Abstract-The renin-angiotensin system is a key regulator of blood pressure (BP), with inhibitors of angiotensinconverting enzyme (ACE) used clinically to treat hypertension and other cardiovascular conditions. ACE2 is a newly identified member of this system, which converts angiotensin II to angiotensin (1-7), and of which the occurrence in plasma has not been investigated. The aim of this study was to determine the heritability of circulating ACE, ACE2, and neprilysin (NEP), which may also be a regulator of BP, in a family study, and to determine covariates that contribute to the variation in plasma activity. ACE, ACE2, and NEP activities were measured in plasma from 534 subjects in the Leeds Family Study using selective fluorogenic substrates. Genetic factors accounted for 24.5%, 67%, and 22.7% of the phenotypic variation in circulating ACE, ACE2, and NEP, respectively. ACE insertion/deletion polymorphism and other measured covariates accounted for 23.8% of variance in circulating ACE. High-density lipoprotein cholesterol was a significant determinant of circulating ACE2. Measured covariates accounted for 17.3% of variation in circulating NEP. ACE and NEP were associated with systolic and diastolic BP in univariate analyses; however, only ACE was independently associated with systolic and diastolic BP after accounting for covariates and shared childhood household. Key Words: angiotensin Ⅲ blood pressure Ⅲ genetics Ⅲ metalloproteinases Ⅲ population T he renin-angiotensin system (RAS) is a complex cascade of bioactive peptides and regulatory enzymes, which acts as a key regulator of blood pressure (BP) and fluid and electrolyte homeostasis. 1 Angiotensin-converting enzyme (ACE) cleaves angiotensin I (Ang I) to form the biologically active peptide angiotensin II (Ang II). Ang II mediates a diverse range of biological effects including vasoconstriction, vascular smooth muscle cell proliferation, and hypertrophy of the heart vessel wall through its interaction with the Ang II type 1 receptor. 2 Although ACE exists primarily as a transmembrane protein on the surface of endothelial and epithelial cells, a soluble form is present in plasma resulting from proteolytic shedding that can be readily measured. 1 The Alu insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene is a strong predictor of plasma ACE levels. 3,4 A recently identified homolog of ACE, ACE2, cleaves Ang II to form Ang (1-7), 5,6 which, in turn, binds to a non-Ang II type 1/Ang II type 2 receptor originally identified as the Mas oncogene 7 and mediates functions that oppose the actions of Ang II. 8 Thus, ACE2 may have a role to counterbalance the action of ACE in producing the vasoconstrictor Ang II, leading to the suggestion that ACE2 and ACE may be correlated. 9 ACE2 displays 42% amino acid identity to ACE and, like ACE, is a type I integral membrane protein that can be proteolytically shed from the plasma membrane. 10 As yet, ACE2 in plasma has not been measured, and its relationship to circulating ACE has not been reported.Neprilysin ([...

IC50 for S247 adhesion to alpha(v)beta3 or alpha(IIB)beta3a substrates was 0.2 nM vs. 244 nM, respectively. Likewise, S247 was not toxic at doses up to 1000 microM. However, osteoclast cultures treated with S247 exhibited marked morphological changes and impaired formation of the actin sealing zone. When S247 was administered prior to tumor cells, there was a significant, dose-dependent reduction (25-50% of vehicle-only-treated mice; P = 0.002) in osseous metastasis. Mice receiving S247 after tumor cell inoculation also developed fewer bone metastases, but the difference was not statistically significant. These data suggest that, in the MDA-MB-435 model, the alpha(v)beta3 integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that alpha(v)beta3 inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.

cell cytoplasmic antibody type 1 (PCA-1, or anti-Yo) paraneoplastic cerebellar ataxia has a poor prognosis, yet little has been published otherwise regarding treatment responses and outcomes among patients with autoimmune cerebellar ataxia.OBJECTIVES To investigate treatment responses and outcomes in adults with autoimmune cerebellar ataxia.

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The authors investigated whether the perception that freshmen gain 15 pounds during their 1st year of college is related to either actual or perceived weight gain. Forty-nine incoming freshmen at a small liberal arts college completed the study by filling out questionnaires and health data at the beginning and end of their 1st year on campus. The findings revealed no significant weight gain at the end of the year. The "Freshman 15" myth was found to play an important role in perpetuating negative attitudes toward weight. Freshmen who were concerned about gaining 15 pounds were more likely to think about their weight, have a poorer body image than others, and categorize themselves as being overweight.