[Hemochromatosis: the most common of rare diseases]. / L'hémochromatose. La plus fréquente des maladies rares.

Familial (hereditary) haemochromatosis (HH) is an iron storage disorder characterized by an increased intestinal absorption of iron and its accumulation in numerous tissues. The disease generates an iron overload with tissue damages also seen in haematologic disturbances (with dyserythropoiesis and haemolysis) and hepatic disorders. Besides typical mutations linked to HH (C282 Y and H63D, HFE locus), three other mutations have been identified and more have to be defined. A complete genetic testing is important to assess the risk of morbidity. Indeed, the clinical picture of HH is dependent upon the specific mutations as well as the individual context (sex, environment, associated hepatic and/or haematologic disorders). Porphyria cutanea tarda (PCT) has for long been found significantly associated with HH. It is now considered that hepatic iron overload related to the combination of heterogeneous genetic traits and environmental factors, including alcoholism and viral hepatitis, precipitates the expression of PCT through the inhibition of uroporphyrinogen decarboxylase (Uro.D).

[Clinical case of the month. MELAS syndrome]. / Le cas clinique du mois. Le syndrome MELAS.

A patient, born in 1961, was first examined for autoimmune hyperthyroïd at the age of 25. Then, several episodes of serious dehydration and alteration of general condition were followed by a severe encephalopathy with a symptomatology of stroke-like episodes, and during a hospitalization, a volvulus of the colon. Epilepsy developed also. A MELAS syndrome was diagnosed when she was 32 years old, based on her clinical metabolic history of the presence of Ragged-Red-Fibers at muscular biopsy and of the genetical analysis. At the age of 37, after a new episode of encephalopathy, the patient fell into a rapidly evolving coma and deces.

Placental growth hormone and IGF-I in a pregnant woman with Pit-1 deficiency.

The respective contributions of pituitary and placental GH to circulating IGF-I in pregnant women have not been well established. We measured the serum concentrations of placental growth hormone (PGH) and IGF-I in a woman with pit-1 deficiency before, during and after pregnancy, resulting in the birth of a healthy child (not pit-1 deficient). Both PGH and IGF-I concentrations were below the assay detection limit before and after pregnancy. During pregnancy, PGH and IGF-I levels increased steadily; the concentrations of PGH and IGF-I in late pregnancy were comparable with levels previously measured in normal pregnancies. PGH and IGF-I concentrations were strongly correlated throughout pregnancy (r = 0.90; P = 0.002). PGH was undetectable in cord serum, whilst the IGF-I concentration was within the normal range. The findings of this case study corroborate the notion that PGH is the prime regulator of maternal serum IGF-I during pregnancy.

A novel messenger ribonucleic acid homologous to human MAGE-D is strongly expressed in rat Sertoli cells and weakly in Leydig cells and is regulated by follitropin, lutropin, and prolactin.

We have cloned a novel complementary DNA whose expression was decreased in rat Sertoli cell cultures after treatment with FSH. This complementary DNA encodes a protein of 570 amino acids and shares 92% homology with the human MAGE-D protein. In contrast to other MAGE genes (A, B, or C), we have shown that MAGE-D expression was ubiquitous in healthy rat tissues. In the seminiferous tubules, the MAGE-D was expressed in Sertoli cells but not in germ cells as demonstrated by RT-PCR and in situ hybridization, whereas for the other MAGE genes, expression has been shown to be restricted to germ cells. Interestingly, MAGE-D was also detected for the first time in the female gonad by Northern blotting. In MLTC-1 cells (mouse Leydig tumor cell line-1), LH and PRL stimulated MAGE-D expression. Using hypophysectomized rats, it was confirmed that FSH decreased MAGE-D expression, whereas LH and PRL increased MAGE-D messenger RNA level in the whole testis most probably through a direct action on Leydig cells. As MAGE-D is present in both the seminiferous compartment and interstitium and hormonally regulated in each, it is possible that it has specific functions in each compartment during the development and the maintenance of the testis.

Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: correlations with fetal growth.

