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PURPOSE: Obesity is a major public health burden. Outpatient clinics are an essential resource for individuals with obesity to access advice for weight loss management. The aim of this study was to compare anthropometric and weight loss outcomes between participants receiving general dietary (GD) advice, and those on a very low energy diet (VLED) under non-trial conditions. METHODS: Data from 276 adults with obesity attending a multidisciplinary weight management clinic were analysed. Changes in anthropometry, body composition, and blood pressure (BP) over 12 months were analysed using linear mixed-effects models. RESULTS: Males on the GD demonstrated statistically greater reductions in body weight (BW), BMI, percent fat mass (FM), systolic BP, waist and hip circumference (p < 0.01). Changes in males on a VLED did not reach significance. Females showed statistically significant reductions in BW, BMI, waist and hip circumference regardless of dietary intervention (p < 0.01); those on the GD significantly reduced percent FM (p < 0.001). Females on a VLED had statistically greater reductions in BW, BMI and systolic BP compared to those on the GD. No effect of exercise physiologist was observed in this study. Participants prescribed a GD attended for significantly longer than those on a VLED (p < 0.05), irrespective of gender. At 12 months, 14.3 and 4.5% of males and females on a VLED were still attending, compared to 10.6 and 4.5% on the GD. CONCLUSIONS: In this retrospective study, females in both dietary intervention groups achieved significant changes across multiple measures. Only men receiving GD advice demonstrated significant changes. LEVEL OF EVIDENCE: Level II-2.
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Índice de Massa Corporal , Restrição Calórica , Dieta Redutora , Obesidade/dietoterapia , Pacientes Ambulatoriais , Adulto , Austrália , Composição Corporal/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Estudos Retrospectivos , Fatores Sexuais , Resultado do TratamentoRESUMO
Hirayama disease is a myelopathy related to flexion movements of the neck that produce ischemic damage in the anterior horn of the cervical cord. The disease affects young people and is characterized by a distal upper extremity deficit that develops gradually. The diagnosis is confirmed by cervical magnetic resonance imaging (MRI) in flexion demonstrating a forward shift of the posterior dural sac and spinal cord compression. On radiology, there should be suggestive signs in neutral position such as cord atrophy, intramedullary bilateral high signal intensity on T2-weighted images, straightening of the cervical spine, and loss of attachment between the posterior dural sac and subjacent lamina. Exploration should be completed by an MR study in neck flexion. We report here on two typical cases of the disease and also include a review of the literature.
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Imageamento por Ressonância Magnética , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/etiologia , Medula Espinal/patologia , Atrofias Musculares Espinais da Infância/complicações , Atrofias Musculares Espinais da Infância/diagnóstico , Humanos , Masculino , Extremidade Superior , Adulto JovemRESUMO
Susceptibility-weighted MR sequences, T2 star weighted angiography (SWAN, General Electric), Susceptibility weighted imaging (SWI, Siemens) and venous blood oxygen level dependant (VenoBOLD, Philips) are 3D spoiled gradient-echo sequence that provide a high sensitivity for the detection of blood degradation products, calcifications, and iron deposits. For all these sequences, an appropriate echo time allows for the visualization of susceptibility differences between adjacent tissues. However, each of these sequences presents a specific technical background. The purpose of this review was to describe 1/the technical aspects of SWAN, VenoBOLD and SWI sequences, 2/the differences observed in term of contrast within the images, 3/the key imaging findings in neuroimaging using susceptibility-weighted MR sequences.
