RESUMO
A 21-yr-old woman with Turner's syndrome presented with signs and symptoms of acromegaly. The serum growth hormone (GH) (95+/-9.4 ng/ml; mean+/-SEM) and somatomedin C (11 U/ml) levels were elevated, and an increase in GH levels after glucose instead of normal suppression, increase after thyrotropin-releasing hormone (TRH) administration instead of no change, and decrease after dopamine administration instead of stimulation were observed. The pituitary fossa volume was greater than normal (1,440 mm(3)) and the presence of a pituitary tumor was assumed. After tissue removal at transsphenoidal surgery, histological study revealed somatotroph hyperplasia rather than a discrete adenoma. Postoperatively, she remained clinically acromegalic and continued to show increased GH and somatomedin levels. A search was made for ectopic source of a growth hormone-releasing factor (GRF). Computer tomographic scan revealed a 5-cm Diam tumor in the tail of the pancreas. Following removal of this tumor, serum GH fell from 70 to 3 ng/ml over 2 h, and remained low for the subsequent 5 mo. Serum somatomedin C levels fell from 7.2 to normal by 6 wk postoperatively. There were no longer paradoxical GH responses to glucose, TRH, and dopamine. Both the medium that held the tumor cells at surgery and extracts of the tumor contained a peptide with GRF activity. The GRF contained in the tumor extract coeluted on Sephadex G-50 chromatography with rat hypothalamic GH-releasing activity. Stimulation of GH from rat somatotrophs in vitro was achieved at the nanomolar range, using the tumor extract. The patient's course demonstrates the importance of careful interpretation of pituitary histology. Elevated serum GH and somatomedin C levels in a patient with an enlarged sella turcica and the characteristic responses seen in acromegaly to TRH, dopamine, and glucose do not occur exclusively in patients with discrete pituitary tumors and acromegaly. This condition can also occur with somatotroph hyperplasia and then revert to normal after removal of the GRF source. Thus, in patients with acromegaly a consideration of ectopic GRF secretion should be made, and therefore, careful pituitary histology is mandatory. Consideration for chest and abdominal computer tomographic scans before pituitary surgery, in spite of their low yield, may be justified.
Assuntos
Acromegalia/cirurgia , Adenoma de Células das Ilhotas Pancreáticas/cirurgia , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Neoplasias Pancreáticas/cirurgia , Acromegalia/complicações , Acromegalia/patologia , Adenoma de Células das Ilhotas Pancreáticas/complicações , Adenoma de Células das Ilhotas Pancreáticas/metabolismo , Adulto , Animais , Cromatografia em Gel , Feminino , Hormônio do Crescimento/sangue , Humanos , Hiperplasia/complicações , Hiperplasia/patologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/metabolismo , Adeno-Hipófise/ultraestrutura , Ratos , Hormônio Liberador de Tireotropina/sangue , Hormônio Liberador de Tireotropina/farmacologia , Síndrome de Turner/complicaçõesRESUMO
Steroid 21-hydroxylase deficiency is the leading cause of impaired cortisol synthesis in congenital adrenal hyperplasia (CAH). We have studied the structure of the CYP21B gene in 30 unrelated CAH patients using the polymerase chain reaction (PCR) to differentiate the active CYP21B gene from its highly related CYP21A pseudogene. The PCR approach obviates the need to distinguish the CYP21A and CYP21B genes by restriction endonuclease digestion and electrophoresis before analysis with labeled probes. Furthermore, direct nucleotide sequence analysis of CYP21B genes is demonstrated on the PCR-amplified DNA. Gene deletion of CYP21B, gene conversion of the entire CYP21B gene to CYP21A, frame shift mutations in exon 3, an intron 2 mutation that causes abnormal RNA splicing, and a mutation leading to a stop codon in exon 8 appear to be the major abnormalities of the CYP21B gene in our patients. These mutations appear to account for 21-hydroxylase deficiency in 22 of 26 of our salt-wasting CAH patients.
Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/genética , Esteroide Hidroxilases/deficiência , Hiperplasia Suprarrenal Congênita/diagnóstico , Alelos , Sequência de Bases , DNA , Humanos , Dados de Sequência Molecular , Mutação , Reação em Cadeia da Polimerase/métodos , Pseudogenes , Esteroide 21-Hidroxilase/genéticaRESUMO
We have characterized mutations in the steroid 21-hydroxylase gene (CYP21) in salt-wasting congenital adrenal hyperplasia (SW-CAH) subjects, healthy control subjects, and affected sibling pairs with SW-CAH. To identify point mutations in CYP21, we have used an improved polymerase chain reaction methodology that allows analysis of the entire CYP21 gene. In addition, we have used polymerase chain reaction to search for abnormally spliced mRNAs resulting from putatively abnormal CYP21 genes transfected into COS1 cells. We found that all 26 SW-CAH subjects from whom DNA could be completely analyzed, had mutations that could account for the 21-hydroxylase enzyme deficiency. These mutations included CYP21 gene deletion, conversion to the inactive CYP21P form, point mutations leading to amino acid substitutions or stop codons, small gene deletions, and a point mutation in intron-2 that leads to an abnormally spliced mRNA. The point mutation in intron-2 was directly shown to activate a cryptic splice site 19 basepairs from exon-3 of CYP21 and thereby cause a reading frame mutation. This CYP21 mutation was frequently found in our white SW-CAH subjects, while the frequency of this mutation was extremely low in a racially matched control population. Furthermore, affected sibling pairs shared this mutation in all cases examined. The results presented should have important applications for the prenatal diagnosis of CAH.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , Mutação , Esteroide 21-Hidroxilase/genética , Hiperplasia Suprarrenal Congênita/enzimologia , Animais , Sequência de Bases , Linhagem Celular , DNA/genética , DNA/isolamento & purificação , Éxons , Humanos , Íntrons , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Reação em Cadeia da Polimerase/métodos , Valores de Referência , TransfecçãoRESUMO
An adolescent boy with a bizarre progressive poikiloderma had episodic acral blistering and the development of palmar and plantar keratosis suggestive of hereditary acrokeratotic poikiloderma. Growth and development had been normal. Vesicobullous lesions were said to be present at birth and during early infancy. No family members were similarly affected. Results of laboratory studies were normal. Histological sections of skin demonstrated epidermal atrophy in some areas, increased epidermal melanin fibrosis of the papillary dermis, and modest capillary proliferation.
Assuntos
Síndrome de Rothmund-Thomson/patologia , Dermatopatias/patologia , Adolescente , Diagnóstico Diferencial , Humanos , Ceratodermia Palmar e Plantar/complicações , Masculino , Síndrome de Rothmund-Thomson/complicações , Síndrome de Rothmund-Thomson/diagnóstico , Xeroderma Pigmentoso/diagnósticoRESUMO
The classification of diabetes mellitus by types (1 or 2), or by age of onset (juvenile or adult), helps to clarify many aspects of pathophysiology, prognosis, and therapy. However, less-commonly encountered patients, presenting in childhood or adolescence, may not fit neatly into one or the other group. These include teenagers who present with new-onset diabetes with ketoacidosis, but who are later able to be managed permanently as type 2 patients. Other adolescent patients present with only minimal glucose intolerance, then proceed to develop type 1 diabetes, with evidence of autoimmune etiology, after a variable number of years. Four patients are presented to illustrate these diagnostic dilemmas.
Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Adolescente , Criança , Feminino , HumanosRESUMO
Athletes with diabetes require intensive diabetes management to balance insulin, carbohydrate intake, and the effects of exercise. Effective care of active patients who have diabetes starts with a targeted preparticipation exam. Decreasing the insulin dosage may be necessary for heavier exercise programs if carbohydrate supplementation alone is insufficient. The documented risk for either hypoglycemia or ketoacidosis requires careful planning for training or competition. Analysis of 'high-risk' activities is essential to determine which may need to be modified, diminished, or restricted.
RESUMO
The adolescent with insulin-dependent diabetes mellitus (IDDM) can safely participate in sports activities without interference from the disease. To ensure safe and successful participation, clinicians must appreciate how diabetes may alter the physiologic adaptation to strenuous exercise and how an individualized self-care plan can empower the adolescent with IDDM to effectively manage meal planning, blood glucose testing, and insulin injections. Various types of insulin, insulin schedules, and insulin delivery devices that may suit a wide variety of training and activity regimens are described.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Esportes/fisiologia , Adaptação Fisiológica , Adolescente , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Masculino , Monitorização Fisiológica , Prevalência , Prognóstico , Medição de RiscoRESUMO
The mechanisms by which adenosine triphosphate, thrombin, and trypsin cause relaxation of vascular smooth muscle were investigated. Relaxation of the rat thoracic aorta with adenosine triphosphate, thrombin, and/or trypsin was associated with increased levels of cyclic guanosine monophosphate in both time- and concentration-dependent manners. Thrombin and trypsin did not alter cyclic adenosine monophosphate levels, whereas adenosine triphosphate increased cyclic adenosine monophosphate levels after significant relaxation occurred. Removal of the endothelium abolished adenosine triphosphate-, thrombin-, and trypsin-induced relaxation and the associated increased levels of cyclic nucleotides. Relaxation due to these agents was also inhibited by exposure to nordihydroguaiaretic acid, a lipoxygenase inhibitor, and eicosatetraynoic acid, a lipoxygenase and cyclooxygenase inhibitor. Indomethacin, a cyclooxygenase inhibitor, potentiated relaxation to these agents, whereas the increased levels of cyclic nucleotides due to adenosine triphosphate were unaltered. Bromophenacyl bromide, a phospholipase A2 inhibitor, decreased relaxation due to adenosine triphosphate, thrombin, and trypsin and the associated increased levels of cyclic nucleotides. Removal of extracellular calcium, which also presumably inhibits phospholipase A2, prevented the elevated levels of cyclic nucleotides and the inhibitory effects of adenosine triphosphate and trypsin on contraction. In contrast, sodium nitroprusside-induced relaxation and/or increased levels of cyclic guanosine monophosphate were unaltered by nordihydroguaiaretic acid, eicosatetraynoic acid, bromophenacyl bromide, and removal of extracellular calcium. After incubation of intact tissue with 32P-orthophosphate, the patterns of protein phosphorylation caused by adenosine triphosphate, thrombin, and trypsin were indistinguishable from those of acetylcholine, sodium nitroprusside and 8-bromo cyclic guanosine monophosphate. All these agents dephosphorylated myosin light chain. Thus, the present study supports the hypothesis that relaxation induced by adenosine triphosphate, thrombin, and trypsin is mediated through the formation of an endothelial factor which elevates cyclic guanosine monophosphate levels and causes cyclic guanosine monophosphate-dependent protein phosphorylation and dephosphorylation of myosin light chain.