We previously described significant changes in GH-binding protein (GHBP) in pathological human pregnancy. There was a substantial elevation of GHBP in cases ofnoninsulin-dependent diabetes mellitus and a reduction in insulin-dependent diabetes mellitus. GHBP has the potential to modulate the proportion of free placental GH (PGH) and hence the impact on the maternal GH/insulin-like growth factor I (IGF-I) axis, fetal growth, and maternal glycemic status. The present study was undertaken to investigate the relationship among glycemia, GHBP, and PGH during pregnancy and to assess the impact of GHBP on the concentration of free PGH. We have extended the analysis of specimens to include measurements of GHBP, PGH, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 and have related these to maternal characteristics, fetal growth, and glycemia. The simultaneous measurement of GHBP and PGH has for the first time allowed calculation of the free component of PGH and correlation of the free component to indexes of fetal growth and other endocrine markers. PGH, free PGH, IGF-I, and IGF-II were substantially decreased in IUGR at 28-30 weeks gestation (K28) and 36-38 weeks gestation (K36). The mean concentration (+/-SEM) of total PGH increased significantly from K28 to K36 (30.0 +/- 2.2 to 50.7 +/- 6.2 ng/mL; n = 40), as did the concentration of free PGH (23.4 +/- 2.3 to 43.7 +/- 6.0 ng/mL; n = 38). The mean percentage of free PGH was significantly less in IUGR than in normal subjects (67% vs. 79%; P < 0.01). Macrosomia was associated with an increase in these parameters that did not reach statistical significance. Multiple regression analysis revealed that PGH/IGF-I and IGFBP-3 account for 40% of the variance in birth weight. IGFBP-3 showed a significant correlation with IGF-I, IGF-II, and free and total PGH at K28 and K36. Noninsulin-dependent diabetes mellitus patients had a lower mean percentage of free PGH (65%; P < 0.01), and insulin-dependent diabetics had a higher mean percentage of free PGH (87%; P < 0.01) than normal subjects. Mean postprandial glucose at K28 correlated positively with PGH and free PGH (consistent with the hyperglycemic action of GH). GHBP correlated negatively with both postprandial and fasting glucose. Although GHBP correlated negatively with PGH (r = -0.52; P < .001), free PGH and total PGH correlated very closely (r = 0.98). The results are consistent with an inhibitory function for GHBP in vivo and support a critical role for placental GH and IGF-I in driving normal fetal growth.

[Cushing syndromes due to aberrant expression of functional receptors other than ACTH. A new organic hypercorticism syndrome entity]. / Syndromes de Cushing dus à l'expression aberrante de récepteurs fonctionnels à des entités autres que l'ACTH. Une nouvelle entité d'hypercorticisme organique.

The diagnosis of Cushing's syndrome remains a challenge in clinical endocrinology. Cushing's syndromes are usually classified as dependent or independent from ACTH. In the first class are Cushing's disease, the ectopic corticotropin syndrome and the rare ectopic CRH syndrome. These ACTH-dependent Cushing's syndromes usually present diffusely hyperplastic adrenal glands. In the second class, are cortisol producing unilateral adrenocortical adenomas or carcinomas. New entities have recently emerged as bilateral adrenal hyperplasia not dependent from ACTH; their etiopathogenies are heterogeneous with illicit expressions at the adrenal level of functional receptors to various ligands: GIP, catecholamines, lutropin... The knowledge of such entities has to be taken into consideration in the diagnostic and management of ACTH independent Cushing syndromes.

[Radioiodine (131I) as the only treatment of hyperthyroidism. Results of 10 years of experience]. / Radioiode (131I) comme seul traitement de l'hyperthyroïdie. Résultats d'une expérience de 10 années.

This work present the results of the use of 131I, as first line and only, antithyroid treatment, applied to 120 patients suffering from autoimmune hyperthyroidism, compared to 64 patients with toxic goiter and adenoma. The diagnostic weight of the determination of the various antithyroid antibodies was assessed in the identification of autoimmune hyperthyroidism, for which TRAb and TPO Ab are the most significant. The evolution after treatment of a preexisting ophthalmopathy (i.e. Graves'disease) was never found to be alarming and in most cases regularly improved with time. A single case (out of 72) of autoimmune hyperthyroidism with no preexisting sign developed a severe ophthalmopathy after treatment, which was well controlled thereafter. Mean cumulated 131I doses to control hyperthyroidism were 22.8 mCi for toxic goiter, 21.6 mCi for adenoma, 14.1 mCi for autoimmune hyperthyroidism and 16.7 mCi for Graves'disease. Post 131I hypothyroidism was found in 28.2% of toxic goiters, 12.1% of adenomas, 66% of autoimmune hyperthyroidisms and 70% of Graves'disease. No relapse was observed after treatment. A surgical indication was proposed for cases requiring more than two 131I doses to control hyperthyroidism.

