Citations

Experimental studies have shown the beneficial effects of antioxidant supplementation on endothelial function in the presence of increased endogenous oxidative stress, whereas limited data are available under normal conditions. The present study tested the hypothesis that in normal pigs long-term antioxidants would have deleterious effects on the cardiovascular system. Normal domestic pigs (V, n=6) were studied 12 weeks after dietary supplementation with vitamin E (100 IU/kg per day) and vitamin C (1 g/day) and compared with normal controls (C, n=7). Myocardial perfusion and permeability index were evaluated by electron beam computed tomography after intravenous adenosine and dobutamine. Coronary endothelial function was evaluated in vitro by organ chamber and coronary tissue studied by immunoblotting and staining. Myocardial perfusion response was lower in V than in C after adenosine (10.1±4.5 versus 53.4±5.2%; P <0.01) and dobutamine (V, 78.4±8.1; C, 193.0±39.0%; P <0.05). The permeability index increased in V after adenosine (48.8±5.1%) and dobutamine (59.9±13.6%) and did not change in C. Coronary vasodilation to bradykinin and substance P was lower in V than in C. Moreover, in V, coronary nitrotyrosine and superoxide content was significantly higher than in C. The groups had similar total monomer expression of endothelial nitric oxide synthase, whereas the dimerized form, reflecting coupled enzyme, was lower in V. These findings suggest that long-term experimental antioxidant vitamin supplementation in normal pigs impairs myocardial perfusion and coronary endothelial function via an increased level of oxidative stress in the arterial wall, which may be partly related to the uncoupling of endothelial nitric oxide synthase and/or the direct prooxidant effect of vitamin radicals.

Purpose The primary goal of this study was to evaluate the feasibility and effectiveness of a structured, multidisciplinary intervention targeted to maintain the overall quality of life (QOL), which is more comprehensive than psychosocial distress, of patients undergoing radiation therapy for advanced-stage cancer. Patients and Methods Radiation therapy patients with advanced cancer and an estimated 5-year survival rate of 0% to 50% were randomly assigned to either an eight-session structured multidisciplinary intervention arm or a standard care arm. The eight 90-minute sessions addressed the five domains of QOL including cognitive, physical, emotional, spiritual, and social functioning. The primary end point of maintaining overall QOL was assessed by a single-item linear analog scale (Linear Analog Scale of Assessment or modified Spitzer Uniscale). QOL was assessed at baseline, week 4 (end of multidisciplinary intervention), week 8, and week 27. Results Of the 103 participants, overall QOL at week 4 was maintained by the patients in the intervention (n = 49), whereas QOL at week 4 significantly decreased for patients in the control group (n = 54). This change reflected a 3-point increase from baseline in the intervention group and a 9-point decrease from baseline in the control group (P = .009). Intervention participants maintained their QOL, and controls gradually returned to baseline by the end of the 6-month follow-up period. Conclusion Although intervention participants maintained and actually improved their QOL during radiation therapy, control participants experienced a significant decrease in their QOL. Thus, a structured multidisciplinary intervention can help maintain or even improve QOL in patients with advanced cancer who are undergoing cancer treatment.

Non-exercise activity thermogenesis (NEAT) is the energy expenditure of all physical activities other than volitional sporting-like exercise. NEAT includes all the activities that render us vibrant, unique, and independent beings such as working, playing, and dancing. Because people of the same weight have markedly variable activity levels, it is not surprising that NEAT varies substantially between people by up to 2000 kcal per day. Evidence suggests that low NEAT may occur in obesity but in a very specific fashion. Obese individuals appear to exhibit an innate tendency to be seated for 2.5 hours per day more than sedentary lean counterparts. If obese individuals were to adopt the lean “NEAT-o-type,” they could potentially expend an additional 350 kcal per day. Obesity was rare a century ago and the human genotype has not changed over that time. Thus, the obesity epidemic may reflect the emergence of a chair-enticing environment to which those with an innate tendency to sit, did so, and became obese. To reverse obesity, we need to develop individual strategies to promote standing and ambulating time by 2.5 hours per day and also re-engineer our work, school, and home environments to render active living the option of choice.

