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OBJECTIVE—Diminished daily physical activity explains, in part, why obesity and diabetes have become worldwide epidemics. In particular, chair use has replaced ambulation, so that obese individuals tend to sit for ∼2.5 h/day more than lean counterparts. Here, we address the hypotheses that free-living daily walking distance is decreased in obesity compared with lean subjects and that experimental weight gain precipitates decreased daily walking. RESEARCH DESIGN AND METHODS—During weight-maintenance feeding, we measured free-living walking using a validated system that captures locomotion and body movement for 10 days in 22 healthy lean and obese sedentary individuals. These measurements were then repeated after the lean and obese subjects were overfed by 1,000 kcal/day for 8 weeks. RESULTS—We found that free-living walking comprises many (∼47) short-duration (<15 min), low-velocity (∼1 mph) walking bouts. Lean subjects walked 3.5 miles/day more than obese subjects (n = 10, 10.3 ± 2.5 vs. n = 12, 6.7 ± 1.8 miles/day; P = 0.0009). With overfeeding, walking distance decreased by 1.5 miles/day compared with baseline values (−1.5 ± 1.7 miles/day; P = 0.0005). The decrease in walking that accompanied overfeeding occurred to a similar degree in the lean (−1.4 ± 1.9 miles/day; P = 0.04) and obese (−1.6 ± 1.7 miles/day; P = 0.008) subjects. CONCLUSIONS—Walking is decreased in obesity and declines with weight gain. This may represent a continuum whereby progressive increases in weight are associated with progressive decreases in walking distance. By identifying walking as pivotal in weight gain and obesity, we hope to add credence to an argument for an ambulatory future.

It is well-known that dynamin 2 (Dyn2) participates in clathrin- and caveolae-mediated endocytosis; however, the role of Dyn2 in coat-independent endocytic processes remains controversial. Here we demonstrate a role for specific spliced variants of Dyn2 in the micropinocytosis of fluid in epithelial cells, independent of coat-mediated endocytic pathways. A general inhibition of Dyn2 was first performed using either microinjection of anti-dynamin antibodies or Dyn2-siRNA treatment. Both of these methods resulted in reduced uptake of transferrin, a marker for clathrin-mediated endocytosis, and, under unstimulated conditions, reduced the uptake of the fluid-phase markers dextran and horseradish peroxidase (HRP). By contrast, cells treated similarly but stimulated with serum or EGF internalized substantial amounts of dextran or HRP, indicating that Dyn2 is not required for stimulated fluid uptake via macropinocytosis. We next tested whether a specific spliced variant might selectively affect fluid-phase endocytosis. Mutation of specific Dyn2 spliced variants resulted in a differential attenuation of transferrin and dextran internalization. Furthermore, the reduction in fluid uptake in Dyn2-siRNA-treated cells was only rescued upon re-expression of select spliced variants. These findings suggest that Dyn2 function is required for the coat-independent internalization of fluid through endocytic pathways distinct from macropinocytosis and, in addition, implicate different Dyn2 spliced variants in specific endocytic functions.

Purpose Studies have suggested good long‐term success rates with bone–patellar tendon–bone (BPTB) autograft and BPTB allograft in anterior cruciate ligament (ACL) reconstruction, but the numbers reported in available prospective studies may be underpowered to elucidate significant differences between the two groups. Here, we present a meta‐analysis to compare the results of BPTB autograft and BPTB allograft in primary ACL reconstruction. Methods A systematic review of prospective trials using BPTB autograft and BPTB allograft tissue for ACL reconstruction with a minimum 2‐year follow‐up was performed. Summary odds ratios (ORs), confidence intervals, and P values were calculated. Results Of 548 studies, 6 fulfilled our inclusion criteria, with 256 patients in the autograft and 278 patients in the allograft group. Allograft patients were more likely to rupture their graft than autograft patients (OR, 5.03; P = .01) and more likely to have a hop test less than 90% of the nonoperative side (OR, 5.66; P < .01). When irradiated and chemically processed grafts were excluded from analysis, no significant differences were found between allograft and autograft patients with respect to graft rupture, rate of reoperation, normal/near normal IKDC scores, Lachman exam, pivot shift exam, patellar crepitus, hop test, or return to sport. Conclusions In this meta‐analysis, ACL reconstruction with BPTB autograft was favored over BPTB allograft for graft rupture and hop test parameters. However, when irradiated and chemically processed grafts were excluded, results were not significantly different between the two graft types. Level of Evidence Level III, systematic review of prospective nonrandomized cohort studies.

