed gap-junction channels

Tunneling nanotubes (TNTs) are recently discovered conduits for a previously unrecognized form of cell-to-cell communication. These nanoscale, F-actin–containing membrane tubes connect cells over long distances and facilitate the intercellular exchange of small molecules and organelles. Using optical membrane-potential measurements combined with mechanical stimulation and whole-cell patch-clamp recording, we demonstrate that TNTs mediate the bidirectional spread of electrical signals between TNT-connected normal rat kidney cells over distances of 10 to 70 μm. Similar results were obtained for other cell types, suggesting that electrical coupling via TNTs may be a widespread characteristic of animal cells. Strength of electrical coupling depended on the length and number of TNT connections. Several lines of evidence implicate a role for gap junctions in this long-distance electrical coupling: punctate connexin 43 immunoreactivity was frequently detected at one end of TNTs, and electrical coupling was voltage-sensitive and inhibited by meclofenamic acid, a gap-junction blocker. Cell types lacking gap junctions did not show TNT-dependent electrical coupling, which suggests that TNT-mediated electrical signals are transmitted through gap junctions at a membrane interface between the TNT and one cell of the connected pair. Measurements of the fluorescent calcium indicator X-rhod-1 revealed that TNT-mediated depolarization elicited threshold-dependent, transient calcium signals in HEK293 cells. These signals were inhibited by the voltage-gated Ca²⁺ channel blocker mibefradil, suggesting they were generated via influx of calcium through low voltage-gated Ca²⁺ channels. Taken together, our data suggest a unique role for TNTs, whereby electrical synchronization between distant cells leads to activation of downstream target signaling.Cell-to-cell communication plays an important role in physiological processes of multicellular organisms. Diverse signaling pathways have been documented for the exchange of molecular information between cells. These include (i) the direct interaction of cell-surface molecules, (ii) the secretion of signaling molecules and their receptor-mediated uptake by target cells, and (iii) the direct transport of molecules through gap junctions. In addition to the exchange of signaling molecules, cells also communicate via electrical signals, where electrical coupling of cells via gap junctions is crucial for information processing and synchronization. Recent studies implicate electrical signaling in developmental processes, such as the establishment of left-right pattern in embryos (1), tail regeneration of Xenopus (2), and wound healing (2).Some years ago, a new route of intercellular communication, based on the formation of tunneling nanotubes (TNTs) or similar structures that connect cells over long distances, was identified (3, 4). These membrane tubes, typically 50 to 200 nm in diameter with lengths up to several cell diameters, contain F-actin and, as a characteristic property, lack contact to the substratum (5). Subsequently, a growing number of cell types have been shown to form and use TNTs for the exchange of diverse cellular components, such as endocytic vesicles, mitochondria, plasma membrane proteins, and cytoplasmic molecules (6, 7). Pathogens, such as HIV (8, 9) and prions (10), have also been found to spread via TNT-like structures. The increasing number of functions attributed to TNTs (6, 7, 11), in conjunction with the recent finding that these structures exist in vivo (12), suggests important roles in intercellular communication of TNTs under physiological conditions.The question arises as to whether, in addition to the exchange of molecules, TNTs also convey electrical signals between distant cells. The demonstration that artificial membrane nanotubes with a similar diameter as TNTs are efficient conductors of electrical currents (13) suggests that TNTs may also accomplish electrical cell-to-cell coupling. To investigate this theory, we combined optical membrane-potential measurements and electrophysiological methods to analyze electrical signals between TNT-connected cell pairs. Our results demonstrate that TNTs can mediate electrical coupling between distant cells and provide evidence that gap junctions participate in this long-distance coupling. Furthermore, we show that the electrical signals transferred from one cell to another are sufficient to induce a transient calcium elevation in the recipient cell by activating low voltage-gated Ca²⁺ channels.     

Parkinson patient fibroblasts show increased alpha-synuclein expression

Parkinson's disease (PD) is a neurodegenerative movement disorder of advanced age with largely unknown etiology, but well documented tissue damage from oxidative stress. Increased α-synuclein (SNCA) expression is known to cause a rare form of PD, early-onset autosomal dominant PARK4. We have previously shown that loss-of-function mutations of the mitochondrial kinase PINK1 which cause the early-onset recessive PARK6 variant result in oxidative damage in patient fibroblasts. We now investigated the molecular chain of events from mitochondrial dysfunction to cell death which is largely unknown. Primary skin fibroblast cultures from patients were analysed for gene expression anomalies. In G309D-PINK1 patient fibroblasts, mainly genes regulated by oxidative stress, as well as genes encoding synaptic proteins such as SNCA showed altered expression. The induction of SNCA was also observed in control fibroblasts with knock-down of PINK1. The induction of SNCA expression was found to constitute a specific disease biomarker in sporadic PD patient fibroblasts. To understand the mechanism of this induction, we exposed control fibroblasts to oxidative, proteasomal and endoplasmic reticulum stress and were able to trigger the SNCA expression upregulation. Our data indicate that loss-of-function of PINK1 leads to enhanced alpha-synuclein expression and altered cell–cell contact. Alpha-synuclein induction might represent a common event for different variants of PD as well as a PD-specific trigger of neurodegeneration. We propose that the expression changes described might potentially serve as biomarkers that allow objective PD patient diagnosis in an accessible, peripheral tissue.     

Der Dämmerzustand. (Zur Frage der Differentialdiagnose und Eingruppierung.)

Ohne Zusammenfassung     

No Effect of the Hemoglobin Solution HBOC-201 on the Response of the Rat R1H Tumor to Fractionated Irradiation

BACKGROUND AND PURPOSE: Tumor hypoxia is regarded as one important underlying feature of radioresistance. The authors report on an experimental approach to improve tumor response to radiation by combining fractionated irradiation with HBOC-201, an ultrapurified polymerized hemoglobin solution, which is currently used in clinical phase II/III trials as alternative oxygen carrier and proved to be highly effective in tissue oxygenation (tpO(2)). MATERIAL AND METHODS: Subcutaneously growing rhabdomyosarcoma R1H tumors of the rat were treated with either 40 Gy (2 Gy/fraction, 20 fractions in 2 weeks, ambient) followed by graded top-up doses (clamped) alone, or in combination with HBOC-201, or with HBOC-201 plus carbogen (95% O(2) + 5% CO(2)). Local tumor control (TCD50%) and growth delay were used as endpoints. In addition, the effect of HBOC-201 alone or in combination with carbogen on the tpO(2) of tumor and muscle was determined using a flexible stationary probe (Licox, GMS). RESULTS: TCD50% values of 119 Gy (95% confidence interval 103;135), 111 Gy (84;138), and 102 Gy (83;120) were determined for tumors irradiated alone, in combination with HBOC-201, and with HBOC-201 plus carbogen, respectively. Although the dose-response curves showed a slight shift to lower doses when HBOC-201 or HBOC-201 plus carbogen was added, the differences in TCD50% were not statistically significant. No effect was seen on the growth delay of recurrent tumors. HBOC-201 alone did not effect tumor or muscle tpO(2). In combination with carbogen the mean tpO(2) of muscle raised from 23.9 mmHg to 59.3 mmHg (p < 0.05), but this effect was less pronounced than the increase in tpO(2) by carbogen alone. CONCLUSION: Low-dose application of HBOC-201 does not improve the response of the rhabdomyosarcoma R1H of the rat to fractionated irradiation.