First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I.

OBJECTIVE: This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I. DESIGN: The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels. The active comparator rhIGF-I was administered at 50µg/kg subcutaneously twice daily for 4days. Safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 were evaluated. RESULTS: PEGylation resulted in long exposure to RO5046013 with a half-life of 140-200h. Exposure to RO5046013 increased approximately dose proportionally. RO5046013 was safe and well tolerated at all doses, injection site erythema after SC administration was the most frequent observed AE. No hypoglycemia occurred. Growth hormone (GH) secretion was almost completely suppressed with rhIGF-I administration, whereas RO5046013 caused only a modest decrease in GH at the highest dose given IV. CONCLUSIONS: PEGylation of IGF-I strongly enhances half-life, reduces the negative GH feedback and hypoglycemia potential, and therefore offers a valuable alternative to rhIGF-I in treatment of relevant diseases.

Persistent left superior vena cava and right superior vena cava drainage into the left atrium without arterial hypoxemia.

A 46 year old patient who presented with an acute myocardial infarction was discovered to have a systemic venous communication with the left heart during attempted insertion of a pulmonary flotation catheter. There was no evidence of cyanosis or systemic arterial desaturation. A right superior vena cava that emptied into the right superior pulmonary vein and a persistent left superior vena cava draining into the coronary sinus were confirmed pathologically after death related to a brain abscess. The embryology, physiology and noninvasive diagnostic approach to this unique venous anomaly are discussed.

Obstruction of right ventricular outflow tract caused by intracavitary metastatic disease: analysis of 14 cases.

Obstruction of the right ventricular outflow tract from metastatic disease is rare. Eleven previous case reports and three new cases are presented. Two tumor types (pancreas and breast), not previously associated with right ventricular outflow tract obstruction, are included. Congestive symptoms, systolic murmur and right axis deviation or right bundle branch conduction abnormality were universal features. Echocardiography is valuable in the delineation of metastatic cardiac involvement and the detection of intracardiac gradients. Adverse hemodynamic consequences developed in 3 of 10 patients who underwent right heart catheterization in which two died. This procedure should be performed only when absolutely necessary. Metastatic obstruction of the right ventricular outflow tract should be considered in the absence of widespread malignancy because the heart was the sole site of metastasis in 5 of 10 autopsy patients. Two patients with solitary cardiac metastasis benefited from resection of the obstructing tumor, underscoring the importance of early identification of this subgroup.

Local steroids in dialysis-associated pericardial effusion. A single intrapericardial administration of triamcinolone.

Five patients receiving maintenance hemodialysis for end-stage renal disease underwent therapeutic pericardiocentesis for pericarditis manifested by either cardiac tamponade or effusion unresponsive to conservative therapy. Pericardiocentesis was followed by a one-time instillation of triamcinolone hexacetonide, a nonabsorbable corticosteroid, into the pericardial space with subsequent needle withdrawal. All patients had prompt hemodynamic and symptomatic improvement. Serial echocardiograms showed resolution of the pericardial effusion in all patients. Follow-up evaluation for six months to six years has shown no clinical or postmortem evidence of recurrence. This procedure appears safe and effective and potentially can obviate the need for prolonged catheter drainage or more invasive surgical procedures as therapy for these patients.

Diagnosis of pericardial effusions from routine gated blood-pool imaging.

Gated blood-pool scintigraphy (GBPS) is often obtained as the initial test to evaluate symptoms suggestive of left ventricular dysfunction. Since large pericardial effusions may also cause such symptoms, the ability to recognize them on routine GBPS is of clinical importance. Characteristic features of the "halo" sign surrounding the cardiac blood pool were developed, based on the GBPS of patients with known pericardial effusions. These criteria were then applied blindly to 154 consecutive patients who underwent both GBPS and echocardiography. All five patients with large effusions (approximately greater than 500 ml) were correctly identified by GBPS (sensitivity 100%); for patients with moderate effusions (approximately 150-500 ml), the sensitivity was only 33% (3/9). There were three false positives (specificity 98%). We conclude that large pericardial effusions can be identified with high sensitivity and specificity on routine GBPS. Although echocardiography remains the method of choice for the diagnosis of effusions, inspection for characteristics suggesting their presence on GBPS should be part of routine interpretations.

