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The aim of this study was to identify nonalcoholic fatty liver in obese children by magnetic resonance imaging (MRI) and to compare the findings with the data from ultrasonography and from clinical and laboratory testing. Sixty obese children, 6 to 14 years old, underwent hepatic MRI and abdominal ultrasonography. Biochemistry determinations included serum aminotransferases, lipid profile, glucose, and insulin. Anthropometry included body mass index, total and trunk fat, and fat-free mass obtained by dual-energy radiographic absorptiometry. Hepatic steatosis, judged as hepatic fat fraction by MRI, was =9%. By MRI, 14 (23%) children had hepatic steatosis; of those, 5 had a fat fraction of 9% to 18%, and 9 had a fat fraction >18%. At univariate analysis, fat fraction was positively associated with being male, serum alanine aminotransferase, aspartate aminotransferase, and ?-glutamyltransferase, body mass index zscore, insulin, systolic pressure, and total and trunk fat mass. Hepatic steatosis was independently associated with alanine aminotransferase (P< 0.01). Overall, liver echogenicity on ultrasonography correlated well with fat fraction by MRI (correlation coefficient 0.527, P< 0.0001). Among the 27 children with increased liver echogenicity, 13 (48%) had hepatic fat fraction =9%, and 89% of children with echogenicity graded 2 or 3 had fat fraction >18%. All of the children (n = 9) with fat fraction >18% had increased liver echogenicity, and in 8 of them it was graded 2 or 3, but the MRI fat fraction ranged greatly (28%–45%). In obese children, nonalcoholic hepatic steatosis may be associated with the metabolic syndrome. Ultrasonography may be valuable in identifying high hepatic fat accumulation, but its ability to identify lower fat accumulation in the liver is scanty compared with MRI.

The aim of this study was to identify nonalcoholic fatty liver in obese children by magnetic resonance imaging (MRI) and to compare the findings with the data from ultrasonography and from clinical and laboratory testing.

We report a patient with a meningioma presenting with Cushing's syndrome, an unprecedented paraneoplastic presentation. Molecular studies, bioassay, and high‐performance liquid chromatography of tumor specimens demonstrated the synthesis and secretion of bioactive corticotropin‐releasing hormone. To our knowledge, this appears to be the first report of a hormone‐secreting meningioma and, further, the first clearly proven case of Cushing's syndrome due to ectopic corticotropin‐releasing hormone secretion without concomitant corticotropin production. Ann Neurol 2003

We report a patient with a meningioma presenting with Cushing's syndrome, an unprecedented paraneoplastic presentation. Molecular studies, bioassay, and high-performance liquid chromatography of tumor specimens demonstrated the synthesis and secretion of bioactive corticotropin-releasing hormone. To our knowledge, this appears to be the first report of a hormone-secreting meningioma and, further, the first clearly proven case of Cushing's syndrome due to ectopic corticotropin-releasing hormone secretion without concomitant corticotropin production. Ann Neurol 2003

In a companion article, we describe the engineering and characterization of pituitary GH3 cell clones stably transfected with a furin-cleavable human insulin cDNA (InsGH3 cells). This article describes the performance of InsGH3 (clones 1 and 7) cell grafts into streptozotocin (STZ)-induced diabetic nude mice. Subcutaneous implantation of 2 × 106InsGH3 cells resulted in the progressive reversal of hyperglycemia and diabetic symptoms, even though the progressive growth of the transplanted cells (clone 7) eventually led to glycemic levels below the normal mouse range. Proinsulin transgene expression was maintained in harvested InsGH3 grafts that, conversely, lose the expression of the prolactin (PRL) gene. Elevated concentrations of circulating mature human insulin were detected in graft recipients, demonstrating that proinsulin processing by InsGH3 cells did occur in vivo. Histologic analysis showed that transplanted InsGH3 grew in forms of encapsulated tumors composed of cells with small cytoplasms weakly stained for the presence of insulin. Conversely, intense insulin immunoreactivity was detected in graft-draining venules. Compared to pancreatic βTC3 cells, InsGH3 cells showed in vitro a higher rate of replication, an elevate resistance to apoptosis induced by serum deprivation and proinflammatory cytokines, and significantly higher antiapoptotic Bcl-2 protein levels. Moreover, InsGH3 cells were resistant to the streptozotocin toxicity that, in contrast, reduced βTC3 cell viability to 50–60% of controls. In conclusion, proinsulin gene expression and mature insulin secretion persisted in transplanted InsGH3 cells that reversed hyperglycemia in vivo. InsGH3 cells might represent a potential β-cell surrogate because they are more resistant than pancreatic β cells to different apoptotic insults and might therefore be particularly suitable for encapsulation.