A novel gene overexpressed in the prostate of castrated rats: hormonal regulation, relationship to apoptosis and to acquired prostatic cell androgen independence.

We have identified a novel complementary DNA (cDNA) corresponding to a gene overexpressed in the rat ventral prostate after castration. This cDNA displays 89.4% identity with 453 bp of a mouse EST and 81.5% identity with 157 bp of a human EST and was named PARM-1 for prostatic androgen-repressed message-1. The complete cDNA is 1187 bp long and codes for a protein of 298 amino acids that contains four potential glycosylation sites and three half cystinyl residues. The PARM-1 gene was found to be expressed at quite low levels in most rat tissues including those of the urogenital tract. The kinetic of induction of PARM-1 gene in the prostate was highly correlated to the development of apoptosis in the whole organ. Supplementation of castrated animals with androgens reversed both the process of apoptosis and the overexpression of PARM-1 gene. Supplementation with estrogens did not result in an increase in the PARM-1 messenger RNA levels when compared with the castration alone. However, the treatment resulted in a more rapid return to intact levels in the castrated plus estrogen group. When apoptosis of testis and prostate was induced in vivo by hypophysectomy, it was found that PARM-1 was only overexpressed in the prostate. Therefore, PARM-1 seems to be regulated by androgens only in the prostate. Using in situ hybridization and immunohistological techniques, we have shown that PARM-1 gene product is found exclusively in the epithelial cells of involuting prostate. Analysis by flow cytometry of MAT LyLu epithelial cells transiently expressing PARM-1 protein did not allow us to demonstrate a direct effect of PARM-1 gene overexpression on the programmed death of the transfected cells. Treatment of MAT LyLu cells by transforming growth factor-beta induced apoptosis but had no effect on PARM-1 production. However PARM-1 protein has been detected by Western blotting in various cell lines such as MAT LyLu, MAT Lu, and PIF, which are androgen independent. This would suggest that PARM-1 gene product would be a marker for acquired androgen-independence of these tumor cells.

Lymphoid cell apoptosis induced by trophoblastic cells: a model of active foeto-placental tolerance.

To test the hypothesis that CD95-L (Fas-L) present on trophoblastic cells plays a part in establishing foeto-placental tolerance by inducing apoptosis of immune defence cells, we cocultured trophoblasts with lymphoid cells and scored the frequency of cell death in these cultures. We prepared human trophoblastic cells from term placentas removed by C-section and placed them in culture for 48 h before introducing the lymphoid cells. We added Jurkat cells, a CD3 + lymphoid cell line, or purified T cells from human blood to the cultured trophoblasts and monitored apoptosis by electron microscopy and flow cytometry after TUNEL or annexin V labelling. The frequency of cell death in the CD3 + cell population was higher when the lymphoid cells were cocultured with trophoblastic cells than when they were cultured alone. This frequency increased with time but was reduced when anti-CD95-L antibodies were added to the culture medium. Cell death was less frequent in the lymphoid cell population when trophoblasts were replaced with human fibroblasts not expressing CD95-L.

Effects of pituitary hormones on the prostate.

