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PURPOSE: Erectile dysfunction (ED) is one of the most prevalent male sexual dysfunctions. ED has been in the past mistakenly considered a purely psycho-sexological symptom by patients and doctors. However, an ever-growing body of evidence supporting the role of several organic factors in the pathophysiological mechanisms underlying ED has been recognized. METHODS: The Italian Society of Andrology and Sexual Medicine (SIAMS) commissioned an expert task force involving several other National Societies to provide an updated guideline on the diagnosis and management of ED. Derived recommendations were based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS: Several evidence-based statements were released providing the necessary up-to-date guidance in the context of ED with organic and psychosexual comorbidities. Many of them were related to incorrect lifestyle habits suggesting how to associate pharmacotherapies and counseling, in a couple-centered approach. Having the oral therapy with phosphodiesterase type 5 inhibitors as the gold standard along with several other medical and surgical therapies, new therapeutic or controversial options were also discussed. CONCLUSIONS: These are the first guidelines based on a multidisciplinary approach that involves the most important Societies related to the field of sexual medicine. This fruitful discussion allowed for a general agreement on several recommendations and suggestions to be reached, which can support all stakeholders in improving couple sexual satisfaction and overall general health.
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Andrologia , Disfunção Erétil , Humanos , Masculino , Disfunção Erétil/diagnóstico , Disfunção Erétil/etiologia , Disfunção Erétil/terapia , Sociedades Científicas , Comportamento Sexual , AconselhamentoRESUMO
PURPOSE: To retrospectively describe the association between thyroid hormones (TH) and platelet activation, as represented by mean platelet volume (MPV), in a cohort of patients hospitalized for COVID-19 with no known thyroid disease, and to correlate these data with the severity of COVID-19 and the occurrence of death/ARDS (Acute Respiratory Distress Syndrome). METHODS: 103 patients with real-time polymerase chain reaction (RT-PCR) testing-confirmed COVID-19 and hospitalized were enrolled. Serum samples were collected from patients upon admission before starting any treatment. Chi-squared test was used to determine the association between euthyroid sick syndrome (ESS) and COVID-19 severity. Multivariate logistic regression was performed to evaluate the best independent predictors of COVID-19 deaths/ARDS. RESULTS: 39/103 (37.9%) of patients were found to have ESS, and this condition was an independent predictor for the severity of COVID-19 (p = 0.003). Lower TSH and lower FT3/FT4 ratio correlated with higher MPV (p = 0,001 and p = 0.010), with an opposite trend with respect to what has been documented in non-COVID patients. Increasing MPV and lower FT3 significantly increased the risk, in COVID-19 patients, of an adverse outcome of death/ARDS. CONCLUSION: Increased platelet activation, as represented by increased MPV, has already been reported to correlate with COVID-19 severity, possibly as a consequence of cytokine release. We demonstrated, in a cohort of 103 patients with COVID-19, that MPV is inversely correlated to TH levels, in particular in the case of ESS, where downregulation of TH axis may occur in case of systemic cytokine inflammation and more severe outcomes (death/ARDS). That ESS itself may directly cause platelet activation, as demonstrated by higher MPV in these patients, is an interesting hypothesis which deserves further investigation.
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COVID-19 , Humanos , Estudos Retrospectivos , Hormônios Tireóideos , Hospitalização , Ativação PlaquetáriaRESUMO
BACKGROUND: Weight loss is a milestone in the prevention of chronic diseases associated with high morbility and mortality in industrialized countries. Very-low calorie ketogenic diets (VLCKDs) are increasingly used in clinical practice for weight loss and management of obesity-related comorbidities. Despite evidence on the clinical benefits of VLCKDs is rapidly emerging, some concern still exists about their potential risks and their use in the long-term, due to paucity of clinical studies. Notably, there is an important lack of guidelines on this topic, and the use and implementation of VLCKDs occurs vastly in the absence of clear evidence-based indications. PURPOSE: We describe here the biochemistry, benefits and risks of VLCKDs, and provide recommendations on the correct use of this therapeutic approach for weight loss and management of metabolic diseases at different stages of life.