Successful β-cell replacement therapy in insulin-dependent (type I) diabetes is hindered by the scarcity of human donor tissue and by the recurrence of autoimmune destruction of transplanted β cells. Availability of non-β cells, capable of releasing insulin and escaping autoimmune recognition, would therefore be important for diabetes cell therapy. We developed rat pituitary GH3 cells stably transfected with a furin-cleavable human proinsulin cDNA linked to the rat PRL promoter. Two clones (InsGH3/clone 1 and 7) were characterized in vitro with regard to basal and stimulated insulin release and proinsulin transgene expression. Mature insulin secretion was obtained in both clones, accounting for about 40% of total released (pro)insulin-like products. Immunocytochemistry of InsGH3 cells showed a cytoplasmic granular insulin staining that colocalized with secretogranin II (SGII) immunoreactivity. InsGH3 cells/clone 7 contained and released in vitro significantly more insulin than clone 1. Secretagogue-stimulated insulin secretion was observed in both InsGH3 clones either under static or dynamic conditions, indicating that insulin was targeted also to the regulated secretory pathway. Proinsulin mRNA levels were elevated in InsGH3 cells, being significantly higher than in PTC3 cells. Moreover, proinsulin gene expression increased in response to various stimuli, thereby showing the regulation of the transfected gene at the transcriptional level. In conclusion, these data point to InsGH3 cells as a potential β-cell surrogate even though additional engineering is required to instruct them to release insulin in response to physiologic stimulations.

OBJECTIVES

There is a great need to learn more about porcine islet physiology because porcine islets represent a promising source of xenogeneic tissue for β-cell replacement therapy in humans.

Pancreatojejunal anastomosis disruption still represents the main postoperative complication after pancreatoduodenectomy. In this study, a technique of occlusion of the residual pancreatic stump instead of pancreatojejunal anastomosis is proposed. Between March, 1981 and August, 1987, we performed 51 pancreatoduodenectomies, using Neoprene®injection in the Wirsung duct, for carcinoma of the pancreatic head (28 cases), ampullary carcinoma (12 cases), islet cell carcinoma (5 cases), and chronic pancreatitis (6 cases). We observed a 33.3% overall morbidity, with a 5.8% operative mortality. The complications observed seemed not to be related to the technique of pancreatic stump occlusion, except for 2 pancreatic fistulas which spontaneously resolved. Abdominal ultrasound and computed tomography scan performed during the follow-up did not show any significant morphological alteration of the residual stump. Pancreatic endocrine function was assessed in 10 patients by evaluating blood glucose, plasma insulin and plasma glucagon levels both fasting and after oral glucose, and intravenous arginine infusion. These tests were performed before surgery and 15 days, 6 months, 1, 2, and 3 years after surgery. The results showed that 60% of the patients had impaired glucose tolerance before surgery and the percentage did not significantly change up to 3 years later (75%). No patient developed diabetes mellitus, and only 1 patient progressed from a normal to an impaired glucose tolerance. In conclusion, intraductal injection of Neoprene®after pancreatoduodenectomy seems to be a safer procedure compared to pancreatojejunal anastomosis and does not induce a postsurgical diabetes.

Histamine stimulates prolactin (PRL) and growth hormone (GH) release in the experimental animal. In order to evaluate the possible effect of histamine on these hormones in man, in our study, 9 normal volunteers underwent an intravenous histamine infusion (200 μg in 15 min). Five of them also underwent an intravenous histidine infusion (200 μg). Histamine induced a significant PRL release in 7 subjects, the maximum level reached being 36.2 ± 12.09 ng/ml, while GH levels were not affected. Histidine was ineffective on both PRL and GH levels. It is known that histamine, administered peripherally, does not cross the blood brain barrier. This fact suggests that, in man, histamine stimulates PRL release by acting directly on the pituitary. In addition, since stressful situations may elicit both PRL and GH release, the fact that the latter was not affected by histamine, suggests that a mere stress-effect is not responsible for the PRL release observed in our subjects.

