Citations

Background— Muscle sympathetic vasoconstrictor nerve activity increases with age in healthy humans but does not result in an augmented forearm vasoconstrictor tone. We tested the hypothesis that this is due to a reduction in postjunctional α-adrenergic responsiveness to endogenous norepinephrine (NE) release and determined whether this was specific to α 1 - or α 2 -adrenergic receptors. Methods and Results— Forearm blood flow (FBF, by strain-gauge plethysmography) responses to local intra-arterial infusions of tyramine (which evokes endogenous NE release), phenylephrine (selective α 1 -agonist), and clonidine (α 2 -agonist) were determined in 10 young (aged 26±1 [mean±SEM] years) and 10 older (aged 65±1 years) healthy normotensive men after local β-adrenergic blockade with propranolol. Basal forearm vascular tone was not different in young men and older men. The percentage reduction in FBF in response to the highest dose of tyramine was blunted in older men compared with young men (−37±3% versus −49±3%, respectively; P <0.01) despite a greater increase in deep venous NE concentration in older men (910±103 versus 565±69 pg/mL, respectively; P <0.001). Maximal reductions in FBF to phenylephrine were also blunted in older men (−47±2% versus −58±3% in young men, P <0.05). In contrast, the reductions in FBF (−36±7% versus −40±3% for older versus young men, respectively) and also in venous NE concentration (−79±24 versus −84±13 pg/mL for older versus young men, respectively) to clonidine were similar in the 2 groups. Finally, forearm sympathetic α-adrenergic vasoconstrictor tone (assessed via nonselective α-blockade with phentolamine) was significantly lower in older men. Conclusions— Our results indicate that human aging is associated with a reduction in forearm postjunctional α-adrenergic responsiveness to endogenous NE release and that this might be specific to α 1 -adrenergic receptors. Furthermore, the contribution of sympathetic α-adrenergic vasoconstriction to basal forearm vascular tone is reduced with age in healthy men.

Background— Restenosis after percutaneous coronary intervention (PCI) is a major problem affecting 15% to 30% of patients after stent placement. No oral agent has shown a beneficial effect on restenosis or on associated major adverse cardiovascular events. In limited trials, the oral agent tranilast has been shown to decrease the frequency of angiographic restenosis after PCI. Methods and Results— In this double-blind, randomized, placebo-controlled trial of tranilast (300 and 450 mg BID for 1 or 3 months), 11 484 patients were enrolled. Enrollment and drug were initiated within 4 hours after successful PCI of at least 1 vessel. The primary end point was the first occurrence of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months and was 15.8% in the placebo group and 15.5% to 16.1% in the tranilast groups ( P =0.77 to 0.81). Myocardial infarction was the only component of major adverse cardiovascular events to show some evidence of a reduction with tranilast (450 mg BID for 3 months): 1.1% versus 1.8% with placebo ( P =0.061 for intent-to-treat population). The primary reason for not completing treatment was ≥1 hepatic laboratory test abnormality (11.4% versus 0.2% with placebo, P <0.01). In the angiographic substudy composed of 2018 patients, minimal lumen diameter (MLD) was measured by quantitative coronary angiography. At follow-up, MLD was 1.76±0.77 mm in the placebo group, which was not different from MLD in the tranilast groups (1.72 to 1.78±0.76 to 80 mm, P =0.49 to 0.89). In a subset of these patients (n=1107), intravascular ultrasound was performed at follow-up. Plaque volume was not different between the placebo and tranilast groups (39.3 versus 37.5 to 46.1 mm 3 , respectively; P =0.16 to 0.72). Conclusions— Tranilast does not improve the quantitative measures of restenosis (angiographic and intravascular ultrasound) or its clinical sequelae.

AbstractThe insulin receptor mediates a proliferative response in certain transformed cells, but little is known about its function in ovarian cancer. We used human epithelial ovarian carcinoma cell lines and lifespan-extended normal ovarian surface epithelial (OSE) cells to examine 125I-insulin binding and mitogenic responses to insulin. All cancer cell and OSE cultures specifically bound 125I-insulin. Except for OV202, the carcinoma lines had elevated insulin binding compared with OSE cells. All carcinoma lines except OV202 expressed insulin receptor as detected by flow cytometry and increased 3H-thymidine incorporation or cell number in response to 0.1–10 nm insulin. Interestingly, similar concentrations of IGF-II also induced proliferation of the insulin-responsive cancer cell lines and displaced 125I-insulin binding. Direct binding of 125I-IGF-II to the insulin receptor was visualized by cross-linking and immunoprecipitation. Binding of IGF-II to the insulin receptor and a proliferative effect of insulin suggest the presence of insulin receptor isoform A. Real-time PCR analyses confirm that insulin receptor isoform A expression predominates over isoform B expression in the ovarian carcinoma cell lines. This report suggests that the insulin receptor may play a role in the regulation of ovarian cancer cell growth.