Assuntos
Trifosfato de Adenosina/farmacologia , Aorta Torácica/fisiologia , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Trombina/farmacologia , Tripsina/farmacologia , Acetofenonas/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Cálcio/farmacologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Endotélio/fisiologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Fosfoproteínas/metabolismo , Ratos , Ratos EndogâmicosRESUMO
The action of some vascular smooth muscle relaxants depends on the presence of the endothelium. We have recently shown that relaxation may be mediated through the formation of cyclic GMP. The nitrovasodilators are another class of relaxants which exert their effects through the formation of cyclic GMP, although their relaxation is independent of the presence of the endothelium. Their relaxant properties seem to depend on free radical formation--specifically, the formation of nitric oxide. The NO-induced smooth muscle relaxation is proposed to occur through activation of guanylate cyclase and the formation of cyclic GMP. Protein phosphorylation is thought to be a common event in the pathway for many biological phenomena. Moreover, sodium nitroprusside and 8-bromo cyclic GMP induce similar patterns of protein phosphorylation in intact rat thoracic aorta. Here we report that the patterns of protein phosphorylation induced by the endothelium-dependent vasodilators and nitrovasodilators were identical. Incorporation of 32P into myosin light chain was decreased by both classes of agents. Removal of the endothelium abolished the changes in phosphorylation with the endothelium-dependent vasodilator (acetylcholine), but not those with the nitrovasodilator (sodium nitroprusside). These results suggest that endothelium-dependent vasodilators and nitrovasodilators induce relaxation through cyclic GMP-dependent protein phosphorylation and dephosphorylation of myosin light chain.
Assuntos
GMP Cíclico/fisiologia , Endotélio/fisiologia , Contração Muscular , Relaxamento Muscular , Músculo Liso Vascular/fisiologia , Fosfoproteínas/fisiologia , Acetilcolina/farmacologia , Animais , Aorta/fisiologia , Ponto Isoelétrico , Masculino , Peso Molecular , Proteínas Musculares/metabolismo , Miosinas/metabolismo , Nitroprussiato/farmacologia , RatosRESUMO
The effects of sodium nitroprusside, 8-bromo cyclic GMP, 8-bromoguanosine 5'-monophosphate, 8-bromo cyclic AMP, dibutyryl cyclic AMP, and isoproterenol on incorporation of (32)P into proteins in intact rat thoracic aorta were studied. Aortas were incubated in [(32)P]orthophosphate in order to label endogenous adenosine triphosphate. Agents were then added for various times and the tissues were homogenized and fractionated (100,000 x g for 60 min) into soluble and particulate fractions. Soluble and particulate fractions were subjected to isoelectric focusing followed by sodium dodecyl sulfate/polyacrylamide gel electrophoresis and autoradiographs were made. Nitroprusside induced a concentration-dependent increase in incorporation of (32)P into nine proteins and a decrease in (32)P incorporation into two proteins. Some of these proteins appeared in both the soluble and particulate fractions of homogenates; others appeared only in the soluble fraction. The pattern of (32)P incorporation was identical after 2- or 15-min exposure to nitroprusside and was mimicked by exposure to 50-500 muM 8-bromo cyclic GMP. 8-Bromoguanosine 5'-monophosphate did not alter (32)P incorporation. Dibutyryl cyclic AMP at 50 muM had no effect upon (32)P incorporation whereas a higher concentration (0.5 mM) caused increased or decreased (32)P incorporation into some, but not all, of the same proteins. 8-Bromo cyclic AMP (5 mM) produced only small changes in (32)P incorporation. The pattern of (32)P incorporation induced by a relatively high concentration of isoproterenol 0.1 mM was similar but not identical to that seen with 0.5 mM dibutyryl cyclic AMP. The present study indicates that the incorporation of (32)P into endogenous proteins of intact rat aorta can be regulated by nitroprusside. These effects can be mimicked by cyclic GMP analogues and only partially by cyclic AMP analogues or isoproterenol. Presumably, these effects of nitroprusside are mediated through a cyclic GMP-dependent process (protein kinase or phosphatase) which may play a role in the relaxant properties of nitroprusside and cyclic GMP.
