Suppression of ventricular arrhythmias by volatile anesthetics in a canine model of chronic myocardial infarction

Ventricular tachycardia likely secondary to a reentrant mechanism may be reliably induced by programmed electrical stimulation in dogs 4-6 days after creating a 2-h experimental, occlusion-reperfusion myocardial infarction. The effects of 1.1 and 1.8 MAC halothane, isoflurane, and enflurane on pacing-induced arrhythmias were studied in this model. The ease of initiation of ventricular tachycardia was measured in both awake and anesthetized dogs (n = 18). Excitation thresholds, conduction times, and refractory periods in both normal and infarcted myocardium were also determined to understand changes in the ease of induction of the arrhythmias secondary to anesthetic exposure. Halothane and enflurane administration suppressed the induction of ventricular tachycardia compared with the unanesthetized control (P less than 0.01 for both). During isoflurane anesthesia, there was a trend that was not statistically significant for pacing-induced ventricular tachycardia to be less frequent than during the conscious state (P = 0.11). Halothane and enflurane prolonged refractory periods in both normal and infarcted myocardium, whereas isoflurane had that effect only in normal myocardium. In addition, halothane and enflurane tended to increase refractory periods more than isoflurane in both regions. Conduction times and excitation thresholds were not altered by anesthetic administration. It is concluded that halothane and enflurane suppress inducible ventricular arrhythmias secondary to a prior myocardial infarction. In addition, the increased efficacy of halothane and enflurane as antiarrhythmic agents compared with isoflurane in this model may be related to their greater prolongation of refractory periods.     

Further evidence for association of GRK3 to bipolar disorder suggests a second disease mutation

OBJECTIVES: Two genome-wide linkage surveys suggest chromosome 22q12 may contain a susceptibility locus for bipolar disorder (BPD) in the immediate region of the gene G protein receptor kinase-3 (GRK3). We previously published evidence that a single nucleotide polymorphism (SNP) in the promoter region of GRK3, designated P5, was associated with BPD. This SNP, however, was too rare (allele frequency 0.007) to explain the evidence for linkage. METHODS: To identify other SNPs or haplotypes associated with illness, we have now sequenced an additional 28-kb genomic segment of GRK3 and tested an additional 35 SNPs for association with BPD in 181 Caucasian nuclear families. RESULTS: Transmission disequilibrium test analyses identified two closely related disease-associated haplotypes defined by four SNPs located upstream of the promoter region: transmission to nontransmission ratios=54:22 and 20:9, odds ratios=2.50 and 2.36, and P values=0.0009 and 0.05. The best P value remained significant after correction for multiple testing. These two haplotypes were found on an entirely different set of chromosomes from the previously identified SNP P5. They had a combined frequency of approximately 0.10 and, therefore, a much greater population attributable risk for disease than the previously identified P5 haplotype. CONCLUSIONS: These data provide evidence that at least two distinct haplotypes, and possibly two or more different underlying mutations, in GRK3 might be associated with BPD. These new findings add support for the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization and thereby predisposes to the development of BPD.     

The continuum of HIV care in Catalonia

The objective was to produce a cascade of care for Catalonia to gain a public health perspective on the overall quality of HIV services and allow comparison with other countries. It was constructed using the Integrated Epidemiological Surveillance System of HIV in Catalonia and data from the PISCIS Cohort. Estimates of the number of people living with HIV in Catalonia are modelled using Spectrum Projection Package 2011 (UNAIDS/WHO). Totals for each stage in the cascade are obtained by applying to the preceding stage a proportion estimated from available surveillance and cohort data. Undiagnosed HIV was estimated from the European literature. The proportions retained in care, on ART and virally suppressed were derived from the PISCIS cohort. Programmatic data on ART consumption was used to validate estimates. By the end of 2011 there were about 33,000 people living with HIV in Catalonia, 71% of which had been both diagnosed and linked to care. We estimate that 61% of all HIV infected persons were retained in care, 56% were on ART and 48% were virally suppressed. These figures data are comparable, although slightly lower, than that of France or the UK. The Cascade of HIV Care in Catalonia is similar to other western European countries such as France and the UK. Direct estimates of the undiagnosed HIV population and linkage to care are desirable but the contribution of cohort data to the cascade highlights their continued importance in HIV surveillance and design of evidence-based health strategies.     

An audit of consent refusals in clinical research at a tertiary care center in India

Background and Rationale:

Ensuring research participants’ autonomy is one of the core ethical obligations of researchers. This fundamental principle confers on every participant the right to refuse to take part in clinical research, and the measure of the number of consent refusals could be an important metric to evaluate the quality of the informed consent process. This audit examined consent refusals among Indian participants in clinical studies done at our center.

Materials and Methods:

The number of consent refusals and their reasons in 10 studies done at our center over a 5-year period were assessed. The studies were classified by the authors according to the type of participant (healthy vs patients), type of sponsor (investigator-initiated vs pharmaceutical industry), type of study (observational vs interventional), level of risk [based on the Indian Council of Medical Research (ICMR) “Ethical Guidelines for Biomedical Research on Human Participants”], available knowledge of the intervention being studied, and each patient''s disease condition.

