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Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p

A shock canine pneumonia model that permitted relief of discomfort with the use of objective criteria was developed and validated. After intrabronchial Staphylococcus aureus challenge, mechanical ventilation, antibiotics, fluids, vasopressors, sedatives, and analgesics were titrated based on algorithms for 96 h. Increasing S. aureus (1 to 8 x [10.sup.9] colonyforming units/kg) produced decreasing survival rates (P = 0.04). From 4 to 96 h, changes in arterial-alveolar oxygen gradients, mean pulmonary artery pressure, IL-1, serum sodium levels, mechanical ventilation, and vasopressor support were ordered based on survival time [acute nonsurvivors ([less than or equal to]24 h until death, n = 8) [greater than or equal to] subacute nonsurvivors (>24 to 96 h until death, n = 8) [greater than or equal to] survivors ([greater than or equal to] 96 h until death, n = 22) (all P < 0.05)]. In the first 12 h, increases in lactate and renal abnormalities were greatest in acute nonsurvivors (all P < 0.05). Compared with survivors, subacute nonsurvivors had greater rises in cytokines and liver enzymes and greater falls in platelets, white cell counts, pH, and urine output from 24 to 96 h (all P < 0.05). Importantly, these changes were not attributable to dosages of sedation, which decreased in nonsurvivors [survivors vs. nonsurvivors: 5.0 [+ or -] 1.0 vs. 3.8 [+ or -] 0.7 ml x [h.sup.-1] x [(fentanyl/midazolam/ medetomidine).sup.-l]; p = 0.02]. In this model, the pain control regimen did not mask changes in metabolic function and lung injury or the need for more hemodynamic and pulmonary support related to increasing severity of sepsis. The integration into this model of both specific and supportive titrated therapies routinely used in septic patients may provide a more realistic setting to evaluate therapies for sepsis. sepsis; dog; Staphylococcus aureus

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2005.01.035 Byline: Motozo Yamashita (1), Sai-Xia Ying (1), Gen-mu Zhang (2), Cuiling Li (3), Steven Y. Cheng (1), Chu-xia Deng (3), Ying E. Zhang (1) Abstract: Bone is constantly resorbed and formed throughout life by coordinated actions of osteoclasts and osteoblasts. Here we show that Smurf1, a HECT domain ubiquitin ligase, has a specific physiological role in suppressing the osteogenic activity of osteoblasts. Smurf1-deficient mice are born normal but exhibit an age-dependent increase of bone mass. The cause of this increase can be traced to enhanced activities of osteoblasts, which become sensitized to bone morphogenesis protein (BMP) in the absence of Smurf1. However, loss of Smurf1 does not affect the canonical Smad-mediated intracellular TGF[beta] or BMP signaling; instead, it leads to accumulation of phosphorylated MEKK2 and activation of the downstream JNK signaling cascade. We demonstrate that Smurf1 physically interacts with MEKK2 and promotes the ubiquitination and turnover of MEKK2. These results indicate that Smurf1 negatively regulates osteoblast activity and response to BMP through controlling MEKK2 degradation. Author Affiliation: (1) Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 (2) Laboratory Animal Science Program, National Cancer Institute at Frederick, Frederick, Maryland 21702 (3) Mammalian Genetics Section, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892 Article History: Received 9 July 2004; Revised 24 November 2004; Accepted 20 January 2005 Article Note: (miscellaneous) Published: April 7, 2005