Physiological and Molecular Function of the Sodium/Hydrogen Exchanger NHA2 (SLC9B2).

NHA2, also known as SLC9B2, is an orphan intracellular Na+/H+ exchanger (NHE) that has been associated with arterial hypertension and diabetes mellitus in humans. The objective of this NCCR TransCure project was to define the physiological and molecular function of NHA2, to develop a high resolution kinetic transport assay for NHA2 and to identify specific and potent compounds targeting NHA2. In this review, we summarize the results of this highly interdisciplinary and interfaculty effort, led by the groups of Proffs. Jean-Louis Reymond, Christoph von Ballmoos and Daniel Fuster.

The impact of digital contact tracing on the SARS-CoV-2 pandemic-a comprehensive modelling study.

Contact tracing is one of several strategies employed in many countries to curb the spread of SARS-CoV-2. Digital contact tracing (DCT) uses tools such as cell-phone applications to improve tracing speed and reach. We model the impact of DCT on the spread of the virus for a large epidemiological parameter space consistent with current literature on SARS-CoV-2. We also model DCT in combination with random testing (RT) and social distancing (SD). Modelling is done with two independently developed individual-based (stochastic) models that use the Monte Carlo technique, benchmarked against each other and against two types of deterministic models. For current best estimates of the number of asymptomatic SARS-CoV-2 carriers (approximately 40%), their contagiousness (similar to that of symptomatic carriers), the reproductive number before interventions ( R 0 at least 3) we find that DCT must be combined with other interventions such as SD and/or RT to push the reproductive number below one. At least 60% of the population would have to use the DCT system for its effect to become significant. On its own, DCT cannot bring the reproductive number below 1 unless nearly the entire population uses the DCT system and follows quarantining and testing protocols strictly. For lower uptake of the DCT system, DCT still reduces the number of people that become infected. When DCT is deployed in a population with an ongoing outbreak where O (0.1%) of the population have already been infected, the gains of the DCT intervention come at the cost of requiring up to 15% of the population to be quarantined (in response to being traced) on average each day for the duration of the epidemic, even when there is sufficient testing capability to test every traced person.

MASP-2 Is a Heparin-Binding Protease; Identification of Blocking Oligosaccharides.

It is well-known that heparin and other glycosaminoglycans (GAGs) inhibit complement activation. It is however not known whether fractionation and/or modification of GAGs might deliver pathway-specific inhibition of the complement system. Therefore, we evaluated a library of GAGs and their derivatives for their functional pathway specific complement inhibition, including the MASP-specific C4 deposition assay. Interaction of human MASP-2 with heparan sulfate/heparin was evaluated by surface plasmon resonance, ELISA and in renal tissue. In vitro pathway-specific complement assays showed that highly sulfated GAGs inhibited all three pathways of complement. Small heparin- and heparan sulfate-derived oligosaccharides were selective inhibitors of the lectin pathway (LP). These small oligosaccharides showed identical inhibition of the ficolin-3 mediated LP activation, failed to inhibit the binding of MBL to mannan, but inhibited C4 cleavage by MASPs. Hexa- and pentasulfated tetrasaccharides represent the smallest MASP inhibitors both in the functional LP assay as well in the MASP-mediated C4 assay. Surface plasmon resonance showed MASP-2 binding with heparin and heparan sulfate, revealing high Kon and Koff rates resulted in a Kd of ~2 µM and confirmed inhibition by heparin-derived tetrasaccharide. In renal tissue, MASP-2 partially colocalized with agrin and heparan sulfate, but not with activated C3, suggesting docking, storage, and potential inactivation of MASP-2 by heparan sulfate in basement membranes. Our data show that highly sulfated GAGs mediated inhibition of all three complement pathways, whereas short heparin- and heparan sulfate-derived oligosaccharides selectively blocked the lectin pathway via MASP-2 inhibition. Binding of MASP-2 to immobilized heparan sulfate/heparin and partial co-localization of agrin/heparan sulfate with MASP, but not C3b, might suggest that in vivo heparan sulfate proteoglycans act as a docking platform for MASP-2 and possibly prevent the lectin pathway from activation.

Injury rates of the German Women's American Football National Team from 2009 to 2011.

