Citations

Purpose Physical impairments cause profound functional declines in patients with cancer. Although common rehabilitation measures can address many impairments, the extent of their delivery is unknown. We studied these issues by quantifying physical impairments in patients with metastatic breast cancer and by assessing how they are addressed. Patients and Methods A consecutive sample of 163 community-dwelling patients with metastatic breast cancer was stratified by Karnofsky performance score and administered the Medical Outcomes Study Physical Function Subscale and the Older Americans Resource Study Activities of Daily Living subscales. Cancer-related physical impairments were identified through a physical examination, the 6-Minute Walk Test, and the Functional Independence Measure Mobility Subscale. Patients were questioned regarding the nature, type, and setting of treatments for impairments. Physical rehabilitation needs were determined through a consensus process involving physiatrists and physical/occupational therapists specializing in cancer. Results Ninety-two percent of patients (150 of 163) had at least one physical impairment. Among 530 identified impairments, 484 (92%) required a physical rehabilitation intervention and 469 (88%) required physical therapy (PT) and/or occupational therapy (OT). Only 30% of impairments requiring rehabilitation services and 21% of those requiring PT/OT received treatment. Impairments detected during hospitalization were overwhelmingly more likely to receive a rehabilitation intervention (odds ratio [OR] = 87.9; 95% CI, 28.5 to 271.4), and PT/OT (OR = 558.8; 95% CI, 187.0 to 1,669.6). Low socioeconomic and minority status were significantly associated with nontreatment. Conclusion Remediable physical impairments were prevalent and poorly addressed among patients with metastatic breast cancer, drastically so in the outpatient setting. Undertreatment was particularly prominent among minority and socioeconomically disadvantaged groups.

Background— Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-α 1 (SNTA1) is known to interact with the cardiac sodium channel (hNa v 1.5), and we hypothesized that SNTA1 mutations might cause phenotypic LQTS in patients with genotypically normal hNa v 1.5 by secondarily disturbing sodium channel function. Methods and Results— Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc≥480 ms) with previously negative genetic screening for the known LQTS-causing genes. We identified a novel A257G- SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only 1 of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNa v 1.5 and transiently transfected with either wild-type or mutant SNTA1 and, in neonatal rat cardiomyocytes, transiently transfected with either wild-type or mutant SNTA1. In both HEK-293 cells and neonatal rat cardiomyocytes, increased peak sodium currents were noted along with a 10-mV negative shift of the onset and peak of currents of the current-voltage relationships. In addition, A257G-SNTA1 shifted the steady-state activation ( V h ) leftward by 9.4 mV, whereas the voltage-dependent inactivation kinetics and the late sodium currents were similar to wild-type SNTA1. Conclusion— SNTA1 is a new susceptibility gene for LQTS. A257G- SNTA1 can cause gain-of-function of Na v 1.5 similar to the LQT3.

Background— Mortality in patients with heart failure (HF) remains high, but causes of death are incompletely defined. As HF is a heterogeneous syndrome categorized according to the ejection fraction (EF), the association between EF and causes of death is important, yet elusive. Methods and Results— Community subjects with HF were classified according to the preserved (≥50%) and the reduced EF (<50%). Deaths were classified as due to coronary heart disease and other cardiovascular and noncardiovascular diseases. Among 1063 persons with HF, 45% had preserved EF with fewer cardiovascular risk factors and less coronary disease than those with reduced EF. At 5 years, survival was 45% (95% CI, 43% to 49%), and 43% of the deaths were noncardiovascular. The leading cause of death in subjects with preserved EF was noncardiovascular disease (49%) versus coronary heart disease (43%) for subjects with reduced EF. The proportion of cardiovascular deaths decreased from 69% in 1979–1984 to 40% in 1997–2002 ( P =0.007) among subjects with preserved EF, which is in contrast to a modest change among those with reduced EF (77% to 64%, P =0.08). Advanced age, male sex, diabetes, smoking, and kidney disease were associated with an increased risk of all-cause and cardiovascular deaths. After adjustment, preserved EF was associated with a lower risk of cardiovascular death but not all-cause death. Conclusions— Community subjects with HF experience a persistently high mortality, and a large proportion of deaths is noncardiovascular. Cardiovascular disease before death is less in subjects with preserved EF, and they are less likely to experience cardiovascular deaths compared with those with reduced EF. In those with preserved EF, the proportion of cardiovascular deaths declined over time.