Prolactin (Prl) release, both in the experimental animal and in man, is stimulated by serotonin (5HT) and inhibited by dopamine (DA). Data also suggest that LH release in the animal is stimulated by norepinephrine and inhibited by DA. The role of 5HT in the control of LH release is less clear. It would appear to stimulate episodic LH release and to inhibit the LH surge at the pro-oestrus in animals, but the effect of 5HT on LH release has not yet been evaluated in man. In the present paper we have studied the effect of various DA-ergic drugs (DA, iv 1-dopa, po 1-dopa and bromoergocriptine) and of two anti-5HT drugs, metergoline and methysergide, on Prl and LH release in normal women. DA-ergic drugs lowered plasma Prl and LH levels; anti-5HT drugs, at doses able to lower Prl levels, did not affect basal LH release nor the inhibiting effect of iv 1-dopa on LH release. These data indicate that DA inhibits both LH and Prl release in normal women, and that 5HT stimulates Prl release but is not involved in the regulation of LH secretion. The fact that, at variance to all the DA-ergic drugs used, the two anti-5HT drugs did not vary LH release, suggests that metergoline and methysergide are devoid of DA-ergic activity in man, at least at the doses able to inhibit Prl release.

The growth hormone response to arginine infusion was greater in normal females than in normal males and was impaired in patients with obesity and/or elevated serum triglyceride levels, but with normal glucose tolerance. In patients with chemical diabetes these differences were smaller and were not statistically significant. Both clofibrate, a hypolipemic agent, and metergoline, an antiserotonin drug, enhanced GH response to arginine in normal subjects, but not in patients with CD.

The detection of chromogranins (Cg) by immunohistochemistry and serology represents a new in vitro diagnostic tool for endocrine tumours. We have recently reported on the feasibility of targeting chromogranin A (CgA) for in vivo detection of pituitary adenomas by immunoscintigraphy (ISG). The scintigraphic procedure, based on an anti-CgA monoclonal antibody and on the avidin-biotin three-step method (Cg-3S-ISG), was evaluated on a group of 29 consecutive patients with known or suspected endocrine tumours other than pituitary adenomas, i.e. medullary thyroid carcinoma, carcinoid, insulinoma and parathormone- or ACTH-producing tumours. Primary tumours (10) and recurrences (16) were visualised in 26 patients, whereas conventional imaging techniques (planar radiography, computerised tomography, magnetic resonance imaging and ultrasonography) failed to detect the tumour sites in ten of the same (Cg-3S-ISG-positive) patients. Therefore, these preliminary results indicate that Cg-3S-ISG, the first immunological method able to detect endocrine tumours in vivo, has a higher diagnostic accuracy than conventional imaging techniques (93.1% compared with 65.5%).

In three hyperthyroid women aged more than 60 years serum TSH levels, inhibited as usual before treatment, rose and remained elevated for more than one year while on treatment with methymazole and l-thyroxine, in spite of serum T3 and T4 levels within the normal range. In two hypothyroid women aged more than 60 years, serum TSH levels, raised under basal conditions, failed to be suppressed by a one-year treatment with 1-thyroxine. Repeated attempts to increase serum T3 and T4 concentrations by giving additional doses of 1-thyroxine or by tapering methymazole dosage, led to clinical signs of hyperthyroidism, not accompanied by a significant reduction of serum TSH levels. These data indicate the possibility of an inappropriate TSH release in some elderly people.