Resection of the entire ulnar head (Darrach operation) and the hemiresection interposition arthroplasty are common methods of treating the arthritic distal radioulnar joint (DRUJ). Biomechnical investigation about both of these procedures is lacking. The purpose of this study was to evaluate the dynamic effects of both the hemiresection interposition arthroplasty and the Darrach procedure on radioulnar convergence and dorsal–palmar displacement and to compare their biomechanical behaviours. With a dynamic computer-controlled testing device, cadaveric forearm rotation was performed with simultaneous loading of relevant muscles. Torque along the forearm axis was generated by simulated muscle action through pneumoactuators attached to relevant tendons while the wrist was constrained to prescribed ranges of motion. The instability of the radius relative to the ulna was evaluated using displacement data of digitized landmarks in an ulnar coordinate system. Seven fresh-frozen cadaver upper extremities were used. The Darrach resection created an extreme instability of the forearm with movement of the radius ulnarly. Anteroposterior translations in each loading condition could also be detected, but the magnitude of displacement was small and less predictable. The results of the hemiresection interposition arthroplasty demonstrated significantly less instability compared with the Darrach results.

Background— Chronobiological rhythms have been shown to influence the occurrence of a variety of cardiovascular disorders. However, the effects of the time of the day, the day of the week, or monthly/seasonal changes on acute aortic dissection (AAD) have not been well studied. Methods and Results— Accordingly, we evaluated 957 patients enrolled in the International Registry of Acute Aortic Dissection (IRAD) between 1996 and 2000 (mean age 62±14 years, type A 61%). A χ 2 test for goodness of fit and partial Fourier analysis were used to evaluate nonuniformity and rhythmicity of AAD during circadian, weekly, and monthly periods. A significantly higher frequency of AAD occurred from 6:00 am to 12:00 noon compared with other time periods (12:00 noon to 6:00 pm , 6:00 pm to 12:00 midnight, and 12:00 midnight to 6:00 am ; P <0.001 by χ 2 test). Fourier analysis showed a highly significant circadian variation ( P <0.001) with a peak between 8:00 am and 9:00 am . Although no significant variation was found for the day of the week, the frequency of AAD was significantly higher during winter ( P =0.008 versus other seasons by χ 2 test). Fourier analysis confirmed this monthly variation with a peak in January ( P <0.001). Subgroup analysis identified a significant association for all subgroups with circadian rhythmicity. However, seasonal/monthly variations were observed only among patients aged <70 years, those with type B AAD, and those without hypertension or diabetes. Conclusions— Similar to other cardiovascular conditions, AAD exhibits significant circadian and seasonal/monthly variations. Our findings may have important implications for the prevention of AAD by tailoring treatment strategies to ensure maximal benefits during the vulnerable periods.

Abstract.Although pancreatectomy is still performed in a few patients with pancreatic cancer, and nearly all patients who develop pancreatic cancer eventually die of their disease, significant improvements have been made recently. Pancreatectomy is now safer, with major morbidity (hemorrhage, pancreatic anastomotic leak, intraabdominal sepsis) occurring in only about 20% and operative mortality of less than 5%. Two (seemingly subtle) issues cannot be overemphasized when someone carefully studies the literature: (1) There is a crucial difference between actuarial and actual survival, with the former generally being higher whereas the latter is true; and (2) careful re‐review of pathologic specimens (especially in long‐term survivors) initially diagnosed as pancreatic cancer, preferably by an independent pathologist before publishing long‐term results is essential. (Erroneous inclusion of patients with nonductal carcinoma substantially and artificially increases survival.) After curative resection, 5‐year actual survival is realistically about 10% with median survivals of 12 to 18 months. In certain subgroups with favorable pathologic characteristics (neoplasms < 2 cm without nodal or perineural invasion) the prognosis appears to be significantly better, with the 5‐year survival about 20%. The recent improvements in postoperative morbidity and mortality and long‐term outcome (resulting also in decreased cost of care of such patients) have occurred typically in centers with an invested interest in and proven record with pancreatic surgery. Further improvements in survival should be sought at the areas of earlier diagnosis and novel treatments designed to prevent locoregional recurrences; the role of extended resections must be determined by prospective, randomized trials.