Citations

Objective— To determine whether serum levels of N-terminal (NT) pro–B-type natriuretic peptide (pro-BNP) are higher in patients with poorly compressible arteries (PCA) than in patients with peripheral artery disease (PAD) and control subjects without PCA or PAD. Methods and Results— Medial arterial calcification in the lower extremities results in PCA and may be associated with increased arterial stiffness and hemodynamic/myocardial stress. PCA was defined as having an ankle-brachial index >1.4 or an ankle blood pressure >255 mm Hg, whereas PAD was defined as having an ankle-brachial index ≤0.9. Study participants with PCA (n=100; aged 71±10 years; 70% men) and age- and sex-matched patients with PAD (n=300) were recruited from the noninvasive vascular laboratory. Age- and sex-matched controls (n=300) were identified from a community-based cohort and had no history of PAD. NT pro-BNP levels were approximately 2.5-fold higher in patients with PCA than in patients with PAD and approximately 4-fold higher than in age- and sex-matched controls. In multivariable regression analyses that adjusted for age, sex, smoking, hypertension, history of coronary heart disease/stroke, systolic blood pressure, and serum creatinine, NT pro-BNP levels remained significantly higher in patients with PCA than in patients with PAD and controls ( P <0.001). Conclusion— Patients with medial arterial calcification and PCA have higher serum levels of NT pro-BNP than patients with PAD and controls, which is suggestive of an adverse hemodynamic milieu and increased risk for adverse cardiovascular outcomes.

Abstract Purpose: REOLYSIN (Oncolytics Biotech) consists of a wild-type oncolytic reovirus, which has selective cytotoxicity for tumor cells while sparing normal cells. In a phase I study as a single agent, repeated infusions of reovirus were safe with evidence of antitumor activity. Preclinical studies indicate potential for synergy between reovirus and chemotherapeutic agents. A multicenter, phase I dose escalation study was designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer. Experimental Design: Patients received 75 mg/m2 docetaxel (day 1) and escalating doses of reovirus up to 3 × 1010 TCID50 (days 1-5) every 3 weeks. Results: Twenty-five patients were enrolled, and 24 patients were exposed to treatment, with 23 completing at least one cycle and 16 suitable for response assessment. Dose-limiting toxicity of grade 4 neutropenia was seen in one patient, but the maximum tolerated dose was not reached. Antitumor activity was seen with one complete response and three partial responses. A disease control rate (combined complete response, partial response, and stable disease) of 88% was observed. Immunohistochemical analysis of reovirus protein expression was observed in posttreatment tumor biopsies from three patients. Conclusion: The combination of reovirus and docetaxel is safe, with evidence of objective disease response, and warrants further evaluation in a phase II study at a recommended schedule of docetaxel (75 mg/m2, three times weekly) and reovirus (3 × 1010 TCID50, days 1-5, every 3 weeks). Clin Cancer Res; 16(22); 5564–72. ©2010 AACR.

Abnormal expression of genes for energy regulation in Parkinson’s disease patients identifies a master regulator as a possible therapeutic target for early intervention.

