Neurotherapeutic potential of erythropoietin after ischemic injury of the central nervous system

Erythropoietin(EPO) is one of the most successful biopharmaceuticals in history and is used for treating anemia of different origins. However, it became clear that EPO could also work in a neuroprotective, antiapoptotic, antioxidative, angiogenetic and neurotropic way. It causes stimulation of cells to delay cell apoptosis, especially in the central nervous system. In rodent models of focal cerebral ischemia, EPO showed an impressive reduction of infarct size by 30% and improvement of neurobehavioral outcome by nearly 40%. A large animal model dealing with ischemia and reperfusion of the spinal cord showed that EPO could reduce the risk of spinal cord injury significantly. In addition, some clinical studies tested whether EPO works in real live clinical settings. One of the most promising studies showed the innocuousness and improvements in follow-up, outcome scales and in infarct size, of EPO-use in humans suffering from ischemic stroke. Another study ended unfortunately in a negative outcome and an increased overall death rate in the EPO group. The most possible reason was the involvement of patients undergoing simultaneously systemic thrombolysis with recombinant tissue plasminogen activator. An experimental study on rats demonstrated that administration of EPO might exacerbate tissue plasminogen activator-induced brain hemorrhage without reducing the ischemic brain damage. This case shows clearly how useful animal models can be to check negative side effects of a treatment before going into clinical trials. Other groups looked in human trials at the effects of EPO on the outcome after ischemic stroke, relation to circulating endothelial progenitor cells, aneurysmal subarachnoid hemorrhage, traumatic brain injury, hemoglobin transfusion thresholds and elective first-time coronary artery bypass surgery. Most of the results were positive, but are based mostly on small group sizes. However, some of the most neglected facts when focusing on experimental setups of ischemia of the central nervous system are issues like age and comorbidities. It might be extremely worthy to consider these points for future projects, because EPO might influence all these factors.     

Heart Rate Variability Predicts Severe Hypotension after Spinal Anesthesia for Elective Cesarean Delivery

Background: Hypotension due to vasodilation during subarachnoid block (SAB) for elective cesarean delivery may be harmful. Heart rate variability (HRV), reflecting autonomic control, may identify patients at risk of hypotension.

Methods: Retrospectively, HRV was analyzed in 41 patients who were classified into one of three groups depending on the decrease in systolic blood pressure (SBP): mild (SBP > 100 mmHg), moderate (100 > SBP > 80 mmHg), or severe (SBP < 80 mmHg). Prospectively, HRV and hemodynamic data of 19 patients were studied. Relative low frequency (LF), relative high frequency (HF), and LF/HF ratio were analyzed.

Results: Retrospective analysis of HRV showed a significantly higher sympathetic and lower parasympathetic drive in the groups with moderate and severe compared with mild hypotension before SAB (median, 25th/75th percentiles): LF/HF: mild: 1.2 (0.9/1.8), moderate: 2.8 (1.8/4.6), P < 0.05 versus mild; severe: 2.7 (2.0/3.5), P < 0.05 versus mild. Results were confirmed by findings of LF and HF. Prospectively, patients were grouped according to LF/HF before SAB: low-LF/HF: 1.5 (1.1/2.0) versus high-LF/HF: 4.0 (2.8/4.7), P < 0.05; low-LF: 58 +/- 9% versus high-LF: 75 +/- 10%, P < 0.05; low-HF: 41 +/- 10% versus high-HF: 25 +/- 10%, P < 0.05. High-risk patients had a significantly lower SBP after SAB (76 +/- 21 vs. 111 +/- 12 mmHg; P < 0.05).     

Regelungssystematische Vorschläge zur Umsetzung der Richtlinie 2004/23/EG (Geweberichtlinie)

Ohne Zusammenfassung     

Variation of the immune response to sheep erythrocytes in several strains of mice and their crosses

Summary There is a continuous variation in the immune response to sheep erythrocytes in inbred and outbred strains of mice. In animals of equal age strain-specific differences are the most important cause of the variation. Female animals are on the average superior to the male ones. Especially in the 7 S response the crossbreds showed positive deviations from the mid-parent values, thus suggesting the existence of non-additive gene effects. In one crossing experiment maternal influences could be shown.

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Zusammenfassung Die Stärke der Immunantwort nach Injektion einer konstanten Dosis Schaferythrocyten variiert kontinuierlich in verschiedenen Mäusestämmen. Bei gleichaltrigen Tieren stellen stammbedingte Unterschiede eine wichtigere Varianzursache dar als das Geschlecht der Tiere. Trotzdem waren die weiblichen Tiere in der Mehrzahl der durchgeführten Tests den männlichen überlegen. Kreuzungstiere zeigten einen Hybrideffekt, der vor allem die Zahl der indirekten plaquebildenden Zellen in der Milz und den Titer der merkaptoäthanolresistenten Hämagglutinine im Serum betraf. In einem Kreuzungsexperiment konnte ein mütterlicher Effekt beobachtet werden.

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This investigation was supported by the Deutsche Forschungsgemeinschaft.     

