Relationship between local and total bone mass in osteoporosis

The relationship between total body calcium (TBC) and local bone calcium mass (BCM) was studied in a group of osteoporotic patients (12 females and two males) with a wide range of body size. Two methods were used to estimate BCM: photon absorptiometry and radiographic morphometry. TBC was estimated by total-body neutron-activation analysis. Since 99% of TBC is located in the skeleton, it was assumed that TBC was essentially a measure of total skeletal (calcium) mass. TBC ranged from 482 to 1076 g. High correlations with r values from 0.84 to 0.94, p < 0.001, were found between TBC and BCM measured by absorptiometry at six different sites of radius, ulna, and humerus. Additionally, high correlations with r values from 0.89 to 0.95, p < 0.001, were found between BCM at the distal tenth of the radius and BCM at the five other sites. A high correlation was also found between body height and TBC, but partial correlations indicated that this accounted for very little of the correlation between TBC and BCM. In contrast to the above, correlations between BCM determined by radiographic morphometry and TBC were weak or nonsignificant. When TBC and BCM were expressed as per cent of their mean value, the slopes of the estimating equations, describing the relationships between TBC and BCM, were essentially the same, but significantly less than one, which is the value of the slope expected if TBC and BCM had changed at the same relative rate. From these relationships, we conclude (1) that the rate of change in BCM was similar in the six sites examined, and (2) that the rate of change in these six sites was relatively more rapid than the change in total body calcium. Whether the change in rate of BCM was related to rate of increase during attainment of maximum BCM or subsequent rate of loss of BCM or both remains to be determined.     

Effect of phenformin on lipid transport in hypertriglyceridemia

The effect of phenformin on lipid metabolism was studied in nine hypertriglyceridemic subjects consuming isocaloric liquid formula diets. On a fat-free, 85% carbohydrate hydrate diet, phenformin reduced plasma triglyceride, cholesterol, and free fatty acid levels, the mean decreases being 14%, 13%, and 16%, respectively. The predominant effect of the drug was on very low density lipoprotein levels, with no change in low density lipoproteins. Plasma triglyceride and cholesterol levels were also reduced in the majority of subjects on a diet containing 40% of calories as fat and 45% as carbohydrate, but phenformin did not have any effect on the carbohydrate induction of triglyceride elevation. Basal insulin levels were reduced by the drug in all subjects (mean change, ?23%) and fasting glucose levels were lowered in the majority. The plasma lipolytic rate measured on endogenous substrate during a prolonged heparin infusion on the fat-free diet was reduced by phenformin (mean change, ?15%), although postheparin lipolytic activity on an artificial substrate was unchanged. Free fatty acid turnover, measured during the same procedure, fell in parallel with the fatty acid levels (mean change, ?27%). It is proposed that phenformin lowers plasma triglyceride levels in most subjects by reducing endogenous triglyceride production, and that the effects of the drug on glucose, insulin, and free fatty acid homeostasis contribute to this action. It is suggested that in some subjects the drug may also impair triglyceride clearance from plasma, and that this may account for the variable therapeutic response, since in three subjects phenformin did not decrease triglyceride levels on both diets.     

Stress-induced inhibition of triglyceride secretion in vivo in sand rats (Psammomys obesus)

The effects of acute stress upon circulating triglyceride, glucose, insulin, free fatty acids, and glycerol were investigated in obese desert sand rats. Three groups of animals, designated “nonstress,” “nonexertional stress,” and “exertional stress,” were studied. Acute stress, with or without accompanying exercise, was associated with significant decreases in circulating triglyceride; significant increases in circulating glucose, free fatty acids, and glycerol; and variable changes in circulating insulin. Since these data indicated that substrate availability and hepatic insulization were adequate and therefore could not explain the observed fall in circulating triglyceride, endogenous triglyceride secretion rates were examined by the Triton method. Compared to predicted rates based upon earlier studies, both nonexertional and exertional stress were associated with significantly decreased endogenous triglyceride secretion. Thus, acute stress in the sand rat, with or without accompanying exercise, appears to induce an immediate decrease in endogenous triglyceride secretion and circulating triglyceride.     

Evidence for diabetes mellitus and genetic forms of hypertriglyceridemia as independent entities.