Background— Mechanisms responsible for anti-ischemic benefits of enhanced external counterpulsation (EECP) remain unknown. This was the first randomized sham-controlled study to investigate the extracardiac effects of EECP on peripheral artery flow-mediated dilation. Methods and Results— Forty-two symptomatic patients with coronary artery disease were randomized (2:1 ratio) to thirty-five 1-hour sessions of either EECP (n=28) or sham EECP (n=14). Flow-mediated dilation of the brachial and femoral arteries was performed with the use of ultrasound. Plasma levels of nitrate and nitrite, 6-keto-prostaglandin F 1α , endothelin-1, asymmetrical dimethylarginine, tumor necrosis factor-α, monocyte chemoattractant protein-1, soluble vascular cell adhesion molecule, high-sensitivity C-reactive protein, and 8-isoprostane were measured. EECP increased brachial (+51% versus +2%) and femoral (+30% versus +3%) artery flow-mediated dilation, the nitric oxide turnover/production markers nitrate and nitrite (+36% versus +2%), and 6-keto-prostaglandin F 1α (+71% versus +1%), whereas it decreased endothelin-1 (−25% versus +5%) and the nitric oxide synthase inhibitor asymmetrical dimethylarginine (−28% versus +0.2%) in treatment versus sham groups, respectively (all P <0.05). EECP decreased the proinflammatory cytokines tumor necrosis factor-α (−16% versus +12%), monocyte chemoattractant protein-1 (−13% versus +0.2%), soluble vascular cell adhesion molecule-1 (−6% versus +1%), high-sensitivity C-reactive protein (−32% versus +5%), and the lipid peroxidation marker 8-isoprostane (−21% versus +1.3%) in treatment versus sham groups, respectively (all P <0.05). EECP reduced angina classification (−62% versus 0%; P <0.001) in treatment versus sham groups, respectively. Conclusions— Our findings provide novel mechanistic evidence that EECP has a beneficial effect on peripheral artery flow-mediated dilation and endothelial-derived vasoactive agents in patients with symptomatic coronary artery disease.

Once excess liquid gains access to air spaces of an injured lung, the act of breathing creates and destroys foam and thereby contributes to the wounding of epithelial cells by interfacial stress. Since cells are not elastic continua, but rather complex network structures composed of solid as well as liquid elements, we hypothesize that plasma membrane (PM) wounding is preceded by a phase separation, which results in blebbing. We postulate that interventions such as a hypertonic treatment increase adhesive PM-cytoskeletal (CSK) interactions, thereby preventing blebbing as well as PM wounds. We formed PM tethers in alveolar epithelial cells and fibroblasts and measured their retractive force as readout of PM-CSK adhesive interactions using optical tweezers. A 50-mOsm increase in media osmolarity consistently increased the tether retractive force in epithelial cells but lowered it in fibroblasts. The osmo-response was abolished by pretreatment with latrunculin, cytochalasin D, and calcium chelation. Epithelial cells and fibroblasts were exposed to interfacial stress in a microchannel, and the fraction of wounded cells were measured. Interventions that increased PM-CSK adhesive interactions prevented blebbing and were cytoprotective regardless of cell type. Finally, we exposed ex vivo perfused rat lungs to injurious mechanical ventilation and showed that hypertonic conditioning reduced the number of wounded subpleural alveolus resident cells to baseline levels. Our observations support the hypothesis that PM-CSK adhesive interactions are important determinants of the cellular response to deforming stress and pave the way for preclinical efficacy trials of hypertonic treatment in experimental models of acute lung injury.

ABSTRACTBackground:Although direct medical costs for constipation‐related medical visits are thought to be high, to date there have been no studies examining whether longitudinal resource use is persistently elevated in children with constipation. Our aim was to estimate the incremental direct medical costs and types of health care use associated with constipation from childhood to early adulthood.Methods:A nested case‐control study was conducted to evaluate the incremental costs associated with constipation. The original sample consisted of 5718 children in a population‐based birth cohort who were born during 1976 to 1982 in Rochester, MN. The cases included individuals who presented to medical facilities with constipation. The controls were matched and randomly selected among all noncases in the sample. Direct medical costs for cases and controls were collected from the time subjects were between 5 and 18 years of age or until the subject emigrated from the community.Results:We identified 250 cases with a diagnosis of constipation in the birth cohort. Although the mean inpatient costs for cases were $9994 (95% Confidence interval [CI] 2538–37,201) compared with $2391 (95% CI 923–7452) for controls (P = 0.22) during the time period, the mean outpatient costs for cases were $13,927 (95% CI 11,325–16,525) compared with $3448 (95% CI 3771–4621) for controls (P < 0.001) during the same time period. The mean annual number of emergency department visits for cases was 0.66 (95% CI 0.62–0.70) compared with 0.34 (95% CI 0.32–0.35) for controls (P < 0.0001).Conclusions:Individuals with constipation have higher medical care use. Outpatient costs and emergency department use were significantly greater for individuals with constipation from childhood to early adulthood.

