Increased renal production of transforming growth factor-beta1 in patients with type II diabetes.

Diabetic nephropathy is a common complication in patients with either type I or type II diabetes. The pathogenesis of diabetic nephropathy is thought to involve both metabolic and vascular factors leading to chronic accumulation of glomerular mesangial matrix. In this context, both transforming growth factor-beta (TGF-beta) and endothelin may contribute to these processes. To determine if diabetic patients demonstrate increased renal production of TGF-beta and endothelin, aortic, renal vein, and urinary levels of these factors were measured in 14 type II diabetic patients and 11 nondiabetic patients who were undergoing elective cardiac catheterization. Renal blood flow was measured in all patients to calculate net mass balance across the kidney. Diabetic patients demonstrated net renal production of immunoreactive TGF-beta1 (830 +/- 429 ng/min [mean +/- SE]), whereas nondiabetic patients demonstrated net renal extraction of circulating TGF-beta1 (-3479 +/- 1010 ng/min, P < 0.001). Urinary levels of bioassayable TGF-beta were also significantly increased in diabetic patients compared with nondiabetic patients (2.435 +/- 0.385 vs. 0.569 +/- 0.190 ng/mg creatinine, respectively; P < 0.001). Renal production of immunoreactive endothelin was not significantly increased in diabetic patients. In summary, type II diabetes is associated with enhanced net renal production of TGF-beta1, whereas nondiabetic patients exhibit net renal extraction of circulating TGF-beta1. Increased renal TGF-beta production may be an important manifestation of diabetic kidney disease.

Sensitivity of isovolumic relaxation to hypothermia during myocardial infarction.

Effects of moderate spontaneous hypothermia on left ventricular systolic and diastolic function during acute myocardial infarction were documented in 17 anesthetized dogs with micromanometric pressure and ventriculographic dimension recordings acquired at baseline and at 1 and 3 h after coronary occlusion. In Group 1 (n = 5), core temperature was allowed to decline spontaneously. In Groups 2 (n = 6) and 3 (n = 6), core temperature was maintained at normothermic levels. Hypothermia impaired isovolumic relaxation markedly despite its lack of effect on ventricular volumes or ejection fraction. At 32.3 degrees C, tau 1/2, defined as the time needed for the left ventricular pressure at the time of peak negative rate of change of left ventricular pressure (dP/dt) to fall by 50%, was increased by 129% 3 h after occlusion. In addition, at this temperature significant changes were found in heart rate, cardiac output, minute work, peak positive and peak negative dP/dt, systolic ejection time, mean velocity of circumferential fiber shortening, mean aortic pressure and end-diastolic pressure. Thus, hypothermia evolving under conditions of general anesthesia profoundly alters left ventricular function in the setting of acute myocardial infarction, a phenomenon that requires consideration and control in studies of myocardial ischemia and left ventricular function in experimental animals.

Diastolic stiffening induced by acute myocardial infarction is reduced by early reperfusion.

Reperfusion early during myocardial infarction improves ejection fraction and this improvement may represent myocardial salvage in the injured segment. Alternatively, reperfusion of injured myocardium may cause intramyocardial hemorrhage with resultant increased stiffness causing a dyskinetic segment to become akinetic, thus improving ejection fraction without concomitant myocardial salvage. To evaluate this possibility, diastolic stiffness was assessed in a closed chest, anesthetized, normothermic dog model immediately after a 1 or 3 h occlusion of the left anterior descending coronary artery and during the 4 weeks after occlusion. Acute myocardial infarction in experimental dogs was accompanied by a fivefold increase in the chamber stiffness constant, a threefold increase in the myocardial stiffness constant and a significant increase in elastic stiffness and end-diastolic pressure. These changes occurred contemporaneously with a marked decline in ejection fraction. Early reperfusion (1 h occlusion) resulted in improvement of the ejection fraction accompanied by simultaneous resolution of the previously increased stiffness. Late reperfusion (3 h occlusion) resulted in permanent depression of ejection fraction with permanent elevation of stiffness. These results indicate that the improved systolic function observed after early reperfusion reflects a process other than increased stiffness, perhaps salvage of jeopardized myocardium.

Antithrombin activity during the period of percutaneous coronary revascularization: relation to heparin use, thrombotic complications and restenosis.