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Dieta Cetogênica/métodos , Dieta Redutora/métodos , Endocrinologia , Doenças Metabólicas/prevenção & controle , Obesidade/terapia , Consenso , Humanos , Sociedades MédicasRESUMO
INTRODUCTION: A new class of drugs in the treatment of cystic fibrosis (CF) includes two agents: lumacaftor, which corrects CFTR channel protein, and ivacaftor, which increases CFTR channel activity. In our previous study we recruited 50 stable adults with CF and 16 of them showed growth hormone deficit (GHD): 7 patients severe and 9 patients partial GHD. MATERIAL AND METHODS: We decided to re-evaluate ten patients with the GHRH + arginine test of whom only five were treated with lumacaftor/ivacaftor. RESULTS: All CF patients in therapy with lumacaftor/ivacaftor showed a marked improvement in GHD. Two patients moved from a severe GHD to a normal response to the GH/IGF-1 axis test, and three patients who had partial GHD moved to normal response. CONCLUSION: The pituitary gland may be damaged by CF disease and could benefit of the action of correcting drugs.
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Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Transtornos do Crescimento/prevenção & controle , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Mutação , Quinolonas/uso terapêutico , Adulto , Fibrose Cística/genética , Fibrose Cística/patologia , Combinação de Medicamentos , Feminino , Seguimentos , Transtornos do Crescimento/patologia , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
PURPOSE: Patients with cystic fibrosis (CF) present with signs and symptoms that overlap with those of adult growth hormone deficiency (GHD) syndrome: loss of muscle mass, bone fragility and lower stress tolerance. In literature, the prevalence of GHD in pediatric CF patients is higher than general population, but these studies have been performed on children with growth delay. To our knowledge, there are no studies on adult patients. The aim of this paper is to evaluate GH-IGF1 axis in an adult CF population. METHODS: Fifty clinically stable adult patients, 30 males; age 36 ± 2 years; BMI 21.39 ± 0.22 kg/m2 and FEV1 67 ± 4% were studied. Data regarding glycometabolic status and results of pituitary, thyroid, parathyroid, gonadal and adrenal function tests were recorded. All patients underwent a GH releasing hormone (GHRH) + Arginine stimulation test to confirm a GHD. RESULTS: GHRH + Arginine test revealed the presence of GHD in 16 patients (32%); specifically 7 patients had a severe deficiency and 9 a partial deficiency. CONCLUSIONS: Adult patients with CF may show GHD. These patients should be followed over time to assess if the GHD could impact the clinical progression of CF.
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Biomarcadores/análise , Fibrose Cística/complicações , Transtornos do Crescimento/diagnóstico , Hormônio do Crescimento Humano/deficiência , Fator de Crescimento Insulin-Like I/metabolismo , Adolescente , Adulto , Arginina/metabolismo , Feminino , Seguimentos , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
OBJECTIVES: Recently metabolic aspects linked to sarcopenic obesity (SO) were investigated. Extant studies involved especially older people from Asian or White-mixed American cohorts. THE AIMS OF OUR STUDY WERE: to explore the prevalence of sarcopenia in Caucasian adult obese subjects using two different indices of sarcopenia, and to investigate the relationship among SO, metabolic syndrome (MS), inflammation, and serum albumin concentrations. DESIGN: Cross- sectional study. SUBJECTS/METHODS: The study was performed from 2011 to 2014 in a hospitalized care setting. Inclusion criteria were: age>18 and <65 years, BMI≥30 Kg/m2. Fat mass (FM) and fat-free mass (FFM) were assessed by DXA. Appendicular skeletal muscle mass (ASMM) was calculated. Sarcopenia was defined as ASMM/height2 or ASMM/weight <2SD than the sex-specific mean of a young population. The cutoffs were ASMM/h2<6.54 Kg/m2 for men and 4.82 Kg/m2 for women, and ASMM/weight<0.2827 for men and 0.2347 for women. ISI-Matsuda was calculated. MS was diagnosed (NCEP-ATPIII). RESULTS: 727 subjects (age: 45.72±13.56 years, BMI: 37.74±5.82 kg/m2) were enrolled. The prevalence of SO was 1.0% or 34.8% in men and 0.6% or 50.1% in women, using ASMM/height2 ratio or ASMM/weight. Subjects with SO based on ASMM/height2 were scarce, only data relying on ASMM/weight were considered. Subjects with SO had higher BMI, waist circumference, FM, and lower FFM and ASMM than nonsarcopenic obese individuals (all p<0.05). ISI-Matsuda was lower and hs-CRP levels were higher in subjects with SO (all p<0.05). MS was more prevalent in subjects with SO than nonsarcopenic obese subjects (47.6% vs 34.3%, p<0.001). ASMM/weight was decreased in subjects with MS (0.2522±0.0410 vs 0.2423±0.0352, p=0.001). CONCLUSION: SO is associated with MS and low- grade inflammation in adult Caucasian subjects. Metabolic profile evaluation should be recommended in subjects with SO.