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Encefalopatias/diagnóstico , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Meios de Contraste , Humanos , Aumento da Imagem/métodos , Angiografia por Ressonância Magnética/métodosRESUMO
BACKGROUND: Lecture recording software is a useful reference tool that allows students to revisit lectures and understand complicated concepts in higher education. It is also a useful tool for students with learning difficulties, allowing them to reference and learn the material at their own pace. A significant advantage of this tool is the accessibility of course material to the students off campus. This study attempted to learn the students' perception of the purpose, use, and benefit of lecture recording software at a medical school. METHODS: The study was conducted using a structured questionnaire delivered, via an Internet-based survey application in the Fall semester of 2017, to 105 students attending the basic sciences courses. A web link was generated after the 18-point questionnaire was uploaded to an online survey software. The link was communicated electronically to each student along with the date and time of the survey. The survey was anonymous. The results of the survey were summarized using descriptive statistics and graphical methods. Students were asked to submit voluntary, informed consent to participate in the study before attempting to answer the questionnaire. The institutional review board approved the research. RESULTS: The results showed 77% students used this resource to understand points they missed in the class, 75% of them relearned complex ideas/concepts, and 62% of them used it to rewrite class notes. Reportedly, the software was used by students (78%) who missed a class due to an illness or while attending clinical shadowing. Of the students, 87% agreed that the software is helpful because of its off-campus availability while 84% of the students liked the service, as it allowed them to listen to the lectures at their own pace. Many students (65%) felt that the service helped them score better in the exams, whereas 38% did not think the recordings was helpful to get the desired grade and 50% student felt it was time-consuming. CONCLUSION: Despite the time-consuming listening process, students expressed a positive opinion about the usefulness of this software. Recording and archiving class lectures could be a useful academic resource. Students could learn from these archived lectures before the class and engage in the discussion later, enhancing active learning. The result suggests that students should also use other study resources and methods to achieve the desired grades. The induction of this student service into a professional curriculum would enhance the students' satisfaction, effectiveness, and outcomes.
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OBJECTIVES: We aimed to report the first 54 cases of pregnant women infected by Zika virus (ZIKV) and their virologic and clinical outcomes, as well as their newborns' outcomes, in 2016, after the emergence of ZIKV in dengue-endemic areas of São Paulo, Brazil. METHODS: This descriptive study was performed from February to October 2016 on 54 quantitative real-time PCR ZIKV-positive pregnant women identified by the public health authority of São José do Rio Preto, São Paulo, Brazil. The women were followed and had clinical and epidemiologic data collected before and after birth. Adverse outcomes in newborns were analysed and reported. Urine or blood samples from newborns were collected to identify ZIKV infection by reverse transcription PCR (RT-PCR). RESULTS: A total of 216 acute Zika-suspected pregnant women were identified, and 54 had the diagnosis confirmed by RT-PCR. None of the 54 women miscarried. Among the 54 newborns, 15 exhibited adverse outcomes at birth. The highest number of ZIKV infections occurred during the second and third trimesters. No cases of microcephaly were reported, though a broad clinical spectrum of outcomes, including lenticulostriate vasculopathy, subependymal cysts, and auditory and ophthalmologic disorders, were identified. ZIKV RNA was detected in 18 of 51 newborns tested and in eight of 15 newborns with adverse outcomes. CONCLUSIONS: Although other studies have associated many newborn outcomes to ZIKV infection during pregnancy, these same adverse outcomes were rare or nonexistent in this study. The clinical presentation the newborns we studied was mild compared to other reports, suggesting that there is significant heterogeneity in congenital Zika infection.
