Usefulness of mean aortic valve gradient and left ventricular diastolic filling pattern for distinguishing symptomatic from asymptomatic patients.

Consecutive, symptomatic (n = 15) and asymptomatic (n = 25) men with aortic stenosis (valve area < 1.2 cm2) and no clinical evidence of myocardial ischemia underwent radionuclide angiography at rest and during supine bicycle ergometry. Ejection fraction, diastolic filling pattern and aortic valve area/gradient were measured on enrollment and when patients became symptomatic (n = 10) or underwent valve replacement (n = 22) during a 2-year follow-up period. Both groups had similar heart rate, blood pressure and ejection fractions, but mean aortic gradients were higher in symptomatic (53 +/- 4 mm Hg) than asymptomatic (37 +/- 2 mm Hg) subjects p < 0.01. Functional limitation evoked by exercise was prevalent even in the asymptomatic group but symptomatic patients exercised to lower work levels than asymptomatic subjects (184 +/- 27 and 307 +/- 32 kg.m/min, respectively, p = 0.02). Ejection fraction failed to increase with exercise in either group. Symptomatic subjects had supranormalization of early diastolic filling with shorter time to the peak filling rate than asymptomatic subjects (137 +/- 16 and 172 +/- 9 ms, respectively, p < 0.05) and a greater first 1/3 filling fraction. The 10 patients who became symptomatic during follow-up had higher first 1/3 filling fractions (53 +/- 7 and 42 +/- 5%, respectively) and mean gradients (41 +/- 4 and 33 +/- 2 mm Hg, respectively) than subjects who remained asymptomatic, p < 0.05. High mean aortic gradients, impaired exercise tolerance and enhanced early diastolic filling distinguish symptomatic from asymptomatic patients.

Effects of opioid blockade with nalmefene in older impotent men.

We evaluated the effect of the opioid antagonist nalmefene on the HPG axis and on food consumption in 14 older impotent men. These patients had low to low normal mean serum testosterone values and normal gonadotrophin levels on screening evaluation. Normal response to GnRH was demonstrated in all the men. The protocol called for 24 hours of evaluation before and during administration of nalmefene 2.0 mg IV every 8 hours for 3 doses. During each 24 hour period, the following determinations were made: serum testosterone, FSH, and LH by five separate determinations between 8 AM and noon; 8 AM and 11 PM serum cortisols; 24 hour urine collections for free cortisol; and nocturnal penile tumescence (NPT). Food consumption was measured from 4 PM to 10 AM during the two periods. Nalmefene resulted in significant rises in testosterone, LH, and FSH. Nalmefene significantly elevated morning and evening cortisol measurements in all the patients. Nalmefene decreased total calorie consumption, principally by decreasing fat consumption. There was no effect on NPT. We conclude that in older impotent men, nalmefene acutely increases activity of the HPG axis and decreases calorie intake predominantly by decreasing fat consumption.

Thyrotropin and prolactin response to thyrotropin-releasing hormone in depressed and nondepressed alcoholic men.

Thyrotropin-releasing hormone (TRH) stimulation tests were performed on 81 alcoholic men after at least 3 weeks of abstinence. Subjects were given 500 micrograms of TRH intravenously, and thyroid-stimulating hormone (TSH) and prolactin (PRL) were measured at baseline, and then 15 and 30 min later. Comparisons were made among alcoholics with (n = 27) and without (n = 54) a lifetime history of depression as determined by the Diagnostic Interview Schedule. Nine nondepressed, nonalcoholic subjects served as controls. Alcoholics with or without a depression history did not differ from each other or from control in TSH or PRL response area under the curve. Blunted TSH responses were present in 10 (12%) of the alcoholics and none of the controls when blunting was defined as a delta max TSH less than 5 microU/ml. When blunting was defined as a delta max TSH less than 7 microU/ml, 18 (22%) of the alcoholics and 1 (1%) of the controls were blunted. Conversely, 2 (2.5%) of the alcoholics had a delta max TSH greater than 32 microU/ml. All subjects were clinically euthyroid. Contrary to expectation, depressed subjects were slightly less likely to show blunted responses than nondepressed subjects. No relationship was found between neuroendocrine measurements and several measurements of alcoholism or depression. Some alcoholic subjects show a blunted TSH response to TRH injection, which may be a function primarily of the alcoholism itself. The precise mechanism remains unknown.

Effects of biliary obstruction on hepatic clearance of bacteria.

