A Protocol that Mandates Postoxygenator and Arterial Blood Gases to Confirm Brain Death on Venoarterial Extracorporeal Membrane Oxygenation.

The apnea test (AT) during clinical brain death (BD) testing does not account for different arterial gas tensions on veno-arterial extracorporeal membrane oxygenation (V-A ECMO). We aimed to develop a protocol and now report our experience with three patients. The protocol was developed and implemented in 2015 at a quaternary center in Australia, measures both right radial and postoxygenator carbon dioxide (CO2) and oxygen (O2) gas tensions during the AT, incorporates regular gas sampling and a gradual reduction in fresh gas flow to ensure patient oxygenation. Patient 1 remained apneic despite both right radial and postoxygenator CO2 gas tensions >60 mmHg. Patient 2, despite having CO2 levels in a right radial arterial sample high enough to diagnose BD, postoxygenator CO2 remained <60 mmHg. Patient 2 did not breathe but radiological tests confirmed BD. Patient 3 showed respiratory effort but only once CO2 levels rose high enough in both right radial and postoxygenator samples. No patient was hypoxic during the AT. Performance of a reliable AT on V-A ECMO requires measurement of both right radial and postoxygenator blood gases. A protocol, which measures both blood gas values, is feasible to implement, while being both safe and easy to perform.

Autoregulation of von Willebrand factor function by a disulfide bond switch.

Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this "mechanopresentation" remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring. Only when the bond is cleaved does the A2 domain bind to the A1 domain and block platelet GPIb binding. Molecular dynamics simulations indicate that cleavage of the disulfide bond modifies the structure and molecular stresses of the A2 domain in a long-range allosteric manner, which provides a structural explanation for redox control of the autoinhibition. Significantly, the A2 disulfide bond is cleaved in ~75% of VWF subunits in healthy human donor plasma but in just ~25% of plasma VWF subunits from heart failure patients who have received extracorporeal membrane oxygenation support. This suggests that the majority of plasma VWF binding sites for platelet GPIb are autoinhibited in healthy donors but are mostly available in heart failure patients. These findings demonstrate that a disulfide bond switch regulates mechanopresentation of VWF.

Design, Synthesis, and Evaluation of a Novel Series of Oxadiazine Gamma Secretase Modulators for Familial Alzheimer's Disease.

Herein we describe the design, synthesis, and evaluation of a novel series of oxadiazine-based gamma secretase modulators obtained via isosteric amide replacement and critical consideration of conformational restriction. Oxadiazine lead 47 possesses good in vitro potency with excellent predicted CNS drug-like properties and desirable ADME/PK profile. This lead compound demonstrated robust Aß42 reductions and subsequent Aß37 increases in both rodent brain and CSF at 30 mg/kg dosed orally.

Characterization of FRM-36143 as a new γ-secretase modulator for the potential treatment of familial Alzheimer's disease.

BACKGROUND: Familial Alzheimer's disease (FAD) is caused by mutations in the amyloid precursor protein (APP) or presenilin (PS). Most PS mutations, which account for the majority of FAD cases, lead to an increased ratio of longer to shorter forms of the amyloid beta (Aß) peptide. The therapeutic rationale of γ-secretase modulators (GSMs) for Alzheimer's disease is based on this genetic evidence as well as on enzyme kinetics measurements showing changes in the processivity of the γ-secretase complex. This analysis suggests that GSMs could potentially offset some of the effects of PS mutations on APP processing, thereby addressing the root cause of early onset FAD. Unfortunately, the field has generated few, if any, molecules with good central nervous system (CNS) drug-like properties to enable proof-of-mechanism studies. METHOD: We characterized the novel GSM FRM-36143 using multiple cellular assays to determine its in vitro potency and off-target activity as well as its potential to reverse the effect of PS mutations. We also tested its efficacy in vivo in wild-type mice and rats. RESULTS: FRM-36143 has much improved CNS drug-like properties compared to published GSMs. It has an in vitro EC50 for Aß42 of 35 nM in H4 cells, can reduce Aß42 to 58 % of the baseline in rat cerebrospinal fluid, and also increases the non-amyloidogenic peptides Aß37 and Aß38. It does not inhibit Notch processing, nor does it inhibit 24-dehydrocholesterol reductase (DHCR24) activity. Most interestingly, it can reverse the effects of presenilin mutations on APP processing in vitro. CONCLUSIONS: FRM-36143 possesses all the characteristics of a GSM in terms of Aß modulation Because FRM-36143 was able to reverse the effect of PS mutations, we suggest that targeting patients with this genetic defect would be the best approach at testing the efficacy of a GSM in the clinic. While the amyloid hypothesis is still being tested with ß-site APP-cleaving enzyme inhibitors and monoclonal antibodies in sporadic AD, we believe it is not a hypothesis for FAD. Since GSMs can correct the molecular defect caused by PS mutations, they have the promise to provide benefits to the patients when treated early enough in the course of the disease.

Extracorporeal membrane oxygenation-hemostatic complications.

The use of extracorporeal membrane oxygenation (ECMO) support for cardiac and respiratory failure has increased in recent years. Improvements in ECMO oxygenator and pump technologies have aided this increase in utilization. Additionally, reports of successful outcomes in supporting patients with respiratory failure during the 2009 H1N1 pandemic and reports of ECMO during cardiopulmonary resuscitation have led to increased uptake of ECMO. Patients requiring ECMO are a heterogenous group of critically ill patients with cardiac and respiratory failure. Bleeding and thrombotic complications remain a leading cause of morbidity and mortality in patients on ECMO. In this review, we describe the mechanisms and management of hemostatic, thrombotic and hemolytic complications during ECMO support.

Long-term right ventricular support with a centrifugal ventricular assist device placed in the right atrium.

This case series outlines the technique and results of right ventricular assist device (RVAD) support with the off-label use of the centrifugal HeartWare HVAD (HeartWare Inc., Framingham, MA, USA) for long-term support. Four patients in our institution have been implanted with BiVADs, using the Heartware device as the RVAD, and supported for between 117 days and 772 days. Three of the patients have been successfully supported for over 18 months. Three patients have successfully been transplanted and one patient remains on the device, now approaching two years of support. None of the patients have had RVAD device-related complications.