Citations

A-kinase anchoring proteins (AKAPs) recruit signaling molecules and present them to downstream targets to achieve efficient spatial and temporal control of their phosphorylation state. In the heart, sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD), mediated by β-adrenergic receptor (βAR) activation, requires assembly of AKAP9 (Yotiao) with the I Ks potassium channel α subunit (KCNQ1). KCNQ1 mutations that disrupt this complex cause type 1 long-QT syndrome (LQT1), one of the potentially lethal heritable arrhythmia syndromes. Here, we report identification of ( i ) regions on Yotiao critical to its binding to KCNQ1 and ( ii ) a single putative LQTS-causing mutation (S1570L) in AKAP9 (Yotiao) localized to the KCNQ1 binding domain in 1/50 (2%) subjects with a clinically robust phenotype for LQTS but absent in 1,320 reference alleles. The inherited S1570L mutation reduces the interaction between KCNQ1 and Yotiao, reduces the cAMP-induced phosphorylation of the channel, eliminates the functional response of the I Ks channel to cAMP, and prolongs the action potential in a computational model of the ventricular cardiocyte. These reconstituted cellular consequences of the inherited S1570L-Yotiao mutation are consistent with delayed repolarization of the ventricular action potential observed in the affected siblings. Thus, we have demonstrated a link between genetic perturbations in AKAP and human disease in general and AKAP9 and LQTS in particular.

Over the past 50 years, survival has improved in patients with systemic lupus erythematosus and associated nephritis. Yet, there are few long-term outcome studies in patients with well-defined nephropathy. We examinbed the outcome of 439 patients with lupus nephritis who were seen at the Mayo Clinic between 1964 and 1986 in whom renal biopsies were assessed using the World Health Organization (WHO) classification. There were 341 women and 98 men (mean ± s.d., age 33.5 ± 14 years); 200 (46%) patients were hypertensive and 249 (57%) had impaired renal function at renal biopsy. All WHO morphologic classes were represented and 339 (77%) patients had class III, IV and V (the more severe forms of nephritis). Follow-up averaged 10.2 years per patient. At last contact, 286 (65%) patients were alive and 153 (35%) were dead. Overall patient survival was 80%, 69% and 53% at 5, 10 and 20 years after biopsy that was significantly worse than expected survival (P < 0.001). Ten-year cumulative patient survival improved comparing earlier to more recent time spans: 64% in 231 patients seen during 1964-75; 76% in 2089 patients studied during 1976-86 (P = 0.03). Survival free of renal failure was 83%, 74% and 64% at 5, 10 and 20 years, and survival was unfavorably influenced by progressive WHO class, hypertension, impaired renal function, nephrotic range proteinuria, hypoalbuminemia and anemia. Multivariate analysis found impaired renal function, increased urine protein, anemia and younger age to be independent predictors of renal failure. WHO class was not a significant predictor when adjusted for these four factors. Cardiovascular events accounted for 48% of the known deaths and were equally distributed across all WHO classes, followed by infections, renal failure, malignancy, respiratory failure and gastrointestinal bleeding. Severe nephritis, nephrotic syndrome, hypertension and anemia remain strong predictors of a poor renal outcome. Prospective randomized studies stratifying for these factors are needed to find optimal immunosuppressive regimens to improve renal survival.

Background: Although angina is a chronic disease, most clinical trials evaluating antiangi nal therapy are of a few weeks or months in duration. Methods and Results: To evaluate the effects of nicardipine, a second-generation dihydro pyridine calcium channel blocker, as long-term therapy, patients with chronic stable angina were treated for 1 year with open-label nicardipine. Anginal symptoms were controlled with 20 mg tid in 24%, 30 mg tid in 34%, and 40 mg tid in 42%. Of 72 patients completing the 1-year trial, only 14 (19%) had required the addition of long-acting nitrates for control of symptoms. The remaining 57 patients, who had anginal symptoms controlled with nicar dipine alone, were continued into the 3-week, double-blind period and were randomized to continue their usual dose of nicardipine or placebo. Throughout the 1-year, open-label treatment period, the number of anginal episodes and exercise parameters of angina were significantly reduced with nicardipine. Conclusions: During the double-blind period, the patients who continued on nicardipine had significantly greater exercise time and time to onset of angina than patients who were randomized to placebo. The exercise parameters in the patients randomized to placebo were improved over baseline after 1 year of therapy; however, the improvement with nicar dipine was significantly greater.

Follow-up survival and health information were obtained, after a median of 27.5 years, from 132 patients who had been seen originally as children with nephrotic syndrome between 1951 and 1967. Ninety seven patients were alive. Recurring edema or proteinuria, or both, persisted in 15 percent of those still alive. Eight of 11 parous women reported relapses during pregnancy. There was no apparent increase in malignancies, atopic diseases, clinical defects in cell-mediated immunity, or cardiovascular diseases. Twenty two patients (17%) died of renal causes between 3 months and 8 years after the onset of nephrotic syndrome. Steroid resistance was the presenting feature universally predictive of a poor outcome; nine of the 11 such patients died and the other two are now receiving hemodialysis. Hematuria was present initially in 41 percent of the patients who died of renal causes, compared with 14 percent of those still alive. Hypertension was noted on the first examination in 22 percent of those who died of renal causes, compared with 10 percent of those alive.