OBJECTIVES: This study evaluated changes in antithrombin (AT) activity around the time of percutaneous transluminal coronary revascularization (PTCR) with unfractionated heparin anticoagulation and the effects these changes had on major thrombotic complications of PTCR. BACKGROUND: Heparin is used during PTCR to prevent thrombosis. However, heparin, a cofactor for AT, causes AT activity to fall. AT activity <70% is associated with thrombosis. There is a prothrombotic state after heparin discontinuation that has not been well explained. METHODS: Antithrombin activity was sampled at the start and end of PTCR and the next two mornings in 250 consecutive patients. We recorded occurrence of major thrombotic events, defined as 1) major thrombotic complications of PTCR; 2) major in-lab thrombus formation; or 3) subacute occlusion. Discriminant analysis was employed to evaluate the relationship of AT activity to these events. Change in AT activity and its relationship to heparin was evaluated. Evidence of restenosis at six months was obtained. RESULTS: There were 14 major thrombotic events. Antithrombin activity <70% was strongly (p = 0.006) associated with these events. The AT activity fell significantly through the morning after PTCR when 21% of patients had AT activity <70%; AT activity did not normalize until >20 h after heparin discontinuation. Pre-PTCR use of heparin led to lower AT activity in proportion to duration of heparin use. There was no relationship between AT activity and restenosis. CONCLUSIONS: Low AT activity may contribute to major thrombotic complications of PTCR. The way heparin is used before and after PTCR is important to development of low AT activity.

Coronary artery ectasia associated with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) is characterized by a variety of cutaneous, mucosal, and visceral vascular anomalies. A patient with classic hereditary hemorrhagic telangiectasia was shown to have three-vessel coronary artery ectasia without evident atherosclerosis, and association not previously demonstrated. The possibility that coronary artery ectasia may be a manifestation of hereditary hemorrhagic telangiectasia is discussed.

Factor V Leiden and prothrombin gene G 20210 A variant in children with ischemic stroke.

OBJECTIVE: To investigate if the factor V Leiden mutation (F-V-LM) and/or the prothrombin gene G 20210 A variant (P-G20210A-V) are risk factors for acute stroke in Austrian children. PATIENTS: 33 children with acute ischemic stroke documented by computer tomography and/or magnetic resonance imaging of the brain were enrolled in an open multicenter survey. RESULTS: 6/33 children had F-V-LM (5 heterozygous, 1 homozygous). This represents 18% (95% CI: 6.7-39.9%) of our pediatric stroke population and thus exceeds the expected prevalence in the Austrian population of 4,6% (Fischer's exact test, p = 0.01). F-V-LM was not found in 11 children with neonatal stroke but in 6/22 children with stroke after the neonatal period. 5/6 children with F-V-LM had an underlying disorder that is a risk factor for stroke in children. The P-G20210A-V was detected in 1/26 (3.85%; 95% CI: 0.1-21.4%) patients. Comparison of the prevalence of P-G20210A-V in our study with that in the general population of Austria of 1% revealed no statistical significance (Fischer's exact test, p = 0.38). CONCLUSION: Our data suggest that the F-V-LM is a risk factor for acute stroke in Austrian children beyond the neonatal period. The P-G20210A-V apparently does not represent a risk factor for stroke in Austrian children.

Improvement in early diastolic filling dynamics after aortic valve replacement.

With use of ultrafast computed tomography, 13 patients undergoing aortic valve replacement for aortic stenosis were prospectively followed to evaluate the relation between left ventricular mass and diastolic function. Studies were done before intervention, and then at 4 and 8 months later. Mass decreased from 161 +/- 11 g/m2 (+/- standard error of the mean) at baseline to 106 +/- 5 g/m2, and then to 97 +/- 7 g/m2 at 4 and 8 months, respectively, in 12 patients who demonstrated significant (greater than 20%) mass regression after operation. One patient failed to show significant changes in mass. Diastolic function, as defined by the peak filling rate of early diastole, improved (p less than 0.02) in the group with mass regression, from 2.11 +/- 0.17 s-1 at baseline to 2.12 +/- 0.23 s-1, and then to 2.62 +/- 0.26 s-1 at 4 and 8 months, respectively. Improvement in the time to peak filling rate was also noted. Heart rates were unchanged, whereas end-diastolic volumes decreased and ejection fractions increased slightly. Postoperative increase in peak filling rate correlated with regression of ventricular mass to within normal range (+/- 2 standard deviations) and attainment of New York Heart Association class I status by 8 months (p less than 0.02). Thus, improvement in diastolic function can be seen after aortic valve surgery and is associated with improved functional class. Diastolic function improves later than the regression in wall mass and may imply a delayed remodeling of the ventricle.

Expected hemoglobin decrease following percutaneous transluminal coronary angioplasty.

To establish expected changes in hemoglobin during and after percutaneous transluminal coronary angioplasty (PTCA), we measured hemoglobin before, at the end of, and on the 2 mornings after PTCA in 177 consecutive patients without obvious out-of-laboratory blood loss. From these data, we calculated confidence intervals that can be used to compare group data, possibly to identify excessive blood loss with new devices or antithrombotic agents, and prediction intervals to identify unexpected blood loss in an individual patient.

