Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.
A B S T R A C T 2-n-Butyl-3-(4'-diethylaminoethoxy-3',5'-diiodobenzoyl) -benzofurane (amiodarone), a drug used in arrythmias and angina pectoris, contains 75 mg of organic iodine/200 mg active substance. Four studies were performed to test its effect on thyroid hormone metabolism: (a) nine male subjects were treated with 400 mg of amiodarone for 28 days; (b) five male subjects received, for the same period of time, 150 mg of iodine in the form of Lugol's solution; (c) five subjects received 300 Ag L-thyroxine (T4) for 16 days; from the 10th to the 16th day, 400 mg of amiodarone was added; and (d) five euthyroid subjects received 300 Ag L-T4 for 16 days. The changes in serum thyroid-stimulating hormone (TSH), serum total T4, 3,5,3'-triiodothyronine (T3), free T3, and 3,5',3'-triiodothyronine (reverse Ta, rT3) were measured, and the pituitary reserve in TSH was evaluated by a thyrotropin-releasing hormone (TRH) test.The results show that amiodarone induced a decrease in serum Ta (28±5.1 ng/100 ml, mean ±SEM, P < 0.05), whereas serum T4 and rTs increased (1.4± 0.4 /g T4/100 ml, NS and 82.7±9.3 ng rTs/100 ml, P < 0.01). The control study with an equal amount of inorganic iodine did not induce these opposite changes but slightly lowered serum rTs, T3, and T4. In the third study, serum rTs increased as under amiodarone treatment, thereby proving that these changes were peripheral.It is suggested that amiodarone changes thyroid hormone metabolism, possibly by reducing deiodination of T4 to Ts and inducing a preferential production of rT3.Received for puiblication 20 August 1975 and in rezised form 15 March 1976.Amiodarone also increased the response of TSH to TRH. The maximal increment of serum TSH above base line was 32±4.5 oU/ml under treatment and 20±3 AU/ml before treatment (P < 0.01). During this test, the serum Ts increase was more pronounced than during the control period (83±+13 and 47+7.4 ng/100 ml, P < 0.05).
In adrenal glomerulosa cells, angiotensin II (Ang II) and potassium stimulate aldosterone synthesis through activation of the calcium messenger system. The ratelimiting step in steroidogenesis is the transfer of cholesterol to the inner mitochondrial membrane. This transfer is believed to depend upon the presence of the steroidogenic acute regulatory (StAR) protein. (Ang II) 1 and K ϩ act as regulators of aldosterone synthesis and secretion in adrenal glomerulosa cells. The crucial role of the Ca 2ϩ messenger in the acute regulation of aldosterone production is firmly established (1-5). Indeed, the steroidogenic response of isolated adrenal cells to Ang II and K ϩ is highly dependent upon extracellular Ca 2ϩ concentration (6) and can be blocked by inhibitors of Ca 2ϩ influx across the plasma membrane (4). Moreover, calmodulin antagonists have been shown to inhibit Ang IIstimulated aldosterone production in zona glomerulosa cells (7).Traditionally, aldosterone biosynthesis is functionally divided into three consecutive phases. (i) In the early mitochondrial steps, cholesterol is transported from intracellular lipid droplets into the outer mitochondrial membrane (OM) and then to the inner mitochondrial membrane (IM). The latter step represents the rate-limiting process in all steroidogenic pathways (8) and is followed by the conversion of cholesterol to pregnenolone by the cytochrome P450 scc enzyme. (ii) The intermediate steps take place on the endoplasmic reticulum and involve the conversion of pregnenolone to progesterone by 3-hydroxysteroid dehydrogenase isomerase and then to 11-deoxycorticosterone. (iii) The late steroidogenic steps are localized back in the mitochondria and include the formation of corticosterone and its conversion to aldosterone by cytochrome P450 11 .The regulation of intramitochondrial cholesterol transfer by cAMP-dependent mechanisms has been extensively studied (9). While the transport of cholesterol from lipid droplets to the outer mitochondrial membrane was found not to be affected by inhibitors of protein synthesis in ACTH-stimulated adrenal