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Doenças Fetais/virologia , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/complicações , Zika virus/isolamento & purificação , Adulto , Brasil , Feminino , Humanos , Recém-Nascido , Filogenia , Gravidez , Adulto Jovem , Zika virus/classificação , Zika virus/genéticaRESUMO
Several putative schizophrenia susceptibility genes have recently been reported, but it is not clear whether these genes are associated with schizophrenia in general or with specific disease subtypes. In a previous study, we found an association of the neuregulin 1 (NRG1) gene with non-deficit schizophrenia only. We now report an association study of four schizophrenia candidate genes in patients with and without deficit schizophrenia, which is characterized by severe and enduring negative symptoms. Single-nucleotide polymorphisms (SNPs) were genotyped in the DTNBP1 (dysbindin), G72/G30 and RGS4 genes, and the relatively unknown PIP5K2A gene, which is located in a region of linkage with both schizophrenia and bipolar disorder. The sample consisted of 273 Dutch schizophrenia patients, 146 of whom were diagnosed with deficit schizophrenia and 580 controls. The strongest evidence for association was found for the A-allele of SNP rs10828317 in the PIP5K2A gene, which was associated with both clinical subtypes (P = 0.0004 in the entire group; non-deficit P = 0.016, deficit P = 0.002). Interestingly, this SNP leads to a change in protein composition. In RGS4, the G-allele of the previously reported SNP RGS4-1 (single and as part of haplotypes with SNP RGS4-18) was associated with non-deficit schizophrenia (P = 0.03) but not with deficit schizophrenia (P = 0.79). SNPs in the DTNBP1 and G72/G30 genes were not significantly associated in any group. In conclusion, our data provide further evidence that specific genes may be involved in different schizophrenia subtypes and suggest that the PIP5K2A gene deserves further study as a general susceptibility gene for schizophrenia.
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Sintomas Afetivos/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Proteínas RGS/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Alelos , Proteínas de Transporte/genética , Estudos de Casos e Controles , Disbindina , Proteínas Associadas à Distrofina , Predisposição Genética para Doença , Variação Genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Escore Lod , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , RNA Mensageiro , Esquizofrenia/classificaçãoRESUMO
INTRODUCTION: Bile salt stimulated lipase (BSSL; Enzyme Commission (EC) number 3.1.1.13) has been a candidate triglyceridase for improving enzyme therapy for pancreatic insufficiency; however, its efficacy is near absent. We hypothesise that similarly to pancreatic lipase, BSSL is inhibited by phospholipids and this inhibition is relieved by Phospholipase A2 (PLA2; EC 3.1.1.4), and the present study was undertaken to explore this possibility. MATERIALS AND METHODS: Synthetic emulsions of triglyceride and phosphatidylcholine (PC) or lysophosphatidylcholine (LPC)/bile salt mixed micelles were used as a model of intestinal digestion-media. The effect of PLA2 treatment of systems containing PC on BSSL activity was also explored. Automatic titration at constant pH (pH-stat) and nuclear magnetic resonance (NMR) spectroscopy were used to measure the rate and identify products of lipolysis. RESULTS: PC was inhibitory to BSSL activity, while LPC became inhibitory only above an LPC/bile salt concentration ratio of 0.3. PLA2 treatment relieved the inhibition only below this ratio, despite its complete phospholipid-hydrolysing action. Thus, LPC had an inhibitory effect at higher concentrations. CONCLUSIONS: These results may implicate a change in the design of enzyme therapy in patients with pancreatic exocrine insufficiency. Supplementation of BSSL with PLA2 could improve patient health with adequate manipulation of phospholipid and lysophospholipid concentrations in the intestinal fluid.
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Fibrose Cística , Gorduras na Dieta/metabolismo , Insuficiência Pancreática Exócrina , Lipase/metabolismo , Fosfolipídeos/metabolismo , Esterol Esterase/metabolismo , Fibrose Cística/complicações , Fibrose Cística/enzimologia , Insuficiência Pancreática Exócrina/etiologia , Insuficiência Pancreática Exócrina/metabolismo , Humanos , Espectroscopia de Ressonância Magnética/métodos , Metabolismo , Modelos Teóricos , Pâncreas/enzimologiaRESUMO
Intact and castrated male DD/S mice were inoculated with androgen-dependent cells (SC 115). All intact animals developed tumors after Day 12 of inoculation; however, six of seven castrated animals presented tumors 48 days postinoculation. The levels of steroids in both tumors were then examined. In castrated mice, dehydroepiandrosterone and androst-5-ene-3 beta, 17 beta-diol levels were diminished by 30% and 70%, respectively, while the amounts of testosterone and androstenedione were reduced by more than 90%. Our data also demonstrate that androstane-3 alpha, 17 beta-diol and androstane-3 beta, 17 beta-diol were decreased to 60% and dihydrotestosterone decreased to 6% of their normal value, respectively. This latter level (0.48 nM) was sufficient to still effect a potent androgenic response in the tumor. Besides, a highly significant correlation was found in these tumors between various C-19 steroids (dehydroepiandrosterone and androstane-3 alpha, 17 beta-diol, r = 0.97, P less than 0.01), suggesting a possible conversion of C-19 precursors into potent androgens in the tumors. Determination of the plasma steroid levels in the castrated animals clearly confirmed that potent androgenic steroids and precursors were still in the circulation 3 days after castration. It thus appears that C-19 steroids from adrenal origin may be also involved in "independent" tumor growth.