BACKGROUND: Although essential, androgens alone are not sufficient to induce normal growth and functionality of the prostate. Nonandrogenic hormones must also be involved in the proliferation of the prostate cancer cells which do not respond to antiandrogenic therapy and which thus become androgen-independent. Prolactin, but also growth hormone and luteinizing hormone, are potentially able to act on both normal and abnormal prostatic cells. METHODS: In this review we summarize data from the literature concerning the physiological and pathological implications of prolactin, growth hormone, and luteinizing hormone on the prostate. RESULTS: In rodent prostates, prolactin and growth hormone can induce a variety of effects independently of androgens (e.g., transactivation of certain genes, or synthesis of the major secretion products). Moreover, hyperprolactinemia is responsible for inflammation and dysplasia of the gland, while growth hormone promotes the development of prostate tumors in vivo in the mouse and rat. Growth hormone acts on the gland directly, through prostatic growth hormone receptors, and/or indirectly via the stimulation of insulin-like growth factor-I (IGF-I) synthesis in the liver. Luteinizing hormone receptor is expressed in rat and human prostates. Luteinizing hormone increases the amount of various transcripts in the rat prostate through an androgen-independent pathway. CONCLUSIONS: Prolactin, growth hormone, and luteinizing hormone, alone or synergistically with androgens, play physiologically significant roles in the normal prostate. The involvement of these hormones in the development of benign prostatic hyperplasia and prostatic carcinoma is an issue that needs to be addressed.

Housekeeping genes as internal standards: use and limits.

Quantitative studies are commonly realised in the biomedical research to compare RNA expression in different experimental or clinical conditions. These quantifications are performed through their comparison to the expression of the housekeeping gene transcripts like glyceraldehyde-3-phosphate dehydrogenase (G3PDH), albumin, actins, tubulins, cyclophilin, hypoxantine phsophoribosyltransferase (HRPT), L32. 28S, and 18S rRNAs are also used as internal standards. In this paper, it is recalled that the commonly used internal standards can quantitatively vary in response to various factors. Possible variations are illustrated using three experimental examples. Preferred types of internal standards are then proposed for each of these samples and thereafter the general procedure concerning the choice of an internal standard and the way to manage its uses are discussed.

Expression of growth hormone receptors by lymphocyte subpopulations in the human tonsil.

The ability of human tonsillar lymphoid cells to express growth hormone receptor (hGH-N-R) was analyzed by flow cytometry. FITC-coupled recombinant human growth hormone (hGH-N) was used to reveal the receptors, in combination with phenotype markers. Unlike T cells, tonsillar B cells constitutively express the hGH-N receptor. Quiescent cells separated from activated cells by Percoll-gradient centrifugation bear fewer receptors than activated ones. Activated T cells express hGH-N-R, but the typical germinal centre CD4+ CD57+ T cells do not. These latter thus appear not to be fully activated. Inside the lymph follicles, the germinal centre CD38+ B-cell population and the mantle-zone CD39+ B-cell population display similar levels of hGH-N-R expression, but receptor density is lower on dividing dark-zone CD38+ CD10+ B cells. Different lymphoid-cell populations thus differ markedly in their ability to express the growth hormone receptor, in relation notably to their activation status. This highlights the link between the neuroendocrine system and the active immune defense.

Maternal serum placental growth hormone and insulinlike growth factor binding proteins 1 and 3 in pregnancies affected by fetal aneuploidy and other abnormalities: implications for prenatal diagnosis of trisomy 21.

In the present study, we determined circulating serum levels of human placental growth hormone (hPGH) and insulinlike growth factor binding proteins 1 and 3 (IGFBP-1 and IGFBP-3) using two-site radioimmunoassays during the gestational midtrimester of pregnancies affected by chromosomal disorders with the aim of identifying potential marker substances that might have a significant discriminative and predictive value for prenatal diagnosis of fetal chromosomal aberrations and of organ malformations such as neural-tube defect. Our results show that the maternal serum levels of hPGH were significantly elevated in pregnancies affected by chromosomal anomalies or organ malformations as compared with controls. The distribution of IGFBP-1 concentrations for all experimental groups except trisomy 21 were closely similar to the normal population. IGFBP-3 decreased slightly in pregnancies affected by Down syndrome. These findings suggest that hPGH may be useful as an additional marker in prenatal screening for Down syndrome.

Hormonal counterregulation and subjective symptoms during induced hypoglycemia in insulin-dependent diabetes mellitus patients during and after pregnancy.