Interval-dependent potentiation of left ventricular contractility is preserved in patients with atrial fibrillation and depressed ejection fraction.

Echocardiographic techniques were used to measure left ventricular isovolumic and ejection phase indexes of contractility in 54 patients with atrial fibrillation, and the relations between cycle lengths and contractility were compared in patients with normal and depressed ejection fractions. Data indicate that variations in contractility occur in a pattern that is consistent with postextrasystolic potentiation and that such interval-dependent potentiation is preserved in patients with atrial fibrillation and depressed ejection fraction.

Effect of rhythm regularization on left ventricular contractility in patients with atrial fibrillation.

In 10 patients with atrial fibrillation, echocardiographic measures of left ventricular function-interval relations were used to assess contractility and to test the hypothesis that rhythm regularization produces a higher contractile state than is seen when the rhythm is irregular. Regularization, following direct-current cardioversion, did not augment ventricular contractility above that seen during atrial fibrillation.

Interval-dependent changes in left ventricular contractile state in lone atrial fibrillation and in atrial fibrillation associated with coronary artery disease.

In atrial fibrillation (AF), beat-to-beat changes in left ventricular (LV) systolic performance are caused by variations in filling (preload), aortic pressure (afterload), and ventricular inotropic or contractile state. These factors are known to be influenced by the preceding diastolic or RR interval (RR1), but the independent impact of variations in the pre-preceding RR interval (RR2) on contractile state is not well defined. This aspect was studied in 10 patients with lone AF and 8 with coronary artery disease by measuring LV peak ejection velocity (V[pe] Doppler echocardiography) in 80 to 100 consecutive cardiac cycles. V(pe) was plotted against RR1 for beats with a short RR2 and for beats with a long RR2. Such function-interval plots indicate a direct relation between V(pe) and RR1 (for RR1 = 500 to 1,000 ms). In lone AF, the slope (linear fit) of V(pe) versus RR1 was similar for short and long RR2 (slopes = 46 and 50 s[-1]). V(pe), calculated from best linear fit and a common RR1, was consistently higher when RR2 was short than when it was long. At an RR1 = 750 ms, V(pe) (% of max) was 87 +/- 6% when RR2 was short versus 76 +/- 6% when RR2 was long, p <0.05. Results were similar in patients with coronary artery disease and the observed interval-dependent potentiation of contractile state was preserved in patients with a low ejection fraction. By comparing V(pe) at a common RR1, the effects of time-dependent changes in LV preload and afterload are minimized if not abolished. Thus, differences in V(pe) reflect differences in contractile state caused by variations in RR2. Data confirm interval-dependent alterations in contractile state that are likely an expression of the force-frequency relation. Studies of LV function in AF should incorporate a consideration of cycle length-dependent changes in LV contractile state.

Derivation of systolic time intervals from Doppler measurement of temporal arterial blood flow.

The carotid pulse method of recording systolic time intervals is limited by significant motion-induced artifact, making it unsuitable for studying patients during exercise. As an approach to overcoming this limitation, a new method utilizing the blood velocity profile of the superficial temporal artery measured by Doppler ultrasound has been developed. When compared with the values obtained from the conventional carotid pulse method, Doppler-derived left ventricular ejection time and preejection period showed excellent correlation (r = 0.99 for both) and the Doppler-derived measurements showed little intra- or interobserver variability. Studies performed during treadmill exercise showed that in 8 of 10 subjects, suitable tracing could be recorded through stage 3 of the Bruce protocol, confirming the enhanced stability of the technique compared with the carotid pulse method.