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Neoplasias Mamárias Experimentais/metabolismo , Esteroides/metabolismo , Animais , Masculino , Neoplasias Mamárias Experimentais/patologia , Camundongos , Ovariectomia , Esteroides/sangueRESUMO
Juvenile polyposis syndrome (JPS; MIM 174900) is an autosomal dominant condition with incomplete penetrance characterized by hamartomatous polyps of the gastrointestinal tract and a risk of gastrointestinal cancer. Gastrointestinal hamartomatous polyps are also present in Cowden syndrome (CS; MIM 158350) and Bannayan-Zonana syndrome (BZS; also called Ruvalcaba-Myhre-Smith syndrome; MIM 153480). The susceptibility locus for both CS and BZS has recently been identified as the novel tumor suppressor gene PTEN, encoding a dual specificity phosphatase, located at 10q23.3. A putative JPS locus, JP1, which most likely functions as a tumor suppressor, had previously been mapped to 10q22-24 in both familial and sporadic juvenile polyps. Given the shared clinical features of gastrointestinal hamartomatous polyps among the three syndromes and the coincident mapping of JP1 to the region of PTEN, we sought to determine whether JPS was allelic to CS and BZS by mutation analysis of PTEN and linkage approaches. Microsatellite markers spanning the CS/BZS locus (D10S219, D10S551, D10S579, and D10S541) were used to compute multipoint lod scores in eight informative families with JPS. Lod scores of < -2.0 were generated for the entire region, thus excluding PTEN and any genes within the flanking 20-cM interval as candidate loci for familial JPS under our statistical models. In addition, analysis of PTEN using a combination of denaturing gradient gel electrophoresis and direct sequencing was unable to identify a germline mutation in 14 families with JPS and 11 sporadic cases. Therefore, at least a proportion of JPS cases are not caused by germline PTEN alteration or by an alternative locus at 10q22-24.
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Cromossomos Humanos Par 10/genética , Neoplasias Gastrointestinais/genética , Genes Supressores de Tumor/genética , Síndrome do Hamartoma Múltiplo/genética , Pólipos/genética , Mutação em Linhagem Germinativa , Haplótipos , Humanos , Escore Lod , Repetições de Microssatélites , Síndrome de Peutz-Jeghers/genéticaRESUMO
Heterozygous germline mutations in PTEN are responsible for most cases of Cowden Syndrome, a rare familial trait characterized by hamartomas and by predisposition to cancer of the breast and thyroid. The variable and often subtle clinical findings that characterize Cowden Syndrome are frequently unrecognized, raising the possibility that germline PTEN mutations may confer susceptibility to breast cancer in women who have not been diagnosed with this syndrome. To determine whether such mutations contribute to genetic predisposition to breast cancer within the general population, we analysed a cohort of women with early-onset breast cancer (< age 40), a subset of the population at increased risk for genetic susceptibility. Lymphoblast cell lines were analysed using either direct nucleotide sequencing (28 cases), denaturing gradient gel electrophoresis (DGGE) (34 cases) or a yeast-based truncation assay (110 cases). No definitive, truncating mutations were observed in 172 patients. Missense changes were noted in the germline of 2/60 patients analysed by direct nucleotide sequencing or DGGE, including a non-conservative amino acid substitution within the phosphatase domain, but neither showed loss of the wild-type allele in the corresponding breast tumor specimen. We conclude that germline mutations in PTEN are an uncommon cause of genetic predisposition to breast cancer within the general population.
