Humoral hypercalcemia of malignancy: A syndrome in search of a hormone

A woman with hypercalcemia and a hypernephroma confined to the left kidney underwent nephrectomy and subsequent resolution of hypercalcemia. Serum parathyroid hormone was undetectable in peripheral blood as well as in the left renal vein at surgery. Parathyroid hormone was also undetectable in the tumor extract using three different antisera to parathyroid hormone. Measurement of plasma prostaglandin E and 13,14-dihydro-15-keto-prostaglandin E₂ revealed levels within the normal range. The serum 1,25-dihydroxyvitamin D concentration was below normal and nephrogenous cyclic adenosine monophosphate was markedly elevated. The humoral agent responsible for hypercalcemia in this patient was not identified. This case emphasizes the need to search for new hypercalcemic factors in patients with hypercalcemia of malignancy.     

Spatial reconstruction of human femoral atheromas showing regression.

Reports of atherosclerotic changes in human subjects previously described have been based on evaluation of arteriographic edge contours. They imply unchanged roentgenographic and physiologic conditions, including identical patient positioning and vascular tone which cannot always be obtained in sequential studies. We have previously described the development of quantitative angiographic densitometry which permits measurement of vascular cross-sectional chord length distributions and areas, independent of rotational changes in vascular position. In this paper we report on application of the method to sequential femoral angiograms in two patients in whom there were significant increases in vascular cross-sectional area after a program of exercise and risk reduction. The method excludes interpretive errors due to circumferential changes in vascular tone.     

Neurogenic factors in low renin essential hypertension

The interrelationships between blood pressure, plasma catecholamines and plasma renin activity (PRA) were studied in 12 patients with low PRA, in 18 patients with essential hypertension and normal PRA and in 11 normal subjects, after being supine for 1 hour, standing 1 hour and after the oral administration of furosemide, 80 mg. Patients with low PRA were older and had higher (p < 0.05) mean blood pressure levels (113 ± 4.2 mg Hg) than patients with normal PRA (103 ± 1.9 mm Hg). Plasma norepinephrine levels were 145 ± 14 ng/liter in normal volunteer subjects, 202 ± 25 ng/liter in hypertensive subjects with normal PRA and 203 ± 26 ng/liter in hypertensive subjects with low PRA. The increase of plasma norepinephrine and epinephrine after standing 1 hour and after the administration of furosemide was similar in hypertensive subjects with low or normal PRA and in normal volunteer subjects. However, the increase in PRA after standing or after the administration of furosemide was significantly reduced in patients with low PRA. These data suggest that patients with low PRA have a normally responsive sympathetic nervous system and that the low PRA may be due to a defective renin response to the sympathetic nerve stimulation. Blood pressure was significantly correlated with plasma catecholamines in normal volunteer subjects (r = 0.71, p < 0.05) and in the hypertensive patients (r = 0.49, p < 0.05). An analysis of the regression lines for the two groups suggests that increased vascular reactivity to catecholamines may account for the increased blood pressure at each level of catecholamines in hypertensive subjects as compared to normal volunteer subjects. Basal plasma aldosterone levels were similar in patients with low and with normal PRA.Norepinephrine clearance was lower in hypertensive than in normotensive subjects.     

A nomogram for digoxin therapy

A nomogram is described for developing loading and maintenance dosage regimens of digoxin for adult euthyrold patients with reasonably normal hepatic function, in normal electrolyte balance, who have no obvious abnormality of gastrointestinal absorption. The nomogram relates observed data of risk of adverse reactions, risk of arrhythmias, serum digoxin levels, calculated maximum total body digoxin concentrations, body weight, total oral loading dose, data of renal function and daily maintenance dose. Physicians may select an acceptable risk or peak serum level depending upon each patient's clinical status, and then develop a loading and maintenance dosage regimen to consider giving, adjusted to the patient's body weight and renal function, to achieve one's selected therapeutic goals with reasonable accuracy for most patients most of the time.     

