Severe factor VIII and factor IX deficiency in females.

A survey of 11 hemophilia centers produced data concerning 28 females with extremely low levels of factor VIII or IX coagulant activity. Ten of the 28 have hemophilia A, six have hemophilia B, and 12 have severe von Willebrand's disease. The 16 females who have severe factor VIII or factor IX deficiency as an isolated defect exemplify several of the possible genetic explanations for the occurrence of hemophilia in females. All 16 bruise excessively, and several have had recurrent hemarthroses. Three of these girls, ages five, 10 and 23 years, have evidence of chronic hemophilic arthropathy. The 12 females with severe von Willebrand's disease are either homozygous for von Willebrand's disease or severely affected heterozygotes. All 12 have mucous membrane bleeding. In addition, five of the 12 have recurrent hemarthroses and three have evidence of chronic joint disease. However, the major problem in the adult females with von Willebrand's disease has been extreme menorrhagia. One of the seven adults underwent irradiation sterilization and another had a hysterectomy because of menorrhagia. The others have been managed with anovulatory drugs or plasma infusions and EACA. Despite menorrhagia, five pregnancies and deliveries have been uneventful in three of these women.     

Metabolic basis for disorders of purine nucleotide degradation

Purine nucleotide degradation refers to a regulated series of reactions by which human purine ribonucleotides and deoxyribonucleotides are degraded to uric acid in humans. Two major types of disorders occur in this pathway. A block of degradation occurs with syndromes involving immune deficiency, myopathy or renal calculi. Increased degradation of nucleotides occurs with syndromes characterized by hyperuricemia and gout, renal calculi, anemia or acute hypoxia. Management of disorders of purine nucleotide degradation is dependent upon modifying the specific molecular pathology underlying each disease state.     

Assessment of potentially salvageable myocardium during acute myocardial infarction: use of postextrasystolic potentiation

Twenty-three patients with evolving acute myocardial infarction (AMI) undergoing catheterization for thrombolytic therapy had interventional contrast ventriculography using programmed atrial stimulation. Postextrasystolic (PES) potentiation was present in 67% of infarct-related segments up to 9 hours after the onset of AMI. The presence of segmental potentiation was not related to time from onset of pain to ventriculography, initial ejection fraction, presence of collaterals, left ventricular end-diastolic pressure or the PES delay. In 18 patients reperfusion was successful using intracoronary streptokinase an average of 6.2 hours after the onset of AMI; in these patients repeat contrast ventriculography was performed an average of 11 days after AMI. Improved chronic segmental ventricular function was predicted by the presence of collaterals to the infarct-related artery at the time of acute catheterization (p = 0.02), but was best predicted by analysis of acute PES potentiation (p less than 0.0001). The predictive value of PES analysis was highest in segments without collaterals. Thus, atrial stimulation is safe during AMI and analysis of segmental ventricular function shows potentially viable myocardium up to 9 hours after the onset of AMI. In addition, analysis of PES segmental function can predict chronic function if reperfusion is successful, especially in segments without collaterals. PES ventriculographic analysis may allow prospective determination of which patients during AMI are most likely to benefit from acute thrombolytic therapy.     

Reversal of progressive, life-threatening gold hypersensitivity pneumonitis by corticosteroids

Hypersensitivity pneumonitis secondary to gold therapy has been described in only a limited number of patients. The clinical presentation is variable and optimal therapy is not well established. Two patients presenting with life-threatening respiratory insufficiency that progressed despite discontinuation of gold therapy are described. Dramatic improvement occurred following corticosteroid administration. Review of previously reported cases shows corticosteroid therapy to be efficacious. Patients with gold hypersensitivity pneumonitis may have a fulminant course and many require corticosteroids for relief.     

