Citations

Abstract The rationale behind gene-disease association studies is that genetic variants (polymorphisms) result in alterations in intermediate phenotypes. However, genotype-phenotype correlations have not been established for most polymorphisms. In this study, we correlated genotype data of genes involved in the nucleotide excision repair pathway with mutagen sensitivity phenotype, quantified by benzo(a)pyrene diol epoxide (BPDE)-induced chromatid breaks in peripheral blood lymphocytes in 422 healthy subjects recruited into a twin study that included 138 pairs of monozygotic twins, 51 pairs of dizygotic twins, and 44 siblings. Among a panel of single nucleotide polymorphisms examined, we found that BPDE sensitivity was modified by individual polymorphisms in XPC, RAD23B, and XPA genes. Specific haplotypes and diplotypes of XPC also modified BPDE sensitivity profiles. In addition, a more consistent and stronger correlation was observed between mutagen sensitivity phenotype and the combination of multiple polymorphisms in the nucleotide excision repair pathway. Specifically, when XPC-PAT, XPC Lys939Gln, XPA A23G, and RAD23B Val249Ala were analyzed together, we observed a significant dose-response relationship between increasing mutagen sensitivity with increasing number of adverse alleles: mutagen sensitivity for those carrying zero to two, three to five, and six or more adverse alleles were 0.64, 0.68, and 1.06, respectively (P for trend = 0.008), and the results remained significant after adjusting for multiple comparisons. Using individuals carrying zero to two adverse alleles as the reference group, the risks of being mutagen sensitive (mutagen sensitivity values greater than the median) were 1.05 (95% confidence interval, 0.68-1.64) and 4.48 (95% confidence interval, 1.21-16.61) for those carrying three to five and six or more adverse alleles, respectively. Analyses of the effects of genotype combinations yielded similar results. These findings underscore the importance of assessing the collective effects of a panel of polymorphisms in the same pathway in modulating mutagen sensitivity. As risk assessment for cancer risk is moving toward a multigenic pathway-based approach, future genotype-phenotype correlation studies should also investigate the combined effects of multiple genetic variants. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2065–71)

Background and Purpose — We sought to determine pedigree availability for a concordant sibling pair study of genetic risk factors in ischemic stroke. Methods — Probands with confirmed ischemic stroke were prospectively enrolled. Family histories were obtained by systematic interview. A study neurologist prospectively assigned stroke subtype. Results — Of 310 probands (median age, 75 years; range, 26 to 97 years; 48% women), 75% had at least 1 living sibling; 10%, at least 1 concordant living sibling; 2%, at least 1 concordant sibling living in the same city; and 7%, at least 1 concordant living and 1 discordant living sibling. Likelihood of having a concordant sibling increased significantly with proband age, even after adjustment for sibship size ( P =0.002). Positive family history of stroke was not related to either proband stroke subtype or risk factor profile. Conclusions — Approximately 10 probands were screened to find 1 potentially concordant living sibling. A concordant sibling pair study should be multicentered and enable enrollment of siblings from diverse geographic areas.

Background and Purpose — Contrast-enhanced magnetic resonance angiography (CEMRA) permits acquisition of high-spatial-resolution, venous-suppressed, 3D MR angiograms of the cervical carotid and vertebral arteries. In this study, an elliptic centric-view ordering with either MR fluoroscopic triggering or test bolus timing was used. The use of CEMRA of the cervical vessels has changed our clinical practice and is replacing conventional angiography for the evaluation of most carotid and vertebral artery diseases. Methods — We retrospectively reviewed our experience with the use of CEMRA performed in 422 patients from January through December 1999. Results — CEMRA was performed to evaluate transient ischemic attack and ischemic stroke in 239 patients, asymptomatic carotid bruit in 88 patients, and other neurological symptoms in 95 patients. Carotid endarterectomies were performed in 97 patients (103 procedures), and conventional angiography was performed in 12 of these patients. CEMRA was used to evaluate for the presence of an arterial dissection in 85 of the 239 patients with transient ischemic attack and ischemic stroke. Of this group, 32 patients had cervical arterial dissection, and pseudoaneurysm was detected in 11 of these patients. Compared with ultrasonography of the cervical vessels, CEMRA provided additional information in 43 of 422 patients and led to changes in the decision as to whether to perform carotid endarterectomy in 5 patients. Conclusions — Use of CEMRA permits noninvasive evaluation of patients suspected of having carotid or vertebral disease and avoids the potential complications of conventional angiography.

Hands-on training courses with local mentoring are excellent educational tools in laparoscopic surgery; however, the need for the physical presence of specialized instructors represents a limitation because of costs, time, and geographic constraints. Remote robotic telementoring using a wireless videoconferencing mobile robot could represent an alternative to local instruction. The authors compare local active and passive mentoring with remote robotic telementoring using the wireless RP-6 Robot that worked through a WiFi 802.11b connection during a hands-on laparoscopic training session. Surgeons were mentored once in France from the United States. Robot mentoring was well received and appreciated (assessment score of 2.65; scale, 0 to 4). There was no statistical difference in the different mentoring sessions (active, passive, and remote). Mobile wireless robot is a valuable tool in laparoscopic telementoring. Robotic-assisted telementoring may not replace onsite mentoring, but it may enhance educational opportunities and the quality of hands-on training courses by implementing tutoring with expert assistance from remote locations.