Regulation of urinary prostaglandins in Bartter's syndrome.

Enhanced prostaglandin production, possibly stimulated by hypokalemia, may mediate the manifestations of Bartter's syndrome. To investigate the cause of increased urinary prostaglandin excretion, we measured urinary immunoreactive prostaglandin E (iPGE) during the oral administration of potassium and the parenteral administration of magnesium, and during water restriction and oral water loading in two subjects with Bartter's syndrome. In one patient (Case 1), iPGE was 0.91 μg/day (normal 0.50 ± 0.20 μg/day, SD). Following the administration of indomethacin, 200 mg/day, iPGE, plasma renin activity (PRA), plasma aldosterone and angiotensin pressor sensitivity returned to normal but serum potassium did not. The oral administration of potassium citrate, acetate, bicarbonate, (Potassium Triplex), 240 meq/day for four days, increased iPGE to 2:3 μg/day and PRA from 47 to 73 ng/ml/hour (normal 1 to 3 ng/ml/hour). In the second patient (Case 2), iPGE was 1.4 μg/day. Therapy with ibuprofen, 1,600 mg/day, and indomethacin, 200 mg/day, again resulted in the return of iPGE, PRA, plasma aldosterone and angiotensin pressor sensitivity to normal, but serum potassium increased only transiently from 2.1 to 3.1 meq/liter. The oral administration of potassium chloride, 240 meq/day for four days, increased potassium to 3.0 meq/liter and increased iPGE to 8.0 μg/day. The administration of potassium triplex, 240 meq/day for four more days, further increased potassium to 3.4 meq/liter and iPGE to 9.3 μg/day, and PRA increased from 7.1 to 13.8 ng/ml/hour. This patient (Case 2) was hypomagnesemic (1.0 meq/liter, normal 1.5 to 2.4 meq/liter), and the intravenous administration of magnesium transiently increased iPGE by 15-fold. Following water restriction iPGE returned to normal (0.35 μg/day), and water loading increased iPGE to 3.0 μg/day, but neither maneuver altered PRA, aldosterone or serum electrolytes. The findings that potassium administration failed to reduce iPGE excretion and that water restriction renormalized iPGE excretion suggest that hypokalemia is not the primary stimulus to prostaglandin excretion.     

Cyclic cushing's syndrome

Cyclic Cushing's syndrome is a rare but increasingly recognized disorder of periodic fluctuations of adrenal steroid production. A case of cyclic Cushing's syndrome due to a pituitary adenoma is described. The patient demonstrated a prolonged cycle length of approximately six months, during which a spontaneous remission occurred both clinically and biochemically. Previously documented cases of cyclic Cushing's syndrome are reviewed, and the pitfalls in interpretation of results of dexamethasone suppression testing in the presence of spontaneous fluctuations in cortisol production are discussed.     

Effects of thyroid hormone on plasma adenosine 3',5'-monophosphate production in man.