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Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Sarcopenia/epidemiologia , Adulto , Composição Corporal/fisiologia , Índice de Massa Corporal , Peso Corporal , Estudos Transversais , Feminino , Humanos , Inflamação , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Obesidade/complicações , Sarcopenia/complicações , Sarcopenia/diagnóstico , Circunferência da Cintura , População BrancaRESUMO
BACKGROUND AND AIM: Obesity is increasing worldwide and is related to undesirable cardiovascular outcomes. Epicardial fat (EF), the heart visceral fat depot, increases with obesity and correlates with cardiovascular risk. SIRT1, an enzyme regulating metabolic circuits linked with obesity, has a cardioprotective effect and is a predictor of cardiovascular events. We aimed to assess the relationship of EF thickness (EFT) with circulating SIRT1 in patients with obesity. METHODS AND RESULTS: Sixty-two patients affected by obesity and 23 lean controls were studied. Plasma SIRT1 concentration was determined by enzyme-linked immunosorbent assay (ELISA). EFT was measured by echocardiography. Body mass index (BMI), waist circumference, heart rate (HR), blood pressure, and laboratory findings (fasting glucose, insulin, HbA1c, cholesterol, and triglycerides) were assessed. SIRT1 was significantly lower (P = 0.002) and EFT was higher (P < 0.0001) in patients with obesity compared with lean controls. SIRT1 showed a negative correlation with EFT and HR in the obesity group (ρ = -0.350, P = 0.005; ρ = -0.303, P = 0.008, respectively). After adjustment for obesity-correlated variables, multiple linear regression analysis showed that EFT remained the best correlate of SIRT1 (ß = -0.352, P = 0.016). CONCLUSIONS: Circulating SIRT1 correlates with the visceral fat content of the heart. Serum SIRT1 levels might provide additional information for risk assessment of coronary artery disease in patients with obesity.
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Adiposidade , Doença da Artéria Coronariana/etiologia , Gordura Intra-Abdominal/fisiopatologia , Obesidade/sangue , Pericárdio/fisiopatologia , Sirtuína 1/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/enzimologia , Doença da Artéria Coronariana/fisiopatologia , Ecocardiografia Doppler , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/complicações , Obesidade/enzimologia , Obesidade/fisiopatologia , Pericárdio/diagnóstico por imagem , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
Recent studies have suggested a possible correlation between obesity and adenovirus 36 (Adv36) infection in humans. As information on adenoviral DNA presence in human adipose tissue are limited, we evaluated the presence of Adv36 DNA in adipose tissue of 21 adult overweight or obese patients. Total DNA was extracted from adipose tissue biopsies. Virus detection was performed using PCR protocols with primers against specific Adv36 fiber protein and the viral oncogenic E4orf1 protein nucleotide sequences. Sequences were aligned with the NCBI database and phylogenetic analyses were carried out with MEGA6 software. Adv36 DNA was found in four samples (19%). This study indicates that some individuals carry Adv36 in the visceral adipose tissue. Further studies are needed to determine the specific effect of Adv36 infection on adipocytes, the prevalence of Adv36 infection and its relationship with obesity in the perspective of developing a vaccine that could potentially prevent or mitigate infection.
