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Biomedical subjects

J Rahier

Publications and source records attributed to J Rahier.

At least 55 records · Page 3Linked to original sources
PubMed1999

Familial adenomatous polyposis associated with multiple adrenal adenomas in a patient with a rare 3' APC mutation.

Familial adenomatous polyposis (FAP) is characterised by hundreds of colorectal adenomas. Endocrine neoplasms have occasionally been reported, as have gastric polyps, which are usually hamartomatous in the fundus of the stomach and adenomatous in the antrum. A 57 year old man with colorectal, gastric, and periampullary adenomatous polyposis, in association with three bilateral adrenocortical adenomas, is presented. Mutation screening showed a 5960delA germline mutation in the adenomatous polyposis coli (APC) gene predicted to lead to a premature stop codon. This mutation was found in three of the four children of the patient. Western blot analysis of a lymphoblastoid cell line derived from the patient failed to detect any truncated APC polypeptide. This rare 3' mutation is responsible for an unusually complex and late onset phenotype of FAP.

Adenomatous Polyposis Coli↗
PubMed1998

Paternal mutation of the sulfonylurea receptor (SUR1) gene and maternal loss of 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia.

Congenital hyperinsulinism, or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is a glucose metabolism disorder characterized by unregulated secretion of insulin and profound hypoglycemia. From a morphological standpoint, there are two types of histopathological lesions, a focal adenomatous hyperplasia of islet cells of the pancreas in approximately 30% of operated sporadic cases, and a diffuse form. In sporadic focal forms, specific losses of maternal alleles (LOH) of the imprinted chromosomal region 11p15, restricted to the hyperplastic area of the pancreas, were observed. Similar mechanisms are observed in embryonal tumors and in the Beckwith-Wiedemann syndrome (BWS), also associated with neonatal but transient hyperinsulinism. However, this region also contains the sulfonylurea receptor (SUR1) gene and the inward rectifying potassium channel subunit (KIR6.2) gene, involved in recessive familial forms of PHHI, but not known to be imprinted. Although the parental bias in loss of maternal alleles did not argue in favor of their direct involvement, the LOH may also unmask a recessive mutation leading to persistent hyperinsulinism. We now report somatic reduction to hemizygosity or homozygosity of a paternal SUR1 constitutional heterozygous mutation in four patients with a focal form of PHHI. Thus, this somatic event which leads both to beta cell proliferation and to hyperinsulinism can be considered as the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation leading to a somatic recessive disorder.

ATP-Binding Cassette Transporters↗
PubMed1998

Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria.

UNLABELLED: Primary persistent hyperinsulinaemic hypoglycaemia of infancy is rare. Diazoxide treatment remains the mainstay of medical therapy in long-term management. We reviewed 77 cases of primary persistent hyperinsulinism in neonates and infants who were treated with diazoxide and studied criteria predictive of therapeutic efficacy. The only criterion identified was age at manifestation. All but 1 of the 31 neonatal cases were unresponsive to diazoxide. Responsiveness increased with age: 12 of 39 early-infantile cases, and all seven late-infantile cases were diazoxide-responsive. In responders, a diazoxide dose of 10-15 mg/kg per day was always effective, suggesting an "all or none" response. Diazoxide-resistant hyperinsulinism is characterized by its severity with higher plasma insulin levels. The analysis of 46 surgically treated patients showed that the efficacy of diazoxide is not related to the aetiology of the pancreatic lesions. In six cases, after many years of management, diazoxide treatment was stopped without recurrence of hypoglycaemia. CONCLUSION: Diazoxide is an efficient treatment in the long-term management of most persistent hyperinsulinaemic hypoglycaemia of infancy revealed in infants and children but is usually ineffective in neonatal forms. Drug efficacy does not correlate with anatomical lesions. Medical treatment can sometimes be stopped after many years of management without recurrence of disease manifestations.

Diazoxide↗
PubMed1998

[Persistent hyperinsulinemic hypoglycemia in the newborn and infants].

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is the most frequent cause of hypoglycaemia in infancy. Clinical presentation is heterogeneous, with variable onset of hypoglycaemia and response to diazoxide, and presence of sporadic or familial forms. Underlying histopathological lesions can be focal or diffuse. Focal lesions are characterised by focal hyperplasia of pancreatic islet-like cells, whereas diffuse lesions implicate the whole pancreas. The distinction between the two forms is important because surgical treatment and genetic counselling are radically different. Focal lesions correspond to somatic defects which are totally cured by limited pancreatic resection, whereas diffuse lesions require a subtotal pancreatectomy exposing to high risk of diabetes mellitus. Diffuse lesions are due to functional abnormalities involving several genes and different transmission forms. Recessively inherited PHHI have been attributed to homozygote mutations for the beta-cell sulfonylurea receptor (SUR1) or the inward-rectifying potassium-channel (Kir6.2) genes. Dominantly inherited PHHI can implicate the glucokinase gene, particularly when PHHI is associated with diabetes, the glutamate dehydrogenase gene when hyperammonaemia is associated, or another locus.

