Perioperative cardiac evaluation: novel interventions and clinical challenges

Cardiac complications are one of the most important sources of morbidity and mortality after noncardiac surgery. In this review, we discuss the pathophysiology of postoperative cardiac complications and published risk indices and guidelines that allow an estimation of preoperative risk. Recent evidence has challenged the primary role of perioperative beta blockers as a risk reduction strategy. The highest level of evidence for their use is for patients with coronary artery disease or multiple risk factors undergoing vascular surgery. Beta blockers may provide no benefit or may be potentially harmful for low- and intermediate-risk patients and surgeries. For patients with contraindications to beta blockers, diltiazem and clonidine are alternative agents that reduce cardiac risk. Statins are emerging as another potential strategy to reduce cardiac risk, although the evidence is based primarily on retrospective analyses. Coronary artery revascularization does not reduce cardiac complications after noncardiac surgery among patients with stable coronary artery disease.     

Comparison of norepinephrine- and benzodiazepine-induced augmentation of Purkinje cell responses to gamma-aminobutyric acid (GABA)

The hypothesis tested in the present study was that the benzodiazepines (i.e., flurazepam) and norepinephrine (NE) share a common mechanism to facilitate cerebellar Purkinje neuron responsiveness to iontophoretically applied gamma-aminobutyric acid (GABA). Extracellular activity was recorded from Purkinje neurons in halothane-anesthetized rats from each of the following groups: 1) naive, 2) acute or chronic flurazepam treated, 3) chronic desmethylimipramine treated and 4) injected with 6-hydroxydopamine. Single unit responses to pulsatile (10 sec duration at 45-sec intervals) iontophoretic administration of GABA were examined before, during and after NE or flurazepam microiontophoresis in all treatment groups. Drug response histograms were generated and used to quantitate NE and flurazepam effects on spontaneous activity and GABA-induced inhibitory responses. Doses of GABA sufficient to produce depression of Purkinje cell activity in naive rats (4-40 nA) suppressed firing rate in all Purkinje cells tested in drug-treated animals. In contrast to its consistent GABA facilitating action in naive controls, iontophoretically applied flurazepam was ineffective in augmenting GABA-induced suppression of Purkinje cell discharge in acute and chronic flurazepam-treated animals. Although GABA facilitation by NE was unaffected by acute systemic administration of a benzodiazepine, chronic treatment with flurazepam produced a subsensitivity to the noradrenergic GABA facilitating effects. Within 48 hr of withdrawal from chronic benzodiazepine treatment, both NE and flurazepam again enhanced GABA-induced suppression of Purkinje cell discharge routinely. Chronic desmethylimipramine treatment as well as iontophoresis of the blocking agents sotalol and fluphenazine which have been shown previously to block or reduce NE-mediated enhancement of GABA actions were ineffective in altering the facilitating effect of flurazepam on GABA. Likewise, 6-hydroxydopamine pretreatment had no effect on GABA augmentation by flurazepam. Thus, although flurazepam appears to act independently from the noradrenergic receptor system in augmenting GABA-induced depression of Purkinje cell discharge, a reversible subsensitivity to the GABA facilitating effects of both flurazepam and NE can be produced by chronic treatment with this benzodiazepine. On the basis of this "cross-subsensitivity" to NE and flurazepam actions, it seems reasonable to suggest that these two agents might enhance GABA inhibitory actions by a common biophysical mechanism subsequent to noradrenergic receptor activation.     

pfcrt Polymorphism and the spread of chloroquine resistance in Plasmodium falciparum populations across the Amazon Basin

The widespread occurrence of drug-resistant malaria parasites in South America presents a formidable obstacle to disease control in this region. To characterize parasite populations and the chloroquine-resistance profile of Plasmodium falciparum in the Amazon Basin, we analyzed a DNA segment of the pfcrt gene, spanning codons 72-76, and genotyped 15 microsatellite (MS) markers in 98 isolates from 6 areas of Brazil, Peru, and Colombia where malaria is endemic. The K76T mutation, which is critical for chloroquine resistance, was found in all isolates. Five pfcrt haplotypes (S[tct]MNT, S[agt]MNT, CMNT, CMET, and CIET) were observed, including 1 previously found in Asian/African isolates. MS genotyping showed relatively homogeneous genetic backgrounds among the isolates, with an average of 3.8 alleles per marker. Isolates with identical 15-loci MS haplotypes were found in different locations, suggesting relatively free gene flow across the Amazon Basin. Allopatric isolates carrying SMNT and CMNT haplotypes have similar genetic backgrounds, although parasites carrying the CIET haplotype have some exclusive MS alleles, suggesting that parasites with CIET alleles were likely to have been introduced into Brazil from Asia or Africa. This study provides the first evidence of the Asian pfcrt allele in Brazil and a detailed analysis of P. falciparum populations, with respect to pfcrt haplotypes, in the Amazon Basin.     