Innovationsunterstützung im BfArM – Erfahrungen aus den Beratungen zu digitalen Gesundheitsanwendungen (DiGA)

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Seit Mai 2020 können Hersteller einen Antrag zur Aufnahme einer digitalen Gesundheitsanwendung (DiGA) in das Verzeichnis...     

What happens after graft loss? A large,long-term,single-center observation

The number of patients returning to dialysis after graft failure increases. Surprisingly, little is known about the clinical and immunological outcomes of this cohort. We retrospectively analyzed 254 patients after kidney allograft loss between 1997 and 2017 and report clinical outcomes such as mortality, relisting, retransplantations, transplant nephrectomies, and immunization status. Of the 254 patients, 49% had died 5 years after graft loss, while 27% were relisted, 14% were on dialysis and not relisted, and only 11% were retransplanted 5 years after graft loss. In the complete observational period, 111/254 (43.7%) patients were relisted. Of these, 72.1% of patients were under 55 years of age at time of graft loss and only 13.5% of patients were ≥65 years. Age at graft loss was associated with relisting in a logistic regression analysis. In the complete observational period, 42 patients (16.5%) were retransplanted. Only 4 of those (9.5%) were ≥65 years at time of graft loss. Nephrectomy had no impact on survival, relisting, or development of dnDSA. Patients after allograft loss have a high overall mortality. Immunization contributes to long waiting times. Only a very limited number of patients are retransplanted especially when ≥65 years at time of graft loss.     

Studies on the pharmacodynamic activity of several drug solvents. 2. Glycerin, N-(beta-hydroxyethyl)-lactamide, polyethylene glycol 400

The drug solvents glycerin, N-(beta-hydroxyethyl)-lactamide, and polyethylene glycol 400 (Lutrol 9) were examined for their pharmacodynamic properties in the following tests: i.p. toxicity, "sign pattern", inclined screen test, balance rod test, and potentiation of hexobarbitone sleeping time in mice, spasmolytic activity in the guinea pig isolated ileum, and cardiovascular studies in anaesthetized rats, cats, and dogs including the i.v. toxicity. In mice and rats glycerin exhibited the highest tocicity as well as the greatest activity in potentiating hexobarbitone sleeping time. In the isolated ileum the solvents showed unspecific spasmolytic activities with histamine, carbachol, and BaCl2 as spasmogens. After i.v. administration in rats, cats, and dogs the solvents caused cardiovascular effects even in very low doses. Based on the pharmacodynamic properties, doses are recommended for each solvent which should not be exceeded without control experiments in the laboratory routine. These tolerable doses do not only depend on the species but also on the test concerned.     

Unexpected brain lesions in lactating Sprague-Dawley rats in a Two-generation Inhalation Reproductive Toxicity Study with pentafluoropropane (HFC-245fa)

The study presented was conducted following the reproductive study guideline OECD Guideline 416 Two-Generation Reproduction Toxicity Study. Sprague-Dawley rats were exposed to 2000, 10,000 and 50,000 ppm of HFC-245fa. There was an unexpected mortality of lactating dams in the medium and high dose group beginning at day 10 of lactation. Statistically significant histopathological alterations were observed in the cerebellum of a total of 9/30 females of the high dose group of the F₀-generation and in 10/27 females of the high dose group of the F₁-generation. In contrast there were no brain lesions found in males or non-pregnant females of all dose groups. Neuronal necrosis and degeneration in the cerebellar cortex were observed as the most severe finding. Furthermore vacuolation of the neuropil in different degrees was diagnosed in 7/30 females of the F₀-generation and in 9/30 females of the F₁-generation. Acute hemorrhages – in particular perivascular – occurred in 5/30 females of the F₀- and in 5/30 females of the F1-generation indicating a disturbed vascular integrity. The main lesions found in the cerebrum were glial scars in the corpus callosum and restricted to 2/30 females of the F₀-generation of the high dose group. The increased incidence of myocardial fibrosis and mononuclear cell infiltration in males – indicating myocarditis – was only seen in the F₀-generation of the high dose group. Females of the F₁-generation of the high dose group showed an increased incidence of minimal myocardial fibrosis. In summary, histopathology revealed that the brain, particularly the cerebellum, and to a minor degree the heart turned out to be the toxicological target organs of the substance. Presumably substance-related energy deprivation may be responsible for the observed changes. One of the metabolites, 3,3,3-trifluoropropanoic acid has been shown to be capable of causing this effect.     

Internal patterned injuries in trauma

Patterned bruising of the internal organs is unusual. In these cases a cutaneous pattern of bruising is not observed but the underlying tissue may show unusual injuries that may even be recognizable as a tramline pattern. We report the suicide of a 23-year-old man by jumping off a bridge. At autopsy, an unusual finding was “tramline” bruising of the right liver lobe. The “blunt objects” that inflicted the bruising were determined to be the right ribs which were pushed against the liver capsule as a consequence of the extensive thoracic and vertebral trauma after a fall from a height with intermediate impact.