Among 91 index cases whose diagnosis of a genetic type of hypertriglyceridemia was based on family studies, 27% had diabetes. To determine whether the familial forms of hypertriglyceridemia and genetic diabetes mellitus are inherited together or independently, the adult first degree relatives of these propositi were investigated for the presence of diabetes. Frequency of diabetes in first degree relatives of the 25 diabetic patients with a familial form of hypertriglyceridemia was identical whether such relatives were hyperlipidemic or not (13% versus 14.7%). The frequency of diabetes in both the hyperlipidemic and normolipidemic relatives of the 66 nondiabetic hypertriglyceridemic index cases also was not significantly different from each other (6.2% versus 4.0%). These results indicate that while diabetes is frequently associated with hypertriglyceridemia, genetic hypertriglyceridemia, per se, does not carry an increased risk of diabetes. Following treatment of diabetes, elevated triglyceride levels in index cases with both familial hypertriglyceridemia and untreated diabetes returned to lower but still elevated levels resembling those of affected (hypertriglyceridemic) relatives. Thus, the interaction of untreated diabetes and a familial form of hypertriglyceridemia determines the level of plasma triglyceride in a patient with both disorders.     

Reversible abnormalities in postheparin lipolytic activity during the late phase of release in diabetes mellitus (postheparin lipolytic activity in diabetes).

To test whether abnormalities in multiphasic release of lipoprotein lipase are associated with hypertriglyceridemia in diabetes mellitus, postheparin lipolytic activity (PHLA) was measured during a high-dose, constant heparin infusion in 20 diabetic subjects with hypertriglyceridemia, 25 nondiabetic hypertriglyceridemic subjects and 7 normal subjects. The standard low heparin dose PHLA and the PHLa during the early phase of the heparin infusion were the same in all groups. In constrast, the PHLA during the late phase of the heparin infusion was lower in the 12 untreated diabetic subjects than in the 25 nondiabetic hypertriglyceridemic and the 7 normal subjects (p less than 0.001). An abnormality in late phase PHLA in the untreated diabetic subjects was more apparent when it was compared to the level of PHLA attained during the early phase of the heparin infusion (Equilibrium PHLA/60 min PHLA). The relative PHLA in the late phase of the infusion was lower in the untreated diabetic subjects (0.671 +/- 0.147) than in the nondiabetic hypertriglyceridemic subjects (0.847 +/- 0.019, p less than 0.001), or in the chronically treated diabetic subjects (0.823 +/- 0.108, p less than 0.05). Among the untreated diabetic subjects, increasing fasting glucose levels were associated with both decreasing absolute PHLA levels at the late phase of the infusion (r = 0.61, p less than 0.02) and greater decreases in relative PHLA during the infusion (r = -0.80, p less than 0.001). Treatment of the diabetes with long-term oral sulfonylurea or insulin therapy corrected the abnormality in the late phase PHLA with an associated decrease in plasma triglyceride levels (p less than 0.001). In five subjects with a deficient PHLA response to a standard, low dose of heparin, the PHLA response was low throughout the heparin infusion. With treatment, the PHLA response to the low heparin dose corrected rapidly toward normal in those two diabetic subjects with PHLa deficiency, and the early PHLA response during the heparin infusion increased. However, the late phase abnormality in all untreated diabetic subjects did not correct to normal until after several months of antihyperglycemic therapy. In the untreated diabetic subjects the degree of elevation of the plasma triglyceride level appeared to result from the interaction of the abnormality in PHLA with the presence or absence of an inherited familial lipid disorder.     

Phentolamine prevents the somatostatin-mediated inhibition of pancreatic glucagon secretion.

This study was undertaken to assess the role of alpha-adrenergic receptors in the somatostatin-mediated inhibition of pancreatic glucagon secretion. In dogs, somatostatin inhibited the pancreatico-duodenal vein output of glucagon. During an infusion of the alpha-adrenergic blocking agent phentolamine, somatostatin did not significantly inhibit the output of glucagon. Thus, alpha-adrenergic mechanisms appear to influence the ability of somatostatin to decrease pancreatic glucagon secretion.     

Left ventricular function before and following surgical treatment of mitral valve disease.

Nineteen patients with mitral valve disease were studied before and a mean 11 months +/- 9 months following valve replacement or reconstruction, which resulted in good postoperative valve function. Biplane left ventricular angiography and pressures were utilized to determine end-diastolic volume/M. (EDV), end-systolic volume/M. (ESV), ejection fraction (EF), left ventricular mass/M. (LVM), and stroke work/M. (SW). There were 19 patients--six with mitral stenosis (MS), six with mitral stenosis and regurgitation (MS + MR), and seven with mitral regurgitation (MR). Those with MS and MS + MR preoperatively had no significant change in left ventricular end-diastolic pressure (LVEDP), EDV, ESV, LVM, or EF following surgery. Patients with MR had a significant reduction in LVEDP, EDV, SV, and SW. More importantly, the EF fell in four of these seven patients and LVM did not decrease following surgery. It is concluded that surgical treatment for MS and MS + MR had little effect on left ventricular performance. Following surgical treatment for MR, reduction in EDV is not associated with reduction in LVM, and frequently left ventricular performance deteriorates as judged by the EF.     