High surgical mortality in patients with obstructive jaundice and sepsis have been attributed to reticuloendothelial system (RES) depression. The purpose of this study was to clarify the effects of mechanical biliary obstruction on RES clearance of pathogenic bacteria by comparing the phagocytic index (K) with the directly measured hepatic uptake of indium 111-labeled bacteria injected into the portal vein of normal dogs and dogs with partial (PBO) or complete biliary obstruction (CBO). No significant difference was observed between the K in normal dogs (0.19 +/- 0.08; n = 6) and that in dogs with PBO (0.24 +/- 0.06; n = 5) or CBO (0.21 +/- 0.03; n = 4). There was no significant difference in uptake of radiolabel by the liver among the three groups of dogs. In our model, biliary obstruction had no effect on hepatic RES function and may not represent a significant determinant of mortality in patients with obstructive jaundice.

Psychoneuroendocrine effects of methadone maintenance.

A variety of neuroendocrine and psychiatric dysfunctions have been demonstrated in humans maintained on opiates, but both have not previously been examined in the same population. We performed a series of neuroendocrine challenge tests in men participating in a methadone maintenance clinic and in normal controls. Psychiatric diagnoses were made with DSM-III Criteria, using the Diagnostic Interview Schedule, and subjects also completed the Symptom Checklist. Our results in the methadone group suggest (a) near-maximal stimulation of prolactin secretion, with a blunted prolactin response to insulin hypoglycemia, (b) mild suppression of cortisol levels, but an exaggerated cortisol response to stimulation, (c) a delayed and inhibited insulin response to food ingestion with resulting mild hyperglycemia, (d) low body weight, but elevated calorie ingestion, and (e) inability to concentrate urine when dehydrated, which was partially corrected by administration of arginine vasopressin. Phobic disorder was associated with a lower prolactin response to both inhibitory and stimulatory challenges. Depression did not appear to be related to the increased cortisol response to stimulation. These results suggest several potentially fruitful areas for future investigation, including the prolactin system and anxiety disorders, nutrient ingestion and metabolism, and posterior pituitary function.

Efficacy of chenodeoxycholic acid and ursodeoxycholic acid for lowering cholesterol saturation index of gallbladder in patients with a sphincterotomy.

After endoscopic retrograde sphincterotomy, patients with an intact gallbladder are at risk for developing symptoms or complications of gallbladder stones. Medical dissolution of such stones would be desirable, especially in elderly patients with an increased surgical risk. However, sphincterotomy alters emptying dynamics of the gallbladder and markedly reduces bile salt pool size, effects that may alter response to chenodeoxycholic acid or ursodeoxycholic acid treatment. Studying two groups of 5 patients with an intact gallbladder after endoscopic retrograde sphincterotomy, we found that 15 mg/kg.day of chenodeoxycholic acid increased the mean (+/- SEM) biliary percentage of chenodeoxycholic acid from 35.5% +/- 4.0% to 88.8% +/- 1.9% (p less than 0.01) and decreased the mean saturation index of gallbladder bile from 1.02 +/- 0.22 to 0.55 +/- 0.08 (p less than 0.05). Ursodeoxycholic acid (10 mg/kg.day) increased the mean biliary percentage of ursodeoxycholic acid from 5.6% +/- 1.5% to 44.7% +/- 5.8% (p less than 0.01) and decreased the mean saturation index of gallbladder bile from 1.04 +/- 0.25 to 0.57 +/- 0.03 (p less than 0.05). A long-term trial of bile acid treatment in sphincterotomy patients with stones in an intact gallbladder is needed.

Opiate antagonist nalmefene inhibits ethanol-induced flushing in Asians: a preliminary study.

Ethanol-induced flushing (EIF) occurs in up to 80% of Asians and is characterized by facial flushing, tachycardia, and increased cardiac output. Since endogenous opiates and prostaglandins may be mediators of flushing syndromes, we attempted to block EIF in four Asian flushers with single doses of either the opiate antagonist nalmefene, or the prostaglandin synthesis inhibitor indomethacin. Nonflushers (2 Caucasian, 2 Asian) and four Asian flushers were given on separate days water, ethanol (0.4 g/kg p.o.), ethanol plus nalmefene (2 mg i.v.), or ethanol plus indomethacin (50 mg p.o.). Ethanol concentrations of flushers and nonflushers were similar. Mean (+/- SEM) plasma acetaldehyde concentrations of flushers (28.2 +/- 11.8 microM) were significantly greater than nonflushers (1.4 +/- 0.5 microM) following ethanol ingestion (p less than 0.001). Ethanol alone always induced a significant rise in facial skin temperature [mean area under the curve (AUC) = 5142 +/- 648 % delta T x min, p less than 0.01] and of pulse (mean AUC = 1622 +/- 120 bpm x min, p less than 0.001) in flushers compared to water ingestion. A single dose of nalmefene (2 mg i.v.) but not indomethacin (50 mg p.o.), reduced the mean (+/- SEM) ethanol-induced rise in facial skin temperature of flushers by 58 +/- 14% (p less than 0.05) without changing plasma acetaldehyde concentrations. These data are preliminary evidence that the opiate antagonist, nalmefene, blocks some of the vascular manifestations of EIF without altering the elevated plasma concentrations of acetaldehyde.