Diazoxide↗
PubMed1998

Partial or near-total pancreatectomy for persistent neonatal hyperinsulinaemic hypoglycaemia: the pathologist's role.

AIMS: To determine whether the presence of abnormal B-cell nuclei predicts the existence of a focal or of a diffuse form of persistent neonatal and infantile hyperinsulinaemic hypoglycaemia in a series of 20 infants. METHODS AND RESULTS: Intra-operative frozen sections were performed on small specimens from the pancreatic head, isthmus and tail. In 13 cases, abnormal B-cell nuclei were identified, but even a near-total pancreatectomy was insufficient to cure some of these patients, in whom no focal lesion was detected. On the other hand, abnormal insular B-cell nuclei were not found in seven cases; based on the results of selective venous catheterization, a limited resection was performed, sufficient to cure each patient, and a focal adenomatous hyperplasia was found in each resected specimen. CONCLUSIONS: Intra-operative examination of small pancreatic specimens taken from the different parts of the gland allows one to determine the type of lesion (focal or diffuse) in neonatal onset hyperinsulinaemic hypoglycaemia, and to decide on the most appropriate surgical treatment.

Cell Nucleolus↗
PubMed1998

Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis.

The two major forms of infantile persistent hyperinsulinemic hypoglycemia require different treatments, but are difficult to differentiate during surgery. Indeed, one is characterized by focal adenomatous hyperplasia often macroscopically invisible, whereas the other consists of a diffuse, but discreet, beta-cell abnormality. We evaluated, in a large series of persistent hyperinsulinemic hypoglycemia, the reliability of two criteria in differentiating these two forms: the mean beta-cell nuclear radius (MNR) and the beta-cell nuclear crowding, i.e. the number of nuclei per 1000 micron 2 beta-cell (BCNC). The values of the largest MNR and of BCNC in cases bearing a focal lesion (respectively, 3.27 microns +/- 0.25 and 14.62 +/- 1.78) were significantly different from those in the diffuse pathology (4.25 microns +/- 0.43 and 10.00 +/- 1.55). Setting the threshold value of MNR at 3.70 microns and that of BCNC at 12.00 enabled correct classification of 90.9% of the diffuse and 100% of the focal forms. beta-Cell nuclear analysis can thus contribute to a subclassification of the syndrome, not allowed by clinical or biological data. If performed during surgery it could help in determining the extent of pancreatectomy necessary to cure the patient, as the diffuse form, with abnormal nuclei in the whole pancreas, requires subtotal to near-total pancreatectomy, whereas the focal form, devoid of abnormal insular beta-cell nuclei, can be cured by partial pancreatectomy.

Cell Nucleus↗
PubMed1998

Loss of imprinted genes and paternal SUR1 mutations lead to hyperinsulinism in focal adenomatous hyperplasia.

Two types of histopathological lesions, a focal adenomatous hyperplasia of islet cells of the pancreas in about 30% of operated sporadic cases, and a diffuse form can be observed in congenital hyperinsulinism, or Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI). In sporadic focal forms, specific losses of maternal alleles (LOH) of the imprinted chromosomal region 11p15, restricted to the hyperplastic area of the pancreas, were observed. Similar mechanisms are observed in embryonal tumors and in the Beckwith-Wiedemann syndrome which is also associated with neonatal but transient hyperinsulinism. However this region also contains the sulfonylurea receptor (SUR1) gene and the inward rectifying potassium channel subunit (KIR6.2) gene, involved in recessive familial forms of PHHI, but not known to be imprinted. We now report somatic reduction to hemizygosity or homozygosity of a paternal SUR1 constitutional heterozygous mutation, in five patients with a focal form of PHHI. Thus this somatic event (LOH) which leads both to b cell proliferation and to hyperinsulinism can be considered as the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation leading to a somatic recessive disorder.