Blood pressure reductions during self-recording of home blood pressure.

Blood pressure readings were taken at home twice a day for one month by 60 subjects with essential hypertension. The average change-perday value based on quadratic curves fit to each subject's data (for the entire month or to the day of medication change) was negative and was statistically significant for both systolic and diastolic and for a.m. and p.m. readings. Clinically significant decreases in blood pressure, defined as systolic and/or diastolic decreases ≥ 10 mm. Hg from the first two to the last two days, occurred in 43 per cent of the subjects.The observed blood pressure decreases may have been due to (1) placebo effects and/or increased compliance associated with the change of treatment program, (2) increased attention of health care practitioners, (3) habituation of blood pressure to the conditions of measurement, or (4) biofeedback effects. The most likely explanation for the initial blood pressure decrease in habituation. The smaller but continuing decrease after the first two days was probably due, at least in part, to a biofeedback effect. If further studies support such an hypothesis, then home blood pressure readings should be used on a wider scale for treatment purposes. They are easier to administer than other behavioral treatments and the observed decreases appear to be of the same order of magnitude.Regardless of the treatment potential of this type of biofeedback, the decreases in home blood pressures while patients are taking their own pressures daily at home suggest the importance of a diagnostic waiting period until blood pressure stabilizes and before pharmacological treatment is prescribed. This period may last a month or longer for some patients.     

Ectopic secretion of chorionic gonadotropin by a lung carcinoma. Pituitary gonadotropin and subunit secretion and prolonged chemotherapeutic remission.

The ability of tumor markers to improve cancer therapy is not established. We studied a man with a human chorionic gonadotropin (HCG)-secreting large cell carcinoma of the lung and gynecomastia. Preoperatively, levels of HCG (109 ng/ml), its alpha and beta subunits (3.2 and 21 ng/ml, respectively) and plasma estradiol were elevated. Despite apparently complete tumor resection and total resolution of gynecomastia, HCG titers remained elevated (3.3 ng/ml), heralding tumor recurrence three weeks later. Because the pathophysiologic consequences of the ectopic secretion of HCG on pituitary function are not established, we administered 100 microgram of gonadotropin-releasing hormone (LHRH) and observed a markedly delayed increase in pituitary gonadotropins. Early chemotherapy, guided by persistence of HCG, reduced HCG to undetectable levels, restored to normal the response to LHRH and resulted in a distinctly unusual 30-month complete remission. Use of HCG as a tumor marker levels is more sensitive than the symptom of gynecomastia and may permit detection of small, potentially curable tumor foci.     

Arterial-venous differences of plasma catecholamines in man

To investigate the relationship between forearm venous levels of catecholamines and systemic levels, simultaneous arterial and forearm vein blood samples were obtained from 14 subjects undergoing elective dental procedures and assayed with a sensitive and specific radioenzymatic assay. Baseline venous levels of norepinephrine were greater than arterial levels (305 ± 30 pg/ml versus 221 ± 18; ± SEM, p < .005). Conversely, arterial epinephrine levels were higher than venous (132 ± 17 pg/ml versus 80 ± 10; p < .005). There was a significant relationship between arterial and venous levels of both norepinephrine (r = .77, p < .01) and epinephrine (r = .67, p < .01). The arterial-venous epinephrine difference increased from the baseline value of 44 ± 14 pg/ml to 108 ± 16 (p < .005) by 3 min after subcutaneous injection of epinephrine (18 μg), but the arterial-venous difference returned to 65 ± 24 by 5 min after injection (p = NS versus baseline). These findings indicate that under the conditions of this study, forearm tissues produced more norepinephrine than they removed, but removed more epinephrine than they produced. Baseline venous and arterial levels were related; when epinephrine production was augmented, there was a short time lag for the venous epinephrine increase.     