AbstractCCG-2961 incorporated 3 new agents, idarubicin, fludarabine and interleukin-2, into a phase 3 AML trial using intensive-timing remission induction/consolidation and related donor marrow transplantation or high-dose cytarabine intensifi-cation. Among 901 patients under age 21 years, 5-year survival was 52%, and event-free survival was 42%. Survival improved from 44% between 1996 and 1998 to 58% between 2000 and 2002 (P = .005), and treatment-related mortality declined from 19% to 12% (P = .025). Partial replacement of daunomycin with idarubicin in the 5-drug induction combination achieved a remission rate of 88%, similar to historical controls. Postremission survival was 56% in patients randomized to either 5-drug reinduction or fludarabine/cytarabine/idarubicin. For patients with or without a related donor, respective 5-year disease-free survival was 61% and 50% (P = .021); respective survival was 68% and 62% (P = .425). Donor availability conferred no benefit on those with inv(16) or t(8;21) cytogenetics. After cytarabine intensification, patients randomized to interleukin-2 or none experienced similar outcomes. Factors predictive of inferior survival were age more than 16 years, non-white ethnicity, absence of related donor, obesity, white blood cell count more than 100 000 × 109/L, −7/7q−, −5/5q−, and/or complex karyotype. No new agent improved outcomes; experience may have contributed to better results time.

The National Heart, Lung, and Blood Institute and Office of Rare Diseases at the National Institutes of Health organized a workshop (September 14 to 15, 2006, in Bethesda, Md) to advise on new research directions needed for improved identification and treatment of rare inherited arrhythmias. These included the following: (1) Na + channelopathies; (2) arrhythmias due to K + channel mutations; and (3) arrhythmias due to other inherited arrhythmogenic mechanisms. Another major goal was to provide recommendations to support, enable, or facilitate research to improve future diagnosis and management of inherited arrhythmias. Classifications of electric heart diseases have proved to be exceedingly complex and in many respects contradictory. A new contemporary and rigorous classification of arrhythmogenic cardiomyopathies is proposed. This consensus report provides an important framework and overview to this increasingly heterogeneous group of primary cardiac membrane channel diseases. Of particular note, the present classification scheme recognizes the rapid evolution of molecular biology and novel therapeutic approaches in cardiology, as well as the introduction of many recently described diseases, and is unique in that it incorporates ion channelopathies as a primary cardiomyopathy in consensus with a recent American Heart Association Scientific Statement.

Abstract HDAC7 associates with Runx2 and represses Runx2 transcriptional activity in a deacetylase-independent manner. HDAC7 suppression accelerates osteoblast maturation. Thus, HDAC7 is a novel Runx2 co-repressor that regulates osteoblast differentiation. Introduction: Runx2 is a key regulator of gene expression in osteoblasts and can activate or repress transcription depending on interactions with various co-factors. Based on previous observations that several histone deacetylases (HDACs) repress Runx2 activity and that HDAC inhibitors accelerate osteoblast differentiation in vitro, we hypothesized that additional HDACs may also affect Runx2 activity. Materials and Methods: A panel of HDACs was screened for repressors of Runx2 activity. Immunofluorescence, co-immunoprecipitation, GST-pulldowns, and chromatin immunoprecipitations were used to characterize the interactions between Runx2 and HDAC7. Expression of osteoblast markers was examined in a C2C12 cell osteoblast differentiation model in which HDAC7 levels were reduced by RNAi. Results: Runx2 activity was repressed by HDAC7 but not by HDAC9, HDRP, HDAC10, or HDAC11. HDAC7 and Runx2 were found co-localized in nuclei and associated with Runx2-responsive promoter elements in osseous cells. A carboxy-terminal domain of Runx2 associated with multiple regions of HDAC7. Although direct interactions with Runx2 were confined to the carboxy terminus of HDAC7, this region was dispensable for repression. In contrast, the amino terminus of HDAC7 bound Runx2 indirectly and was necessary and sufficient for transcriptional repression. Treatment with HDAC inhibitors did not decrease inhibition by HDAC7, indicating that HDAC7 repressed Runx2 by deacetylation-independent mechanism(s). Suppression of HDAC7 expression in C2C12 multipotent cells by RNAi accelerated their BMP2-dependent osteoblast differentiation program. Consistent with this observation, BMP2 decreased nuclear localization of HDAC7. Conclusions: These results establish HDAC7 as a regulator of Runx2's transcriptional activity and suggest that HDAC7 may be an important regulator of the timing and/ or rate of osteoblast maturation.