ATP-Binding Cassette Transporters↗
PubMed1998

Pancreatic B-cell proliferation in persistent hyperinsulinemic hypoglycemia of infancy: an immunohistochemical study of 18 cases.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is characterized by severe hypoglycemia related to inappropriate insulin secretion. Morphologically, a tumoral and a nontumoral form are recognized. The tumoral form can be subdivided into adenomatous hyperplasia (in infants) and adenoma (in children). On the other hand, nesidioblastosis, considered until recently as a persistent B-cell replication, has repeatedly been proposed as the condition responsible for the nontumoral form of PHHI. We studied the proliferation rate of B cells in 18 patients affected by PHHI (7 nontumoral and 11 tumoral cases, including 4 adenomas and 7 adenomatous hyperplasias) and in 18 age-matched controls, using a double immunohistochemical technique detecting Ki-67, a nuclear endogenous antigen only present during cell proliferation, and insulin as pancreatic B-cell markers. Our results clearly show that "nesidioblastosis" is not related to an abnormal B-cell proliferation, because the B-cell labeling index (LI), reported as the mean plus or minus the standard error of the mean, is not statistically different between nontumoral PHHI (29.4 +/- 7.4) and age-matched controls (19.6 +/- 5.3). Furthermore, the Ki-67 positivity was not more prominent in small clusters of B cells in nesidioblastosis than in large islets. In tumoral PHHI, the LI was significantly higher in cases of focal adenomatous hyperplasia (77.6 +/- 10.9) than in either age-matched controls (19.9 +/- 6.9; P < .005) or in adenomas (27.9 +/- 13.7; P < .025); the values of this last group did not differ from those of age-matched controls (18.5 +/- 8.5). These data definitely demonstrate that nesidioblastosis does not correspond to an abnormal B-cell proliferation and that the focal forms of PHHI must be subclassified.

Adenoma↗
PubMed1998

[Prevalence of thyroid cancer in hot nodules].

The prevalence of thyroid cancer is not nodules is low, as it is estimated to be between 0 and 4% in adults. In order to more accurately estimate this prevalence and to recommend optimal treatment, 93 hot nodules operated between 1976 and 1995 were reviewed. 52 of these subjects (56%) were euthyroid, 11 (12%) suffered from clinical hyperthyroidism and 30 (32%) a presented subclinical hyperthyroidism. All patients were operated for a hot nodule, 1.5 to 6 cm in diameter. Two groups of patients were considered on the basis on the histological examination. Group I consisted of 47 patients (39 F, 8 M, mean age: 44 years +/- 15) with multinodular goitre; 16 (34%) of them underwent total thyroidectomy. Group II was composed of 46 patients (38 F, 8 M, mean age: 44 years +/- 15) with a solitary hot nodule; 39 (85%) patients underwent unilateral lobectomy. Microscopic carcinoma (diameter less tha 1 cm) ws discovered in 2(4%) patients of group 1 and 5 (11%) patients of group 11, corresponding to a total prevalence of 7/93 (7.5%). The microscopic carcinoma was located in the nodule or in the capsule in four cases, and away from the nodule but in the ipsilateral lobe in three cases. In every case, this was an incidental finding and no clinical features distinguished patients with or without microscopic carcinoma. This study suggests that the probability of discovering a microscopic carcinoma associated with a hot nodule is considerable. However, microscopic carcinoma is an incidental discovery in a number of subjects undergoing thyroidectomy and is present in 10 to 20% of autopsied thyroids. As surgical treatment is devoid of risks, it appears indicated, particularly when the nodule exceeds 3 cm in diameter.

Adolescent↗
PubMed1997

Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy.

Sporadic persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or nesidioblastosis is a heterogeneous disorder characterized by profound hypoglycemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI) because management strategies differ significantly. 16 infants with sporadic PHHI resistant to diazoxide and who underwent pancreatectomy were investigated. Selective pancreatic venous sampling coupled with peroperative surgical examination and analysis of extemporaneous frozen sections allowed us to identify 10 cases with FoPHHI and 6 cases with DiPHHI. We show here that in cases of FoPHHI, but not those of DiPHHI, there was specific loss of maternal alleles of the imprinted chromosome region 11p15 in cells of the hyperplastic area of the pancreas but not in normal pancreatic cells. This somatic event is consistent with a proliferative monoclonal lesion. It involves disruption of the balance between monoallelic expression of several maternally and paternally expressed genes. Thus, we provide the first molecular explanation of the heterogeneity of sporadic forms of PHHI such that it is possible to perform only partial pancreatectomy, limited to the focal somatic lesion, so as to avoid iatrogenic diabetes in patients with focal adenomatous hyperplasia.

Chromosome Deletion↗
PubMed1997

Developmental and nutritional changes of ob and PPAR gamma 2 gene expression in rat white adipose tissue.

