Cardiac function after intermittent antegrade warm blood cardioplegia: contribution of the double-indicator dilution technique

Objective: To evaluate cardiac performance following coronary artery surgery using two different techniques of cardioplegia¶Design: Randomized prospective study¶Setting: Adult cardiothoracic intensive care unit in a university hospital¶Study population: Thirty patients undergoing isolated coronary surgery¶Interventions: Patients were randomized to receive either intermittent antegrade warm blood cardioplegia with normothermic bypass (group 1) or combined antegrade and retrograde cold crystalloid cardioplegia with hypothermic bypass (group 2). Hemodynamic evaluation included conventional measurements from a pulmonary artery catheter and data obtained by thermal dye dilution utilizing an arterial thermistor-tipped fiberoptic catheter¶Results: The only major difference between groups was a significantly higher right atrial pressure in group 2, from 4 h to 24 h after surgery (8.8 ± 2.6 vs. 11.8 ± 3.2 mmHg at 4 h and 11 ± 3.1 vs. 8.5 ± 1.8 mmHg at 24 h, P = 0.04). After cold cardioplegia a significant increase in right atrial pressure was observed (7.5 ± 3.1 before surgery vs. 11.4 ± 3 mmHg at 8 h, P = 0.003) whereas right ventricular end diastolic volume index did not increase significantly, suggesting impaired right ventricular diastolic compliance in this group¶Conclusions: Until 24 h after surgery cold cardioplegia is associated with impaired right ventricular filling, which seems better preserved by intermittent antegrade warm blood cardioplegia. End-diastolic volume measurement with the double-indicator technique allows differentiation between systolic and diastolic dysfunction.     

Combined treatment of liver failure and hepatorenal syndrome with orthotopic liver transplantation.

Hepatorenal syndrome (HRS) is a severe complication of liver failure with high mortality. The pathogenesis of this reversible functional renal failure is not yet clearly understood. Diagnosis is based upon the association of clinical and biological criteria. A patient was admitted to our institution for severe liver failure secondary to an exacerbation of cirrhosis, where he developed a fulminant hepatorenal syndrome. Both, the renal and hepatic failure were successfully treated by orthotopic liver transplantation. Special attention was paid to the immunosuppressive treatment with Cyclosporine whose use, we believe, should be delayed until function has partially recovered.     

Dramatic decrease in malaria transmission after large-scale indoor residual spraying with bendiocarb in Benin, an area of high resistance of Anopheles gambiae to pyrethroids

In 2008, the National Malaria Control Program in Benin implemented a vector control intervention based on indoor residual spraying (IRS). Four districts of high resistance of Anopheles gambiae to pyrethroids were sprayed with bendiocarb. More than 350,000 inhabitants have been protected. Entomologic parameters in the control area were compared with those in intervention sites. The study has shown a drastic decrease in the An. gambiae biting rate in the sprayed areas. Results of an enzyme-linked immunosorbent assay were negative for Plasmodium falciparum antigen during the entire period of the intervention. No household members received infected bites (entomologic inoculation rate = 0 during January-July). Parous rates were low in areas covered by IRS because bendiocarb is not conducive to long-term mosquito survival. Bendiocarb was found to be a good alternative insecticide for IRS in Benin, in areas where An. gambiae has developed high resistance to pyrethroids.     

Dialysis dose in acute kidney injury: no time for therapeutic nihilism--a critical appraisal of the Acute Renal Failure Trial Network study

The optimal dialysis dose for acute kidney injury is a matter of great controversy. Clinical trials, predominantly single-center studies, have shown conflicting results. The Acute Renal Failure Trial Network (ATN) Study was designed to compare clinical outcomes between patients allocated to an intensive dose versus a less-intensive dose of renal replacement therapy. Recently, the results of this large randomized controlled multicenter study were published. The present article will discuss certain aspects of this trial: the overall design, the baseline patient characteristics, and comparison of the results with earlier studies. Finally, the article will address the implications of the ATN Study results for clinical practice.     

Central pituitary adenylate cyclase 1 receptors modulate nociceptive behaviors in both inflammatory and neuropathic pain states.

The pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC(1)-R) is a member of the 7-transmembrane domain, group 2 G-protein coupled receptor family. PAC(1)-Rs modulate neurotransmission and neurotrophic actions and have been implicated in both pronociception and antinociception. To better understand the role of PAC(1)-Rs in pain, PACAP 6-38, a PAC(1)-R antagonist, was evaluated in several inflammatory and neuropathic pain models after intrathecal (i.t.) administration. PACAP 6-38 potently reduced mechanical allodynia in a neuropathic spinal nerve ligation model (77% +/- 15% maximal effect at 12 nmol, P < .01) and was also effective in reducing thermal hyperalgesia in the carrageenan model of inflammatory pain (89% +/- 17% maximal effect at 12 nmol, P < .01). Although nociceptive responses were also attenuated with PACAP 6-38 in a dose-dependent manner in models of chronic inflammatory and persistent pain, no effects on motor performance were observed at analgesic doses. Taken together, these data demonstrate that blockade of the PAC(1)-R/PACAP complex by PACAP 6-38 can effectively attenuate thermal hyperalgesia and mechanical allodynia associated with inflammatory and neuropathic pain states. These results further emphasize that at the level of the spinal cord, PAC(1)-R activation is pronociceptive. PERSPECTIVE: This article presents the analgesic profile generated by the blockade, at the spinal cord level, of the PAC-1 receptor by a potent peptide antagonist. This comprehensive data set demonstrates that if small molecule PAC-1 receptor antagonists could be identified, they would potentially produce broad-spectrum analgesia in both inflammatory and neuropathic pain states.     

A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel and selective transient receptor potential type V1 receptor antagonist, blocks channel activation by vanilloids, heat, and acid

The vanilloid receptor transient receptor potential type V1 (TRPV1) integrates responses to multiple stimuli, such as capsaicin, acid, heat, and endovanilloids and plays an important role in the transmission of inflammatory pain. Here, we report the identification and in vitro characterization of A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel, potent, and selective TRPV1 antagonist. A-425619 was found to potently block capsaicin-evoked increases in intracellular calcium concentrations in HEK293 cells expressing recombinant human TRPV1 receptors (IC50 = 5 nM). A-425619 showed similar potency (IC50 = 3-4 nM) to block TRPV1 receptor activation by anandamide and N-arachidonoyl-dopamine. Electrophysiological experiments showed that A-425619 also potently blocked the activation of native TRPV1 channels in rat dorsal root ganglion neurons (IC50 = 9 nM). When compared with other known TRPV1 antagonists, A-425619 exhibited superior potency in blocking both naive and phorbol ester-sensitized TRPV1 receptors. Like capsazepine, A-425619 demonstrated competitive antagonism (pA2 = 2.5 nM) of capsaicin-evoked calcium flux. Moreover, A-425619 was 25- to 50-fold more potent than capsazepine in blocking TRPV1 activation. A-425619 showed no significant interaction with a wide range of receptors, enzymes, and ion channels, indicating a high degree of selectivity for TRPV1 receptors. These data show that A-425619 is a structurally novel, potent, and selective TRPV1 antagonist.