Sequencing and structural homology modeling of the ecdysone receptor in two chrysopids used in biological control of pest insects

In insects, the process of molting and metamorphosis are mainly regulated by a steroidal hormone 20-hydroxyecdysone (20E) and its analogs (ecdysteroids) that specifically bind to the ecdysone receptor ligand-binding domain (EcR-LBD). Currently, several synthetic non-steroidal ecdysone agonists, including tebufenozide, are commercially available as insecticides. Tebufenozide exerts its activity by binding to the 20E-binding site and thus activating EcR permanently. It appears that subtle differences in the architecture among LBDs may underpin the differential binding affinity of tebufenozide across taxonomic orders. In brief, first we demonstrated the harmlessness of tebufenozide towards Chrysoperla externa (Ce). Then, a molecular analysis of EcR-LBD of two neuropteran insects Chrysoperla carnea and Ce was presented. Finally, we constructed a chrysopid in silico homology model docked ponasterone A (PonA) and tebufenozide into the binding pocket and analyzed the amino acids indentified as critical for binding to PonA and tebufenozide. Due to a restrict extent in the cavity at the bottom of the ecdysone-binding pocket a steric clash occurred upon docking of tebufenozide. The absence of harm biological effect and the docking results suggest that tebufenozide is prevented of any deleterious effects on chrysopids.     

The case for utilizing more strict quantitative Doppler echocardiographic criterions for diagnosis of subclinical rheumatic carditis

AIM: Our aim was to perform a comparative, quantitative and qualitative, analysis of valvar echocardiographic findings in patients with acute rheumatic fever, with or without clinical manifestations of carditis, as compared to healthy controls. METHODS AND RESULTS: We analyzed cross-sectional Doppler echocardiographic images of 31 patients with acute rheumatic fever diagnosed according to the Jones criterions as modified in 1992. Of 31 patients, 22 presented with clinical carditis, while 9 had subclinical carditis. The patients, and a control group of 20 healthy individuals, underwent cardiac examination and echocardiographic assessment, assessing quantitative and qualitative findings of mitral and aortic valvar abnormalities. The leaflets of the mitral valve were statistically thicker in those with clinical and subclinical carditis when compared to controls (p less than 0.001). We observed a greater frequency of mitral variance, convergence of mitral flow, and aortic regurgitation for those with clinical and subclinical carditis when compared to controls (p less than 0.001, p less than 0.001 and p equal to 0.003, respectively). Patients with clinical and subclinical carditis had more quantitative and qualitative changes in the parameters than did the controls. CONCLUSION: Echocardiography is a sensitive method to detect valvar abnormalities in patients with acute rheumatic fever and carditis. Additionally, by using regular standardized criterions, abnormalities that lead to a diagnosis of subclinical carditis are found in those patients with acute rheumatic fever in the apparent absence of cardiac involvement.     

Ryanodine receptor Ca2+-release channels are an output pathway for the circadian clock in the rat suprachiasmatic nuclei

Ryanodine-sensitive intracellular Ca2+ channels (RyRs) are present in suprachiasmatic nuclei (SCN) neurons, but the functions served by these channels are not known. Here we addressed whether mobilization of intracellular Ca2+ stores through the RyRs may be a link between the molecular clock and the firing rate in SCN neurons. Activation of the RyRs by administration of either 1 mM caffeine or 100 nM ryanodine increased the firing frequency, whereas inhibition of RyRs by 10 microM dantrolene or 80 microm ryanodine decreased firing rate. Similar results were obtained in experiments conducted at either midday or midnight. Furthermore, these effects were not mediated by synaptic transmission as blockade of GABA A, AMPA and NMDA receptors did not prevent the excitatory or inhibitory effects induced by either dose of ryanodine on SCN firing. We conclude that gating of RyRs is a key element of the intricate output pathway from the circadian clock within SCN neurons in rats.