The ob gene encodes leptin, a hormone which induces satiety and increases energy expenditure. The peroxisome proliferator-activated receptor gamma 2 isoform (PPAR gamma 2) gene encodes a transcription factor which controls adipocyte differentiation and expression of fat-specific genes. We have studied the regulation of these two genes in white adipose tissue (WAT) during the suckling-weaning transition. Suckling rats ingest a high-fat diet (milk). Fat-pad weight barely varied during the last week of suckling. ob mRNA levels, which were very low in 15-day-old rats, rose approximately 6-fold until weaning at 21 days. When the rats were weaned on to a standard (high-carbohydrate) laboratory chow, epididymal WAT enlarged approximately 7-fold, and ob mRNA kept increasing progressively and doubled between 21 and 30 days. This evolution contrasted with that of fatty acid synthase (FAS) mRNA, which increased sharply, but only after weaning. To distinguish between the influence of developmental and nutritional factors on ob expression, a group of rats was weaned on to a high-fat diet. This prevented the rise in glycaemia and insulinaemia and the decrease in plasma non-esterified fatty acids which otherwise occurred at weaning. This also resulted in a slight (10-15%) decrease in food intake and body weight gain. Under this high-fat diet, the rise of ob mRNA in WAT was augmented (3.7-fold in 30- versus 21-day-old pups), whereas the normal rise in FAS mRNA levels was attenuated. Fat-pad weights and adipocyte cell size and number were roughly similar in high-carbohydrate- and high-fat-weaned pups. mRNA levels of PPAR gamma 2, like those of ob, were low in the WAT of 15-day-old suckling pups, doubled at 21 days, and reached a maximum as soon as 23 days. This evolution further differed from that of ob mRNA in not being influenced by diet composition. In conclusion, ob expression markedly increases during the suckling-weaning transition, and this effect is accentuated by a high-fat diet. Qualitative nutritional changes in ob mRNA were correlated with neither acute changes in adipose-tissue mass, nor cell size/number, nor variations in insulinaemia. PPAR gamma 2 also increased during suckling, but rapidly reached a plateau after weaning and no longer changed thereafter. Unlike ob, PPAR gamma 2 was not influenced by the diet composition.

Adipose Tissue↗
PubMed1997

Severe radiation-induced liver disease following localized radiation therapy for biliopancreatic carcinoma: activation of hepatic stellate cells as an early event.

Radiation-induced liver disease is recorded as a form of veno-occlusive disease. Its pathogenesis remains unclear even if the initial injury likely occurs in the endothelial cells of central veins. The aim of our study was to investigate liver morphological features in relation to alpha-isoform of smooth muscle actin expression in hepatic stellate cells in six patients treated by localized radiotherapy on the biliopancreatic area. Within the month after completion of treatment, an activation of hepatic stellate cells strictly confined to irradiated areas and coinciding with congestive changes was observed. At a later stage, collagen deposition gradually increased, replacing the congestive and destroyed areas. This new fibrotic tissue also contained numerous alpha-smooth muscle positive cells. Our data suggest that early hepatic stellate cells activation coinciding with congestive changes plays an important role in radiation liver injury and ensuing fibrosis.

Actins↗
PubMed1997

Validation of nonradioactive in situ hybridization as a quantitative approach of messenger ribonucleic acid variations: a comparison with northern blot.

The recent improvement of in situ hybridization (ISH) procedures, the increased sensitivity of immunohistochemical detection systems, and the development of assisted image analysis now enable the quantification of specific messenger RNAs (mRNAs) detected by nonisotopic probes on histological sections. However, the reliability and accuracy of this type of mRNA quantification are still to be determined. To this end, we compared in an experimental model of rat malnutrition the densitometric analysis of proinsulin mRNA detected by nonradioactive ISH with those obtained from radioactive Northern blot hybridization (NBH). Proinsulin gene expression was quantified by ISH and by NBH in the pancreatic islets of normally fed rats, rats fasted for 3 days, and rats refed for 8, 24, and 48 h after fasting. Starvation decreased the pancreatic proinsulin mRNA signal by 34% and 38%, as evaluated by ISH and NBH, respectively. Also, with both methods, mRNA levels returned to normal after refeeding. Taken together, the results derived from nonradioactive quantitative ISH were closely correlated to those obtained by quantitative NBH (r = 0.975, p < 0.005). It is thus possible to evaluate variations of mRNA content accurately by quantitative ISH as is currently done by NBH, but with the invaluable advantage of integrating the data with a morphological analysis.

Animals↗
PubMed1997

Acute lobular hepatitis as the first manifestation of recurrent autoimmune hepatitis after orthotopic liver transplantation.