In order to evaluate the spontaneous variability of prolactin (PRL) release in response to various stimuli applied repeatedly on different occasions, groups of 5 to 12 subjects each underwent consecutive identical tests with one of the following stimuli applied at 3–6 days' intervals: sulpiride (100 mg im), benserazide (50 mg po), insulin hypoglycaemia (0.1 U/kg b. w. iv) and arginine infusion (25 g iv in 30 min). When repeated in the same subjects, arginine and benserazide yielded superimposable results. In contrast to this, insulin hypoglycaemia yielded significantly lower PRL release, while the PRL response to the second sulpiride test was significantly higher than to the first one. When an interval of 10 days was left between two consecutive sulpiride tests, an identical PRL release was observed. These results indicate that arginine and benserazide are reproducible tests for PRL secretion and it is possible that the decreasing effect of insulin hypoglycaemia on PRL release is due to the stressful effect of the stimulus. Finally, sulpiride probably enhances both PRL release and synthesis thus making greater amounts of PRL available to a subsequent stimulus. Since some of the above stimuli are usual tools for the study of the neuroendocrine control of PRL secretion, our findings suggest that caution appears necessary in attributing to any (neuroactive) drug an effect which might be merely due to a lack of reproducibility of the stimulus employed.

Pancreatic transplantation is intended to normalize carbohydrate metabolism in insulin-dependent diabetics by restoring endogenous insulin release, and it is usually performed together with kidney transplantation in patients with end-stage renal failure. A major problem in these patients is the daily control of the grafted pancreas because traditional measurements do not appear to be adequate to evaluate pancreatic function. Aiming at early detection of graft failure, we have analyzed in 8 such patients and in 20 nondiabetic kidney-grafted patients (a control group) the following variables: 24-hr glycosuria (absolute values, or values after natural logarithmic transformation) and 24-hr urinary C-peptide excretion (corrected for 24-hr urinary creatinine). These measurements, considered alone, did not detect pancreatic graft failure; for instance, glycosuria can depend on immunosuppressive steroid treatment, and it was often found even in the control group. On the contrary, the ratio Ln 24-hr glycosuria: 24-hr urinary C-peptide varied from 0.00 to 0.18 in the control group and in normally working pancreatic grafts; when the pancreatic grafts failed, however, as confirmed by arteriographic evidence, histologic findings, or dynamic endocrine tests, this ratio rose far higher than 0.18, reaching values as high as 12.2. Use of this ratio provides a simple technique for daily evaluation of pan-creatic graft function and for early detection of graft failure.

A laparoscopic approach was used to remove the adrenal gland in 7 patients with aldosterone-producing adenoma (Conn’s disease), 2 with corticosteroid-producing adenoma (pituitary-independent Cushing’s syndrome) and 2 with pheochromocytoma. The affected gland was on the right side in 3 patients and on the left side in 8. Mean operative time was 3hours 10minutes (range 140 to 370minutes). The operation was uneventful in all patients and blood transfusions were never required. Mean postoperative hospitalization was 2.9 ± 0.8 days (standard error). Only minimal doses of analgesics were used postoperatively. All patients returned to work within 10 days postoperatively (mean 8.4 ± 1.2 days). Two months postoperatively no patient had clinical, biochemical or hormonal evidence of recurrent or persistent disease. We conclude that laparoscopic adrenalectomy is a safe and effective, minimally invasive approach for patients with benign adrenal neoplasms.