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Adenoviridae/isolamento & purificação , Infecções por Adenovirus Humanos/epidemiologia , Adenovírus Humanos/isolamento & purificação , Gordura Intra-Abdominal/virologia , Obesidade/virologia , Adenoviridae/genética , Infecções por Adenovirus Humanos/sangue , Infecções por Adenovirus Humanos/imunologia , Adenovírus Humanos/imunologia , Adulto , Índice de Massa Corporal , DNA Viral/isolamento & purificação , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/imunologia , FilogeniaRESUMO
The anaplastic thyroid cancer (ATC) is among the most aggressive human tumors which fail to respond to all the currently available therapeutic approaches. As a consequence most patients die within a few months from diagnosis. In the present preclinical study, the effects of the ZM447439, a functional inhibitor of Aurora kinases, on the growth and tumorigenicity of a panel of ATC derived cell lines (CAL-62, 8305C, 8505C and BHT-101) were evaluated. The treatment of the different ATC cells with ZM447439 inhibited proliferation in a time- and dose-dependent manner, with IC50 comprised between 0.5 mM and 5 mM. Moreover, the drug remarkably impaired the formation of colonies in soft agar of all the cell lines. Consistently with Aurora inhibition, immunofluorescence and immunoblotting experiments demonstrated that Aurora auto-phosphorylation following drug treatment was completely abrogated, and treated cells were characterized by the presence of multiple spindles with short microtubules. In the same experiments we observed the loss of histone H3 phosphorylation on Ser10, specifically due to Aurora-B, after ZM447439 treatment. Time-lapse videomicroscopy and flow cytometric analysis demonstrated that in presence of ZM447439 the cells were able to enter mitosis but not to complete it, becoming polyploid. Almost all the ATC cell lines studied showed increased apoptosis after only 48 h of treatment. In conclusion, our data demonstrate that ZM447439 is effective in reducing cell growth and tumorigenicity of different ATC derived cell lines, and further investigations are needed to exploit its potential therapeutic value for ATC treatment.
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Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Benzamidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide/patologiaRESUMO
BACKGROUND: Clinical studies suggest that testosterone (T) plays an important role in the male predominance of the clinical manifestations of the Brugada syndrome (BS). However, no statistically significant correlations have been observed between T levels and electrocardiogram (ECG) parameters in the BS patients. We investigated whether the hormonal pattern and the variation within CAG repeat polymorphism in exon 1 of the androgen receptor (AR) gene, affecting androgen sensitivity, are associated with the Brugada ECG phenotype in males. METHODS AND RESULTS: 16 male patients with BS (mean age 45.06 ± 11.3 years) were studied. 12-lead ECG was recorded. Blood levels of follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, free-T, dihydrotestosterone, 17-ß-estradiol, estrone, 3-alpha-androstanediol-glucuronide, delta-4-androstenedione, dehydroepiandrosterone sulphate, progesterone, 17-hydroxyprogesterone, and sex hormone binding globulin were assayed. Genotyping of CAG repeats on DNA extracted from leukocytes was carried out. No relationship was found between hormone values and ECG parameters of BS. BS patients showed the CAG length normally recognized in the human polymorphism range and the number of CAG repeats did not correlate with the ECG pattern of BS. CONCLUSIONS: The AR CAG repeat length does not correlate with the ECG features of the patients affected by BS. The search for genes downstream AR activation as possibly responsible for the increased risk of spontaneous arrhythmias in BS males after puberty is warranted.