Frequency of low-grade residual coronary stenosis after thrombolysis during acute myocardial infarction.

The clinical, angiographic and demographic characteristics of 42 patients with low-grade (less than 50%) residual stenosis at the infarct lesion after thrombolysis for acute myocardial infarction (MI) were assessed. The study group (group I) represented 21% of 198 consecutive patients receiving thrombolytic therapy over a 59-month period. Data on the 156 remaining patients were pooled for comparison (group II). Group I patients were predominantly men (86%) who were cigarette smokers (81%). Group II patients were predominantly men (75%, p greater than 0.10) but were significantly older (52 +/- 12 vs 56 +/- 10 years, p = 0.02). Prior acute MI or angina was unusual in group I. Sixty percent had no significant (greater than 50%) residual coronary artery disease while 25% had residual single artery disease. Average significant (greater than 50% diameter stenosis) residual vessel disease was 0.6 +/- 1.0 for group I and 1.9 +/- 0.9 for group II (p less than 0.001). In group I, average residual infarct lesion diameter stenosis was 36 +/- 7% in the right anterior oblique and 34 +/- 8% in the left anterior oblique views. Thirty-nine group I patients were discharged with medical therapy and 100% follow-up was obtained over a mean interval of 18 +/- 17 months. Fifteen patients experienced chest pain after acute MI accounting for 17 discrete events. Fifty-nine percent of group I had a benign course on follow-up. Eight events were classified as unstable angina, 4 as acute MI and 5 as atypical angina. Documented coronary vasospasm occurred in 3.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial infarct artery patency and reocclusion rates after treatment with duteplase at the dose used in the International Study of Infarct Survival-3. Burroughs Wellcome Study Group.

Duteplase, 98% double-chain recombinant tissue-type plasminogen activator, was administered intravenously in 488 patients with acute myocardial infarction in a multicenter, open, safety and patency study. Duteplase dosing was based on body weight. Duteplase was administered as a bolus of 0.04 MIU/kg of thrombolytic activity followed by 0.36 MIU/kg over 1 hour and 0.067 MIU/kg/hour for 3 additional hours. The patency rate of the infarct-related artery at 90 minutes was 69% (330 of 478). The reocclusion rate at 3 to 48 hours was 6% (18 of 301). Reinfarction occurred in 7.6% of patients (37 of 488), but 12 reinfarctions occurred after coronary angioplasty. Serious bleeding occurred in 7.6% of patients (37 of 488), predominantly at the catheterization entry site. There were 3 instances of central nervous system bleeding, 1 fatal. Fibrinogen levels declined to 83% of baseline at 24 hours. Weight-based dosing may explain the low incidence of serious bleeding in this study. The in-hospital mortality was 6.6% (32 of 488). This study documents that the dose of duteplase used in the International Study of Infarct Survival-3 results in a 90-minute coronary artery patency rate and safety profile comparable to those reported in published studies on the approved dose of alteplase.

Peripheral hemodynamic effects of intraventricular and intracoronary contrast media in man.

The effects of intraventricular and intracoronary contrast media on the peripheral arterial and venous beds were directly measured with forearm plethysmography. Standard dose intraventricular radiographic contrast produces a potent peripheral arterial vasodilator effect accompanied by a hypotensive and tachycardic response, followed by peripheral venoconstriction, suggesting that the net hemodynamic response is mediated peripherally. Coronary arteriography is associated with a differing pattern of response, suggesting that the most important hemodynamic effects are mediated via myocardial depression with secondary peripheral vascular responses. Hemodynamic changes occur earlier than those following ventriculography and reflect peripheral arterial and venous constriction. Dose and osmolarity of the contrast are important determinants as well as the site of administration.

Adverse effects of calcium binding contrast agents in diagnostic cardiac angiography. A comparison between formulations with and without calcium binding additives.

RATIONALE AND OBJECTIVES: The authors compared complications and hemodynamic and electrophysiologic effects of two formulations of diatrizoate, one with additives that bind calcium and one without, in diagnostic cardiac angiography. METHODS: Two hundred twenty-three consecutive low-risk patients alternately received Hypaque 76 (group 1, little calcium binding effect), and MD 76 (group 2, significant calcium binding). Electrocardiographic and hemodynamic changes related to coronary angiography and left ventriculography were measured, and complications requiring treatment were recorded. RESULTS: There were more complications in patients in group 2 than in group 1 (18 versus 8, P = 0.04). Arterial pressure fell more, the QT interval increased more, and the heart rate fell more in group 2 after coronary angiography. CONCLUSIONS: Formulations of diatrizoate that minimize calcium binding are advocated for cardiac angiography when using high osmolality contrast media. The more detrimental effects that calcium binding has on myocardial function and cardiac conduction may lead to the higher incidence of complications.