Pancreatojejunal anastomosis disruption still represents the main postoperative complication after pancreatoduodenectomy. In this study, a technique of occlusion of the residual pancreatic stump instead of pancreatojejunal anastomosis is proposed. Between March, 1981 and August, 1987, we performed 51 pancreatoduodenectomies, using Neoprene®injection in the Wirsung duct, for carcinoma of the pancreatic head (28 cases), ampullary carcinoma (12 cases), islet cell carcinoma (5 cases), and chronic pancreatitis (6 cases). We observed a 33.3% overall morbidity, with a 5.8% operative mortality. The complications observed seemed not to be related to the technique of pancreatic stump occlusion, except for 2 pancreatic fistulas which spontaneously resolved. Abdominal ultrasound and computed tomography scan performed during the follow-up did not show any significant morphological alteration of the residual stump. Pancreatic endocrine function was assessed in 10 patients by evaluating blood glucose, plasma insulin and plasma glucagon levels both fasting and after oral glucose, and intravenous arginine infusion. These tests were performed before surgery and 15 days, 6 months, 1, 2, and 3 years after surgery. The results showed that 60% of the patients had impaired glucose tolerance before surgery and the percentage did not significantly change up to 3 years later (75%). No patient developed diabetes mellitus, and only 1 patient progressed from a normal to an impaired glucose tolerance. In conclusion, intraductal injection of Neoprene®after pancreatoduodenectomy seems to be a safer procedure compared to pancreatojejunal anastomosis and does not induce a postsurgical diabetes. La fistule de l'anastomose pancréaticojéjunale représente toujours la source principale des complications après duodénopancréatectomie céphalique. Dans cette étude, on a évalué les résultats d'une méthode d'occlusion du moignon pancréatique, alternative proposée à la place de l'anastomose. Entre mars 1981 et août 1985, 51 duodénopancréatectomies avec occlusion du canal de Wirsung par la colle néoprène ont été réalisées. Leurs indications étaient un cancer de la tête du pancréas chez 28 patients, un cancer ampullaire chez 12, un cancer insulaire chez 5, et une pancréatite chronique chez 6. La morbidité était de 33.3%; la mortalité opératoire, de 5.8%. Les complications observées ne semblaient pas être en rapport avec la méthode d'occlusion, sauf dans 2 cas de fistules pancréatiques spontanément résolutives. L'échographie et la tomodensitométrie abdominales réalisées après l'intervention n'ont pas mis en évidence de changements morphologiques significatifs du moignon pancréatique. La fonction pancréatique endocrine a été évaluée chez 10 patients en determinant la glycémie, l'insulinémie et les niveaux de glucagon dans le plasma, à jeun, après ingestion de glucose par voie orale et après perfusion intraveineuse d'arginine. Ces examens ont été effectués avant, 15 jours, 6 mois, 1, 2, et 3 ans après la chirurgie. Les résultats ont démontré que 60% des patients avaient une tolérance au glucose perturbée avant l'intervention et que cette proportion n'avait pas tellement changé 3 ans après (75%). Aucun patient n'a développé de diabète postopératoire et 1 patient seulement qui avait une tolérance normale préopératoire a présenté une perturbation de la tolérance au glucose postopératoire. En conclusion, l'injection intracanalaire de néoprène après duodénopancréatectomie céphalique est un procédé sûr comparé à l'anastomose pancréaticojéjunale et elle ne provoque pas de diabète postopératoire. La dehiscencia de la pancreatoyeyunostomía todavía representa la mayor complicación postoperatoria de la pancreatoduodenectómía. En este estudio se propone una técnica de oclusión del muñón pancreático residual, en cambio de la anastomosis pancreatoyeyunal. Cincuenta y una pancreatoduodenectomías fueron practicadas entre marzo de 1981 y agosto de 1987, usando una inyección de Neoprene®en el canal de Wirsung, para carcinoma de la cabeza del páncreas (28 casos), carcinoma ampular (12 casos), carcinoma de los islotes (5 casos), y pancreatitis crónica (6 casos). La mortalidad global fue de 33.3%, con una mortalidad operatoria del 5.8%. Las complicaciones observadas parecen no estar relacionadas con la técnica de oclusión del muñón pancreático, excepto por 2 fistulas pancreáticas que se resolvieron espontáneamente. La ultrasonografía y escanografía computadorizada practicadas durante el período de seguimiento, no mostraron alteración morfológica significativa del muñón residual. La función endocrina del páncreas fue valorada en 10 pacientes mediante la determinación de glicemia y niveles plasmáticos de insulina y glucagón, tanto en ayunas como después de la administración de glucosa oral y arginina intravenosa. Estos exámenes fueron realizados antes de la cirugía y a los 15 días, 6 meses, 1, 2, y 3 años después de la cirugía. Los resultados mostraron que el 60% de los pacientes presentó intolerancia a la glucosa antes de la cirugía y que este porcentaje no mostró cambios significativos hasta 3 años más tarde (75%). Ningún paciente desarrolló diabetes mellitus, y solamente un patiente progresó al estado normal hasta la intolerancia a la glucosa. En conclusión, la inyección intraductal de Neoprene®después de la pancreatoduodenectomía parece ser un procedimiento seguro comparado con la anastomosis pancreatoyeyunal y no induce diabetes postoperatoria.