Citations

More than 30 years ago, Darley, Aronson, and Brown (1969) proposed clinicoanatomic correlations for seven perceptual types of dysarthria. These correlations have not been systematically re-examined even though imaging technologies developed in recent years provide the means to do so. This review considers data from published imaging studies as well as data from selected medical interventions to evaluate the current state of knowledge that relates lesion site to the nature of a speech disturbance. Although the extant data are not sufficient to allow a complete evaluation of the seven types of dysarthria described by Darley et al., relevant information has been reported on lesions of the pyramidal pathway, extrapyramidal pathway, and cerebellum. In general, the results are best explained by an equivalence mode of brain-behavior relationship in which a type of dysarthria is associated with a lesion in one of two or more brain structures. Criteria also are proposed for future studies of clinicoanatomic relationships in neurogenic communication disorders.

AbstractWe have organized the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium to identify susceptibility genes in familial pancreatic cancer (FPC). The Consortium comprises seven data collection centers, a statistical genetics core, and a pathology/archival genotyping core. We recruit kindreds containing two or more affected blood relatives ascertained through incident pancreatic adenocarcinoma cases, physician referrals, and/or through Internet recruitment. Accrual to a database containing core clinical, demographic, lifestyle, and family history information from questionnaires is ongoing, along with biospecimen collection. To date, 13,147 patients have been screened for family history, of whom 476 (50% male) probands and 1,912 of their adult (99% unaffected) relatives have been enrolled. Of these, 379 kindreds meet criteria for FPC, having at least two first-degree relatives with pancreatic cancer. Cumulative incidence curves using available age of diagnosis (onset) among and affected relatives were compared with those for incident pancreatic cancer cases reported to 13 U.S. Surveillance Epidemiology and End Results (SEER) sites from 1973 to 2000 (N = 72,700). The mean age ± SD at diagnosis among 466 PACGENE probands and 670 affected relatives was 64.1 ± 11.8 and was 65.4 ± 11.6 for the subset of 369 FPC probands and 429 relatives. Both samples were significantly younger than the mean age at diagnosis in the SEER population (70.0 ± 12.1 years; differences in curves versus SEER, P < 0.001). Age at diagnosis (excluding probands) in FPC kindreds does not decrease with increasing number of affected individuals. In our sample, younger age at diagnosis was observed whether we grouped probands by recruitment sites that predominantly recruited through high-risk referrals, or through screening all pancreatic cancer patients for family history. Linkage studies are ongoing. The PACGENE Consortium will be a valuable family-based resource that will greatly enhance genetic epidemiology research in pancreatic cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(4):704–10)

Abstract Background: Controversy exists over the association of estrogen and cardiovascular disease. Estrogen receptors (ERs) α and β are expressed in the endothelial cells and vascular smooth muscle cells (VSMCs) of many arteries, but the relative importance of ERα or ERβ in mediating the vascular response to estrogens is not well defined, particularly in humans. We have shown previously that postmenopausal women receiving hormone therapy (HT) had lower mean coronary artery calcium, plaque area, and calcium-to-plaque ratio compared with untreated women. In this study, we examined coronary artery ERα and ERβ expression in pre- and postmenopausal women as a function of plaque area, calcium area, calcium-to-plaque ratio, and estrogen status. Methods: Coronary arteries were obtained at autopsy from a total of 55 women: nine premenopausal women, 13 postmenopausal women on HT and 33 untreated postmenopausal women (non-HT). Coronary calcification was quantified by contact microradiography, and atherosclerotic plaque area was measured histologically. Coronary artery cross-sections were immunostained for ERα and ERβ, and the amount of receptors was estimated semiquantitatively in each arterial wall layer (intima, adventitia, and media). Double immunofluorescence was used to colocalize ERα and ERβ with smooth muscle actin, a marker of VSMCs. Results: ERβ and ERα were expressed in all artery wall layers, but most avidly in the media (P = 0.001), and colocalized with VSMCs. ERβ expression exceeded ERα expression in all wall layers (P < 0.001) and was adjacent to areas of calcium deposition. ERβ expression in the intimal layer correlated with calcium content, plaque area, and calcium-to-plaque ratio (all P < 0.01) and tended to be greater in non-HT than in HT women (P = 0.06). ERα expression did not vary significantly among groups, nor did it correlate with calcium content, plaque area or calcium-to-plaque ratio. Expression of ERα but not ERβ declined with age (P < 0.01) in HT women only. Age had no effect on ERα or ERβ expression in non-HT or premenopausal women. Conclusions: ERβ is the predominant ER in human coronary arteries and correlates with coronary calcification, a marker of severe atherosclerosis. Increased ERβ expression is linked to advanced atherosclerosis and calcification independent of age or hormone status. Future pharmacogenetic studies that target this receptor are needed to confirm causality.