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Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , Monoéster Fosfórico Hidrolases , Proteínas Tirosina Fosfatases/genética , Proteínas Supressoras de Tumor , Adulto , Idade de Início , Neoplasias da Mama/epidemiologia , Causalidade , Estudos de Coortes , Feminino , Síndrome do Hamartoma Múltiplo/genética , Humanos , PTEN Fosfo-Hidrolase , Terminação Traducional da Cadeia Peptídica/genética , Fatores de Risco , Análise de Sequência de DNARESUMO
Mouse NPDC-1 (Neural Proliferation Differentiation and Control-1) is specifically expressed in neural cells when they stop dividing and start to differentiate. The NPDC-1 protein has been shown to interact with the E2F1 transcription factor, D-type cyclins and Cdk2. Immunocytochemical studies and subcellular fractionation of rat brains disclosed a partial colocalization of NPDC-1 with synaptic vesicle proteins, suggesting additional functional interactions. Here, we report the characterization of the mouse and human genes that were found to display very similar structures. We mapped the human gene to chromosome 9q34.3. No obvious pathological defect has been previously linked to this region. In order to gain further insights into its function(s), we generated null mice for the NPDC-1 gene. We did not detect any macroscopic phenotypical defect. Analysis of the upstream sequence of the mouse NPDC-1 gene delineated two regions involved in its negative and positive transcriptional regulation. Evidence for the regulation of NPDC-1 by Krox family transcription factors is presented.
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Proteínas do Tecido Nervoso/genética , Vesículas Sinápticas/fisiologia , Animais , Sequência de Bases , Encéfalo/fisiologia , Diferenciação Celular , Fracionamento Celular , Núcleo Celular/fisiologia , Mapeamento Cromossômico , Cromossomos Humanos Par 9/genética , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/fisiologia , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
The present study investigates the levels of a large series of 18 non-conjugated or conjugated steroids in 71 samples of human breast cyst fluid (BCF) as divided into three groups corresponding to different electrolyte composition. In the type 1 group, the K+/Na+ ratio was higher than 1.5, while in type 2 it was lower than 0.66 and finally type 3 had an intermediate ratio. Pregnenolone (PREG) and progesterone (PROG) levels were approximately 2-fold higher (P less than 0.05) in the type 2 than in the type 1 group while both 17-OH-pregnenolone (17-OH-PREG) and 17-OH-progesterone (17-OH-PROG) concentrations were similar in these two groups. Most of the C-19 steroids analyzed, namely dehydroepiandrosterone sulfate (DHEAS), androst-5-ene-3 beta, 17 beta-diol (5-ene-DIOL), testosterone (TESTO), dihydrotestosterone (DHT), androstane-3 alpha, 17 beta-diol (3 alpha-DIOL), androsterone (ADT), androstane-3 alpha, 17 beta-diol glucuronide (3 alpha-DIOL-G) and androsterone glucuronide (ADT-G) were 180-360% (P less than 0.05) higher in type 1 than in type 2 cysts while no difference in C-18 steroid and C-18 steroid glucuronide levels was observed. A small or no difference was seen in steroid levels between types 2 and 3. We conclude that the arbitrary division according to the electrolyte composition of BCF permits identification of different patterns of steroid concentrations in BCF. However, the mechanism responsible for both sets of parameters remain unclear.
