The serpin protease nexin-1 regulates vascular smooth muscle cell adhesion, spreading, migration and response to thrombin

BACKGROUND: Protease nexin-1 (PN-1) is an important physiological regulator of thrombin in the brain. PN-1 is also present in aortic smooth muscle cells and may thus participate in vascular biology. However, little is known about its function in the vessel wall. OBJECTIVES: In this study, we investigated the effect of PN-1 overexpression in smooth muscle cells (SMCs), on their sensitivity to thrombin, and their capacity for adhesion, spreading and migration. RESULTS: Two clones exhibiting a two- to threefold increase in PN-1 expression were selected and compared with untransfected and mock-transfected cells. Overexpression of PN-1 was observed to inhibit thrombin-induced cell responses as indicated by a twofold decrease in induction of PAI-1 expression, a decreased calcium mobilization in response to low thrombin concentrations and a twofold increase in the capacity to inhibit thrombin catalytic activity. Overexpression of PN-1 did not modify adhesion, spreading, and migration of SMCs on type I collagen. In contrast, SMCs overexpressing PN-1 exhibited a 40% reduction in adhesion, a 50% reduction in spreading and a complete absence of migration on vitronectin when compared with control SMCs. CONCLUSIONS: Our studies thus reveal that PN-1 is likely to play a critical role in regulating essential cell functions such as (i) thrombin-induced responses, which are dependent on its antiprotease activity, and (ii) adhesion, spreading, and migration, which are independent of its antiprotease activity and may be related to its interaction with other partners, such as vitronectin in the present case.     

Ablation of Ventricular Tachycardia with a Saline-Cooled Radiofrequency Catheter:

INTRODUCTION: In animal models, active cooling of the electrode during radiofrequency (RF) ablation allows creation of larger lesions, presumably by increasing the power that can be delivered without coagulum formation. These RF lesions have not been characterized in human myocardium in regions of infarction and scarring. METHODS AND RESULTS: Cooled-tip RF catheter ablation of ventricular tachycardias (VTs) was performed in two patients who had severe congestive heart failure and subsequently underwent cardiac transplantation. The first patient had four different monomorphic VTs. RF applications along the inferoseptal margin of a scarred region abolished all inducible VTs. The second patient had sarcoidosis involving the myocardium and four different inducible VTs. RF current applied at an inferobasal VT exit and at the right and left septa failed to abolish the VTs. The explanted hearts were examined at the time of cardiac transplantation 18 and 21 days later, respectively. Lesions extended to depths up to 7 mm, reaching clusters of myocardial cells deep to regions of fibrosis. Microscopically, the ablation sites contained coagulation necrosis with hemorrhage, surrounded by a rim of granulation tissue. CONCLUSION: Saline-irrigated RF catheter ablation produces relatively large lesions capable of penetrating deep into scarred myocardium.     

Measurement of HIV risk behaviors among intravenous drug users

This paper reviews issues related to the measurement of drug use and other behaviors in studies of human immunodeficiency virus (HIV) infection in intravenous drug users. These issues include: (1) choice of variables, (2) study design, (3) time frame of measurement, (4) categories of measurement, (5) interviewer effects, and (6) validity of measurement. Difficulties and approaches for measuring drug use and other intimate behaviors in intravenous drug users are discussed. Attempts to come to terms with these measurement issues in the context of HIV infection in intravenous drug users should lead to the Junker development of methods for use in the general context of drug abuse research.     

Does demographic entrapment challenge the two-child paradigm?

Local demographic entrapment has been discussed informally formany years, but is taboo to the UN agencies and to much of academia.There are also indications that the world as a whole may bedemographically trapped in that global per capita grain productionis falling. Arguments for and against recognizing entrapmentare discussed. Policy implications of entrapment are outlinedin the light of the 1994 International Conference on Populationand Development (ICPD). The case for a one-child world is argued.Carrying capacity, disentrapment, the two-child paradigm, abortion,Rwanda and North/South tensions are considered.     

Chronic Feeding Study of Pyrilamine in Fischer 344 Rats

The antihistamine, pyrilamine maleate, was fed for up to 2 yearsto groups of 57 Fischer 344 (F344) rats of each sex at dietarylevels of 0, 300,1500, or 3000 ppm (free base). Eight or nineof these rats per sex and dose group were killed at 65 weeksto analyze hematology and clinical chemistry in all groups andhistopathology of control and high-dose animals. Histopathologyalso was performed on all dead or moribund rats and on all thatsurvived for 2 years. Average daily exposures were 11 to 150mg/kg pyrilamine compared to human dosages up to 3 mg/kg. Pyrilaminetreatment did not reduce survival. Final body weights were reducedrelative to controls (mid-dose males, 93%, females, 82%: high-dosemales, 82%, females, 70%). The incidences of inflammation ofthe nasolacrimal duct (chronic in females; suppurative in males),liver cytoplasmic vacuolization (males), and the combinationof animals with either liver basophilic or clear cell foci (males)tended to significantly increase with dose. Adrenal pheochromocytomas,mammary gland fibroadenomas, and neoplasms of the clitoral gland,thyroid ccell, and pituitary gland all tended to decrease withincreasing dose in females. In males only preputial gland neoplasmsexhibited a similar negative trend. While two ovarian granulosathecacell benign tumors occurred in high-dose females, these werethought to be a random occurrence. There was no evidence forthe carcinogenicity of pyrilamine in F344 rats in the currentstudy.     

The relationship between stressful life situations and changes in alcohol consumption in a general population sample

Studies on the relationship between stressful life situations and alcohol consumption have almost exclusively been based on retrospective information from clinical populations. We conducted multiple regression analyses of the relationship between presumed stressful life conditions in 1965, life events during 1966–73 and psychosocial factors and amount of increase or decrease in alcohol consumption from 1965 to 1974 adjusting for age, alcohol consumption, education and health status in 1965. Data from surveys in 1965 and in 1974 in a general population sample of 4,864 subjects from Alameda County, California were used. The magnitude of the associations between the presumed stressful life situations and amount of change was generally low, although a few were statistically significant. However, among those aged 65 years and above, and especially among men, some of the associations were strong, but imprecise due to the low number of subjects in those ages. While a number of variables were associated with increase or decrease in alcohol consumption, the R²-values indicated that these variables explained little of the variation over time in alcohol consumption. Thus, people in general seem to cope with stressful life situations by means, other than a longstanding increase in alcohol consumption.     

Role of toll-like receptor 2 and toll-like receptor 4 in post-ischemic coronary endothelial dysfunction in mice

AIM: A growing body of evidence suggests a role of the toll-like receptors (TLR) in inflammatory processes. In addition to LPS,TLR are activated by many endogenous ligands such as heat shock proteins and oxygeil-derived free radicals which are both produced during cardiac ischemia-reperfusion (I/R). Among TLR,TLR-2 and TLR-4 are expressed in endothelial and myocardial cells and appear to regulate neutrophil-endothelial interactions.Since neutrophil adhesion is a critical event in endothelial injury