Summary In nine women studied serially before conception and through the first trimester, plasma osmolality (Posm) started to decline with the first missed menstrual period, was significantly decreased by the fifth week of pregnancy and was 10 mosmol/kg lower than preconception values by the tenth week, changing little thereafter. Changes in plasma sodium (and its attendant anion) accounted for the majority of the decrement. In separate studies, urinary concentration and dilution, assessed by water deprivation and loading, were studied in nine women during their last trimester and again 10–12 weeks post partum. Basal Posm was 9 mosmol/kg lower in the last trimester than post partum (p < 0.001) but the results of concentration and dilution tests were similar during and after pregnancy. Basal urinary arginine vasopressin (AVP) excretion was similar during and after pregnancy and water loading suppressed AVP excretion in both pregnant and postpartum women. An unanticipated observation was that lateral recumbency interfered with urinary concentration tests in both pregnant and postpartum women. The results demonstrate that the decrement in Posm during pregnancy is an early event. The data (urinary AVP excretion, its suppression by water loading and normal concentration and dilution despite a lower plasma tonicity) also suggest that human pregnancy is accompanied by a resetting of the threshold for vasopressin secretion to a lower Posm
The expression of protein kinase C (PKC) isoenzymes and the effects of PKC activation on myocardial phospholipase A2 (PLA2) activity, platelet-activating factor (PAF) generation and eicosanoid release were studied in spontaneously beating cultured rat cardiomyocytes. Western blotting analysis indicated that these cells contain PKC alpha, beta, delta and zeta, but not PKC gamma or epsilon. Stimulation of cardiomyocytes with 4 beta-phorbol 12-myristate 13-acetate (PMA) led to a rapid increase in particulate-bound PKC activity, a response attributed to the activation of alpha-, delta- and zeta- type PKCs but not beta-type PKC. Translocation of PKC alpha, delta and zeta was accompanied by simultaneous increases in cellular lysophosphatidylcholine (lyso-PC), PAF, 15(S)-hydroxy-5,8,-11,13-eicosatetraenoic acid (15-HETE), prostaglandin E2 (PGE2) and prostacyclin (PGI2) generation, suggesting that one or more of these isoenzymes directly or indirectly activates a PLA2 in these cells. Confirming this, 4 beta-phorbol 12-monoacetate and 4 alpha-phorbol had no effect on cellular eicosanoid formation, while the PMA-induced response was fully abolished both in the presence of the PKC inhibitors staurosporine and CGP 41251 and in PKC-down-regulated cells. PKC alpha, delta and/or zeta therefore appear to play an important role in the PMA-mediated activation of cardiomyocyte PLA2, an event leading to subsequent production of PGI2, PGE2, 15-HETE, lyso-PC and PAF in this tissue.
Plasma renin activity, renin substrate, angiotensin II, aldosterone and cortisol were measured concurrently and renin concentration calculated in plasma from mothers during labor and delivery, from cord and from newborn infants. The renin-angiotensin-aldosterone system was found strongly stimulated in both mother and fetus. The high values of plasma renin activity in fetus were due exclusively to the high renin concentrations the substrate concentration being normal. In the mother, however, the markedly elevated renin substrate resulted in a doubling of relative values of renin activity compared to renin concentration. Therefore gradients of renin and renin substrate across the placenta are established, but the resulting renin activity is similar on both sides and the levels of generated angiotensin II are also nearly indentical with a good correlation between these last parameters. Aldosterone is as elevated in mother as in fetus whereas cortisol, due to its binding to transcortin, is twice as high in mother as in fetus. No correlation was found between renin activity or concentration of angiotensin II and aldosterone or cortisol indicating that other factors controlling aldosterone are involved.
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