AbstractBackgroundRepair of complex incisional hernias poses a major challenge.AimThe aim of this study was to review the outcomes of the modified Rives‐Stoppa repair of complex incisional hernias using a synthetic prosthesis.MethodsWe reviewed patients undergoing a modified Rives‐Stoppa repair of complex incisional hernias from 1990 to 2003. Patients were followed through clinic visits and mailed questionnaires. Follow‐up data were complete in all patients (mean 70 months, range 24–177 months), and 87% of patients completed a mailed questionnaire. Primary outcome included mortality, morbidity, and hernia recurrence. Secondary outcome measures were duration of hospital stay, long‐term abdominal wall pain, and self‐reported patient satisfaction.ResultsAltogether, 254 patients underwent a modified Rives‐Stoppa repair. Among them, 60% had a significant co‐morbidity, and 30% had one or more previously failed hernia repairs. Mortality was zero, and overall morbidity was 13% (wound infection 4%, prosthetic infection 3%, seroma/hematoma 4%). The overall hernia recurrence rate was 5%, including explantation of mesh because of infection. Wound/prosthetic infection was predictive for hernia recurrence (31% vs. 4%, p = 0.003). Among the respondents, 89% reported overall satisfaction with their repair.ConclusionThe Rives‐Stoppa repair of complex incisional hernias using synthetic prosthetic materials is safe with a low recurrence rate (5%) and high patient satisfaction. Postoperative wound infection is a risk factor for hernia recurrence.

Background Percutaneous coronary revascularization (PCI) has been increasingly applied to unprotected left main trunk (LMT) lesions, with varied long-term success. This study attempts to define the predictors of outcome in this population. Methods and Results Two hundred seventy-nine consecutive patients who had LMT PCI at 1 of 25 sites between 1993 and 1998 were studied. Forty-six percent of these patients were deemed inoperable or at high surgical risk. Thirty-eight patients (13.7%) died in hospital, and the rest were followed up for a mean of 19 months. The 1-year incidence was 24.2% for all-cause mortality, 20.2% for cardiac mortality, 9.8% for myocardial infarction, and 9.4% for CABG. Independent correlates of all-cause mortality were left ventricular ejection fraction ≤30%, mitral regurgitation grade 3 or 4, presentation with myocardial infarction and shock, creatinine ≥2.0 mg/dL, and severe lesion calcification. For the 32% of patients <65 years old with left ventricular ejection fraction >30% and without shock, the prevalence of these adverse risk factors was low. No periprocedural deaths were observed in this low-risk subset, and the 1-year mortality was only 3.4%. Conclusions Patients undergoing unprotected LMT PCI have frequent serious comorbidities and consequently have high event rates. PCI may be an alternative to CABG for a select proportion of elective patients and may also be appropriate for highly symptomatic inoperable patients. Meticulous follow-up of hospital survivors is required because of the rather high mortality during the first few months after treatment.

Background Electron-beam CT (EBCT) quantification of coronary artery calcification (CAC) allows noninvasive assessment of coronary atherosclerosis. We undertook a follow-up study to determine whether CAC extent, measured at the time of angiography by EBCT, predicted future hard cardiac events, comprising cardiac death and nonfatal myocardial infarction (MI). We also assessed the potential of selected coronary artery disease (CAD) risk factors, prior CAD event history (MI or revascularization), and angiographic findings (number of diseased vessels and overall disease burden) to predict subsequent hard events. Methods and Results Two hundred eighty-eight patients who underwent contemporaneous coronary angiography and EBCT scanning were contacted after a mean of 6.9 years. Vital status and history of MI during follow-up were determined. Cox proportional hazards models were used to compare the predictive ability of CAC extent with selected CAD risk factors, CAD event history, and angiographic findings. Median CAC score was 160 (range 0 to 7633). The 22 patients who experienced hard events during follow-up were older and had more extensive CAC and angiographic disease ( P <0.05). Only 1 of 87 patients with CAC score <20 experienced a subsequent hard event during follow-up. Event-free survival was significantly higher for patients with CAC scores <100 than for those with scores ≥100 (relative risk 3.20; 95% CI 1.17 to 8.71). When a stepwise multivariable model was used, only age and CAC extent predicted hard events (risk ratios 1.72 and 1.88, respectively; P <0.05). Conclusions In patients undergoing angiography, CAC extent on EBCT is highly predictive of future hard cardiac events and adds valuable prognostic information.

Purpose We update Radiation Therapy Oncology Group trial 8911 (USA Intergroup 113), a comparison of chemotherapy plus surgery versus surgery alone for patients with localized esophageal cancer. The relationship between resection type and between tumor response and outcome were also analyzed. Patients and Methods The chemotherapy group received preoperative cisplatin plus fluorouracil. Outcome based on the type of resection (R0, R1, R2, or no resection) was evaluated. The main end point was overall survival. Disease-free survival, relapse pattern, the influence of postoperative treatment, and the relationship between response to preoperative chemotherapy and outcome were also evaluated. Results Two hundred sixteen patients received preoperative chemotherapy, 227 underwent immediate surgery. Fifty-nine percent of surgery only and 63% of chemotherapy plus surgery patients underwent R0 resections (P = .5137). Patients undergoing less than an R0 resection had an ominous prognosis; 32% of patients with R0 resections were alive and free of disease at 5 years, only 5% of patients undergoing an R1 resection survived for longer than 5 years. The median survival rates for patients with R1, R2, or no resections were not significantly different. While, as initially reported, there was no difference in overall survival for patients receiving perioperative chemotherapy compared with the surgery only group, patients with objective tumor regression after preoperative chemotherapy had improved survival. Conclusion For patients with localized esophageal cancer, whether or not preoperative chemotherapy is administered, only an R0 resection results in substantial long-term survival. Even microscopically positive margins are an ominous prognostic factor. After a R1 resection, postoperative chemoradiotherapy therapy offers the possibility of long-term disease-free survival to a small percentage of patients.