The effect of dexfenfluramine on eating habits in a Dutch ambulatory android overweight population with an overconsumption of snacks.

OBJECTIVE: To investigate the effect of the serotonin receptor agonist dexfenfluramine on eating habits and weight loss in ambulatory, android type, moderately obese patients with an overconsumption of snacks. DESIGN: 9 week, randomized, double-blind treatment with either dexfenfluramine (30 mg/day) or placebo, without dietary intervention. SETTING: Outpatient clinics of four University Hospitals in The Netherlands. SUBJECTS: 112 healthy obese subjects, body mass index 28-35 kg/m2, waist-to-hip ratio > or = 1.0 for men and > or = 0.8 for women, consuming more than five snacks containing in total more than 500 kcal/day and/or more than 25% of total calorie intake in the form of snacks. MAIN OUTCOME MEASURES: Changes in macronutrient composition of the diet, food intake (total, at principal meals and in between meals in the form of snacks) and weight loss. RESULTS: 104 subjects were included for efficacy analysis. In both the dexfenfluramine group (n = 51) and the placebo group (n = 53) the total energy intake decreased. The decrease during main meals was significantly greater in the dexfenfluramine group for all parameters tested except for simple carbohydrates. In between meals the decrease in intake was significantly greater in the dexfenfluramine group for total energy intake (P < 0.05) and intake in unsaturated fat (P < 0.05). The reported reduction in total food intake in the dexfenfluramine group was similarly due to reductions in carbohydrate and fat intake. No weight loss was seen in the placebo group. The treated group lost 3.1 +/- 0.2 kg (P < 0.01). CONCLUSION: Dexfenfluramine effectively reduces the intake of carbohydrates as well as fat in ambulatory, non diet restricted android obese subjects by reducing food intake during and in between main meals.

Value of autopsy in internal medicine: a 1-year prospective study of hospital deaths.

In a university Department of Internal Medicine, we compared the clinical information, as written down immediately post mortem, with the demand for autopsy and with the autopsy findings during one complete year. Autopsies were performed in 143 of 306 consecutive deaths. In autopsied patients clinicians had recorded more diagnoses per patient, but with less certainty than in non-autopsied patients. Patients with a diagnosis of a solid tumour were autopsied less often, and patients with infections or gastrointestinal disease more often than the average patient. These findings indicate selection of cases for autopsy. In 41% of patients erroneous diagnoses were detected that might have influenced management of the patient. In 28% of patients autopsy offered no additional information about one or more diagnoses. Both the proportion of errors and the proportion of uninformative autopsies increased with decreasing clinical certainty about the diagnosis. We conclude that autopsy offers useful information in most cases, and that selection of cases for autopsy is probably not justified.

Direct measurement of human plasma corticotropin-releasing hormone by "two-site" immunoradiometric assay.

A "two-site" immunoradiometric assay (IRMA) which allows the direct estimation of human CRH (hCRH) in plasma is described. Using this IRMA, basal levels of CRH in normal subjects ranged from 2-28 pg/mL [mean, 15 +/- 7 (+/- SD) pg/mL; n = 58]. Values in men and women were similar. Plasma CRH values within this range were also found in patients with Cushing's syndrome, Addison's disease, and Nelson's syndrome, with no correlation between plasma CRH and ACTH levels in these patients. Elevated plasma CRH levels were found in pregnant women near term [1462 +/- 752 (+/- SD) pg/mL; n = 55], and the dilution curve of this CRH-like immunoreactivity paralleled the IRMA standard curve. After its immunoadsorption from maternal plasma, this CRH-like material eluted on reverse phase high performance liquid chromatography with a retention time identical to that of synthetic CRH and had equipotent bioactivity with the synthetic peptide in the perfused anterior pituitary cell bioassay. Circulating CRH was not detected in Wistar rats, even after adrenalectomy and subsequent ether stress. Synthetic hCRH was degraded by fresh human plasma relatively slowly; 65% of added CRH remained after 1 h of incubation at 37 C. Degradation was inhibited by heat treatment (54 C; 1 h), cold treatment (4 C; 4 h), or freezing and thawing. Loss of synthetic rat CRH occurred more rapidly when fresh rat plasma was used; only 20% of added CRH remained under the same conditions. The inability to measure CRH in peripheral rat plasma may be due to the presence of active CRH-degrading enzymes which fragment the CRH molecule into forms not recognized by the CRH IRMA.

Immunohistochemical localization and chromatographic characterization of human chorionic gonadotropin in a bladder carcinoma.

We describe a patient with advanced bladder carcinoma, in which ectopic synthesis and secretion of human chorionic gonadotropinlike immunoreactivity (ihCG) was demonstrated. Concanavalin A-sepharose affinity chromatography of serum revealed that the ihCG differed from placental human chorionic gonadotropin in its carbohydrate moiety. Treatment of the patient with a cisplatin-containing regimen did not result in regression of the tumor. Since immunohistochemistry revealed ihCG in five of 13 additional cases of bladder carcinoma, it is concluded that ectopic production of ihCG by bladder carcinomas is probably not rare.

Growth hormone releasing factor (GRF) immunoreactivity in human and rat gastrointestinal tract and pancreas.