Background— Ambrisentan is a propanoic acid–based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension. Methods and Results— Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m ( P =0.008) and 51 m ( P <0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m ( P =0.022) and 59 m ( P <0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m. Conclusions— Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

Background— Bicuspid aortic valve is frequent and is reported to cause numerous complications, but the clinical outcome of patients diagnosed with normal or mildly dysfunctional valve is undefined. Methods and Results— In 212 asymptomatic community residents from Olmsted County, Minn (age, 32±20 years; 65% male), bicuspid aortic valve was diagnosed between 1980 and 1999 with ejection fraction ≥50% and aortic regurgitation or stenosis, absent or mild. Aortic valve degeneration at diagnosis was scored echocardiographically for calcification, thickening, and mobility reduction (0 to 3 each), with scores ranging from 0 to 9. At diagnosis, ejection fraction was 63±5% and left ventricular diameter was 48±9 mm. Survival 20 years after diagnosis was 90±3%, identical to the general population ( P =0.72). Twenty years after diagnosis, heart failure, new cardiac symptoms, and cardiovascular medical events occurred in 7±2%, 26±4%, and 33±5%, respectively. Twenty years after diagnosis, aortic valve surgery, ascending aortic surgery, or any cardiovascular surgery was required in 24±4%, 5±2%, and 27±4% at a younger age than the general population ( P <0.0001). No aortic dissection occurred. Thus, cardiovascular medical or surgical events occurred in 42±5% 20 years after diagnosis. Independent predictors of cardiovascular events were age ≥50 years (risk ratio, 3.0; 95% confidence interval, 1.5 to 5.7; P <0.01) and valve degeneration at diagnosis (risk ratio, 2.4; 95% confidence interval, 1.2 to 4.5; P =0.016; >70% events at 20 years). Baseline ascending aorta ≥40 mm independently predicted surgery for aorta dilatation (risk ratio, 10.8; 95% confidence interval, 1.8 to 77.3; P <0.01). Conclusions— In the community, asymptomatic patients with bicuspid aortic valve and no or minimal hemodynamic abnormality enjoy excellent long-term survival but incur frequent cardiovascular events, particularly with progressive valve dysfunction. Echocardiographic valve degeneration at diagnosis separates higher-risk patients who require regular assessment from lower-risk patients who require only episodic follow-up.

Cholangiocytes, the epithelial cells lining bile ducts, provide the first line of defense against lumenal microbes in the biliary system. Recent advances in biliary immunity indicate that cholangiocytes express a variety of pathogen‐recognition receptors and can activate a set of intracellular signaling cascades to initiate a profound antimicrobial defense, including release of proinflammatory cytokines and chemokines, production of antimicrobial peptides and maintenance of biliary epithelial integrity. Cholangiocytes also interact with other cell types in the liver (for example, lymphocytes and Kupffer cells) through expression and release of adhesion molecules and immune mediators. Subsequently, through an intricate feedback mechanism involving both epithelial and other liver cells, a set of intracellular signaling pathways are activated to regulate the functional state of cholangiocyte responses during microbial infection. Thus, cholangiocytes are actively involved in mucosal immunity of the biliary system and represent a fine‐tuned, integral component of liver immunity.

The importance of the DNA damage response (DDR) pathway in development, genomic stability, and tumor suppression is well recognized. Although 53BP1 and MDC1 have been recently identified as critical upstream mediators in the cellular response to DNA double-strand breaks, their relative hierarchy in the ataxia telangiectasia mutated (ATM) signaling cascade remains controversial. To investigate the divergent and potentially overlapping functions of MDC1 and 53BP1 in the ATM response pathway, we generated mice deficient for both genes. Unexpectedly, the loss of both MDC1 and 53BP1 neither significantly increases the severity of defects in DDR nor increases tumor incidence compared with the loss of MDC1 alone. We additionally show that MDC1 regulates 53BP1 foci formation and phosphorylation in response to DNA damage. These results suggest that MDC1 functions as an upstream regulator of 53BP1 in the DDR pathway and in tumor suppression.