Monoclonal antibody-targeted radiotherapy of renal cell carcinoma using a nude mouse model.

Radiation dosimetry and monoclonal antibody (MAB)-targeted radiotherapy studies were performed to evaluate the feasibility of using tumor-preferential MAB as targeting agents for internal radiotherapy of renal cell carcinoma (RCC). Two human RCC xenograft lines, TK-177G and TK-82, were established in nude mice and studied using MAB A6H as a targeting agent. This MAB has previously demonstrated excellent in vivo localization to RCC xenografts. Two doses of A6H (13 to 19 micrograms) labeled with iodine 131 (110 to 130 microCi) caused the tumor to regress or arrested the tumor growth in both xenografts. Similar doses (18 to 43 micrograms; 120 microCi) of 131I-labeled control MAB AFP-22 or of unlabeled A6H did not inhibit tumor growth. While most mice in the control groups had tumors greater than 250 mg in weight by day 43, none of the tumors in mice treated with 131I-labeled A6H grew to that size during the 3-month observation period. Sequential computerized scintigraphy was used to calculate the amount of radioisotope localized in tumor versus normal mouse tissue. Therapeutic doses of 131I-labeled A6H delivered a median calculated radiation dose of 38 cGy/microCi (range, 28 to 57) injected dose to RCC xenografts, and a median of 0.9 cGy/microCi to normal mouse tissues. These findings suggest that A6H is able to target radioisotopes highly specifically to RCC and achieve a therapeutic effect in the experimental setting.

Spontaneous passage of glass beads from the canine gallbladder: facilitation by sphincterotomy.

To investigate the mechanism by which ablation of the sphincter of Oddi prevents gallstone formation, we assessed passage of glass beads out of the gallbladders of dogs with sphincterotomy and sham sphincterotomy. One month after bead implantation, dogs with an intact sphincter passed 52%, 26%, 22%, 10%, 0%, and 0% of beads with diameters of 2, 3, 4, 5, 6, and 8 mm, respectively. For the same respective bead diameters, dogs with a sphincterotomy passed 90%, 90%, 88%, 75%, 75%, and 42% of beads (p less than 0.05 for all bead diameters). No beads were in the common bile duct of any dog. In separate dogs studied by cholescintigraphy, sphincterotomy significantly increased gallbladder ejection fraction from 0.46 to 0.76 (p less than 0.01). In addition, sphincterotomy significantly lowered resting gallbladder volume from 24.4 to 15.8 ml (p less than 0.025) and lowered cholecystokinin-stimulated gallbladder volume from 13.3 to 5.9 ml (p less than 0.025). These data indicate that even with an intact sphincter, small solids can pass from the gallbladder and into the duodenum. Sphincterotomy facilitates passage of solids, apparently by general improvement in gallbladder emptying. Facilitated passage of crystals, microliths, or small stones seems the most likely explanation for prevention of gallstone formation by sphincterotomy.

Effects of xylitol on gastric emptying and food intake.

We studied the effects of xylitol, the pentose-sugar alcohol, on gastric emptying of the solid-food component of a complex meal. Gastric emptying was measured in human volunteers by utilizing a standardized radiolabeled scrambled-egg meal. After ingestion of 25 g xylitol, gastric emptying was markedly prolonged (T-1/2 58 +/- 5 min control vs 91 +/- 7 min after xylitol [p less than 0.01]). Since delayed gastric emptying may affect food intake, we evaluated the effects of xylitol on calorie intake. Food intake after oral preloading with water resulted in intake of 920 +/- 60 kcal vs 690 +/- 45 kcal after 25 g of xylitol. In contrast, a preload of glucose, fructose, or sucrose failed to suppress food intake. Although xylitol decreased food intake and also delayed gastric emptying, these effects may be unrelated. Our data suggest a role for xylitol as a potentially important agent in dietary control.

Scintigraphic findings in chronic actinomycosis osteomyelitis and associated soft tissue infection.

Scintigraphic findings are reported in a patient with actinomycosis osteomyelitis and soft tissue infection to illustrate the need to understand the mechanism of localization of the radiopharmaceutical to accurately assess the clinical pathology.

