Citations

BACKGROUND: Four-meter gait speed (4MGS) has been associated with functional capacity and overall mortality in elderly patients, and may easily be translated to daily practice. We evaluated the association of 4MGS with meaningful outcomes. METHODS: In 70 subjects we conducted the 4MGS, 6-min walk test (6MWT), objectively measured physical activity, and assessed dyspnea, quality of life, and self-efficacy for walking and routine physical activity. 4MGS was measured in 3 separate time epochs during the 6MWT, to explore 4MGS variability. RESULTS: Diagnoses included COPD (51.4%), interstitial lung disease (38.6%), and other pulmonary conditions (10%). The mean ± SD values were: 4MGS 0.85 ± 0.21 m/s, 6-min walk distance (6MWD) 305 ± 115 m, and physical activity level 1.28 ± 0.17, which is consistent with severe physical inactivity. The gait speeds within the time epochs 1–2, 3–4, and 5–6 min during the 6MWT were not significantly different: 1.01 ± 0.29 m/s, 0.98 ± 0.31 m/s, and 1.00 ± 0.31 m/s, respectively. 4MGS had a significant correlation with 6MWD ( r = 0.70, P < .001). 6MWD was the dominant variable for predicting 4MGS. Other significant predictors of 4MGS included dyspnea, self-efficacy, quality of life, and objectively measured physical activity. CONCLUSIONS: 4MGS is significantly and independently associated with 6MWD, and may serve as a reasonable simple surrogate for 6MWD in subjects with chronic lung disease. Gait speed was remarkably stable throughout the 6MWT, which supports the validity of an abbreviated walk test such as 4MGS.

We present a 33-year-old dialysis-dependent female who presented with new onset split second heart sound. Following a failed left upper extremity dialysis fistula, a right upper extremity hemodialysis reliable outflow (HeRO) graft was performed in 2011. Her subsequent cadaveric renal transplant had delayed function necessitating concurrent use of hemodialysis. However, as renal function improved, hemodialysis was discontinued. Two weeks following transplantation, the HeRO graft occluded. Subsequent clinical and radiological assessment confirmed widespread pulmonary emboli. Following cessation of hemodialysis and subsequent HeRO graft occlusion, removal was deemed appropriate to reduce further thromboembolic phenomenon. Right atrial thrombi are complications associated with central venous catheters. However, their actual incidence varies significantly. Right heart thromboemboli are associated with a 4% to 6% pulmonary embolism rate. Katzman et al assessed 38 patients who underwent HeRO graft and reported 1 (2.6%) patient with right atrial emboli and likely pulmonary embolism. Although thrombotic complications remain rare, consideration of graft removal should always be evaluated particularly in the absence of an alternative thrombotic source.

Inactivating mutations of the SOST (sclerostin) gene are associated with overgrowth and sclerosis of the skeleton. To determine mechanisms by which increased amounts of calcium and phosphorus are accreted to enable enhanced bone mineralization in the absence of sclerostin, we measured concentrations of calciotropic and phosphaturic hormones, and urine and serum calcium and inorganic phosphorus in mice in which the sclerostin ( sost ) gene was replaced by the β-D-galactosidase ( lacZ ) gene in the germ line. Knockout (KO) ( sost −/− ) mice had increased bone mineral density and content, increased cortical and trabecular bone thickness, and greater net bone formation as a result of increased osteoblast and decreased osteoclast surfaces compared with wild-type (WT) mice. β-Galactosidase activity was detected in osteocytes of sost KO mice but was undetectable in WT mice. Eight-week-old, male sost KO mice had increased serum 1α,25-dihydroxyvitamin D, decreased 24,25-dihydroxyvitamin D, decreased intact fibroblast growth factor 23, and elevated inorganic phosphorus concentrations compared with age-matched WT mice. 25-Hydroxyvitamin D 1α-hydroxylase cytochrome P450 ( cyp27B1 ) mRNA was increased in kidneys of sost KO mice compared with WT mice. Treatment of cultured proximal tubule cells with mouse recombinant sclerostin decreased cyp27B1 mRNA transcripts. Urinary calcium and renal fractional excretion of calcium were decreased in sost KO mice compared with WT mice. Sost KO and WT mice had similar serum calcium and parathyroid hormone concentrations. The data show that sclerostin not only alters bone mineralization, but also influences mineral metabolism by altering concentrations of hormones that regulate mineral accretion.

Abstract Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987–. ©2013 AACR.

