We study the thermodynamics of de Sitter black holes with a conformally coupled scalar field. The geometry is that of the lukewarm Reissner-Nordstrom-de Sitter black holes, with the event and cosmological horizons at the same temperature. This means that the region between the event and cosmological horizons can form a regular Euclidean instanton. The entropy is modified by the nonminimal coupling of the scalar field to the geometry, but can still be derived from the Euclidean action, provided suitable modifications are made to deal with the electrically charged case. We use the first law as derived from the isolated horizons formalism to compute the local horizon energies for the event and cosmological horizons.

Learn about upcoming treatments for life-threatening hemorrhage. PROTHROMBIN COMPLEX CONCENTRATES (PCCs) and recombinant factor VIIa (rfVIIa) have been used for many years to control bleeding in patients with hemophilia. Now they’re being tested for control of bleeding in trauma patients and patients with hemorrhagic strokes associated with anticoagulation therapy. Uncontrolled hemorrhage is a major cause of death in about 40% of trauma patients. Research has shown that intracerebral bleeding is larger and more likely to be fatal in patients on anticoagulation. For patients on anticoagulation therapy such as warfarin, minor bleeding can be controlled by discontinuing the drug and administering vitamin K. However, the anticoagulant effect isn’t fully reversed for up to 72 hours. Giving vitamin K intravenously can reverse the anticoagulant effect in up to 6 hours, but even that’s not fast enough in a patient with hemorrhagic stroke or traumatic injury. The current practice in those cases is to administer fresh-frozen plasma (FFP), which replaces clotting factors. However, FFP has drawbacks. The large volume of fluid required can cause fluid overload in patients with cardiovascular compromise. Also, before FFP can be administered, the patient’s blood type must be identified; then the FFP is thawed and administered. This process can take 2 or more hours. In cases of severe, acute hemorrhage, even this time frame is too long. A more rapid and possibly more effective therapy for hemorrhagic stroke is to replace deficient coagulation factors via PCCs. Studies have found that using PCCs in life-threatening bleeding reduced the patient’s international normalized ratio significantly within 15 minutes of PCC administration. Patients treated with PCCs also showed significantly less clinical deterioration compared with those receiving FFP. The risks of PCCs include possible induction of disseminated intravascular coagulation, myocardial infarction, venous thrombosis, and pulmonary emboli. Another promising treatment for acute hemorrhage is NovoSeven, an rfVIIa now in clinical trials. Structurally similar to human plasma factor VIIa, NovoSeven is a vitamin-K-dependent glycoprotein. At the site of injury, NovoSeven works with tissue factor to generate thrombin, activate platelets, and form a clot. Between June 1999 and January 2001, seven critically ill, coagulopathic, multitransfused trauma patients were treated with NovoSeven. In all seven patients, diffuse bleeding “dried out” within 15 minutes after one to three doses of NovoSeven were given. Patients also required significantly less blood replacement, and prothrombin and partial thromboplastin time shortened from 24 to 10.1 seconds and 79 to 41 seconds, respectively. The risk of thrombotic events after treatment with NovoSeven isn’t known, but is considered low. The infusion should be reduced or discontinued if the patient shows any signs of thrombosis or pulmonary embolism, such as fluctuations in blood pressure, pulse, and respirations; or chest pain and cough. Death from hemorrhage has been greatly decreased in recent years, thanks to improved surgical techniques, packing of intra-abdominal wounds, use of angiographic embolization in surgical hemostasis, emphasis on correcting hypothermia, and aggressive transfusion practices. Future challenges with the use of PCCs or NovoSeven include determining the uniform indications for treatment, optimal timing of first dose, dose interval, and delivery as a bolus or continuous infusion. Although clinical trials are just beginning, initial results are promising, and you could soon be using these agents to control life-threatening hemorrhage.

Administration of extracellular hemoglobin-based oxygen carriers often induces mild increases in blood pressure. In order to test whether nitric oxide (NO) scavenging is responsible for the hypertensive effect, we constructed and tested a set of recombinant hemoglobins that vary in rates of reaction with NO. The results suggest that the rapid reactions of oxy- and deoxyhemoglobin with nitric oxide are the fundamental cause of the hypertension. The magnitude of the blood-pressure effect correlates directly with the in vitro rate of NO oxidation. Hemoglobins with decreased NO-scavenging activity may be more suitable for certain therapeutic applications than those that cause depletion of nitric oxide.

The objective of this investigation was to compare the gastric motility effects of two recombinant hemoglobin variants, rHb1.1, and rHb3011, the latter having decreased nitric oxide reactivity via mutagenic alteration. Variants were administered to rats at 750 and 1500 mg/kg, i.v., prior to feeding a meal. The percentage of meal emptied was determined 45 min after feeding. rHb1.1 reduced gastric emptying significantly (48% and 71%), whereas rHb3011 was significant (42%) only at the higher dose (p < 0.05). The results suggest that rHb1.1 inhibits gastric emptying by scavenging NO, and this effect is significantly reduced by rHb3011, which has decreased NO reactivity.

Nitric oxide (NO) has been implicated as mediator in a variety of physiological functions, including neurotransmission, platelet aggregation, macrophage function, and vasodilation. The consumption of NO by extracellular hemoglobin and subsequent vasoconstriction have been suggested to be the cause of the mild hypertensive events reported during in vivo trials of hemoglobin-based O2 carriers. The depletion of NO from endothelial cells is most likely due to the oxidative reaction of NO with oxyhemoglobin in arterioles and surrounding tissue. In order to determine the mechanism of this key reaction, we have measured the kinetics of NO-induced oxidation of a variety of different recombinant sperm whale myoglobins (Mb) and human hemoglobins (Hb). The observed rates depend linearly on [NO] but show no dependence on [O2]. The bimolecular rate constants for NO-induced oxidation of MbO2 and HbO2 are large (k.ox,NO = 30-50 microM-1 s-1 for the wild-type proteins) and similar to those for simple nitric oxide binding to deoxygenated Mb and Hb. Both reversible NO binding and NO-induced oxidation occur in two steps: (1) bimolecular entry of nitric oxide into the distal portion of the heme pocket and (2) rapid reaction of noncovalently bound nitric oxide with the iron atom to produce Fe(2+)-N=O or with Fe(2+)-O-O delta- to produce Fe(3+)-OH2 and nitrate. Both the oxidation and binding rate constants for sperm whale Mb were increased when His(E7) was replaced by aliphatic residues. These mutants lack polar interactions in the distal pocket which normally hinder NO entry into the protein. Decreasing the volume of the distal pocket by replacing Leu(B10) and Val(E11) with aromatic amino acids markedly inhibits NO-induced oxidation of MbO2. The latter results provide a protein engineering strategy for reducing hypertensive events caused by extracellular hemoglobin-based O2 carriers. This approach has been explored by examining the effects of Phe(B10) and Phe(E11) substitutions on the rates of NO-induced oxidation of the alpha and beta subunits in recombinant human hemoglobin.