Background: An uncontrolled pilot study demonstrated that daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), might be effective for the treatment of active ulcerative colitis. Methods: A randomised, double blind, placebo controlled trial was conducted to evaluate the efficacy of daclizumab induction therapy in patients with active ulcerative colitis. A total of 159 patients with moderate ulcerative colitis were randomised to receive induction therapy with daclizumab 1 mg/kg intravenously at weeks 0 and 4, or 2 mg/kg intravenously at weeks 0, 2, 4, and 6, or placebo. The primary end point was induction of remission at week 8. Remission was defined as a Mayo score of 0 on both endoscopy and rectal bleeding components and a score of 0 or 1 on stool frequency and physician’s global assessment components. Response was defined as a decrease from baseline in the Mayo score of at least 3 points. Results: Two per cent of patients receiving daclizumab 1 mg/kg (p = 0.11 v placebo) and 7% of patients receiving 2 mg/kg (p = 0.73) were in remission at week 8, compared with 10% of those who received placebo. Response occurred at week 8 in 25% of patients receiving daclizumab 1 mg/kg (p = 0.04) and in 33% of patients receiving 2 mg/kg (p = 0.30) versus 44% of those receiving placebo. Daclizumab was well tolerated. The most frequently reported adverse events in daclizumab treated patients compared with placebo treated patients were nasopharyngitis (14.6%) and pyrexia (10.7%). Conclusion: Patients with moderate ulcerative colitis who are treated with daclizumab are not more likely to be in remission or response at eight weeks than patients treated with placebo.

Integrative neuroendocrine control of the gonadotropic and somatotropic axes in childhood, puberty, and young adulthood proceeds via multiple convergent and divergent pathways in the human and experimental animal. Emerging ensemble concepts are required to embody independent, parallel, and interacting mechanisms that subserve physiological adaptations and pathological disruption of reproduction and growth. Significant advances in systems biology will be needed to address these challenges.

Widespread applications of totally laparoscopic aortic reconstructions have been limited by the long cross-clamp time required to suture the aortic anastomosis despite improvement in instrumentation. The authors' hypothesis was that a “one-step anastomosis concept” using an intraluminal stapler would allow shorter cross-clamp time but similar patency and imperviousness as videoscopic suturing techniques. An intraluminal stapler (Endopath-ILS, Ethicon) with a modified anvil was used to perform videoscopic-assisted thoracic aorta-to-iliac artery bypass with a 21 mm by 8 mm polytetrafluoroethylene (PTFE) graft in 22 sheep through a minimally invasive approach using a 5 cm thoracotomy. The graft-to-iliac artery anastomoses were hand sutured through a flank incision. Twelve sheep were used to establish the technique and 10 subsequent animals constituted the study group. Aortic cross-clamp time, imperviousness, and need for additional sutures were recorded and compared to previously reported data using videoscopic suturing in pigs. Patency was assessed by comparing lower limb arterial pressures. Macroscopic and microscopic examinations of the anastomoses were performed at different time-points within the first 3 months. Videoscopic-assisted stapled anastomoses were also performed on atherosclerotic aortas of 3 human cadavers. Stapled anastomoses between the thoracic aorta and PTFE graft were completed in 8 of 10 animals. Two animals were euthanized after stapler failure and anastomotic bleeding. Sutures to strengthen the anastomosis had to be used in 4 cases. Mean aortic cross-clamp time in 8 successful cases was 4.3 ±2.9 minutes (range 2–11 minutes) and was significantly shorter than clamp time of videoscopic suturing technique (48.7 ±9.4 minutes, p<0.0001). Imperviousness was good or excellent in 4 animals and fair in 4 animals. All anastomoses were patent at the end of the procedure. Examination of the anastomosis of the 2 failed interventions showed medial aortic tear surrounding the anastomosis in 1 case and misfired staples in the other. No graft occlusion was noted during follow-up ranging from 0 to 12 weeks. At the time of harvest, no bleeding was noted after epinephrine and volume infusion to increase mean arterial pressure to 200 mm Hg for 15 minutes. Macroscopic examination of the anastomoses revealed adequate healing with circumferential stapling of the prosthesis to the aortic wall and no stenosis or thrombus except in 1 false aneurysm (1/7, 14%). Surface electron microscopy showed cells coverage of the anastomosis surface. When applied on human cadaver thoracic and abdominal aorta with atherosclerotic changes, clamping times of less than 5 minutes were achieved. However, imperviousness tested with saline was poor. An automatic stapling device allows performance of a graft-to-aorta anastomosis through a minimally invasive approach with shorter clamping time than a videoscopic suturing technique. However, the current technique of aortic stapling is unreliable and further improvements are needed.

