There is a significant risk of developing hypertension and renal dysfunction among patients receiving sunitinib. Adequate monitoring and treatment of hypertension is recommended.

Previous studies have shown that chemical regulation of connexin43 (Cx43) depends on the presence of the carboxyl terminal (CT) domain. A particle-receptor (or "ball-and-chain") model has been proposed to explain the mechanism of gating. We tested whether the CT region behaved as a functional domain for other members of the connexin family. The pH sensitivity of wild-type and Ct-truncated connexins was quantified by use of electrophysiological and optical techniques and the Xenopus oocyte system. The CT domain of Cx45 had no role in pH regulation, although a partial role was shown for Cx37 and Cx50. A prominent effect was observed for Cx40 and Cx43. In addition, we found that the CT domain of Cx40 that was expressed as a separate fragment rescued the pH sensitivity of the truncated Cx40 (Cx40tr), which was in agreement with a particle-receptor model. Because Cx40 and Cx43 often colocalize and possibly heteromerize, we tested the pH sensitivity of Cx40tr when coexpressed with the CT domain of Cx43 (hetero-domain interactions). We found that the CT domain of Cx43 enhanced the pH sensitivity of Cx40tr; similarly, the CT domain of Cx40 restored the pH sensitivity of the truncated Cx43. In addition, the CT domain of Cx43 granted insulin sensitivity to the otherwise insulin-insensitive Cx26 or Cx32 channels. These data show that the particle-receptor model is preserved in Cx40 and the regulatory domain of one connexin can specifically interact with a channel formed by another connexin. Hetero-domain interactions could be critical for the regulation of heteromeric channels.

IMPORTANCE Myocardial ischemia in patients with stable coronary artery disease (CAD) has been repeatedly associated with impaired survival. However, it is unclear if revascularization with percutaneous coronary intervention (PCI) to relieve ischemia improves outcomes compared with medical therapy (MT).OBJECTIVE The objective of this study was to compare the effect of PCI and MT with MT alone exclusively in patients with stable CAD and objectively documented myocardial ischemia on clinical outcomes. DATA SOURCES MEDLINE, Cochrane, and PubMed databases from 1970 to November 2012. Unpublished data were obtained from investigators. STUDY SELECTION Randomized clinical trials of PCI and MT vs MT alone for stable coronary artery disease in which stents and statins were used in more than 50% of patients.DATA EXTRACTION For studies in which myocardial ischemia diagnosed by stress testing or fractional flow reserve was required for enrollment, descriptive and quantitative data were extracted from the published report. For studies in which myocardial ischemia was not a requirement for enrollment, authors provided data for only those patients with ischemia determined by stress testing prior to randomization. The outcomes analyzed included death from any cause, nonfatal myocardial infarction (MI), unplanned revascularization, and angina. Summary odds ratios (ORs) were obtained using a random-effects model. Heterogeneity was assessed using the Q statistic and I 2 . RESULTSIn 5 trials enrolling 5286 patients, myocardial ischemia was diagnosed in 4064 patients by exercise stress testing, nuclear or echocardiographic stress imaging, or fractional flow reserve. Follow-up ranged from 231 days to 5 years (median, 5 years). The respective event rates for PCI with MT vs MT alone for death were 6.5% and 7.3% (OR, 0.90 [95% CI, 0.71-1.16); for nonfatal MI, 9.2% and 7.6% (OR, 1.24 [95% CI, 0.99-1.56]); for unplanned revascularization, 18.3% and 28.4% (OR, 0.64 [95% CI, 0.35-1.17); and for angina, 20.3% and 23.3% (OR, 0.91 [95% CI, 0.57-1.44]). CONCLUSIONS AND RELEVANCEIn patients with stable CAD and objectively documented myocardial ischemia, PCI with MT was not associated with a reduction in death, nonfatal MI, unplanned revascularization, or angina compared with MT alone.

Initial stent implantation for stable CAD shows no evidence of benefit compared with initial medical therapy for prevention of death, nonfatal MI, unplanned revascularization, or angina.