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Androgênios/análise , Estrogênios/análise , Doença da Mama Fibrocística/metabolismo , Progestinas/análise , Adulto , Feminino , Doença da Mama Fibrocística/classificação , Humanos , Pessoa de Meia-Idade , Potássio/análise , Sódio/análiseRESUMO
A review of the process research and development of CP-195543 is presented. This chronological depiction from the original medicinal chemistry synthesis, which yielded a few grams of final product, to a novel route which allowed the compound to be prepared in multi-kilogram quantities, demonstrates some of the challenges which pace environment. This project also exemplifies the necessity of communication and collaboration between discovery and the different departments of process research and development in order to proceed quickly from the discovery of a compound to its evaluation in the clinic.
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The presence and production of 5-ene-steroid fatty acid esters (SFA) has been previously reported in bovine adrenals. A study was conducted, using a series of chromatographic procedures and radioimmunoassays, to determine the levels of SFA in adrenals from man, cattle, dog, rat and guinea-pig, and to assess, in both rats and guinea-pigs, the effect of ACTH on SFA production by adrenals and their subsequent secretion into the circulation. The effects of ACTH on plasma SFA and non-conjugated steroid levels were also investigated in human subjects. Our data indicated that adrenal pregnenolone fatty acid ester (PREG-FA) levels were below 40% of PREG levels in cattle, dog, rat and guinea-pig while, in man, PREG-FA levels were threefold those of PREG. A large proportion of dehydroepiandrosterone (DHEA) and 5-androstene-3 beta, 17 beta-diol were present as fatty acid ester derivatives in the adrenals of all species, with the exception of cattle. In both rats and guinea-pigs, administration of ACTH caused a sharp increase in adrenal PREG of approximately threefold which lasted for 6 h, while the concentration of adrenal PREG-FA was slightly increased for a short time. In plasma, however, a marked rise in PREG-FA occurred, while the changes in PREG levels were much lower than those of its acylated counterpart. In man, PREG and DHEA concentrations were rapidly stimulated two-fold in the first 30 min following the administration of ACTH, while PREG-FA and DHEA-FA levels were increased by approximately 2.5-fold (P less than 0.01) at 120 and 180 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/farmacologia , Androstenodiol/metabolismo , Desidroepiandrosterona/metabolismo , Pregnenolona/metabolismo , Glândulas Suprarrenais/química , Glândulas Suprarrenais/efeitos dos fármacos , Adulto , Animais , Bovinos , Desidroepiandrosterona/sangue , Cães , Ácidos Graxos/análise , Ácidos Graxos/sangue , Cobaias , Humanos , Masculino , Pessoa de Meia-Idade , Pregnenolona/sangue , Ratos , Fatores de TempoRESUMO
Rabbit peripheral serum and uterine tissue (embryonic (EZ) and interembryonic (IEZ) zones) were assayed for the main C21, C19 and C18 steroids throughout pregnancy and pseudopregnancy (PSPG). Pregnenolone concentrations in PSPG and IEZ were comparable and remained relatively stable, while its level in EZ increased, reaching a peak value of 18.2 +/- 0.8 ng/g by day 15, and decreasing thereafter to a level comparable to oestrus by day 25. Tissue concentrations of progesterone were comparable in PSPG and IEZ, reached their maximal level on days 6.5 and 9, and decreased significantly (P less than 0.01) on day 15. In EZ, progesterone level was significantly lower than in IEZ and decreased on day 9 compared to day 6.5. A further decrease was observed from days 9 to 15 but no difference between tissues was observed on the latter day. Thus, the blastocyst-foetus exerts a local effect by decreasing progesterone content and increasing pregnenolone level in the uterine tissue adjacent to its implantation (EZ). The conversion of progesterone in uterine tissue to less-active metabolites does not appear to occur towards the C19 and C18 steroids.