Hepatobiliary imaging: the diagnostic use of intravenous morphine in fasting patients.

Fasting and parenteral nutrition are associated with a spectrum of gallbladder disorders. We reviewed the use of hepatobiliary imaging in patients (N = 42) with fasting-induced gallbladder dysfunction. Intravenous morphine was administered in patients (N = 20) whose gallbladders did not visualize at 40 minutes after administration of diisopropyl iminodiacetic acid. In those patients whose gallbladders visualized with morphine (N = 8), the diagnosis of acute cholecystitis was excluded. Of those that did not visualize after morphine administration (N = 12), all were clinically diagnosed as acute cholecystitis. Although ultrasound is effective in demonstrating the anatomical features of prolonged gallbladder stasis including sludge, stones, and thickened gallbladder wall, it cannot detect cystic duct patency. Cholescintigraphy is an accurate test of cystic duct patency, but gallbladder stasis interferes with the ability of cholescintigraphy to visualize the gallbladder. From our experience, we propose that cholescintigraphy with intravenous morphine is beneficial in demonstrating cystic duct patency in fasting patients.

Localization of human renal cell carcinoma xenografts with a tumor-preferential monoclonal antibody.

We previously described an immunoglobulin G1 monoclonal antibody (UMVA-RCC-A6H) that is highly reactive with human renal cell carcinoma (RCC) and has little cross-reactivity to other cell types both normal and malignant. In efforts detailed herein, radiolabeled A6H selectively localized to RCC xenografts and provided high resolution images of the xenografts. Also, A6H clearly discriminated between RCC xenografts and other human tumor xenografts. Consistent images of RCC xenografts (greater than 60 mg) were obtained without background subtraction. The amount of radiolabeled A6H in the tumor usually ranged from five to twenty times that of the blood. Normal mouse tissues, abscesses, and other human tumor xenografts contained less radiolabel per mg than did blood. A control monoclonal antibody of the same isotype failed to exhibit any localization in xenografts or normal tissues. Approximately 40% of the radiolabeled A6H dose per g was localized in the RCC xenograft 2 days after injection, although at the time of imaging about 60% of the radiolabel remaining in the mouse was associated with the xenograft. These results demonstrate that a RCC restrictive monoclonal antibody does specifically localize to RCC xenografts and supports the hope that this approach may have clinical value for diagnosis, staging, or treatment.

Serum tests for pancreatitis in patients with abdominal pain.

Though the serum total amylase test has been used for the diagnosis of pancreatitis for over 50 years, both its clinical sensitivity and specificity are far from perfect. We first present the results of serial serum total amylase, pancreatic isoamylase, lipase, and immunoreactive trypsin tests in nine patients during the week after their admission to the hospital with a diagnosis of acute pancreatitis, and then compare the serum total amylase, lipase, and immunoreactive trypsin levels in the initial serum submitted for amylase analysis from 100 patients because of the clinical suspicion of acute pancreatitis. In the former group of patients, the serum total amylase test was the least sensitive of the tests for pancreatitis after the first hospital day. In the latter group of patients, the largest discordance was found in patients with elevated serum total amylase levels, but normal lipase and immunoreactive trypsin levels. In 90% of these discordant cases, the elevation of serum total amylase was due to salivary amylase, yielding a maximum clinical specificity of only 71% for serum total amylase. Based on these data, we conclude that alternate tests deserve careful consideration as replacements for the serum total amylase test.

Do calories, osmolality, or calcium determine gastric emptying?

To determine whether calories, osmolality, or calcium mediate gastric emptying we employed a standardized radioactive meal in 10 normal human volunteers. A variety of simple and complex sugars, medium-chain fatty acid (MCFA), pectin, and gluten were dissolved in water and ingested with the test meal. The studies were also performed with calcium chloride, EDTA, and an equimolar combination of these chemicals. Results of gastric emptying showed that incremental glucose produced an increase in emptying time with a tendency for emptying time to show a proportionally greater delay with increasing glucose concentrations. Fructose and polyhexose had similar effects to glucose. Pentoses (xylose and arabanose) markedly prolonged gastric emptying when compared with the same amount of glucose. The effect of sucrose and gluten on gastric emptying did not significantly differ from controls. Twenty-five grams MCFA had an effect similar to 50 g glucose. Pectin, a complex carbohydrate, produced a varied effect in different individuals. There was no obvious relationship between osmolality and gastric emptying. Calcium chloride and EDTA prolonged gastric emptying, but the equimolar combination gave values similar to controls. Our findings suggest 1) calories nor osmolality alone determine gastric emptying, 2) both calcium and calcium chelation with EDTA prolong gastric emptying, and 3) a specific food does not necessarily produce the same effect on gastric emptying in different individuals.