IMPORTANCE Significant variations in dose requirements of warfarin and its analogues (acenocoumarol and phenprocoumon) make selecting the appropriate dose for an individual patient difficult. Genetic factors account for approximately one-third of the variation in dose requirement. The clinical usefulness of genotype-guided dosing of warfarin has been previously assessed in randomized clinical trials that were limited by lack of power and inconsistent results.OBJECTIVE To compare genotype-guided initial dosing of warfarin and its analogues with clinical dosing protocols. MEDLINE (inception to December 31, 2013), EMBASE (inception to December 31, 2013), and the Cochrane Library Central Register of Controlled Trials (inception to December 31, 2013) were searched for randomized clinical trials comparing genotype-guided warfarin dosing vs clinical dosing for adults with indications for anticoagulation. DATA SOURCES AND STUDY SELECTION DATA EXTRACTION AND SYNTHESISTwo investigators extracted data independently on trial design, baseline characteristics, and outcomes. High-quality studies were considered those that described an appropriate method of randomization, allocation concealment, blinding, and completeness of follow-up. MAIN OUTCOMES AND MEASURESThe outcomes analyzed included the percentage of time that the international normalized ratio (INR) was within the therapeutic range, the percentage of patients with an INR greater than 4, and the incidence of major bleeding and thromboembolic events. Summary standardized differences in means (or Mantel-Haenszel risk ratios) were obtained using a random-effects model. RESULTSIn 9 trials, 2812 patients were randomized to receive warfarin, acenocoumarol, or phenprocoumon according to a genotype-guided algorithm or a clinical dosing algorithm. Follow-up ranged from 4 weeks to 6 months (median, 12 weeks). The standardized difference in means of the percentage of time that the INR was within the therapeutic range was 0.14 (95% CI, −0.10 to 0.39) in the genotype-guided dosing cohort (P = .25). The risk ratio for an INR greater than 4 was 0.92 (95% CI, 0.82 to 1.05) for genotype-guided dosing vs clinical dosing. The risk ratios for major bleeding and thromboembolic events were 0.60 (95% CI, 0.29 to 1.22) and 0.97 (95% CI, 0.46 to 2.05), respectively, for genotype-guided vs clinical dosing. CONCLUSIONS AND RELEVANCEIn this meta-analysis of randomized clinical trials, a genotype-guided dosing strategy did not result in a greater percentage of time that the INR was within the therapeutic range, fewer patients with an INR greater than 4, or a reduction in major bleeding or thromboembolic events compared with clinical dosing algorithms.

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Connexin43(Cx43) channels can be regulated by a variety of factors, including low pHi. Structure/function studies from this laboratory have demonstrated that pH gating follows a particle-receptor mechanism, similar to the "ball-and-chain" model of voltage-dependent inactivation of ion channels. The question whether the particle-receptor model is applicable only to pH gating or to other forms of Cx43 regulation as well remains. To address this question, we looked at the uncoupling effects of insulin and of insulin-like growth factor-1 (IGF) on Cx43 channels expressed in Xenopus oocytes. These agonists do not induce changes in pHi. Junctional conductance (Gj) was measured by the dual 2-electrode voltage-clamp technique. Control studies showed that relative Gj did not change spontaneously as a function of time. Continuous exposure of Cx43-expressing oocytes to insulin (10 micro/L) led to a decrease in Gj. After 80 minutes, Gj was 54+/-5% from control (n= 12). Exposure of oocytes to IGF (10 nmol/L) caused an even more pronounced change in Gj (37+/-4% of control, n=6). The time course of the IGF-induced uncoupling was similar to that observed after insulin exposure. The effect of insulin was abolished by truncation of the carboxyl-terminal domain of Cx43 at amino acid 257 (M257). Interestingly, as in the case of pH gating, coexpression of the carboxyl-terminal domain (amino acids 258 to 282) together with M257 rescued the ability of insulin to reduce coupling (Gj, 39+/-12% from control; n=6). Structure/function experiments using various deletion mutants of the carboxyl-terminal domain showed that insulin treatment does not modify Gj if amino acids 261 to 280 are missing from the Cx43 sequence. Our results suggest that a particle-receptor (or ball-and-chain) mechanism, similar to that described for pH gating, also applies to chemical regulation of Cx43 by other factors.

Abstract:The association between testosterone-replacement therapy and cardiovascular risk remains unclear with most reports suggesting a neutral or possibly benefi cial effect of the hormone in men and women. However, several cardiovascular complications including hypertension, cardiomyopathy, stroke, pulmonary embolism, fatal and nonfatal arrhythmias, and myocardial infarction have been reported with supraphysiologic doses of anabolic steroids. We report a case of an acute ST-segment elevation myocardial infarction in a patient with traditional cardiac risk factors using supraphysiologic doses of supplemental, intramuscular testosterone. In addition, this patient also had polycythemia, likely secondary to high-dose testosterone. The patient underwent successful percutaneous intervention of the right coronary artery. Phlebotomy was used to treat the polycythemia acutely. We suggest that the chronic and recent "stacked" use of intramuscular testosterone as well as the resultant polycythemia and likely increased plasma viscosity may have been contributing factors to this cardiovascular event, in addition to traditional coronary risk factors. Physicians and patients should be aware of the clinical consequences of anabolic steroid abuse.