BACKGROUND: The objective was to elicit whether hormonal responses to and subjective symptoms of hypoglycemia are modified during pregnancy in patients with insulin-dependent diabetes mellitus. METHODS: In ten type I diabetic women, hyperinsulinemic hypoglycemic clamps, with target arterial blood glucose content of 2.2 mmol/l, were performed during the third trimester of pregnancy and 5-13 months after delivery. The levels of arterial glucose and venous catecholamines, pituitary growth hormone, cortisol, glucagon, dehydroepiandrosterone and free insulin were assessed repeatedly. Subjective symptoms of hypoglycemia were recorded on a visual analog scale. The paired t-test and Wilcoxon signed rank test were used for statistical comparisons. RESULTS: Adrenaline and dehydroepiandrosterone increased during hypoglycemia on both occasions, but dehydroepiandrosterone disclosed a significantly different pattern of response during pregnancy (p=0.016). The cortisol increase was augmented during pregnancy (420+/-50 vs. 310+/-30 nmol/l non-pregnant, p=0.039), while the increase in pituitary growth hormone (hGH) was diminished (5.4+/-1.2 vs. 27.9+/-5.4 microg/l non-pregnant, p=0.001), but nevertheless the increase during pregnancy was significant (p=0.002). Three of the eight subjective symptoms of hypoglycemia recorded were less prominent during pregnancy, namely 'inability to concentrate' (p=0.03), 'headache' (p=0.01) and 'pounding heart' (p=0.03). CONCLUSIONS: Albeit some subjective symptoms were diminished during pregnancy, the study gives no evidence that, in diabetic patients, pregnancy per se impairs the counterregulatory response to hypoglycemia, with the exception of growth hormone. However, despite the suppressed basal growth hormone secretion in late pregnancy, the study disclosed a secretory response of this hormone at hypoglycemia.

Placental hormones during induced hypoglycaemia in pregnant women with insulin-dependent diabetes mellitus: evidence of an active role for placenta in hormonal counter-regulation.

OBJECTIVE: To study the effect of induced hypoglycaemia on serum levels of the placental hormones oestriol, human placental lactogen, placental growth hormone and progesterone in the third trimester of pregnancy. DESIGN: A prospective experimental investigation. SETTING: High risk pregnancy unit and diabetes research unit at Karolinska Institutet Danderyd Hospital, a university hospital. PARTICIPANTS: Ten women with insulin-dependent diabetes mellitus in the third trimester of pregnancy. METHODS: Venous blood samples were collected every 15 minutes for analyses of oestriol, progesterone, human placental lactogen and placental growth hormone, during the 150 min of a hyperinsulinaemic hypoglycaemic clamp, which maintained arterial blood-glucose level of about 2.2 mmol/l. MAIN OUTCOME MEASURES: Levels of analysed placental hormones during hypoglycaemia. RESULTS: A statistically significant increase was observed in placental growth hormone during hypoglycaemia (P < 0.0001), whereas the placental hormones progesterone, human placental lactogen and oestriol did not show changes of clinical significance. CONCLUSIONS: The increase in placental growth hormone indicates that the placenta is an endocrine organ which may take an active part in acute metabolic processes, such as here in the hormonal counterregulation of hypoglycaemia.

Demonstration of the expression of CD95 ligand transcript and protein in human placenta.

Tolerance of the fetal allograft enables the human conceptus to implant itself into the maternal uterus and survive and grow there. This tolerance phenomenon remains largely obscure, notably because it appears to be controlled by multiple mechanisms. CD95 ligand (CD95-L), which can trigger death of CD95-positive cells by apoptosis, may participate in inducing anti-fetus-sensitized CD95-positive T lymphocytes to enter apoptosis. Using immunohistochemistry (first trimester and term placentae), FACS assays (term placenta) and RT-PCR assays (term placenta), the presence of CD95-L protein and mRNA has been shown in crude placental tissue preparations and isolated placental cells. Among the latter, CD95-L expression was detected in trophoblastic cells, fetal blood cells (mRNA only) and also the Hofbauer macrophages. No CD95-L was detected in fibroblasts or fetal endothelial cells. Thus trophoblastic cells, Hofbauer macrophages, and perhaps also fetal blood cells could form a sequential barrier blocking maternal activated defence cells bearing CD95 molecules.

Surgical management of amiodarone-associated thyrotoxicosis: too risky or too effective?