Thromboangiitis obliterans (TAO) is often cited as an extreme phenotype of vasculopathy and tobacco dependence. Although tobacco exposure is essential to progression of arterial ischemia in TAO, expert opinion differs regarding the degree of tobacco dependence in this population. The authors designed a prospective, case-control study to test the hypothesis that subjects with TAO have a greater degree of tobacco dependence than control subjects with coronary atherosclerosis (coronary artery disease [CAD]) do. Subjects with TAO (n=218, confirmed by angiography, biopsy, or noninvasive arterial testing) or CAD (n=343, diagnosed by coronary angiography) were mailed a standardized questionnaire regarding tobacco use, to which 103 and 273 responded, respectively. The degree of tobacco dependence in each group was ascertained by several methods, including the Fagerström Test for Nicotine Dependence Questionnaire. The TAO group was younger at index date (year of first diagnosis for TAO patients, year of percutaneous transluminal coronary angioplasty [PTCA] for CAD patients) (TAO 37.6 ±9.0 vs CAD 43.3 ±4.9 yr, p<0.0001), but the groups did not differ in age at first tobacco exposure (TAO 16.7 ±3.1 vs CAD 17.3 ±4.2 yr, p=0.67), current tobacco use at time of survey (TAO 54% vs CAD 46%, p=0.17), or Fagerström score (TAO 4.7 ±2.3 vs CAD 5.1 ±2.3, p=0.24). Kaplan-Meier curves showed no significant difference in time to stopping tobacco use after first diagnosis (p=0.076). TAO subjects smoked fewer cigarettes per day than CAD subjects (TAO 22.3 ±10.7 vs CAD 27.7 ±15.3 cigarettes/day, p=0.003). Among current smokers (n=170), TAO subjects also smoked fewer cigarettes/day (20.2 ±8.2 vs 24.6 ±12.7, p=0.03), and were more likely to have made a serious attempt to stop (97% vs 90%, p=0.03). In contrast to case reports of extreme tobacco dependence in the TAO population, the degree of tobacco dependence in subjects with TAO is similar to that in subjects with CAD.

Abstract Intervention trials with supplemental β-carotene have observed either no effect or a harmful effect on lung cancer risk. Because food composition databases for specific carotenoids have only become available recently, epidemiological evidence relating usual dietary levels of these carotenoids with lung cancer risk is limited. We analyzed the association between lung cancer risk and intakes of specific carotenoids using the primary data from seven cohort studies in North America and Europe. Carotenoid intakes were estimated from dietary questionnaires administered at baseline in each study. We calculated study-specific multivariate relative risks (RRs) and combined these using a random-effects model. The multivariate models included smoking history and other potential risk factors. During follow-up of up to 7–16 years across studies, 3,155 incident lung cancer cases were diagnosed among 399,765 participants. β-Carotene intake was not associated with lung cancer risk (pooled multivariate RR = 0.98; 95% confidence interval, 0.87–1.11; highest versus lowest quintile). The RRs for α-carotene, lutein/zeaxanthin, and lycopene were also close to unity. β-Cryptoxanthin intake was inversely associated with lung cancer risk (RR = 0.76; 95% confidence interval, 0.67–0.86; highest versus lowest quintile). These results did not change after adjustment for intakes of vitamin C (with or without supplements), folate (with or without supplements), and other carotenoids and multivitamin use. The associations generally were similar among never, past, or current smokers and by histological type. Although smoking is the strongest risk factor for lung cancer, greater intake of foods high in β-cryptoxanthin, such as citrus fruit, may modestly lower the risk.

AbstractThe etiology of acute myeloid leukemia (AML) is relatively unknown. Incidence rates are highest in the agricultural Midwest region compared with other regions of the United States. Many studies have examined the relationship between farming and leukemia, but most have mainly focused on men. We examined the potential association between farm or rural residence and AML in the Iowa Women's Health Study. In 1986, 37,693 women who were free of prior cancer completed a lifestyle and health questionnaire, which included a question on the place of residence. Women were subsequently followed until 2002 for cancer incidence; 79 women developed AML during the time period. Women who lived on a farm at baseline were more likely (relative risk, 1.91; 95% confidence interval, 1.19-3.05) to develop AML compared with women who did not live on a farm. Further, women who reported living on a farm or in a rural area were twice as likely (relative risk, 2.38; 95% confidence interval, 1.33-4.26) to develop AML compared with women who lived in a city with a population of &gt;10,000 people. These results provide evidence that women who live on farms or rural areas are at an increased risk of AML.