Myocardial perfusion imaging with 99mTc or 113mIn macroaggregated albumin: Correlation of the perfusion image with clinical,angiographic, surgical,and histologic findings

Scintillation camera myocardial perfusion images were performed in 77 patients with proved or suspected ischemic heart disease following the intracoronary injection of 1.5 mCi ^99mTc or ^113mIn macroaggregated albumin. Perfusion images were classified as normal (36) or abnormal (41), and the location of abnormality was noted. Thirty-seven out of 41 patients with abnormal images had prior myocardial infarction based on history (30), ECG Q-waves (27), local contraction pattern abnormality (23), or direct surgical (9) or histologic (4) inspection, either singly or in combination. Three out of five patients with pre-infarction angina had image defects-none had evidence of infarction by ECG, ventriculogram, or surgical inspection. Coronary artery stenosis correlated with image defects to the extent that myocardial infarction was associated; 28 out of 29 patients with total occlusions and other evidence of infarction had image defects, four patients with complete occlusions but without other evidence of infarction had normal images.We conclude that, excepting patients with pre-infarction angina, this technique is more sensitive and direct in the identification of myocardial scar than standard ECG, clinical evaluation, or biplane left ventriculography.     

Effects of coronary stenoses on coronary flow reserve and resistance

Resting coronary flow and regional distribution are not affected by narrowing of up to 85 percent of arterial diameter and therefore provide little insight into the effects of stenoses on coronary hemodynamics. However, maximal coronary flow and coronary flow reserve are markedly reduced by constrictions that do not affect resting flow. Accordingly, coronary flow reserve and its relations to pressure-flow-resis-tance characteristics of 177 single (10 dogs) and 125 double coronary stenoses in series (7 dogs) were studied in open chest preparations. Coronary flow, aortic pressure and left circumflex coronary pressure distal to a single or to each of two separate adjustable coronary constrictors in series were simultaneously recorded while flow was varied from basal to maximum by intracoronary injections of contrast medium.The hyperemic response to contrast medium is a quantitative measure of coronary flow reserve which was closely related to, and predictive of, the following characteristics of single and double stenoses in series: (1) total pressure gradient and distal circumflex perfusion pressure at resting coronary flow; (2) total pressure gradient and distal circumflex pressure at hyperemic flow when effects of stenoses are greatest; and (3) coronary stenoses resistance. Thus, the hyperemic response after injection of contrast medium, or coronary flow reserve, is in itself a quantitative measure of the pressure-flow-resistance characteristics of coronary constrictions. In addition, resistances of coronary stenoses in series are shown to be additive; the flow effects of stenoses in series are not generally determined by the dominant or most severe lesion, contrary to common clinical precepts. These concepts are applicable to patients in assessing the effects of stenoses on coronary hemodynamics.     

Left ventricular hypertrophy in coronary artery disease. A cardiomyopathy syndrome following myocardial infarction

Eighty-five patients with ventricular dysfunction due to coronary disease and to nonobstructive cardiomyopathy were studied by biplane angiocardiography (12/sec) to determine the extent of hypertrophy and the distinguishing features between primary myocardial and coronary disease. Patients with cardiomyopathy and equally severe dysfunction due to coronary disease had identical end-diastolic, end-systolic and stroke volume and work per square meter, stroke work per gram of ventricular mass, end-diastolic pressure, peak equatorial wall stress, ejection fraction, peak circumferential shortening velocity, peak ventricular ejection rate, peak external pump power, left ventricular mass and mass to diastolic volume ratio. Hypertrophy develops after myocardial infarction in proportion to ventricular dilatation and may result in a syndrome of massive hypertrophy, hypokinesis and congestive failure quantitatively identical to that found in primary cardiomyopathy except for etiology. Hypertrophy is associated with normalization of wall stress in both coronary and primary myocardial disease and is thus not dependent on the type of insult to the contractile mechanism.     

Evidence that parathyroid hormone is not required for phosphate homeostasis in renal failure

Varying degrees of renal failure were produced by surgical reduction of renal mass in normal dogs and in thyroparathyroidectomized dogs (TPTX) in whom serum calcium levels were maintained in the normal range by the administration of vitamin D. Both groups of dogs maintained normal serum phosphate levels in spite of progressive decreases in glomerular filtration rates (GFR). Furthermore, both groups of dogs were able to increase the fractional excretion of phosphate as GFR decreased. Thus the same renal response to loss of GFR was maintained in the complete absence of parathyroid tissue. Finally, stable serum phosphate levels and increased fractional excretion of phosphate in response to a decrease in GFR were also demonstrated in acutely TPTX dogs who were not receiving vitamin D. These results indicate that phosphate homeostasis can be maintained in renal failure in the total absence of parathyroid hormone secretion.