Comparison of determinants of myocardial oxygen consumption during arm and leg exercise in normal persons.

Arm exercise assumes an increasingly important role in clinical cardiology as it is used in both exercise testing and training of patients with coronary artery disease. The effects of arm exercise on myocardial oxygen consumption are not well understood; they may differ from the effects of leg exercise. Previous studies have shown that the ischemic threshold is higher in patients performing arm exercise and leg exercise at the same heart rate-blood pressure product. The contribution of other determinants of myocardial oxygen consumption--left ventricular (LV) peak meridional systolic wall stress and contractility--to these observed differences were studied. Thirty healthy subjects exercised to the same peak rate-pressure product during dynamic upper- and lower-extremity exercise. Peak workload was lower during arm exercise (100 +/- 16 W) than during leg exercise (170 +/- 21 W, p less than 0.001). LV wall stress did not differ during either form of exercise (197 +/- 44 vs 204 +/- 33 dynes/cm2 X 10(3), arm vs leg, respectively). This was also true of contractility as assessed by the velocity of circumferential fiber shortening (2.8 +/- 0.6 vs 2.5 +/- 0.4 circ/s, arm vs leg, respectively) and the preejection period/LV ejection time ratio (0.33 +/- 0.11 vs 0.31 +/- 0.07, arm vs leg, respectively). Normal subjects exercising to a similar rate-pressure product showed the same levels of LV wall stress and contractility for arm and leg exercise despite the lower workload performed with arm exercise.

Sensitivity and specificity of the echocardiographic features of cardiac amyloidosis.

Thirty-one patients with documented cardiac amyloidosis were compared to 39 control subjects with left ventricular hypertrophy to determine specific 2-dimensional echocardiographic features of amyloid. In 16 patients, increased myocardial echogenicity was present when a single short-axis view was examined, and had a sensitivity of 63% and a specificity of 74% for the diagnosis of amyloidosis. When complete echocardiograms were reviewed (15 patients), an improved sensitivity of 87% and specificity of 81% based on increased echogenicity was seen. Increased atrial septal thickness was present in 60% of amyloid patients and no controls. The combination of increased myocardial echogenicity and increased atrial thickness was 60% sensitive and 100% specific for the diagnosis of amyloidosis. The ratio of electrocardiographic voltage (S in V1 + R in V5 or V6) to left ventricular cross-sectional area also was examined. A ratio of less than 1.5 was 82% sensitive and 83% specific for amyloid (excluding the 2 patients with left bundle branch block), but added little to the diagnosis as determined from the 2-dimensional echocardiogram.

Pericardial pseudotumor. Echocardiographic observation of juxtacardiac pulmonary collapse.

Despite its value in the diagnosis of pericardial disease, two-dimensional echocardiography also is known to produce confounding results. Ten patients had juxtacardiac masses simulating pericardial tumor implants on echocardiographic examination ("pericardial pseudotumor") caused by juxtacardiac pulmonary atelectasis or lobar collapse. The atelectatic nature of these masses was based on echocardiographic delineation of pericardial and pleural anatomy, combined with ancillary radiographic and CT studies. Drainage of pleural fluid also led to disappearance of the masses on echocardiographic examination, suggesting that the masses were an ultrasonic manifestation of pulmonary atelectasis resulting from surrounding compressive effusive fluid. Finally, clinical follow-up failed to show development of malignant disease in any patient. The possibility of pericardial pseudotumor should be considered when ultrasound studies show juxtacardiac masses within large collections of pleural fluid, especially in the clinical absence of malignant disease.

ST-segment elevation during recovery from exercise. A new manifestation of Prinzmetal's variant angina.