American football is one of the leading causes of athletic-related injuries. Injury rates in female elite players are mostly unknown. We hypothesized that the injury rates of female was comparable to those in men's football during practice, as well as games. From 2009 to 2011, injury data were collected from the German female national team during training camps, World Championship 2010 and International friendly matches. The injury was categorized by location on the body and recorded as fracture/dislocation, strain, concussion, contusion or other injury. Injury rates were determined based on the exposure of an athlete to a game or practice event. The injury rate was calculated as the ratio of injuries per 1000 athlete exposures (AE). The rate of injury was significantly higher during games (58.8/1000 AE) than practices [16.3/1000 AE, (P<0.01)]. Furthermore, the injury rate in the tryouts was significantly higher (24.05/1000 AE) compared to other training sessions with the national team (11.24/1000 AE). Our findings show that the injury rates in female elite American football players can be compared to those described for male players. Higher injury rates during matches than in training should also be underlined.

Peripheral antinociceptive effects of exogenous and immune cell-derived endomorphins in prolonged inflammatory pain.

Endomorphins (EMs) are endogenous selective mu-opioid receptor agonists. Their role in inflammatory pain has not been fully elucidated. Here we examine peripheral antinociception elicited by exogenously applied EM-1 and EM-2 and the contribution of EM-containing leukocytes to stress- and corticotropin-releasing factor (CRF)-induced antinociception. To this end, we applied behavioral (paw pressure) testing, radioligand binding, immunohistochemistry, and flow cytometry in rats with unilateral hindpaw inflammation induced with Freund's adjuvant. EMs injected directly into both hindpaws produced antinociception exclusively in inflamed paws. This was blocked by locally applied mu-receptor-selective (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) but not kappa-receptor-selective (nor-binaltorphimine) antagonists. Delta-receptor antagonists (naltrindole and N,N-diallyl-Tyr-Aib-Aib-Phe-Leu) did not influence EM-1-induced but dose-dependently decreased EM-2-induced antinociception. Antibodies against beta-endorphin, methionine-enkephalin, or leucine-enkephalin did not significantly change EM-2-induced antinociception. Both EMs displaced binding of [3H]-[D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin to mu-receptors in dorsal root ganglia (DRG). Using [3H]-naltrindole or [(125)I]-[D-Pen2,5]-enkephalin, no detectable delta-binding was found in DRG of inflamed hindlimbs. Numerous beta-endorphin-containing and fewer EM-1- and EM-2-containing leukocytes were detected in subcutaneous tissue of inflamed paws. Leukocyte-depleting serum decreased the number of immigrating opioid-containing immune cells and attenuated swim stress- and CRF-induced antinociception in inflamed paws. Both forms of antinociception were strongly attenuated by anti-beta-endorphin and to a lesser degree by anti-EM-1 and anti-EM-2 antibodies injected into inflamed paws. Together, exogenously applied and immune cell-derived EMs alleviate prolonged inflammatory pain through selective activation of peripheral opioid receptors. Exogenous EM-2 in addition to mu-receptors also activates peripheral delta-receptors, which does not involve actions via other opioid peptides.

Arcuate ligament vascular compression syndrome in infants and children.

BACKGROUND: Arcuate ligament vascular compression syndrome has not been described previously in the pediatric or pediatric surgical literature. However, it is mentioned in the literature of vascular and general surgery and in journals of radiology and orthopedics. In this review, the intraoperative pathological anatomy and the principles of treatment for 8 children will be presented. METHODS: The chart records and the anatomical sketches that were documented by the surgeon immediately after each procedure were analyzed retrospectively. In addition, preoperative courses and long-term follow-up (range, 3-18 years) were evaluated by a defined program. RESULTS: The diagnosis of celiac artery compression by an arcuate ligament was suspected in children presenting with a history of several years of recurrent acute abdominal pain associated with a typical arterial bruit in the midline of the epigastric region. CONCLUSIONS: Other diseases with recurrent abdominal pain and an arterial bruit must be excluded before making the decision for an operative intervention. Duplex ultrasound and angiography are possibly helpful tools to establish the respective diagnosis, but in the patients of the present series, these techniques neither confirmed compression of the celiac axis nor demonstrated decreased perfusion of the superior mesenteric artery. However, as the clinical symptoms clearly announce the disease, these diagnostic measures are not mandatory.