Two-dimensional echocardiographic determination of aortic and pulmonary artery sizes from infancy to adulthood in normal subjects

The aorta, right pulmonary artery and pulmonary trunk were measured from the 2-dimensional echocardiogram (2?D echo) of 110 normal subjects aged 1 day to 18 years. The vessel diameters were measured from the parasternal short-axis view, the suprasternal long-axis view and the suprasternal short-axis view. Measurements were made at end-systole and at end-diastole and in both an axial and lateral direction where possible. When analyzed with respect to body surface area (BSA), the echocardiographic measurements were linearly related to the square root of the BSA, and there was inequality of variance around the relation. To establish a range of normal values for each vessel dimension, a weighted regression analysis was used to produce estimates of the regression line and a set of tolerance intervals. The systolic vessel dimension was larger than the diastolic vessel dimension and the measurement of a vessel in an axial direction was larger than the measurement of the same vessel in a lateral direction. In general, when a vessel was measured in several views, the largest diameter was obtained using the view that imaged the vessel in cross section. These data on normal values for the echocardiographic measurement of the aorta and pulmonary arteries at different BSAs should be useful for identifying patients with abnormalities in arterial size and for the serial assessment of arterial size in children who have undergone surgical or medical therapy.     

Use of balloon angioplasty to treat peripheral pulmonary stenosis

Balloon angioplasty was attempted in 13 children with peripheral pulmonary arterial (PA) stenosis. In 5 patients, angioplasty was successful in relieving the peripheral PA stenosis as judged by an increase in PA size of more than 75% over the predilatation size and a more than 50% reduction in the distal PA to main PA peak systolic pressure gradient. Each child has been followed for 6 to 30 months. All remain well, without signs of subsequent deterioration, and follow-up angiograms in 2 patients (at 10 and 12 months) showed persistence of anatomic and hemodynamic improvement. In 8 patients, angioplasty was unsuccessful: In 4 patients, stenosis at the site of a previous systemic-to-PA shunt could not be dilated and in 4 patients, angioplasty could not be performed because of technical difficulties. Thus, we could not dilate the stenosis in more than 60% of the patients; we also had a significant complication with the angioplasty procedure (perforation of a distal branch of the right pulmonary artery). Thus, although balloon angioplasty was not effective in all patients, it did provide significant improvement in some patients in whom traditional operative management is usually unsuccessful.     

Secretion of pancreatic polypeptide in man in response to beef ingestion is mediated in part by an extravagal cholinergic mechanism

The effect of atropine, a muscarinic cholinergic blocking agent, on the response of plasma pancreatic polypeptide (hPP) to the ingestion of beef was investigated. Six healthy subjects ingested 250 g broiled ground beef on three occasions. After beef ingestion alone, the expected biphasic plasma hPP response was observed. On the two other occasions atropine (intravenous bolus followed by infusion) was begun either at 4 or 60 min after the beginning of beef ingestion so as to coincide with the early (first) and late (second) phases of hPP response to beef ingestion. On both occasions plasma hPP concentrations returned rapidly to baseline. Mean integrated incremental hPP responses in the absence of atropine were 9.1 +/- 3.4 ng min ml-1 for the first phase (0-40 min) and 29.7 +/- 5.7 ng min ml-1 for the second phase (60-180 min); with atropine at 4 min, respective responses were 0.8 +/- 0.9 and -1.0 +/- 1.3 ng min ml,-1 and with atropine at 60 min they were 10.6 +/- 5.0 and 1.3 +/- 1.6 ng min ml.-1 After atropine administration, the half-time of disappearance of hPP from the circulation was 4-6 min, suggesting the complete cessation of stimulated hPP secretion. We conclude that the mechanisms of both the early and late phases of beef meal-stimulated release of hPP involve muscarinic cholinergic-neural transmission. The portion of the second (late) phase response which has been shown to persist after truncal vagotomy must be mediated by a cholinergic mechanism which is extravagal in character.     