Four patients underwent exercise testing because of a history of pain in the chest; all four developed marked elevation of the S-T segment only during recovery after exercise. Three of the four patients showed ST-segment depression during exercise, but ST-segment elevation was absent until two or more minutes after cessation of exercise. ST-segment elevation after exercise was accompanied by hypotension in three patients and by ventricular arrhythmias in one. Subsequent coronary angiographic studies revealed normal or minimally diseased coronary arteries in two patients and significant coronary lesions in the other two. Review of the literature shows that contrary to the prevailing belief, over half of the patients with Prinzmetal's variant angina have electrocardiographic changes diagnostic of ischemia during exercise testing. Over half of the patients with abnormal findings on tests during exercise display ST-segment elevation as a manifestation of ischemia; however, delayed ST-segment elevation of the type seen in these four patients is distinctly uncommon, having previously been described in only three individual case reports. The pathophysiology of this response is uncertain but may relate to rapid alterations in the autonomic balance during recovery after exercise.

Determinants of operative mortality and long-term survival in patients with unstable angina. The CASS experience.

To identify the factors that determine operative mortality and long-term survival, we analyzed the data from 3,311 patients who underwent surgical therapy for unstable angina according to clinical presentation. Overall operative mortality was 3.9% and no differences in operative mortality were found between patients with coronary insufficiency, new-onset angina, rest angina, or changing patterns of angina. Logistic regression analysis indicated that age, left ventricular score, and presence of a left main stenosis in a left dominant circulation were related to operative mortality. The 7 year cumulative survival rate was 79%. Features predictive of long-term outcome by Cox analysis included left ventricular score, congestive heart failure score, other illness, extent of coronary disease, and cardiomegaly. Operative mortality of those patients who underwent coronary bypass during their initial hospitalization with unstable angina was similar to that of patients who were discharged and readmitted for operation at a later date. Thus, patients with unstable angina demonstrate a relatively low operative mortality, which is unrelated to the clinical presentation. Long-term survival is primarily determined by clinical and angiographic markers of left ventricular dysfunction, associated illness, and the extent of coronary disease.

Effects of coronary revascularization on regional wall motion. An intraoperative two-dimensional echocardiographic study.

Although coronary artery bypass grafting effectively reduces the symptoms of myocardial ischemia, its immediate effect on regional wall motion dysfunction is not well defined. This intraoperative study was undertaken to determine whether bypass grafting improves regional wall motion in areas of preoperative ischemic dysfunction. In 17 patients undergoing coronary bypass, short-axis echocardiograms were obtained with the chest open 30 minutes before and after cardiopulmonary bypass. Regional wall motion was calculated quantitatively as the percent increase in segmental wall thickness during systole, with 40% thickening or less defined as indicating ischemic dysfunction. Qualitatively, it was evaluated by visual changes in endocardial wall motion according to a graded score (0 = normal to 4 = dyskinesia). Of the 136 segments studied, 44 (32%) had evidence of ischemic dysfunction before coronary bypass. When regional wall motion was analyzed in all 136 segments after coronary bypass, there was no significant change in either quantitative indices (62% +/- 7% before grafting versus 58% +/- 6% after grafting) or qualitative indices (0.19 +/- 0.06 versus 0.17 +/- 0.06). However, in those segments with ischemic dysfunction before grafting, there was a significant increase in quantitative indices of regional wall motion after grafting (24% +/- 2% versus 50% +/- 5%; p less than 0.02). By contrast, qualitative indices continued to show no significant improvement (1.3 +/- 0.1 versus 1.05 +/- 0.2). We conclude that coronary artery bypass grafting significantly improves areas of ischemic regional wall dysfunction. These changes can be difficult to detect with visual qualitative methods and are best analyzed by techniques assessing changes in segmental wall thickness.

The effect of cigarette smoking on the pattern of coronary atherosclerosis. A case-control study.