Thyroid hormone may nonspecifically modulate cAMP production and end-organ responsiveness to diverse hormonal stimuli. This hypothesis was tested in 18 hyperthyroid, 16 euthyroid, and 8 hypothyroid human subjects by measurement of cAMP in plasma and urine both in the basal state and following stimulation by epinephrine, parathyroid hormone, and glucagon—hormones known to act through cAMP. Supine fasting plasma cAMP (PcAMP) concentrations (mean ± SEM) were minimally elevated in the hyperthyroid patients (23.5 ± 1.3 nM, p < 0.001) when compared with the euthyroid (17.1 ± 0.6 nM) or hypothyroid (20.5 ± 1.7 nM) groups. Infusion of propranolol over 45 min failed to lower basal PcAMP concentrations in 5 hyperthyroid subjects. Epinephrine infusions (0.05 μg/kg/min) caused an exaggerated peak PcAMP response (58.7 ± 5.7 nM) in 5 hyperthyroid patients and a diminished response (27.3 ± 3.2 nM) in 5 hypothyroid patients when compared with 5 euthyroid subjects (42.3 ± 2.6 nM, p < 0.05). Administration of parathyroid hormone, 200 units intravenously, also caused significant differences in urinary cAMP excretion (μmole/hr) in the hyperthyroid (11.37 ± 0.96, p < 0.005) and hypothyroid patients (2.4 ± 0.58, p < 0.001) when compared to the euthyroid group (6.59 ± 0.74). Glucagon (1 mg intravenously) caused an enhanced peak PcAMP response in the hyperthyroid patients (514 ± 34 nM) compared with the euthyroid (240 ± 29 nM) or hypothyroid (223 ± 28 nM) groups (p < 0.005). The PcAMP disappearance half-time following the peak response to glucagon was similar in all three groups, indicating that plasma sampling is probably a valid indicator of cAMP production. These studies demonstrate that thyroid hormone may modulate the response of multiple hormonal effects mediated by cAMP. The findings suggest a further cellular mode of action of thyroid hormone which may account for a number of the metabolic disturbances observed in patients with thyroid disease.     

A defect in platelet aggregation in Bartter's syndrome

A defect in both the first and second phase of platelet aggregation was found in four subjects with Bartter's syndrome, although template bleeding times were normal. The platelet abnormality was exacerbated by restriction of dietary sodium and lessened by the administration of inhibitors of prostaglandin synthesis. The aggregation defect was not found in other hypokalemic patients or in sodium-restricted normal control subjects. Platelet rich plasma from the subjects with Bartter's syndrome had an abnormally high content of cyclic adenosine 5′monophosphate (AMP), which may have been responsible for the disordered platelet function. Plasma of these subjects induced both the high content of cyclic AMP and the aggregation defect in normal platelets, whereas suspension of the subjects' platelets in normal plasma improved their aggregation. These findings describe a unique defect of platelet aggregation in Bartter's syndrome, which may be associated with the altered prostaglandin metabolism found in this condition.     

A-V conduction disturbances in Reiter's syndrome

High grade atrioventricular (A-V) block is a rarely described complication of Reiter's syndrome. This 65 year old man had recurrent episodes of arthritis, conjunctivitis and urethritis beginning at age 16. A prolonged P-R interval was first noted at age 32. The conduction disturbance progressed to intermittent episodes of high grade and complete heart block by age 65. His bundle electrograms located the site of block above the level of the bundle of His. Atrial pacing to rates of 150/min produced 5:1 A-V block, whereas exercise and atropine administration resulted in 1:1 A-V conduction. In view of these results, artificial pacemaker therapy is not indicated. The association of conduction disorders and Reiter's syndrome is reviewed.     

Lupus nephritis: Experience with 230 patients in a private practice from 1950 to 1980

Nephritis developed in 230 of 609 private patients with systemic lupus erythematosus (SLE) (38 percent) followed up from 1950 to 1980. Eighty-seven percent of patients with nephritis were female; 71 percent were Caucasian. They were observed a mean of 10 years. Five- and 10-year survival rates were 80 percent and 65 percent, with improvement to 86 percent and 76 percent in the last decade. Normalization of urinary sediment and protein levels, blood pressure and serum albumin levels correlated with improved survival and tended to occur during the first year. Life-threatening complications of SLE were more common after the onset of nephritis but decreased as renal function worsened. Infection was the most frequent cause of death in the last decade. Forty-four patients received nitrogen mustard; 55 percent of the courses were followed by significant improvement in renal function and reduced steroid dosage. Control of the disease was associated with improved long-term survival of patients with SLE.     