Hyperprolactinaemia in male diabetics.

We recently investigated two patients with diabetes and elevated serum prolactin levels in whom no cause of hyperprolactinaemia could be found. For this reason we measured fasting serum prolactin levels in 72 diabetic males and compared the results with those of 63 healthy males and 90 nondiabetic males attending an Impotence Clinic. The diabetic group had significantly higher serum prolactin levels (13.1 +/- 0.9 ng/ml) than the two control groups (9.9 +/- 0.6 ng/ml for normal males and 7.7 +/- 0.3 ng/ml for the non-diabetic impotent group). Eighteen percent of the diabetics studied had serum prolactin levels above the normal range for males (greater than 20 ng/ml). There was no correlation between serum prolactin levels and duration of diabetes, glycosylated haemoglobin level or presence of clinically apparent retinopathy. The correlation between serum prolactin level and fasting plasma glucose was weak though statistically significant (r = 0.26, P less than 0.05).

Effect of cholestasis on hepatic transport of 99mtechnetium p-isopropyl-iminodiacetic acid.

Hepatobiliary imaging with 99mTc-p-isopropyl-iminodiacetic acid (PIPIDA) and other acetanilidoiminodiacetic acid derivatives is a frequently used clinical tool in evaluating patients with jaundice. However, there has been little objective assessment of the effects of cholestasis on hepatic transport of acetanilioiminodiacetic acid derivatives. In our studies, transport of 99mTc-PIPIDA by isolated rat hepatocytes obtained from animals with extrahepatic obstruction secondary to bile duct ligation or intrahepatic cholestasis induced by ethinyl estradiol therapy was determined. Uptake constants for 99mTc-PIPIDA by hepatocytes isolated from livers of animals with ligated bile ducts were significantly decreased compared with uptake by liver cells from sham-operated controls (0.0030 +/- 0.0003 vs. 0.0089 +/- 0.0010 femtomole X 10(6) cells-1 X min-1 X pmol/L-1; p less than 0.001). Hepatocytes isolated from livers of animals given ethinyl estradiol also demonstrated significantly reduced 99mTc-PIPIDA uptake compared with controls given propylene glycol (0.0034 +/- 0.0002 vs. 0.0060 +/- 0.0004 fmol X 10(6) cells-1 X min-1 X pmol/L-1; p less than 0.001). Fractional rates of efflux of the study compound from hepatocytes preincubated with 99mTc-PIPIDA were significantly decreased in experiments using ethinyl estradiol (p less than 0.005) but did not differ significantly from controls in studies of bile duct ligation. 99mTc-PIPIDA uptake was significantly decreased in the presence of high bile salt concentrations (100 to 200 mumol/L), but unconjugated bilirubin concentrations as high as 200 mumol/L (approximately 12 mg/dl) had no effect on hepatocyte uptake of the ligand. The finding that cholestasis significantly impairs hepatocyte uptake of 99mTc-PIPIDA provides a possible explanation for the clinical observation that a patent biliary tree and normal serum bilirubin level are not always sufficient to ensure normal hepatobiliary imaging. These data also suggest that elevation of bile acid levels during cholestasis may either contribute to impaired uptake of hepatobiliary imaging agents or serve as a marker of cholestasis-induced abnormalities in the liver functions responsible for hepatic transport of these compounds.

Can the three-phase bone scan differentiate osteomyelitis from metabolic or metastatic bone disease?

The three-phase bone scan has been reported of value in the diagnosis of osteomyelitis. The use of a radionuclide angiogram, an immediate postinjection "blood pool" image, and 2 to 3 hour delayed image have been useful in separating nonosseous inflammatory disease from osteomyelitis. However, dependence on increased blood flow and focal hyperemia for this diagnosis may limit the use of the study if other processes are shown to produce similar results. To identify limitations of the three-phase bone scan we studied 14 patients with metastatic bone disease and nine patients with Paget's disease. Blood flow results showed no increase in three of 14 patients with metastases, intermediate increase in seven of 14 patients with metastases and two of nine patients with Paget's, and intense increase in four of 14 patients with metastases and seven of nine patients with Paget's. All patients showed increased focal activity in the immediate "blood pool" and delayed images. We conclude that because of increased flow Paget's disease may be difficult to separate from osteomyelitis. However, metastatic disease can often be differentiated on the basis of quantitative focal hyperemia. The three-phase bone scan remains of value in the diagnosis of osteomyelitis, but other diseases of bone must be included in the differential diagnosis.