Purpose Serum B-lymphocyte stimulator (BLyS) levels have been found to be elevated in a number of immune disease models. Therefore, we sought to establish whether BLyS levels were elevated in patients with B-cell lymphoproliferative disorders and to determine whether elevated BLyS levels correlated with clinical characteristics of the disease. Patients and Methods Specimens were collected from the peripheral blood of individuals diagnosed with B-cell chronic lymphocytic leukemia (B-CLL; n = 70) or from age- and sex-matched patients seen at the same institution (n = 41). Serum BLyS levels were determined by enzyme-linked immunosorbent assay, and sequencing of the BLyS promoter was performed by conventional methods and confirmed by restriction fragment length polymorphism analysis. Results We found that elevated BLyS levels were more common in patients with familial B-CLL than individuals with sporadic B-CLL or normal controls. Because of this association, we sequenced the BLyS promoter in patients with B-CLL and normal controls and identified a polymorphic site, −871 C/T. We found that the wild-type sequence was significantly underrepresented in patients with familial B-CLL (4%) compared with patients with sporadic B-CLL (30%; P = .01) or controls (24%; P = .04). Furthermore, using a luciferase reporter under control of the BLyS promoter containing either a C or a T at position −871, we found that the reporter construct containing a T at −871 had a 2.6-fold increase in activity (P = .004). Conclusion Our data suggest serum BLyS levels are elevated in patients with familial B-CLL and that elevated BLyS levels correlate with the presence of a T at −871 in the BLyS promoter.

Purpose Results of a prospective randomized trial conducted by the Intergroupe Francais du Myélome (IFM 90) indicated that autologous hematopoietic cell–supported high-dose therapy (HDT) effected higher complete response rates and extended progression-free survial (PFS) and overall survival (OS) compared with standard-dose therapies (SDT) for patients with multiple myeloma (MM). Patients and Methods In 1993, three North American cooperative groups launched a prospective randomized trial (S9321) comparing HDT (melphalan [MEL] 140 mg/m 2 plus total-body irradiation 12 Gy) with SDT using the vincristine, carmustine, MEL, cyclophosphamide, and prednisone regimen. Responders on both arms (≥ 75%) were randomly assigned to interferon (IFN) or no maintenance treatment. Results With a median follow-up time of 76 months, no differences were observed in response rates between the two study arms (HDT, n = 261 patients; SDT, n = 255 patients). Similarly, PFS and OS durations did not differ between the HDT and SDT arms, with 7-year estimates of PFS of 17% and 16%, respectively, and OS of 37% and 42%, respectively. Of 242 patients achieving at least 75% tumor reduction, no difference was observed in PFS or OS among the 121 patients randomly assigned to IFN and the 121 patients randomly assigned to no maintenance therapy. Among 157 patients relapsing on SDT, 87 received a salvage autotransplantation; their median survival time of 30 months was only slightly better than the survival time of the remaining patients who were managed with further SDT (23 months; P = .13). Conclusion The HDT and SDT regimens used in S9321 yielded comparable response rates and PFS and OS durations. IFN maintenance therapy did not benefit patients who achieved ≥ 75% tumor reduction on either arm.

Background— The KCNH2 or human ether-a-go-go related gene ( hERG ) encodes the Kv11.1 α-subunit of the rapidly activating delayed rectifier K + current ( I Kr ) in the heart. Type 2 congenital long-QT syndrome (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function. Several mechanisms have been identified, including disruption of Kv11.1 channel synthesis (class 1), protein trafficking (class 2), gating (class 3), or permeation (class 4). For a few class 2 LQT2-Kv11.1 channels, it is possible to increase surface membrane expression of Kv11.1 current ( I Kv11.1 ). We tested the hypotheses that (1) most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels, and (2) their trafficking-deficient phenotype can be corrected. Methods and Results— Wild-type (WT)-Kv11.1 channels and 34 missense LQT2-Kv11.1 channels were expressed in HEK293 cells. With Western blot analyses, 28 LQT2-Kv11.1 channels had a trafficking-deficient (class 2) phenotype. For the majority of these mutations, the class 2 phenotype could be corrected when cells were incubated for 24 hours at reduced temperature (27°C) or in the drugs E4031 or thapsigargin. Four of the 6 LQT2-Kv11.1 channels that had a wild-type–like trafficking phenotype did not cause loss of Kv11.1 function, which suggests that these channels are uncommon sequence variants. Conclusions— This is the first study to identify a dominant mechanism, class 2, for the loss of Kv11.1 channel function in LQT2 and to report that the class 2 phenotype for many of these mutant channels can be corrected. This suggests that if therapeutic strategies to correct protein trafficking abnormalities can be developed, it may offer clinical benefits for LQT2 patients.