Identification of the increased frequency of cardiovascular abnormalities associated with mitral valve prolapse by two-dimensional echocardiography

Two-dimensional echocardiography (2-D echo) was performed in 86 consecutive patients with mitral valve prolapse (MVP) and in 25 normal subjects. In normal subjects, mitral leaflet thickness was 3.5 +/- 0.8 mm (mean +/- standard deviation) and the mitral leaflet thickness to aortic wall thickness ratio was 1.0 +/- 0.2. Patients with MVP were separated into 2 groups: those with normal mitral thickness (less than or equal to mean + 2 SD observed in normal subjects, i.e., less than or equal to 5.1 mm) and normal mitral thickness to aortic wall thickness ratio (less than or equal to mean + 2 SD observed in normal subjects, i.e., less than or equal to 1.4) (group I) and others in whom these values were increased (group II). In group I, mitral thickness was 3.6 +/- 0.6 mm and mitral thickness to aortic wall thickness ratio was 1.1 +/- 0.1, and in group II, mitral thickness was 8.8 +/- 1.2 mm and mitral thickness to aortic wall thickness ratio was 2.2 +/- 0.5. The only significant cardiovascular abnormalities in group I were mitral regurgitation in 2 patients and tricuspid valve prolapse in 1 patient. In group II, 7 patients had clinically significant mitral regurgitation, 8 had aortic root abnormalities, 4 had tricuspid valve prolapse and 6 had Marfan's syndrome. Cardiovascular abnormalities were present in 60% (18 of 30) of patients in group II and in 6% (3 of 56) of patients in group I (p less than 0.001). Two-dimensional echo enabled the identification of a subset of patients with MVP who had thickened mitral leaflets. These patients had an increased incidence of cardiovascular abnormalities.     

Peripheral metabolism of bovine parathyroid hormone in the dog

Four dogs were infused with highly purified bovine parathyroid hormone until constant levels of immunoreactive hormone were attained in the circulation. Simultaneous samples of plasma were then obtained from the aorta, from hepatic, renal, and femoral veins, and later from a pulmonary artery and the left ventricle. Radioimmunoassay of these samples revealed mean arteriovenous differences of ?23% across the liver and ?19% across the kidney. No significant differences were found across the lung or lower extremity. After termination of the infusion the disappearance rate of immunoreactive hormone in external jugular-venous blood was multiexponential: the predominant initial $\text{T}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ was 4, 6, and 8 min, and the terminal component was 60, 54, and 99 min, respectively, in 3 dogs.     

Favorable effects of hydralazine on the hemodynamic response to isometric exercise in chronic severe aortic regurgitation

The hemodynamic effects of isometric exercise and the response to hydralazine therapy were evaluated in 11 patients with chronic, severe aortic regurgitation (AR). Isometric exercise produced a significant increase in heart rate (from 78 ± 11 to 93 ± 19 beats/min [mean ± standard deviation], p < 0.05), mean blood pressure (from 83 ± 8 to 104 ± 20 mm Hg, p < 0.05), mean right atrial pressure (from 3 ± 2 to 7 ± 5 mm Hg, p < 0.05) and mean pulmonary artery wedge pressure (from 12 ± 7 to 18 ± 10 mm Hg, p < 0.05). Small and insignificant changes were seen in cardiac index (from 3.4 ± 0.8 to 3.9 ± 1.0 liters/min/m²), systemic vascular resistance (from 1,097 ± 257 to 1,171 ± 284 dynes s cm^?5), pulmonary vascular resistance (from 120 ± 76 to 130 ± 89 dynes s cm^?5) and stroke volume index (from 44 ± 10 to 43 ± 12 ml/m²). After oral hydralazine administration (100 to 300 mg), hemodynamic values during isometric exercise were: Heart rate increased further, to 105 ± 14 beats/min (p < 0.05), mean blood pressure was 102 ± 16 mm Hg (difference not significant [NS]) cardiac index increased markedly, to 5.2 ± 1.4 liters/min/m² (p < 0.05), stroke volume index increased to 49 ± 12 ml/m² (p < 0.05), right atrial pressure decreased slightly, to 5 ± 5 mm Hg (NS), pulmonary artery wedge pressure decreased to 14 ± 7 mm Hg (p < 0.05), systemic vascular resistance decreased to 903 ± 288 dynes s cm^?5 (p < 0.05), and pulmonary vascular resistance changed to 100 ± 66 dynes s crrr^?5 (NS). Thus, isometric exercise in patients with chronic severe AR is associated with only a slight and insignificant increase in systemic vascular resistance, but a marked increase in pulmonary artery wedge pressure. Direct arteriolar vasodilation with hydralazine results in a significant attenuation of pulmonary artery wedge pressure increase during isometric exercise and leads concomitantly to a significant augmentation of stroke volume and cardiac output. These findings substantiate the value of hydralazine therapy in patients with chronic, severe AR.     