Cigarette smoking is a risk factor for development of coronary atherosclerosis. We examined the relationship between smoking and the anatomic location of coronary artery stenosis in 8,705 patients undergoing cardiac catheterization for suspected coronary artery disease (CAD). The smoking history of patients with CAD (greater than or equal to 70 percent stenosis) was compared with that of control subjects (0 percent stenosis) for each of nine anatomic locations (proximal, middle, and distal segments of right [RCA], anterior descending [LAD], and circumflex arteries [LCX]), using a case-control method. The odds ratio (OR) estimate of relative risk of CAD for smokers relative to nonsmokers was 2.8, with a 95 percent confidence interval (CI) of 2.5 to 3.1. Relative risk was greater for RCA stenosis (OR = 5.8; CI = 4.6-7.2) than for LCX (OR = 3.5; CI = 2.7-4.5) or LAD (OR = 2.1; CI = 1.8-2.4) lesions when comparing smokers with nonsmokers. After control for age, gender, history of diabetes mellitus, and serum cholesterol level, the adjusted relative risk for an RCA lesion (Mantel-Haenszel odds ratio [MOR] = 4.9) was significantly elevated (p less than 0.05) compared with the LAD (MOR = 1.9) but not with the LCX (MOR = 3.1). The relative risks of CAD were the same (p greater than 0.05) for the proximal, middle, and distal coronary segments. Thus, smoking increased the risk of all coronary lesions but did so more for the RCA than for other vessels, suggesting a spatial pattern to the increased risk produced by smoking.

Central nervous side effects following ifosfamide monotherapy of advanced renal carcinoma.

Ten patients with advanced renal carcinoma were treated by ifosfamide (50-60 mg/kd/day x 5 days). The treatment was repeated every 4 weeks and continued until progression appeared. Two patients came into partial remission, two had subjective improvement, and six did not respond. Seven patients developed acute psychopathological symptoms during the first ifosfamide-cycle. Five patients had visual and paranoid hallucinations, four patients were completely confused. Follow-up for up to 10 weeks showed a persisting organic brain syndrome in five patients.

Surgical therapy for Prinzmetal's variant angina.

Fifty-two patients underwent coronary artery bypass grafting between 1973 and 1979 for variant angina, defined as pain, usually at rest, associated with S-T segment elevation. Only patients with fixed occlusive coronary artery disease, defined as greater than 70% narrowing in diameter, were included. When fixed coronary artery stenosis is present, variant angina--whether presenting as stable, unstable, or postinfarction angina, and regardless of the number of vessels diseased--is effectively treated by myocardial revascularization. Preoperative intraaortic balloon pumping is a useful therapeutic adjunct in the unstable subset refractory to medical therapy. The results of revascularization in patients with Prinzmetal's variant angina and fixed coronary disease were no different from those in patients with classic angina pectoris of comparable clinical categories.

Objective assessment of resistance of female urethra to stress. A scale to establish degree of urethral incompetence.

During urethral pressure profile (UPP) studies under gradually increasing stress, the maximum urethral closure pressure decreases. This observation led to a simple urodynamic test which allows the estimation of the maximum stress (intensity of cough) tolerated by the urethra before leakage begins. The determination of this critical pressure forms the basis of the urethral incompetence scale. The urethra of a female patient can be characterized by the amplitude of this maximum stress (in cm H2O) the urethra can handle and still remain continent. The cough intensity scale has been divided into 5 segments, defining 5 degrees of urethral incompetence. The critical pressure, which determines the degree of urethral incompetence is a constant value for a given patient, provided the bladder volume is kept constant and the position of the patient during the examination is unchanged. This method establishes the functional status of the female urethra as far as its sphincteric capabilities are concerned under different stress conditions. It represents the degree of pressure transmission from the abdominal cavity to the proximal urethra during stress. It evaluates objectively the functional results of different surgical or medical therapeutic modalities to cure genuine stress incontinence. It allows a better selection of patients with unstable bladder and genuine stress incontinence who will more likely benefit from a retropubic cystourethropexy.

Penile gangrene: an unusual complication of priapism. How to avoid it?

A case of penile gangrene following priapism is reported. The 13 previously reported cases in the literature are reviewed. Avoidance of pressure dressing, local infection, and the use of urethral catheter should probably prevent this serious complication.