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OBJECTIVES: Anaplastic thyroid carcinomas (ATC) are highly aggressive tumours unresponsive to any available radio- or chemotherapeutic protocol, with a median survival rate of 4-5 months from the time of diagnosis. We previously demonstrated that ATC are characterized by increased expression of the kinases Aurora-A, -B and -C, involved in the regulation of multiple steps of the mitotic phase. In this study, the in vitro effects of SNS-314 mesylate, a pan-inhibitor of the Aurora kinases, on growth and tumorigenicity of ATC cells were evaluated. MATERIALS AND METHODS: The effects of SNS-314 mesylate were assessed on the ATC derived cell lines CAL-62, 8305C, 8505C and BHT-101 by means of cell proliferation assay, immunofluorescence, cytofluorimetry, time lapse microscopy, and colony formation in soft agar. RESULTS: Treatment of the different ATC cells with SNS-314 mesylate inhibited proliferation in a time- and dose-dependent manner, with IC(50) comprised between 2.6 nM and 26.6 nM. CAL-62 cells exposed for 24 h to SNS-314 mesylate 100 nM evidenced a significant augmentation of the apoptotic index. Time-lapse video-microscopy of CAL-62 cells showed that SNS-314 mesylate prevents the completion of mitosis leading to polyploidy. Western blot experiments demonstrated that the auto-phosphorylation of the Aurora kinases as well as histone H3 phosphorylation in CAL-62 treated cells was inhibited. Finally, the drug inhibited colony formation in soft agar of all cell lines. CONCLUSIONS: Our results demonstrated that SNS-314 mesylate is capable to efficiently reduce cell growth and tumorigenicity of different ATC derived cell lines suggesting its potential therapeutic value for ATC treatment.
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Compostos de Fenilureia/farmacologia , Tiazóis/farmacologia , Neoplasias da Glândula Tireoide/patologia , Células Tumorais Cultivadas/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Mesilatos , Carcinoma Anaplásico da TireoideRESUMO
Genetic instability, a hallmark of solid tumors including thyroid cancers, is thought to represent the mean by which premalignant cells acquire novel functional capabilities responsible for cancer cell growth and tumour progression. Over the last few years, the knowledge of the molecular processes controlling the mitotic phase of the cell cycle has increased considerably, and different mitotic proteins, whose expression or function has been found altered in human cancer tissues, have been associated to tumour genetic instability and aneuploidy. These include the three members of the Aurora kinase family (Aurora-A, -B and -C), serine/threonine kinases that regulate multiple aspects of chromosome segregation and cytokinesis. The genes encoding the Aurora kinases have been shown to induce cell malignant transformation, and their overexpression has been detected in several tumor derived cell lines and tissues, being often associated with a poor prognosis. Over the last decade, specific inhibitors of Aurora kinases exhibited in preclinical and early phase clinical studies a good therapeutic efficacy against several tumour types, including the highly aggressive anaplastic thyroid cancer and the medullary thyroid cancer. In the present review we'll first focus on the Aurora mitotic functions in normal cells; then we shall describe the main implications of their overexpression in the onset of genetic instability and consequent aneuploidy. We shall finally discuss on the effects of the functional inhibition of Aurora kinases on thyroid cancer cells growth and tumorigenicity.
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Aurora Quinases/antagonistas & inibidores , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/enzimologia , HumanosRESUMO
The recent development of new medications for the treatment of the sexual dysfunction increased the possibility of improving the altered sexual performance. Although initially designed for the treatment of male sexual dysfunction, erectile dysfunction in particular, these substances have now been tested for the therapy of a broad range of sexual dysfunction also in the female. Here we will briefly review the therapeutic options currently available and the potential of new pharmacological treatments for male and female sexual dysfunction.