Rabbit antisera were raised against a synthetic growth hormone releasing factor, which was originally isolated from a human pancreatic endocrine tumor (hpGRF-44). The antisera obtained showed no significant cross-reactivity with a variety of neurohormonal peptides. In addition to its occurrence in the human, but not in the rat, hypothalamus, hpGRF-44-like immunoreactivity was identified in human gastric antrum and human as well as rat pancreatic islets, using an indirect immunoperoxidase technique. Staining of serial sections and double staining revealed that in the gastric antrum the immunoreactivity was largely confined to gastrin (G) cells, whereas in pancreatic islets polypeptide (pp) cells were reactive. The physiological significance of these findings remains to be established.

Glucose-induced changes in somatostatin-14 and somatostatin-28 released from rat hypothalamic fragments 'in vitro'.

Previous data suggest that somatostatin is present and released from the hypothalamus in several molecular forms, basally and after K+ or electrical stimulation. In order to evaluate the proportions of somatostatin-14 (S14) and somatostatin-28 (S28) released during a stimulus which may be more closely related to the control of growth hormone secretion 'in vivo', we studied the molecular forms of somatostatin released from hypothalamic fragments ' in vitro', during incubations with different glucose concentrations (1.35 and 22mM), which we have previously shown to be inversely related to somatostatin release. Sephadex G-50 chromatography demonstrated that both forms are released in the same proportions (S14: 70%; S28: 30%) during incubation with different glucose concentrations; there is a parallel increase in both forms when low glucose is used. Although on a molar basis less S28 is released than S14, the higher potency, longer duration of action and higher affinity for pituitary receptors of S28 suggests that it may be of major physiological importance.

Glucose modulation of somatostatin and LHRH release from rat hypothalamic fragments in vitro.

In the rat, hypoglycaemia inhibits growth hormone secretion, but the mechanism is unclear. To investigate this further, we have studied the effects of glucose and 2-deoxy-D-glucose on somatostatin and LHRH release from rat hypothalamic fragments incubated in vitro. Glucose (1.35-22 mM) was added to glucose-free medium and 5 and 50 mM 2-deoxy-D-glucose were added to medium containing 5.5 mM glucose. Medium somatostatin and LHRH levels were measured by RIA. Somatostatin and LHRH released diluted in parallel with synthetic somatostatin and LHRH. Sephadex gel filtration demonstrated two molecular forms of somatostatin, 70% coeluting with somatostatin-14 and 30% with somatostatin-28; LHRH coeluted with synthetic LHRH. KCl (30-100 mM) resulted in release of somatostatin and LHRH; this was reduced in calcium-free medium. Basal and K+-stimulated somatostatin release were significantly increased by reducing glucose levels (r = -0.6, p less than 0.001). Basal LHRH was not influenced by glucose. Basal and K+-induced somatostatin release were significantly increased by 2-deoxy-D-glucose (p less than 0.05), while LHRH levels remained unchanged. Our results demonstrate that basal and K+-induced somatostatin release from rat hypothalamic fragments are modulated by local glucose concentrations, and this effect is specific as it is not paralleled by LHRH changes. We suggest that the reduction in growth hormone secretion during hypoglycaemia in the rat might be mediated, at least in part, via a direct effect of glucose on somatostatin release.

Heterogeneous immunocytochemical reactivities of oCRF-41-like material in the human hypothalamus, pituitary and gastrointestinal tract.

Tissue specimens of human hypothalami, pituitaries and gastrointestinal tract were studied with an indirect immunoperoxidase technique using 6 different rabbit ovine corticotrophin-releasing factor (oCRF-41) antisera. All these antisera detected oCRF-41-like immunoreactivity in parvocellular neurones of the paraventricular nucleus of the hypothalamus and their nerve terminals adjacent to portal capillaries in the infundibular stem and posterior pituitary. 1 antiserum recognised oCRF-41-like immunoreactivity in the growth hormone cells of the anterior pituitary. 3 other antisera recognised oCRF-41-like immunoreactivity in mucosal cells of the gastric antrum. Pre-treatment of the antisera with sauvagine did not affect the immunostaining of the hypothalamic and gastric cells, but quenched the immunostaining of growth hormone cells in the anterior pituitary. It is concluded that (1) in human hypothalami a CRF is synthesized that is structurally very similar to oCRF-41; (2) in growth hormone cells of the anterior pituitary oCRF-41-like immunoreactive material can be detected which shares antigenic determinants with sauvagine; (3) in mucosal cells of the gastric antrum oCRF-41-like immunoreactivity is present that is comparable but probably not identical to hypothalamic CRF and is not sauvagine-like.

Use of immunohistochemical and morphologic methods for the identification of human growth hormone-producing pituitary adenomas.

Indirect immunoperoxidase and immunofluorescent techniques were used for the detection of growth hormone in routinely processed human pituitary adenomas. With the immunoperoxidase method, distinct immunoreactive cells could be demonstrated in 15 adenomas; all except for one were associated with acromegaly. Immunofluorescence was less useful because of autofluorescence due to the fixation. In histologic stainings, the immunoreactive cells were acidophyl. With immunohistochemistry and electron microscopy, densely granulated and sparsely granulated adenomas could be distinguished. Sparse granulation was associated with an expanded rough-surfaced endoplasmic reticulum and Golgi complex. Clinically, the sparsely granulated adenomas were characterized both by active hormone secretion and aggressive local growth. It is concluded that the immunoperosidase method is of value for functional classification of pituitary adenomas. For information about secretory activity we suggest that electron micrographs of adenoma cells be examined.