Acute peripheral arterial and graft occlusion: treatment with selective infusion of urokinase and lysyl plasminogen

Thirty-five patients hospitalized for recent angiographically documented arterial occlusion in the legs (27 femoropopliteal arteries and eight grafts) benefited from local fibrinolytic therapy delivered at the site of the occlusion with a 4- or 5-F catheter. This therapy combined a continuous urokinase (UK) infusion of 1,000 U/kg/hour and a lysyl plasminogen (LYS-PLG) infusion of 15 microkatals every 30 minutes. Angiographically confirmed lysis was obtained in 85% of the cases. Only 3% of the patients had major and 6% had minor groin hematomas. Only two patients had concentrations of fibrinogen as low as 100 mg/dl. Intravascular infusion of UK-LYS-PLG is as effective as streptokinase. Its excellent tolerance makes it a good alternative in the treatment of acute ischemia in the lower limbs.     

Source of raised serum estrogens in male rats with portal bypass.

We sought to establish the mechanism for the raised serum estrogen levels that occur in male rats with portal hypertension and resultant portal bypass. Using the portal vein ligated (PVL) rat model, we evaluated plasma steroid hormone concentrations, metabolic clearance rate (MCR) of estradiol, and hepatic metabolism of androstenedione to estrogens and other products. In contrast to serum testosterone levels that were reduced, serum androstenedione levels were normal in the PVL rat. Estradiol MCR was measured by a constant intravenous infusion technique and was found to be similar in PVL and control animals. Androstenedione MCR was determined during constant intravenous infusion of [3H]androstenedione, and the resultant radiolabeled steroids present in plasma were separated by thin layer chromatography. The MCR of androstenedione was not diminished in PVL rats compared with controls. However, there was a sevenfold increase in the plasma estradiol derived from [3H]androstenedione in rats with portal bypass. Examination of radiolabel excreted in bile during infusion of [3H]androstenedione showed that 25-46% of this steroid was converted to estradiol in PVL rats compared with less than 3% in control male rats (P less than 0.001). Moreover, there was a selective reduction in the excretion of 16 alpha-hydroxyandrostenedione, a finding which suggested that the metabolism of androstenedione via this pathway was decreased. Androstenedione 16 alpha-hydroxylation is known to be catalyzed by a male-specific cytochrome P-450 isoform, P-450UT-A. We conclude that raised plasma estradiol levels after portal bypass in male rats are due to increased production rates, resulting in turn from enhanced aromatization of androstenedione to estradiol. On the basis of the observed specific changes in androstenedione hydroxylation pathways, it is proposed that alterations in levels of sex-specific forms of cytochrome P-450 occur in male rats with portal bypass and could account for the enhanced formation of estradiol.     

A murine cytomegalovirus-neutralizing monoclonal antibody exhibits autoreactivity and induces tissue damage in vivo.

The autoreactivity of murine cytomegalovirus (MCMV)-neutralizing monoclonal antibody (mAb) AC1 was examined in vitro and in vivo. Both mAb AC1 and a human antiserum reactive with U1-small nuclear ribonucleoprotein (U1-snRNP) stained uninfected mouse embryo fibroblasts (MEF) in a speckled nuclear pattern and reacted with 70,000 molecular weight (MW) MEF nuclear antigens by immunoblotting, suggesting that mAb AC1 cross-reacted with the 70,000 MW component of U1-snRNP. However, only mAb AC1 cross-reacted with an additional epithelial cytoplasmic autoantigen present in cultured HEp2 cells. On tissue sections from uninfected mice, mAb AC1 predominantly reacted with a component of central and peripheral nervous systems, although cross-reactivity with the stratum spinosum of the skin and the outer sheath of hair follicles was also observed. Immunoblotting revealed that mAb AC1 reacted with phosphorylated epitopes present on a 98,000 MW MCMV structural protein and the 200,000 MW mouse neurofilament protein (NFP). Treatment of uninfected mice with mAb AC1 resulted in a severe interstitial pneumonia with greatly thickened and congested alveolar septa. Severe oedema of the hypodermis and a mild mesangial proliferative glomerulonephritis were also observed. These results demonstrate that a mAb reacting with a MCMV structural phosphoprotein which can protect mice against the dissemination of MCMV, can also promote the development of autoimmune disease. Therefore, the production of such cross-reactive antibodies may be an important mechanism in the development of autoimmunity following viral infection.     

The Association of Different Measures of Insulinaemia with Vascular Risk Factors in Healthy Normoglycaemic Normotensive Non-obese Men and Women

Hyperinsulinaemia is said to be a risk factor for cardiovasculardisease, but the extent to which different insulinaemic measuresare associated with vascular risk factors in ostensibly healthyindividuals, and whether they operate independently in men andwomen, remains uncertain. The association between risk factors and various insulinaemicmeasures was examined in 148 men and 118 women who were normoglycaemic,normotensive, and non-obese (body mass index in men <27,in women <25). A 75 g glucose tolerance test was administeredafter blood sampling for fibrinogen, lipids, lipoproteins andinsulin. Insulin was also measured after 1 and 2 hours. Significantunivariate correlations (p<0.01) were most consistently recordedbetween insulinaemic measures and fasting serum triglyceridesin men and women, whilst systolic blood pressure only correlatedwith insulinaemia in women, and diastolic blood pressure correlatedwith fasting and 2 hour insulinaemic measures in men and women.Inconsistent associations were noted with total serum cholesterolin men and women, with high density lipoprotein cholesterol,body mass index, apoprotein B and A1 in men, and with fibrinogenin women. Age was not correlated with any insulinaemic measurein men or women. Differences in vascular risk factors between quintiles of theinsulinaemic measures were examined, after correction for bodymass index. The dominant association with fasting and post-glucoseload insulinaemic measures was with triglycerides, especiallyin women, with less frequent graded differences between quintilesobserved for total cholesterol, and diastolic and systolic bloodpressures in men and women. The incidence of other risk factors often only differed in thelowest or highest quintile in comparison to other quintiles,suggesting a threshold rather than a graded effect. Furthermore,differences in HDL cholesterol and apoprotein B were only recordedfor top quintiles of post-glucose challenge/integrated insulinaemicmeasures in men, whilst serum fibrinogen concentrations onlydiffered significantly in women in the top insulinaemic areaunder the curve quintile. In the absence of additional risk factors such as diabetes,hypertension and obesity, insulinaemic measures are not consistentlyrelated to blood pressure and measures of lipid metabolism andcoagulation, and are thus a weak predictor of other cardiovascularrisk factors. The vascular risk profile associated with insulinappears somewhat different in apparently healthy men and women.     

Parents' knowledge of neonatal screening and response to false-positive cystic fibrosis testing.

Neonatal screening for cystic fibrosis (CF) has become feasible through analyzing dried blood specimens for immunoreactive trypsinogen (IRT), but the benefits and risks of such a screening program remain to be delineated. This study, a survey of the parents of 104 Wisconsin infants with false-positive IRT tests, showed parents had knowledge deficits about neonatal screening in general, misconceptions about test results, and high levels of anxiety. Parenting behaviors were reportedly unchanged during the usual 3-day waiting period between the news of the abnormal screening test and the diagnostic sweat test. Most, but not all, parents were relieved by negative sweat test results subsequent to the abnormal IRT test. Factors associated with continued parental concern included having less than a high school education and/or having an infant with low Apgar scores. Additionally, those contacted by telephone were more likely to have misinformation and lingering concerns about the presence of CF in their child.