Assuntos
AMP Cíclico/análogos & derivados , Ferricianetos/farmacologia , Proteínas Musculares/metabolismo , Músculo Liso Vascular/metabolismo , Nitroprussiato/farmacologia , Fosfoproteínas/biossíntese , 8-Bromo Monofosfato de Adenosina Cíclica , Animais , Aorta/metabolismo , Bucladesina/farmacologia , AMP Cíclico/farmacologia , Masculino , Peso Molecular , RatosRESUMO
Myosin light chain phosphorylation in intact rat thoracic aorta was elevated during contraction induced by 0.3 microM norepinephrine, but was not maintained. Addition of 0.5 microM sodium nitroprusside to norepinephrine treated rat aorta strips led to elevation of cyclic GMP levels, relaxation of tension, and dephosphorylation of myosin light chain. Depletion of extracellular calcium or addition of calmodulin antagonists trifluoperazine and W7 diminished the contraction and phosphorylation of myosin light chain by norepinephrine, but did not prevent dephosphorylation by sodium nitroprusside or the elevated levels of cyclic GMP. Isoproterenol, 8-bromo cyclic GMP, and dibutyryl cyclic AMP all caused dephosphorylation of myosin light chain and induced relaxation during the period of development of tone. Eight other proteins had increased phosphorylation following norepinephrine treatment and one protein had less phosphorylation. The different proteins phosphorylated by norepinephrine showed varying degrees of sensitivity to Ca2+-free solution and to the calmodulin antagonists. The pattern of protein phosphorylation caused by sodium nitroprusside was best mimicked by 8-bromo cyclic GMP, rather than isoproterenol and dibutyryl cyclic AMP. These proteins were, generally, unaffected by Ca2+-free solution and the calmodulin antagonists. The present observations support the hypothesis that vasodilators inhibit tone development through myosin light chain dephosphorylation. Furthermore, the nitrovasodilators act through elevation of cyclic GMP and phosphorylation of proteins by cyclic GMP-dependent protein kinase.
Assuntos
Aorta Torácica/metabolismo , Miosinas/metabolismo , Vasoconstrição , Animais , Aorta Torácica/efeitos dos fármacos , Cálcio/farmacologia , GMP Cíclico/metabolismo , Técnicas In Vitro , Masculino , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Fosforilação , Ratos , Ratos Endogâmicos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
We present an improved method for the prenatal diagnosis of congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. The polymerase chain reaction (PCR) was used to analyze DNA from an affected index case, the parents, and a cultured chorionic villus sample, for point mutations in the steroid 21-hydroxylase (CYP21) gene. We can predict that the fetus is an unaffected carrier.
Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/diagnóstico , Doenças Fetais/diagnóstico , Diagnóstico Pré-Natal , Hiperplasia Suprarrenal Congênita/enzimologia , Hiperplasia Suprarrenal Congênita/genética , Sequência de Bases , Células Cultivadas , Feminino , Doenças Fetais/enzimologia , Doenças Fetais/genética , Humanos , Dados de Sequência Molecular , Mutação/genética , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Gravidez , Esteroide 21-Hidroxilase/genéticaRESUMO
A 3-week-old girl who was born with club feet had signs of failure to thrive. On physical examination the child appeared normal; she had no abnormalities in the mucous membranes of the mouth, the eyelids, or in the neck, and her other systems, including heart, chest, abdomen, and neurologic systems, were clinically normal. Radiologically, the gastrointestinal tract was normal, but rectal biopsy showed neuromas. Her serum calcitonin level was measured both at basal and after pentagastrin stimulation at 5 weeks of age and found to be high, but whether it was consistent with the normal level at this early age or was caused by medullary thyroid carcinoma was not clear. At 3 months, the corneal nerves of both eyes were examined and showed considerable thickening, and multiple endocrine syndrome type IIb was suspected. The serum calcitonin level at 8 and 14 months was increased. A total thyroidectomy was done, and C-cell nodular hyperplasia and adenomatosis was found in the isthmus. The postoperative serum calcitonin level decreased to low normal and did not increase after pentagastrin stimulation. To the authors' knowledge, this case represents the youngest patient diagnosed with multiple endocrine syndrome type IIb in the absence of family history of the disease.