Pregnancy-associated plasma protein-A (PAPP-A) functions to increase local IGF-I bioactivity. In this study, we used transgenic mice that constitutively express human PAPP-A in arterial smooth muscle to test the hypothesis that overexpression of PAPP-A enhances vascular smooth muscle cell (SMC) response to IGF-I in vivo. PAPP-A transgenic (Tg) and wild-type (WT) mice underwent unilateral carotid ligation, a model of injury-induced SMC hyperplasia and neointimal formation. In both WT and PAPP-A Tg mice, endogenous PAPP-A mRNA expression showed peak elevation 5 days after carotid ligation. However, PAPP-A Tg mice had 70–75% less neointima than WT at 5 and 10 days postligation, with a significant reduction in occlusion of the ligated artery. WT and PAPP-A Tg mice had equivalent increases in medial area and vessel remodeling postligation. There was little change in medial area and no evidence of neointima in the contralateral carotid of WT or PAPP-A Tg mice. Both WT and PAPP-A Tg carotids exhibited signs of dedifferentiation of SMC, which precedes the increase in proliferation and migration that results in neointimal formation. However, the number of proliferating cells in the media and neointima of the ligated PAPP-A Tg artery was reduced by 90% on day 5 postsurgery compared with WT. This decrease was associated with a significant decrease in an in vivo marker of IGF-I bioactivity and reduced IGF-I-stimulated receptor phosphorylation ex vivo. These data suggest differential effects of chronic (transgenic) and transient (endogenous) PAPP-A expression on neointimal formation following vascular injury that may be due in part to the differential impact on IGF-I signaling.

Pregnancy-associated plasma protein-A (PAPP-A) is a large multidomain metalloprotease involved in cleavage of IGF binding protein (IGFBP)-4 and -5 thereby causing release of bioactive IGF. Individual domains of PAPP-A have been characterized in vitro, including the metzincin proteolytic domain important for IGFBP proteolytic activity, short consensus repeats critical for cell surface association, and Lin-12/Notch repeat module demonstrated to determine IGFBP substrate specificity. To test the hypothesis that specific cleavage of IGFBP-4 by PAPP-A in close proximity to the cell surface is required for development of lesions in a murine model of atherosclerosis, the following PAPP-A transgenic (Tg) mice were generated: TgE483A, which lacks all PAPP-A proteolytic activity; TgD1499A, which selectively lacks proteolytic activity against IGFBP-4; and TgK1296A/K1316A, in which cell surface binding is compromised. Following cross-breeding with apolipoprotein E (ApoE) knockout (KO) mice, ApoE KO/Tg mice were fed a high-fat diet to promote aortic lesion development. Lesion area was increased 2-fold in aortas from ApoE KO/Tg wild-type compared with ApoE KO mice (P &lt; 0.001). However, there was no significant increase in the lesion area in any of the ApoE KO/Tg mutant mice. We conclude that PAPP-A proteolytic activity is required for the lesion-promoting effect of PAPP-A and that its specificity must be directed against IGFBP-4. Furthermore, our data demonstrate that cleavage of IGFBP-4 at a distance from the cell surface, and hence from the IGF receptor, is not effective in promoting the development of the atherosclerotic lesions. Thus, PAPP-A exerts its effect while bound to the cell surface in vivo.

Objectively measured severe physical inactivity (SPI) has been reported as the strongest independent predictor of mortality in patients with chronic obstructive pulmonary disease (COPD). Activity monitoring is not feasible in routine clinical practice; therefore, we set out to determine the utility of simple clinical measures for predicting SPI in patients with COPD. A total of 165 patients with COPD wore an activity monitor for 5 days to define the presence or absence of SPI. Logistic models were generated including the modified Medical Research Council (MMRC) dyspnea grade, spirometry and the age–dyspnea–airflow obstruction (ADO) index. Physical Activity Scale for the Elderly (PASE) and Stanford Brief Activity Scale (SBAS) were also tested for validity and reliability in a subgroup of 67 patients. The MMRC dyspnea grade, PASE score, ADO index and SBAS score were associated with SPI, but general self-efficacy and spirometry were not. An MMRC dyspnea grade ≥3 was the best independent predictor of SPI (AUC: 0.74; PPV: 0.83; NPV: 0.68) followed closely by a PASE score of <111. The combination of MMRC dyspnea grade and PASE score provided the most robust model (AUC: 0.83; Positive Predictive Value (PPV): 0.95; Negative Predictive Value (NPV): 0.63). The results were confirmed using 5000 bootstrapped models from the cohort of 165 patients. MMRC dyspnea grade ≥3 may be the best triage tool for SPI in patients with COPD. The combination of the MMRC and PASE score provided the most robust prediction. Our results may have significant practical applicability for clinicians caring for patients with COPD.