Practical implications of circadian variations in thrombolytic and antithrombotic activities.

It recently has been demonstrated that thrombolytic therapy has circadian pattern of efficacy, as assessed by the ability to rapidly provide coronary patency. A study of 692 patients receiving intravenous tPA and undergoing acute coronary arteriography demonstrated a substantial diurnal pattern in patency with a peak at 8:00 pm. The heightened tendency for a coronary artery to be opened in the evening correlates well with the substantial tendency demonstrated in the same study and in multiple other studies for coronary arteries to thrombose and cause myocardial infarction in the morning hours. Circadian variations have been defined for a number of hemostatic and physiologic factors that would predispose toward clotting in the late morning, and converse circadian patterns have been described for a number of factors associated with thrombolysis that would predispose towards enhanced fibrinolysis in the evening hours. Methods by which efficacy of lytic therapy potentially could be enhanced include development of tPA variants or adjunctive agents that eliminate the circadian nadirs of efficacy, modification of dosage or choice of lytic agent as a function of time of treatment, and selection between pharmacologic lysis and direct angioplasty as a function of time of day.

Mycobacterium gordonae as a human hepato-peritoneal pathogen, with a review of the literature.

Mycobacterium gordonae was cultured from the liver of a 39-year-old woman who presented with ascites, weight loss, and fever. Laparoscopic examination revealed white nodules studding the peritoneum and liver surface, and histopathology revealed caseating granulomas. She was successfully treated with rifampin, ethambutol, and isoniazid. A review of the literature on M. gordonae as a human pathogen in presented. Our patient represents the third reported case of disseminated disease due to this organism and the first to be successfully treated by medical therapy alone.

Dose-ranging study with a new two-chain rt-PA in patients with acute myocardial infarction: a multicenter trial.

Tissue-type plasminogen activator (t-PA) derived from a melanoma cell line was first used in patients with acute myocardial infarction in the early 1980s. Recombinant DNA technology then allowed production of large amounts of t-PA. The TIMI-I trial used a two-chain recombinant (rt-PA) product. A predominantly single-chain rt-PA (alteplase) was used in the majority of the TIMI II trial. The present study used a different form of two-chain rt-PA (duteplase) to determine the effective dose for thrombolysis at 60 min, and to evaluate time to reperfusion, reocclusion at 72-96 h, coagulation profiles, and bleeding events. Duteplase was given intravenously to 75 patients a mean of 3.8 +/- 1 h after the onset of myocardial infarction. Following angiography demonstrating coronary occlusion, 23 patients received a low dose of duteplase [0.16-0.29 million international units per kilogram (MIU/kg)] over 60 min followed by a 5-h infusion in conjunction with heparin, 25 patients received a middle dose (0.30-0.41 MIU/kg) and 23 patients received a high dose (0.43-0.74 MIU/kg). Angiography was then performed every 15 min x 4. Progressive recanalization occurred over 60 min (median 45 min) with an overall success rate of 59% (mean 60-min dose: 0.37 MIU/kg). No dose-response relationship was observed. The reocclusion rate was 9% at 72-96 h. Reductions in fibrinogen and plasminogen correlated with dose, but clinical events did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical, cytogenetic and molecular analysis of three 46,XX males.

Cytogenetic analysis, fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) were applied to characterize the Y-chromosomal breakpoints of three XX male patients. Two of these patients show a breakpoint within a protein kinase gene, PRKY, previously described as a hotspot of ectopic recombination between homologous regions on X and Y chromosomes during male meiosis. The slightly different clinical phenotypes of the three patients cannot be correlated with the localization of the breakpoints.

Tritium intake by exposure to plastic case watches.

In recent years tritium has been used in plastic case watches as permanent light sources on watch dials. To measure the release of tritium through the plastic cases, 82 different waterproofed watches were immersed in a water bath for 24 h, and the tritium concentration of the water was measured. The mean tritium release rate was 24,400 Bq d(-1) ranging from 110-162,000 Bq d(-1). Parallel measurements were made to determine the tritium concentration in the urine of 108 wearers of plastic case watches. The mean tritium concentration in urine was 197 Bq L(-1) up to 1,133 Bq L(-1). The whole body dose resulting from exposure to plastic case is negligibly small but given the pathway of skin absorption, the annual skin dose is 3-4 times higher than the dose limit for the public. Plastic case watches are collector's items and are often kept with other watches in glass cabinets or other containers. Storage of a large number of such watches in one container causes tritium to diffuse through the plastic cases and to contaminate watches that did not contain tritium at first. If the container is more or less airtight, the tritium concentration in the container and the tritium release rate from the watches can reach levels up to 4 MBq d(-1).