Amiodarone-associated thyrotoxicosis, often clinically mild and resolutive after amiodarone discontinuation or under medical therapy, is sometimes drug unresponsive and not uncommonly follows a dramatic, even fatal course. Therefore, we considered a surgical solution in 15 severely amiodarone-associated thyrotoxic patients. Twelve men and three women (mean age 68 years, range 50-84 years) underwent radical thyroidectomy for clinical and biologically proved amiodarone-associated thyrotoxicosis. In six surgery was the first-line therapeutic option. In the other nine thyroidectomy seemed unavoidable considering the unresponsiveness to medical therapy and rapid deterioration of the patients' clinical condition, with life-threatening cardiac failure in three. In every patient surgery was conducted without immediate or delayed complications. Total thyroidectomy proved uniformly, definitively, and rapidly effective in controlling thyrotoxicosis in all patients, with a spectacular reversal of cardiac failure in the three most critical cases. Surgery was beneficial to our 15 patients and undoubtedly life-saving in the three most worrying cases. These results suggest that thyroidectomy should be more liberally regarded as an interesting alternative to conventional, but unpredictably effective, medical therapies.

Serum level of placental growth hormone is raised in pregnancy rhinitis.

OBJECTIVE: To describe any relationship between pregnancy rhinitis and weight gain or serum levels of estradiol, progesterone, placental growth hormone, or insulinlike growth factor I. PATIENTS: Twenty-seven nonsmoking healthy pregnant women aged 22 to 38 years (mean age, 28 years) who had no history of respiratory allergy or chronic nasal or sinus problems volunteered to enter the study. They had no nasal complaints at entry. METHODS: Nasal patency was registered daily from early pregnancy until 1 month after delivery. Nasal and oral peak expiratory flow rates were established, and the subjective blockage was scored from 0 to 4, with 0 indicating no blockage. Serum samples were collected and weight was measured on 4 occasions during pregnancy and again at the end of the study. Pregnancy rhinitis was diagnosed if the subjective nasal obstruction score was 1 or higher every morning for at least 6 weeks immediately preceding delivery, then returned to 0 within 2 weeks and remained at 0 until the end of the study. If on any day other signs of respiratory tract infection occurred, that day was excluded. RESULTS: Pregnancy rhinitis was diagnosed in 5 women. These 5 women showed significantly higher levels of placental growth hormone than the women without the diagnosis. No significant difference was found between the 2 groups regarding body weight or any of the other serum levels studied. CONCLUSIONS: Serum level of placental growth hormone is raised in pregnancy rhinitis and may be involved in its pathogeny. Pregnancy rhinitis does not significantly raise weight gain or serum levels of estradiol, progesterone, or insulinlike growth factor I.

[Sugar diabetes. Update elements]. / Le diabète sucré. Eléments de mise au point.

The various types of diabetes mellitus are now more precisely classified according to their etiopathogenies. Therefore, type 1 (autoimmune or not), type 2, gestational diabetes, as well as MODY (Maturity Onset-Diabetes of the Young) and secondary diabetes are considered as separate entities. Any type of diabetes brings its set of complications. Biological chemistry is directed to define the etiopathogenic characteristics of the various types of diabetes and to assess the severity of metabolic and functional disturbances. Diagnostic criteria in term of glycemia have also been reviewed to asses diabetes and glucose intolerance.

Both pituitary and placental growth hormone transcripts are expressed in human peripheral blood mononuclear cells (PBMC).

The hGH-V gene codes for a variant of human pituitary growth hormone (hGH-N) named placental growth hormone (hPGH). hPGH shares 93% amino acid identity with hGH-N. Until now the hGH-V gene was considered to be exclusively expressed in human placenta, where it replaces maternal circulating hGH-N at the end of pregnancy. In this study we investigated by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis hGH-N, and hGH-V, gene expression in PBMC in men, women and pregnant women. We have demonstrated that hGH-N and hGH-V transcripts are simultaneously produced by PBMC in both men and women as well as pregnant women. The PBMC of a PIT-1-negative woman expressed only the hGH-V transcript, but not the hGH-N one as expected. In conclusion, hGH-V mRNA is expressed by cells other than the syncytiotrophoblast, is not regulated by PIT-1, and may be involved in immune regulation, as is pituitary GH.