Lymphomatoid granulomatosis: A T-cell disorder?

The histogenesis of lymphomatoid granulomatosis has been controversial since it was first defined by Liebow and colleagues. We report a typical clinical and histopathologic case of lymphomatoid granulomatosis. Immunologic markers indicate the lymphocytes comprising this patient's initial lesion were predominantly T lymphocytes.     

Surreptitious diuretic ingestion and pseudo-Bartter's syndrome

A patient with profound hypokalemia satisfied the criteria for Bartter's syndrome, including hyperreninemia, aldosteronism, normal blood pressure, and hyperplasia of the juxtaglomerular apparatus. Two screening tests of urine and one of plasma for diuretic agents gave negative results. A third urinary sample gave negative results for thiazide but positive for furosemide; the fourth and fifth samples gave negative results for furosemide but positive for thiazide. Urinary prostaglandin excretion was normal. We conclude that this apparent case of Bartter's syndrome was caused by long term surreptitious diuretic ingestion and suggest this may occur more frequently than is generally appreciated.     

Noninvasive assessment of atherosclerosis

The application of ultrasound to clinical evaluation of the symptomatic patient requires less precision and accuracy than when it is used as an instrument to study atherogenesis. The clinician's goal is to locate hemodynamically significant lesions; studies of atherogenesis require auxometry (measurement of the growth of lesions) and the instruments used must have a sensitivity matched to an average growth rate that can be expected in a general population. This dictates that ultrasound equipment be designed specifically for high resolution imaging and the target vessels of choice appear to be the carotid arteries. Correlations of disease patterns among various vessel beds indicate that inferences can be made between coronary and carotid vessels on a population level, but should not be made on an individual basis. While the ultimate goal of the cardiologist is to be able to do repetitive, accurate, noninvasive scanning of coronary arterial lesions, present technology limits us to making such inferences about coronary disease from the best available substitute. The carotid appears to be the artery of choice for this purpose because of its proclivity toward developing the disease and its ready availability for clinical scanning. It is an important target in its own right, and should be of interest to cardiologists given the likelihood that the coronary bypass patient will tend to develop atherosclerosis in the cerebral system. The ideal noninvasive imaging equipment for today's clinician is one which offers flexibility in being able to image various vessel beds with the same transducer head. This flexibility, however, may not be appropriate for equipment which is designed for auxometric application. Rather, lesion tracking image systems will need to be designed for narrow application: all variables will be controlled to maximize precise visualization of the carotid artery. If we were to project an ideal, hypothetical carotid scanning device to track lesion change over one year, it would probably have the following characteristics: It would be a B-mode imaging system rather than a Doppler in favor of ther increased axial resolution offered by B-mode. It would function at 8 MHz to 10 MHz to provide maximum axial resolution. The crystal would be the maximum size permitted by anatomy. The near/far field transition would be focused at the depth of the carotid (1 cm to 2 cm) to offer maximum azimuthal resolution. The system would utilize a head positioner to orient the patient's neck the same way on repeat scans.(ABSTRACT TRUNCATED AT 250 WORDS)