Transforming growth factor (TGF)-β family proteins form heteromeric complexes with transmembrane serine/threonine kinases referred to as type I and type II receptors. Ligand binding initiates a signaling cascade that generates a variety of cell type-specific phenotypes. Whereas numerous studies have investigated the regulatory activities controlling TGF-β signaling, there is relatively little information addressing the endocytic and trafficking itinerary of TGF-β receptor subunits. In the current study we have investigated the role of the clathrin-associated sorting protein Disabled-2 (Dab2) in TGF-β receptor endocytosis. Although small interfering RNA-mediated Dab2 knockdown had no affect on the internalization of various clathrin-dependent (i.e., TGF-β, low-density lipoprotein, or transferrin) or -independent (i.e., LacCer) cargo, TGF-β receptor recycling was abrogated. Loss of Dab2 resulted in enlarged early endosomal antigen 1-positive endosomes, reflecting the inability of cargo to traffic from the early endosome to the endosomal recycling compartment and, as documented previously, diminished Smad2 phosphorylation. The results support a model whereby Dab2 acts as a multifunctional adaptor in mesenchymal cells required for TGF-β receptor recycling as well as Smad2 phosphorylation.

Purpose We performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse events (MS-AEs) in women treated with aromatase inhibitors (AIs) for early breast cancer. Patients and Methods A nested case-control design was used to select patients enrolled onto the MA.27 phase III trial comparing anastrozole with exemestane. Cases were matched to two controls and were defined as patients with grade 3 or 4 MS-AEs (according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0) or those who discontinued treatment for any grade of MS-AE within the first 2 years. Genotyping was performed with the Illumina Human610-Quad BeadChip. Results The GWAS included 293 cases and 585 controls. A total of 551,358 SNPs were analyzed, followed by imputation and fine mapping of a region of interest on chromosome 14. Four SNPs on chromosome 14 had the lowest P values (2.23E-06 to 6.67E-07). T-cell leukemia 1A (TCL1A) was the gene closest (926-7000 bp) to the four SNPs. Functional genomic studies revealed that one of these SNPs (rs11849538) created an estrogen response element and that TCL1A expression was estrogen dependent, was associated with the variant SNP genotypes in estradiol-treated lymphoblastoid cells transfected with estrogen receptor alpha and was directly related to interleukin 17 receptor A (IL17RA) expression. Conclusion This GWAS identified SNPs associated with MS-AEs in women treated with AIs and with a gene (TCL1A) which, in turn, was related to a cytokine (IL17). These findings provide a focus for further research to identify patients at risk for MS-AEs and to explore the mechanisms for these adverse events.

Background and Purpose— Carotid artery stenosis causes up to 10% of all ischemic strokes. Carotid endarterectomy (CEA) was introduced as a treatment to prevent stroke in the early 1950s. Carotid stenting (CAS) was introduced as a treatment to prevent stroke in 1994. Methods— The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is a randomized trial with blinded end point adjudication. Symptomatic and asymptomatic patients were randomized to CAS or CEA. The primary end point was the composite of any stroke, myocardial infarction, or death during the periprocedural period and ipsilateral stroke thereafter, up to 4 years. Results— There was no significant difference in the rates of the primary end point between CAS and CEA (7.2% versus 6.8%; hazard ratio, 1.11; 95% CI, 0.81 to 1.51; P =0.51). Symptomatic status and sex did not modify the treatment effect, but an interaction with age and treatment was detected ( P =0.02). Outcomes were slightly better after CAS for patients aged <70 years and better after CEA for patients aged >70 years. The periprocedural end point did not differ for CAS and CEA, but there were differences in the components, CAS versus CEA (stroke 4.1% versus 2.3%, P =0.012; and myocardial infarction 1.1% versus 2.3%, P =0.032). Conclusions— In CREST, CAS and CEA had similar short- and longer-term outcomes. During the periprocedural period, there was higher risk of stroke with CAS and higher risk of myocardial infarction with CEA. Clinical Trial Registration— www.clinicaltrials.gov. Unique identifier: NCT00004732.

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R 2 for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.