Results:

The overall consent refusal rate was 21%. This rate was higher among patient participants [23.8% vs. healthy people (14.9%); P = 0.002], in interventional studies [33.6% vs observational studies (7.5%); P < 0.0001], in pharmaceutical industry-sponsored studies [34.7% vs investigator-initiated studies (7.2%); P < 0.0001], and in studies with greater risk (P < 0.0001). The most common reasons for consent refusals were multiple blood collections (28%), inability to comply with the study protocol (20%), and the risks involved (20%).

Conclusion:

Our audit suggests the adequacy and reasonable quality of the informed consent process using consent refusals as a metric.KEY WORDS: Autonomy, consent, India, reason, refusal, risk     

Vascular structure enhances regional resistance responses in mild essential hypertension

Forearm blood flow (FABF) and forearm vascular resistance (FAVR) responses to sequential regional infusions of norepinephrine (NE) and angiotensin II (Ang II) were examined in 24 hypertensive and 18 matched normotensive subjects. Sensitivity to both vasoconstrictors, defined as the percentage increase in FAVR in response to the lowest dose of each agonist, was similar in the two groups. Also, the FABF response curve to the full range of both agonists did not differ between hypertensives and normotensives by analysis of variance (ANOVA). While the FAVR responses at the lowest doses of both NE and Ang II were similar in hypertensives and normotensives, FAVR responses in hypertensives diverged progressively from the normotensive response pattern, P less than 0.01 according to ANOVA. The hypertensives achieved greater maximum FAVR levels at the highest doses of both agonists, P less than 0.05 according to repeated measures ANOVA. After 10 min of ischaemic exercise, FAVR was higher in hypertensives than in normotensives (2.24 +/- 0.10 versus 1.87 +/- 0.08; P = 0.02, respectively). This value for FAVR was termed the minimum FAVR (mFAVR). The overall response pattern characterized by increased mFAVR, unchanged threshold sensitivity, steeper slope, greater maximum response and similarity of responses to both NE and Ang II is most consistent with a structural augmentation of resistance responses. A model was used in an effort to increase understanding of the vessel morphology. This model suggested that an increased wall/lumen ratio, perhaps without an actual increase in vascular smooth muscle mass, played an important role in the observed FAVR pattern.     

Value of treadmill exercise test in pre- and postoperative children with valvular aortic stenosis

To determine the utility of graded treadmill exercise test (ETT) in estimating severity of obstruction in postoperative patients with aortic stenosis, we compared results to a nonoperated aortic stenosis group. Cardiac catheterization was performed in all patients. The interval between surgery and ETT in the postoperative group was 7.5 years (range 1.1-12.9). Mean and range values for postoperative versus nonoperative aortic stenosis groups respectively were: age 14.5 (7.9-20.8) versus 12.5 years (5.9-19.7); peak left ventricular pressure 150 (101-190) versus 144 mmHg (100-183); peak systolic ejection gradient (PSEG) 41 (15-75) versus 38 mmHg (14-80); left ventricular end-diastolic pressure (LVEDP) 13.4 (7-20) versus 13.5 mmHg (8-20); and cardiac index 3.7 (2.4-5.6) versus 3.8 liters/min/m2 (2.6-4.9) (p for each = NS). ETT in the nonoperated patients correctly identified all those with PSEG greater than or equal to 50 mmHg (sensitivity 100%), but specificity was 56%, (i.e., the proportion correctly identified with PSEG less than 50 mmHg). By contrast, sensitivity and specificity for postoperative aortic stenosis patients were 67% and 63%, respectively. Furthermore, among nonoperated aortic stenosis patients ST depression on ETT identified those with increased left ventricular end-diastolic pressure. For LVEDP greater than or equal to 12 mmHg, sensitivity was 75% and specificity 100%, corresponding values for postoperative aortic stenosis patients were 45% and 33%, respectively. In the nonoperated aortic stenosis group with a PSEG greater than or equal to 50 mmHg, sensitivity and specificity for ETT-induced change in systolic blood pressure of less than or equal to 30 mmHg were 100% and 56%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fractionated total-body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients with chronic myelogenous leukemia in chronic phase

Ninety-four consecutive patients with chronic myelogenous leukemia in first clinical chronic phase, median age of 34.0 years (range, 6.8 to 52.4 years), with a histocompatible sibling donor, were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation (BMT). The median time from diagnosis to BMT was 7.0 months (range, 2.3 to 72.0 months). Sixty patients were treated before BMT with hydroxyurea alone, four patients with busulfan alone, one patient with interferon alone, and the other 29 patients were treated with various combinations of these drugs. Cumulative probabilities of overall survival, event- free survival, and relapse at 5 years were 73%, 64%, and 14%, respectively. The median follow-up time for surviving patients was 38 months, ranging from 12 to 88 months. By stepwise Cox regression analysis, significant prognostic variables were age at transplant, acute graft-versus-host disease > or = grade II, cytomegalovirus- associated interstitial pneumonitis, and years from diagnosis to BMT.     

In vivo confocal microscopy of climatic droplet keratopathy

We describe the corneal microstructural changes in a patient with spheroidal degeneration using in vivo confocal microscopy. Multiple hypo‐ and hyper‐reflective spherical lesions were observed in the anterior corneal stroma and Bowman's layer ranging from 45 to 220 μm in size. The corneal epithelium, posterior stroma and endothelium were otherwise unaffected. In vivo confocal microscopy demonstrates good correlation with excised histological samples in climatic droplet keratopathy. It provides a non‐invasive technique to examine the living cornea for degenerative disease and acts as a bridge between clinical and laboratory observations.