Recurrence of autoimmune hepatitis after orthotopic liver transplantation and after reduction in immunosuppressive treatment is reported in a 43-year-old man. Diagnosis was based on biological, serological and morphological data, as well as on a complete biological recovery following steroid resumption. Recurrence was observed only 4 months after transplantation, when an abrupt increase in liver function tests was observed in association with a mainly lobular hepatitis in liver biopsy. Such a histological appearance has been previously described in the case of recurrence after immunosuppressive treatment weaning in non-transplanted patients. In contrast, this histological feature has not been reported in the rare transplanted patients in whom such recurrence has been observed. Thereafter, the evolution of the disease in our patient remained slow, likely dampened by the administration of cyclosporine and azathioprine. Morphological features are detailed, and importance of immunosuppressive therapy in patients transplanted for end-stage autoimmune hepatitis is emphasized.

Acute Disease↗
PubMed1997

Expression of insulin receptors and of 60-kDa receptor substrate in rat mature and immature enterocytes.

The mechanism(s) by which rat immature enterocytes exhibit increased responsiveness to insulin before weaning is unknown. Therefore, we have analyzed the distribution, ontogeny, and molecular properties of insulin receptors (IR) and of related substrates in immature and mature enterocytes. IR were studied by radioligand binding assays, cross-linking labeling, immunohistochemistry, and in vitro phosphorylated substrates by immunoprecipitation. Regardless of age, 125I-insulin binding to IR was five times higher in crypt cells than in villus cells and two times higher in the ileum than in the jejunum. Binding capacity to villus cells from sucklings (day 14) exceeded three times that of older animals (day 30 and day 60). Scatchard analysis of equilibrium binding data confirmed an age-related decrease in low- and high-affinity receptor classes without change in affinity constants. In concordance, both alpha- and beta-IR subunits were more abundant in immature than in mature membranes. In vitro, insulin elicited the phosphorylation of three membrane proteins (96, 60 and 42 kDa), whose signals were virtually inhibited by preincubating membranes with antireceptor monoclonal antibodies. By immunoprecipitation, the 60-kDa signal was rapidly detected as a tyrosine-phosphorylated protein, expressed in mature and immature membranes, and identified as a receptor substrate phosphorylated in vitro by the IR tyrosine kinase. In conclusion, 1) increased responsiveness of rat immature enterocytes to insulin could be related to high membrane concentrations of IR and 2) normal rat enterocytes express a 60-kDa phosphotyrosine protein identified as a direct substrate of the IR tyrosine kinase.

Aging↗
PubMed1997

[Pancreatic adenomatous hyperplasia and sudden infant death].

We report the observation of a sudden infant death in which autopsy revealed a focal pancreatic lesion called adenomatous hyperplasia. Histopathological and immunohistochemical characteristics of this lesion are detailed. Adenomatous hyperplasia and endocrine cell dysplasia are the two pancreatic lesions responsible for hyperinsulinemic hypoglycemia in infants, with a possible fatal evolution. An organic pancreatic lesion is exceptionally reported in observations of sudden infant death. These observations and ours point out the necessity of a meticulous post-mortem examination of the pancreas in sudden infant death.

Adenoma↗
PubMed1996

Preoperative lymph node staging in rectal cancer: a difficult challenge.

The specimens of 59 rectal cancers that had been scanned by preoperative endorectal ultrasound (EUS) were analysed by the pathologist in order to draw a map of the pararectal lymph nodes that should be detected by preoperative staging. 389 lymph nodes (LNs) were detected in the mesorectum, close to the tumour. Malignant LNs were larger than the non invaded: 17% of the LNs less than 6 mm in diameter were invaded whereas 23% of the LNs 6 mm or more in diameter were free of metastatic invasion. The non invaded LNs displayed three main patterns: follicle, sinusoidal and mixed types. Metastatic LNs were partially (n = 25) or totally (n = 76) invaded by tumoural cells. Diffuse involvement includes 4 different patterns: cellular proliferation, fibrosis, necrosis and cyst formation. Accuracy of EUS evaluated by a "patient by patient" comparison was 61%, with a sensitivity of 84% and a specificity of 39%. However, a comparison "lymph node by lymph node" showed a detection rate of 21% of the lymph nodes of 3 mm and more. It is concluded that a low percentage of LNs are detected by EUS in our experience. Metastatic and non metastatic LNs exhibit a great variety of morphological features and it seems difficult to reliably correlate metastatic invasion with a specific endosonic appearance. LN size remains the most reliable parameter.

Humans↗