The purpose of this study was to evaluate the short-term outcomes after laparoscopic and conventional parastomal hernia repairs. A retrospective review of parastomal hernia repairs was performed. Conventional repairs included primary suture repair, stoma relocation, and mesh repair. Laparoscopic repairs included the Sugarbaker and keyhole techniques. Forty-nine patients underwent repair of symptomatic parastomal hernias: 19 ileostomies, 13 colostomies, and 17 urostomies. Thirty patients underwent 39 conventional repairs. Nineteen patients underwent laparoscopic surgical repairs. Operative times were longer for laparoscopic repair (208 ± 58 vs 162 ± 114 minutes, P = .06). The mean length of stay was 6 days for both groups ( P = .74). The mean follow-up was shorter in the laparoscopic group (20 vs 65 months, P ≤ .001). There were no significant differences in the incidence of surgical site infections (11% laparoscopic vs 5% conventional, P = .60) or complication rates (63% laparoscopic vs 36% conventional, P = .67). Laparoscopic parastomal hernia repair is a feasible operation with similar short-term outcomes to conventional repairs.

Background and Purpose — The Questionnaire for Verifying Stroke-Free Status (QVSFS) is an 8-item structured interview designed to identify stroke-free individuals. Previously, the QVSFS was validated with medical record review in a cohort with a low prevalence (7.1%) of stroke or transient ischemic attack (TIA). The objective of this study was to evaluate the validity of the QVSFS by comparing it with stroke status as determined by neurological history and examination in a population with a higher prevalence of stroke. Methods — A research assistant administered the QVSFS to outpatients from Veterans Administration stroke and general medicine clinics. Subjects were defined as QVSFS negative if responses to all 8 questions were negative. Questions requiring rephrasing or clarification were noted. Neurologists, blinded to QVSFS scores, interviewed and examined all subjects to determine stroke-free status, defined as no history or examination findings of previous stroke and/or TIA. Results — One hundred fifty-five subjects were examined; mean age was 70 years; 98.1% were male. Seventy-eight subjects were determined to be stroke free by the neurologist. The negative predictive value of the QVSFS was 0.96, with positive predictive value of 0.71. No question required rephrasing or clarification >5 times. Twenty-two subjects (14.2%) required rephrasing or clarification of at least 1 question. Conclusions — The QVSFS can effectively identify stroke-free individuals with a high degree of accuracy, even in a population with a large proportion of patients with prior stroke or TIA. Accuracy for identifying subjects with stroke and/or TIA is lower, but the QVSFS may still be useful as a screening tool in that regard.

Purpose To report a multicenter experience treating anal canal cancer patients with concurrent chemotherapy and intensity-modulated radiation therapy (IMRT). Patients and Methods From October 2000 to June 2006, 53 patients were treated with concurrent chemotherapy and IMRT for anal squamous cell carcinoma at three tertiary-care academic medical centers. Sixty-two percent were T1-2, and 67% were N0; eight patients were HIV positive. Forty-eight patients received fluorouracil (FU)/mitomycin, one received FU/cisplatin, and four received FU alone. All patients underwent computed tomography–based treatment planning with pelvic regions and inguinal nodes receiving a median of 45 Gy. Primary sites and involved nodes were boosted to a median dose of 51.5 Gy. All acute toxicity was scored according to the Common Terminology Criteria for Adverse Events, version 3.0. All late toxicity was scored using Radiation Therapy Oncology Group criteria. Results Median follow-up was 14.5 months (range, 5.2 to 102.8 months). Acute grade 3+ toxicity included 15.1% GI and 37.7% dermatologic toxicity; all acute grade 4 toxicities were hematologic; and acute grade 4 leukopenia and neutropenia occurred in 30.2% and 34.0% of patients, respectively. Treatment breaks occurred in 41.5% of patients, lasting a median of 4 days. Forty-nine patients (92.5%) had a complete response, one patient had a partial response, and three had stable disease. All HIV-positive patients achieved a complete response. Eighteen-month colostomy-free survival, overall survival, freedom from local failure, and freedom from distant failure were 83.7%, 93.4%, 83.9%, and 92.9%, respectively. Conclusion Preliminary outcomes suggest that concurrent chemotherapy and IMRT for anal canal cancers is effective and tolerated favorably compared with historical standards.

For many years, β-adrenergic receptor antagonists (β-blockers or βAR antagonists) have provided significant morbidity and mortality benefits in patients who have sustained acute myocardial infarction. More recently, β-adrenergic receptor antagonists have been found to provide survival benefits in patients suffering from heart failure, although the efficacy of different β-blockers varies widely in this condition. One drug, carvedilol, a nonsubtype-selective βAR antagonist, has proven particularly effective in the treatment of heart failure, although the mechanism(s) responsible for this are controversial. Here, we report that among 16 clinically relevant βAR antagonists, carvedilol displays a unique profile of in vitro signaling characteristics. We observed that in β2 adrenergic receptor (β2AR)-expressing HEK-293 cells, carvedilol has inverse efficacy for stimulating G s -dependent adenylyl cyclase but, nonetheless, stimulates ( i ) phosphorylation of the receptor's cytoplasmic tail on previously documented G protein-coupled receptor kinase sites; ( ii ) recruitment of β-arrestin to the β2AR; ( iii ) receptor internalization; and ( iv ) activation of extracellular regulated kinase 1/2 (ERK 1/2), which is maintained in the G protein-uncoupled mutant β2AR T68F,Y132G,Y219A (β2AR TYY ) and abolished by β-arrestin2 siRNA. Taken together, these data indicate that carvedilol is able to stabilize a receptor conformation which, although uncoupled from G s , is nonetheless able to stimulate β-arrestin-mediated signaling. We hypothesize that such signaling may contribute to the special efficacy of carvedilol in the treatment of heart failure and may serve as a prototype for a new generation of therapeutic β2AR ligands.