Atrial pacing for cardioversion of atrial flutter in digitalized patients

To test the safety and reliability of atrial pacing as a conversion technique in patients with atrial flutter who are receiving digitalis therapy, atrial pacing conversion was attempted for 49 episodes of atrial flutter in 32 consecutive patients. All patients except one were receiving digitalis. To control ventricular rates most patients had received larger than usual therapeutic doses of digitalis glycoside before pacing. Fourteen of the 25 patients whose serum levels were measured had glycoside concentrations greater than 2 ng/ml. Before atrial pacing the mean atrial and ventricular rates were, respectively, 290 +/- 20.6 and 134 +/- 27.9/min (mean +/- standard deviation). Successful rhythm conversion was achieved on 48 occasions (98%) in 31 patients. One patient required transthoracic direct current synchronized countershock cardioversion. With atrial pacing, the atrial flutter rhythm reverted immediately to sinus mechanism in 23 instances, and there were 25 episodes of atrial fibrillation. Among those who experienced atrial fibrillation, the rhythm spontaneously reverted to sinus mechanism within 24 hours on 14 occasions; on 11 occasions; the rhythm reverted to atrial flutter and repeat pacing was required. Sinus mechanism was eventually established in all 31 patients.     

Effect of minoxidil on blood pressure and hemodynamics in severe hypertension

Eighteen patients with diastolic hypertension (100 to 120 mm Hg), in addition to propranolol, 160 mg daily, and hydrochlorothiazide, 100 mg daily, received progressively increased doses of either minoxidil or placebo in a double-blind crossover study. With minoxidil (average dose 19.7 mg) blood pressure decreased from 165/109 to 138/89 mm Hg without the appearance of orthostatic hypotension. Hypertrichosis and fluid retention did occur, with an average weight gain of 1.8 kg, concomitant with an increased plasma volume. Pulse rate and cardiac output increased; no significant changes were observed in plasma renin activity, renal plasma flow, glomerular filtration rate or excretion of catecholamines or aldosterone. Minoxidil appears to be a useful antihypertensive drug for treating patients who do not respond adequately to therapy with diuretic and beta adrenergic blocking agents.     

R-wave amplitude changes during exercise in adolescents with left ventricular pressure and volume overload

To determine the diagnostic value of exerciseinduced R-wave changes in adolescents with congenital heart disease, the responses of 50 adolescents without significant heart disease were compared with those of 72 patients with either a left ventricular (LV) pressure or volume overload lesion. Among the pressure overload group, 24 patients had valvular aortic stenosis (AS) and 27 had coarctation of the aorta. The volume overload group included 12 patients with mitral regurgitation (MR) and 9 with aortic regurgitation (AR). Severity of the cardiac lesion was assessed using cardiac catheterization in patients with AS, physical examination in patients with coarctation of the aorta and clinical or angiographiec criteria, or both, in patients with valvular regurgitation. The R wave was measured in 10 consecutive QRS complexes in leads II, aVF and V₅ at rest, maximal exercise and 1-minute recovery. At maximal exercise, control subjects had a mean decrease in amplitude (ΔR) of ?3.6 mm (p < 0.0001). Compared with the control group, the AS group had a similar decrease of ?3.5 mm, but the coarctation group had a ΔR of ?1.4 (p < 0.005) and the volume overload group a ΔR of ?1.1 mm (p < 0.003). Patients with AS and ischemic ST-segment changes during exercise (n = 12) had greater decreases in R-wave amplitude than did those with no ST changes (n = 12) (p < 0.04). In patients with AS and an LV end-diastolic pressure ? 12 mm Hg (n = 7), the decrease in ΔR was also greater than that in patients with LV end-diastolic pressure ≤ 12 mm Hg (n = 14) (p < 0.006). Among patients with volume overload, more severe valvular regurgitation was associated with a smaller ΔR (p < 0.03). In patients with AS an increased ΔR reflects ischemia or diminished LV compliance, or both, whereas in patients with volume overload a decrease in ΔR is an indicator of the severity of regurgitation.     

Suppression of insulin secretion by protein deprivation in obesity.