Assuntos
Blastocisto/fisiologia , Embrião de Mamíferos/fisiologia , Estradiol/metabolismo , Prenhez/metabolismo , Pregnenolona/metabolismo , Progesterona/metabolismo , Animais , Feminino , Gravidez , Pseudogravidez/metabolismo , Coelhos , Útero/metabolismoRESUMO
We report here the effects of a 7-day treatment of guinea-pigs with ACTH on adrenal mRNA levels for steroid-transforming enzymes. Adrenal 3 beta-hydroxysteroid dehydrogenase 4-ene-5-ene-isomerase (3 beta-HSD), 17-hydroxylase, 17,20-lyase, 21-hydroxylase and 11-hydroxylase activities were also examined as well as plasma and adrenal steroid levels. Our data reveal that chronic ACTH-treatment stimulated all post-pregnenolone enzyme activities in glomerulosa-fasciculata cells. Plasma steroid levels increased 8 h after the last injection of ACTH and returned to the control levels 24 h later whereas, in the adrenal, the content in steroids in the group sacrificed 8 h after the last injection of ACTH were similar to the values of the control group and decreased markedly 24 h later. It is suggested that the steroid turn-over in the adrenal may be affected by the chronic ACTH-treatment. On the other hand, despite the significant stimulation in steroid-transforming enzyme activities, our data reveal that chronic ACTH administration caused a decrease in mRNA levels for P450c21 and P450c17 while P450scc, 3 beta-HSD and P450c11 remained unchanged. Taken together, these results suggest that in vivo chronic ACTH-treatment of guinea-pigs increases adrenal steroidogenic capacity by increasing steroid secretion and steroid enzyme activity. Moreover, the chronic treatment with ACTH may have a post-transcriptional effect on steroidogenic enzymes gene expression by affecting the half-life of their mRNAs.
Assuntos
3-Hidroxiesteroide Desidrogenases/metabolismo , Corticosteroides/metabolismo , Glândulas Suprarrenais/fisiologia , Hormônio Adrenocorticotrópico/farmacologia , Aldeído Liases/metabolismo , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , RNA Mensageiro/metabolismo , Esteroide Hidroxilases/metabolismo , Esteroides/metabolismo , 3-Hidroxiesteroide Desidrogenases/genética , Corticosteroides/sangue , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/enzimologia , Aldeído Liases/genética , Animais , Northern Blotting , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Sistema Enzimático do Citocromo P-450/genética , Cobaias , Masculino , Progestinas/sangue , Progestinas/metabolismo , RNA Mensageiro/análise , Esteroide 17-alfa-Hidroxilase , Esteroide Hidroxilases/genética , Esteroides/sangueRESUMO
We studied the relationship between circulating androsterone glucuronide, androstane-3 alpha, 17 beta-diol glucuronide and androstane-3 beta, 17 beta-diol glucuronide concentrations and adrenal as well as testicular C-19 steroids in men. Among the three 5 alpha-reduced steroid glucuronides, androsterone glucuronide is the predominant C-19 steroid glucuronide measured in plasma and its levels are markedly elevated compared to those of the non-conjugated steroid. The marked rise in testosterone during puberty was strongly correlated with the increase in both androsterone glucuronide and androstane-3 alpha, 17 beta-diol glucuronide, thus suggesting that testicular C-19 steroids are the main precursors of the steroid glucuronides. We also found that the presence of testicular androgen in plasma contributes to approx. 70% of plasma androsterone glucuronide and androstane-3 alpha, 17 beta-diol glucuronide. Our data suggest that the adrenal C-19 steroids remaining in circulation after castration in men are converted into potent androgen which are then glucuronidated by UDP-glucuronyltransferase. We also demonstrated that the human prostate cell line LNCaP is capable of converting to a large extent androstenedione into androsterone glucuronide. Our data further confirm that glucuronidation is a major pathway of steroid metabolism in steroid target tissues.
