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     

In vivo and in vitro degradation of poly(ether ester) block copolymers based on poly(ethylene glycol) and poly(butylene terephthalate)

Two in vivo degradation studies were performed on segmented poly(ether ester)s based on polyethylene glycol (PEG) and poly(butylene terephthalate) (PBT) (PEOT/PBT). In a first series of experiments, the in vivo degradation of melt-pressed discs of different copolymer compositions were followed up for 24 weeks after subcutaneous implantation in rats. The second series of experiments aimed to simulate long-term in vivo degradation. For this, PEOT/PBT samples were pre-degraded in phosphate buffer saline (PBS) at 100 degrees C and subsequently implanted. In both series, explanted materials were characterized by intrinsic viscosity measurements, mass loss, proton nuclear magnetic resonance spectroscopy (1H-NMR) and differential scanning calorimetry (DSC). In both studies the copolymer with the higher PEO content degraded the fastest, although all materials degraded relatively slowly. To determine the nature of the degradation products formed during hydrolysis of the copolymers, 1000 PEOT71PBT29 (a copolymer based on PEG with a molecular weight of 1000 g/mol and 71 wt% of PEO-containing soft segments) was degraded in vitro at 100 degrees C in phosphate buffer saline (PBS) during 14 days. The degradation products present in PBS were analyzed by 1H-NMR and high performance liquid chromatography/mass spectroscopy (HPLC/MS). These degradation products consisted of a fraction with high contents of PEO that was soluble in PBS and a PEOT/PBT fraction that was insoluble at room temperature. From the different in vitro and in vivo degradation experiments performed, it can be concluded that PEOT/PBT degradation is a slow process and generates insoluble polymeric residues with high PBT contents.     

Improving the fixation of an artificial intervertebral disc

The fixation of an artificial intervertebral disc has been studied especially with respect to the dimensions, the convexity of the endplates and the size of the fixation elements. From literature and cadaveric vertebrae, the dimensions and shape of the lumbar vertebral endplates were determined and the dimensions of fixation ribs for the artificial intervertebral disc were calculated. To withstand shear forces and prevent dislocation, two sagittal ribs, each 3.5 mm in height and at least 20 mm in length and four transversal ribs, each 1.5 mm in height and with a total length of 60 mm are sufficient. A range of five different sagittal diameters was selected as sufficient for all patients. At least 72.6 % of the endplate of the vertebrae is covered. A convexity with a radius of 140 mm limits the gap to 0.62 mm.     

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.     

Overexpression of the pp32r1 (ANP32C) oncogene or its functional mutant pp32r1Y140H confers enhanced resistance to FTY720 (Finguimod)

pp32r1 (ANP32C) is oncogenic and has been shown to be overexpressed in tumors of the breast, prostate, and pancreas. In this work we show that pp32 family proteins are able to bind to the sphingosine analog FTY720 (Finguimod). Molecular docking studies highlight that a conserved residue F136 is likely to be a key determinant of the FTY720 binding site on the pp32 leucine-rich repeat domain. Transduction of the renal carcinoma cell line ACHN or cervical cancer cell line HeLa with lentivirus expressing the oncogenic family member pp32r1 or a pp32r1Y140H functional mutant illustrated an enhanced resistance to FTY720 induced apoptosis. These findings highlight that certain cancers overexpressing pp32r1 or pp32r1 mutants are likely to demonstrate enhanced resistance to FTY720 treatment.     

Acidified seawater impacts sea urchin larvae pH regulatory systems relevant for calcification

Calcifying echinoid larvae respond to changes in seawater carbonate chemistry with reduced growth and developmental delay. To date, no information exists on how ocean acidification acts on pH homeostasis in echinoderm larvae. Understanding acid–base regulatory capacities is important because intracellular formation and maintenance of the calcium carbonate skeleton is dependent on pH homeostasis. Using H⁺-selective microelectrodes and the pH-sensitive fluorescent dye BCECF, we conducted in vivo measurements of extracellular and intracellular pH (pH_e and pH_i) in echinoderm larvae. We exposed pluteus larvae to a range of seawater CO₂ conditions and demonstrated that the extracellular compartment surrounding the calcifying primary mesenchyme cells (PMCs) conforms to the surrounding seawater with respect to pH during exposure to elevated seawater pCO₂. Using FITC dextran conjugates, we demonstrate that sea urchin larvae have a leaky integument. PMCs and spicules are therefore directly exposed to strong changes in pH_e whenever seawater pH changes. However, measurements of pH_i demonstrated that PMCs are able to fully compensate an induced intracellular acidosis. This was highly dependent on Na⁺ and HCO₃⁻, suggesting a bicarbonate buffer mechanism involving secondary active Na⁺-dependent membrane transport proteins. We suggest that, under ocean acidification, maintained pH_i enables calcification to proceed despite decreased pH_e. However, this probably causes enhanced costs. Increased costs for calcification or cellular homeostasis can be one of the main factors leading to modifications in energy partitioning, which then impacts growth and, ultimately, results in increased mortality of echinoid larvae during the pelagic life stage.