The effect of low protein diets on insulin levels was studied in 17 obese, nondiabetic hyperinsulinemic subjects. Their mean weight was 271% of ideal weight. Nine patients were fed a weight-maintaining 3700-calorie diet for 14 days; this diet contained 398 g carbohydrate and 170 g protein. The patients were then fed an isocaloric diet containing only 6 g protein and 587 g carbohydrate for 14 more days. Mean basal insulin levels decreased from 50.4 to 34.7 μU/ml. This decrease was accompanied by a significant decrease in mean plasma glucose. In seven patients who were fed the low-protein diet after a 4-day period of total fast, the low-protein diet prevented the recovery of basal insulin levels decreased during fasting. These findings were in contrast to the apparent recovery of basal insulin levels observed when the control rather than the low-protein diet was refed in 4 patients following a fast. The suppression of basal insulin levels by protein deprivation was not correlated with changes in plasma glucose, glucagon, urinary 17-hydroxycorticoids, or body weight. Although urinary 17-hydroxycorticoids and free cortisol decreased significantly on protein-restricted diets, treatment with cortisol did not prevent the effect of protein deprivation on basal insulin and glucose levels. Plasma levels of branched chain amino acids (valine, leucine, and isoleucine) decreased in parallel to insulin levels on the isocaloric low-protein diets. We conclude that protein-restricted diets can decrease basal plasma insulin levels in obesity even in the presence of sufficient calories to maintain weight and high carbohydrate content. Of the factors investigated that may account for this phenomenon, it is unlikely that glucagon, glucose, or cortisol play a direct role. It is possible that protein as well as carbohydrate plays a role in the development of hyperinsulinemia and insulin resistance in obesity.     

Virilizing syndrome associated with an adrenal cortical adenoma secreting predominantly testosterone.

A 22 year old woman had virilization and mild Cushing's syndrome. Serum testosterone levels were high (3.2 ng/ml), urinary 17-ketosteroid levels slightly elevated (17.5 mg/d) and plasma cortisol at 16:00 hours normal (7.2 μg/dl). Basal level of cortisol secretion was normal but with evidence of autonomy. An abnormal adrenal scan led to an adrenal venogram showing a tumor image in the left adrenal gland. Selective adrenal venous catheterization indicated that the tumor was secreting testosterone and cortisol; left/right adrenal venous values were $\text{53.5}\text{3.7}$ ng/ml for testosterone and $\text{92.8}\text{13.6}$ μg/dl for cortisol. Testosterone levels did not rise with human chorionic gonadotropin (hCG). The basal serum level of Δ₄ androstenedione was at the upper limit of normal and of 17 α-hydroxyprogesterone high. The patient underwent surgical removal of a well circumscribed, 19 g left adrenal adenoma. Values for serum testosterone, DHEA-S and 17β-estradiol (E₂) decreased markedly postoperatively. The in vivo biochemical findings were corroborated in vitro by incubation of tumor tissue slices and nontumorous adrenal cortex. The tumor was capable of secreting testosterone, cortisol, DHEA and E₂, but the capacity was greatest for testosterone, DHEA and E₂. Analysis of tissue homogenates also revealed the presence of testosterone, cortisol, DHEA and E₂. The pattern of steroid production suggests partial 21-hydroxylase deficiency and enhanced 17β-reductase activity.     

Evaluation of platelet reactivity in patients with valvular heart disease

Transmission electron microscopy with a standardized in vitro method was used to evaluate the degree of blood platelet reactivity in 72 normal subjects and 72 patients with valvular heart disease. Among the patients with abnormal natural heart valves, 51 had either aortic insufficiency or aortic stenosis, and 21 patients showed either mitral insufficiency or mitral stenosis. For normal subjects, the platelet differential counts were dominated by the dendritic type platelet, and only a few platelets showed cytoplasmic spreading between adjacent pseudopodia (spread type). A hyperactive response was defined as greater than 20% of the spread type platelet or more than 93 aggregates per 100 single platelets counted, or both. Only 6 (8%) of the 72 normal subjects showed hyperactive platelets. In contrast, 45 (62%) of the 72 patients with valvular heart disease had hyperactive platelets (p less than 0.01). For patients with abnormal valves, the mean percent of the spread type platelet was 35% with a mean value of 105 platelet aggregates. The increased level of platelet reactivity was independent of both the position of the valve (aortic versus mitral) and its functional status (insufficient versus stenotic). Disturbed flow and the exposure of subendothelial thrombus-producing materials are features associated with abnormal heart valves. These factors, which usually occur in combination, may explain the hyperactive platelet response found in these patients.