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Androstano-3,17-diol/análogos & derivados , Glucuronatos/metabolismo , Adolescente , Adulto , Envelhecimento , Androstano-3,17-diol/metabolismo , Androstenodiona/metabolismo , Criança , Pré-Escolar , Desidroepiandrosterona/metabolismo , Glucuronatos/sangue , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Globulina de Ligação a Hormônio Sexual/metabolismo , Sulfatos , Células Tumorais CultivadasRESUMO
An accurate method is described for analysis of C-21, C-19, and C-18 steroids as well as steroid conjugates, namely, androstane-3 alpha,17 beta-diol glucuronide, androsterone glucuronide, estradiol glucuronide, and estrone glucuronide as well as dehydroepiandrosterone sulfate and androst-5-ene-3 beta,17 beta-diol sulfate. This technique involves an extraction step, aimed at solubilizing the nonconjugated steroids as well as the steroid sulfates and glucuronides, C-18 column chromatography, permitting the separation of nonconjugated steroids and the conjugated group followed by specific hydrolysis of the glucuronide and, finally, solvolysis of the steroid sulfates. Our data indicated that using 1 ml of plasma or 1 g of prostate, good recovery of the three groups of steroids was obtained. Moreover, an accurate determination of steroids could be achieved. The plasma levels of steroids in normal adult women and men found using our technique were within the range of those previously reported by us and other authors.
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Próstata/análise , Esteroides/sangue , Feminino , Fase Folicular , Glucuronatos/análise , Humanos , Masculino , RadioimunoensaioRESUMO
In humans, the onset of adrenache has been found to occur with the appearance of the zona reticularis, the inner zone of the adrenal cortex. Since an increase in the volume of adrenal cortex during maturation in the guinea pig has been associated with the growth of the zona reticularis, we were interested in investigating the changes in adrenal steroidogenesis during maturation in this species. In addition, the effect of androgens on adrenal steroidogenesis was studied. We demonstrated that between 1 and 10 weeks of age, a period of maximal growth of the adrenals in the guinea pig, there is a decrease in the concentrations of adrenal pregnenolone, cortisol, dehydroepiandrosterone, testosterone, androstenedione, and 11 beta-hydroxyandrostenedione, suggesting lower steroid production by the guinea pig adrenals. In plasma, we observed that the concentration of 11 beta-hydroxyandrostenedione (the sole C19 steroid present after castration) remained unchanged during maturation, while cortisol and corticosterone were lower between 1 and 4 weeks of age. Although castration as well as the administration of the antiandrogen flutamide had no effect on adrenal steroidogenesis, dihydrotestosterone caused an inhibition of cortisol and corticosterone levels in the adrenals while the concentrations of progestins (namely, pregnenolone, 17-hydroxypregnenolone, progesterone, and 17-hydroxyprogesterone) tended to increase in the adrenals, thus suggesting that dihydrotestosterone induces a blockade in the steroidogenic pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Córtex Suprarrenal/metabolismo , Di-Hidrotestosterona/farmacologia , Esteroides/biossíntese , Zona Reticular/metabolismo , Córtex Suprarrenal/crescimento & desenvolvimento , Androstanos/sangue , Androstanos/metabolismo , Animais , Castração , Flutamida/farmacologia , Cobaias , Masculino , Pregnenos/sangue , Pregnenos/metabolismo , Radioimunoensaio , Esteroides/sangue , Zona Reticular/crescimento & desenvolvimentoRESUMO
In order to better understand the effects of LHRH administration on testicular function in adult rat, we compared the inhibitory effects of LH and LHRH analogue [D-Ser-(TBU)6, des-Gly-NH2(10)]LHRH ethylamide upon testicular steroidogenesis and LH, FSH and prolactin receptor contents. Administration of LH as well as LHRH analogue resulted in a marked decrease of LH receptor levels, accompanied by a blockage at the level of 17-hydroxylase activity. We have been able to demonstrate that multiple LH administration can achieve a testicular desensitization comparable to that observed after LHRH agonist treatment.