Interactions between fibrin and the plasminogen activators produced by cultured endothelial cells

Serum-free conditioned medium (CM) from cultured bovine aortic endothelial cells (BAEs) was fractionated by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and analyzed for plasminogen activator (PA) activity by fibrin autography. Distinct size forms of PA with molecular weights (mol wt) of 100,000, 74,000, and 52,000 were readily identified by this approach. When fibrinogen and thrombin were added to CM containing these forms, approximately 55% of the total activity was found to associate with the resultant fibrin clot. The other 45% remained free in the supernatant. This relationship did not change at higher fibrin concentrations. Subsequent analysis revealed that only the larger PA forms (mol wt 74,000-100,000) were recovered in the clot. The 52,000 form did not bind to the polymerizing fibrin under these conditions. The fibrin-binding forms also bound to immobilized concanavalin-A and could be separated from those forms that did not interact with fibrin by concanavalin-A affinity chromatography. The PA activity of the separated forms was then compared by assessing their ability to cleave 125I-plasminogen. Although cleavage by the 52,000 mol wt form was apparent, little if any cleavage was initiated by the mixture containing the 74,000-100,000 forms. The addition of fibrin to this sample resulted in the generation of a potent PA activity. These results indicate that cultured BAEs produce multiple forms of PA that differ both in size and in behavior toward fibrin and concanavalin-A. These forms include molecules that functionally and immunochemically resemble human urokinase, and others that resemble human tissue-type PA.     

Chronic Q fever endocarditis.

Eight patients with chronic Q fever endocarditis were treated with tetracycline for up to 40 months. In addition, five of these patients received co-trimoxazole. Six patients had prosthetic valves. Two patients who had Q fever endocarditis on their native valves required valve replacement because of haemodynamic difficulties: in only one did the Q fever endocarditis contribute to the haemodynamic difficulty. One patient died. It is suggested that medical treatment is continued until clinically and haematologically there is no evidence of endocarditis and the Q fever phase 1 antibody titre is less than 200. No recurrence of Q fever endocarditis has been detected in three of our patients who have now stopped treatment.     

Nonadherence to antihypertensive medications amongst patients with uncontrolled hypertension: A retrospective study

Medication nonadherence represents a modifiable risk factor for patients with hypertension. Identification of nonadherent patients could have significant clinical and economic implications in the management of uncontrolled hypertension.We analysed the results of 174 urinary adherence screens from patients referred to Addenbrooke''s Hospital, Cambridge, for uncontrolled hypertension. Cases were identified for evaluation by results of liquid chromatography-tandem mass spectrometry of urine samples (males: 91; females: 83; age range: 17–87). We performed a binary logistic regression analysis for nonadherence using age, sex, and number of medications prescribed (both antihypertensives and non-antihypertensives separately) as independent predictors. Rates of nonadherence for individual antihypertensive drugs were calculated if prescribed to ≥10 patients.The overall rate of nonadherence to one or more prescribed antihypertensive medications was 40.3%. 14.4% of all patients were nonadherent to all prescribed antihypertensive medications (complete nonadherence), whereas 25.9% of all patients were nonadherent to at least 1, (but not all) prescribed antihypertensive medications (partial nonadherence). 72% of patients were prescribed ≥3 antihypertensives And for every increase in the number of antihypertensive medications prescribed, nonadherence increased with adjusted odds ratios of 2.9 (P < .001). Logistic regression showed that women were 3.3 times more likely to be nonadherent (P = .004). Polypharmacy (≥6 medications prescribed for hypertension and/or concomitant comorbidities) was prevalent in 52%. Bendroflumethiazide and chlortalidone demonstrated the highest and lowest nonadherences respectively (45.5% and 11.8%).Rate of nonadherence in patients with hypertension was significantly impacted by sex and number of antihypertensive medications prescribed. Understanding these factors is crucial in identifying and managing nonadherence.     

Intravenous Fluid Administration: Improving Patient Outcomes With Evidence-based Care

Intravenous (IV) fluid administration is one of the most common interventions in the hospital setting. The associated complication rate is higher than previously believed, with adverse effects impacting recovery, length of stay, cost, patient safety, and survival. Several patient populations are at increased risk, and there are substantial data implicating inappropriate fluid administration as a contributing factor to increased morbidity and mortality. Related complications are largely preventable, and unmet educational needs are well-documented. An increase in evidence-based management has the potential to improve outcomes related to a number of quality indicators.     

Biology‐Driven Gene‐Gene Interaction Analysis of Age‐Related Cataract in the eMERGE Network

Bioinformatics approaches to examine gene‐gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge‐driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty‐three SNP‐SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)–rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell‐to‐cell adhesion signaling, cell‐cell junction organization, and cell‐cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP‐SNP models, which included signal transduction and PI3K‐Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology‐driven method, applicable for any genome‐wide association study dataset.     

Likelihood of residential aged care use in later life: a simple approach to estimation with international comparison

Objectives: In New Zealand (NZ), place of death among decedents aged 65+ years has been reported as residential aged care (RAC, 38%), acute hospital (34%) or elsewhere (28%). However, lifetime risk of use of RAC (or nursing homes) is unknown. A simple method of estimation is demonstrated for NZ and Australia, with comparisons to other countries. Methods: Deaths of RAC residents in acute hospitals were estimated for NZ from four separate studies and added to deaths occurring in RAC, to derive the likelihood of using RAC after age 65 years. Academic and other sources were searched for comparative reports. Results: An estimated 18% of RAC residents died in acute hospital in NZ. When added to those who died in RAC, the proportion using RAC for late‐life care was estimated at over 47% (66% if aged 85+ years). Of 12 US reports, the median report was 41%. Elsewhere, Finland was 47%, UK 28%, Australia 34% to 53%, and Germany 22% & 26%. Conclusions: Simple estimation using existing data demonstrates that RAC in late life is common. Implications: Late‐life care services will continue to evolve. Monitoring RAC utilisation is necessary for informed debate about palliative care provision in RAC, use of hospital by RAC residents and for planning and policy setting.     

Outcomes of pregnancy in women with tetralogy of Fallot

OBJECTIVES: We sought to determine pregnancy outcomes in patients with tetralogy of Fallot (TOF). BACKGROUND: Pregnancy outcomes in patients with TOF are incompletely defined. METHODS: Clinical, hemodynamic, and obstetric data were reviewed for women with TOF and prior pregnancy. RESULTS: Of 72 respondents, 43 (mean age, 26 years) had 112 pregnancies (range, 1 to 5); 82 pregnancies were successful. Eight women had unrepaired TOF at the time of their 20 successful pregnancies. At first assessment (age > or =18 years), six patients had pulmonary hypertension, three had moderate or severe right ventricular (RV) systolic dysfunction, and 13 had severe RV dilation due to pulmonic regurgitation. Sixteen patients had 30 miscarriages (27%) and one term stillbirth. Mean overall birth weight was 3.2 kg (range, 2.1 to 4.2 kg). Unrepaired TOF (p = 0.05) and morphologic pulmonary artery abnormality (p = 0.03) were independently predictive of infant birth weight. Six patients had cardiovascular complications during pregnancy: supraventricular tachycardia in two, heart failure in two, pulmonary embolism in a patient with pulmonary hypertension, and progressive RV dilation in a patient with severe pulmonic regurgitation. Five infants (6%) had congenital anomalies. CONCLUSIONS: Patients with TOF have an increased risk of fetal loss, and their offspring are more likely to have congenital anomalies than offspring in the general population. Adverse maternal events, although rare, may be associated with left ventricular dysfunction, severe pulmonary hypertension, and severe pulmonic regurgitation with RV dysfunction.