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Disfunções Sexuais Fisiológicas/tratamento farmacológico , Feminino , Humanos , Doença Iatrogênica , Masculino , Disfunções Sexuais Fisiológicas/diagnóstico , Disfunções Sexuais Fisiológicas/etiologiaRESUMO
Platelet-derived growth factor (PDGF) overactivity has been implicated in atherosclerosis and several fibrotic conditions including lung and kidney fibrosis, liver cirrhosis and myelofibrosis. Low oxygen tension (hypoxia) is a known stimulus for transcriptional induction of PDGF ligand and receptor genes in different tissues. We studied the expression and localization of PDGF-A, PDGF-B, and PDGF receptor (PDGFR)-alpha and -beta subunits in adult rat isolated corpus cavernosum (CC) under generalized transient hypoxia (pO(2) 10%) in comparison with normoxic conditions. Semi-quantitative RT-PCR analysis of mRNA extracted from rat penis showed higher amounts of PDGF-A, PDGF-B and PDGFR-beta mRNA transcripts in hypoxic versus normoxic animals. The immunohistochemical analysis showed that the localization of PDGF subunits and PDGFR-beta was confined to the cytoplasm of the perivascular smooth muscle cells, endothelium and trabecular fibroblasts. Our findings indicate that transient low oxygen tension induces PDGF overexpression in rat CC, which in the long term may lead to an increase of connective tissue production. We suggest that a local impairment of the PDGF/PDGFR system may contribute to CC fibrosis, which is an established cause of erectile dysfunction in man.
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Disfunção Erétil/metabolismo , Hipóxia/metabolismo , Músculo Liso/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Fibrose , Imuno-Histoquímica , Masculino , Músculo Liso/química , Técnicas de Cultura de Órgãos , Pênis , Fator de Crescimento Derivado de Plaquetas/análise , Fator de Crescimento Derivado de Plaquetas/genética , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/análise , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
In mice, the Fas/Fas ligand (FasL) system has been shown to be involved in germ cell apoptosis. In the present study we evaluated the expression of Fas and Fas ligand (FasL) in fetal and adult human testis. Semiquantitative RT-PCR demonstrated the expression of Fas and FasL messenger ribonucleic acids in adult testis, but not in fetal testis (20-22 weeks gestation). In situ RT-PCR and immunohistochemistry experiments on adult human testis demonstrated the expression of FasL messenger ribonucleic acid and protein in Sertoli and Leydig cells, whereas the expression of Fas was confined to the Leydig cells and sporadic degenerating spermatocytes. The number of Fas-positive germ cells per 100 Sertoli cell nuclei was increased in 10 biopsies with postmeiotic germ cell arrest compared to 10 normal testis biopsies (mean, 3.82 +/- 0.45 vs. 2.02 +/- 0.29; P = 0.0001), but not in 10 biopsies with meiotic germ cell arrest (mean, 1.56 +/- 1.07). Fas and FasL proteins were not expressed in cases of idiopathic hypogonadotropic hypogonadism. Together, these findings may suggest that Fas/FasL expression in the human testis is developmentally regulated and under gonadotropin control. The increased germ cell expression of Fas in patients with postmeiotic germ cell arrest suggests that the Fas/FasL system may be involved in the quality control mechanism of the produced gametes.
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Glicoproteínas de Membrana/genética , Oligospermia/fisiopatologia , Espermatogênese , Testículo/fisiologia , Receptor fas/genética , Aborto Terapêutico , Adulto , Animais , Apoptose , Proteína Ligante Fas , Feto , Idade Gestacional , Humanos , Células Intersticiais do Testículo/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Oligospermia/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células de Sertoli/imunologia , Testículo/embriologia , Testículo/fisiopatologia , Transcrição GênicaRESUMO
Platelet-derived growth factor (PDGF)- A-deficient male mice were found to develop progressive reduction of testicular size, Leydig cells loss, and spermatogenic arrest. In normal mice, the PDGF-A and PDGF-Ralpha expression pattern showed positive cells in the seminiferous epithelium and in interstitial mesenchymal cells, respectively. The testicular defects seen in PDGF-A-/- mice, combined with the normal developmental expression of PDGF-A and PDGF-Ralpha, indicate that through an epithelial-mesenchymal signaling, the PDGF-A gene is essential for the development of the Leydig cell lineage. These findings suggest that PDGF-A may play a role in the cascade of genes involved in male gonad differentiation. The Leydig cell loss and the spermatogenic impairment in the mutant mice are reminiscent of cases of testicular failure in man.
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Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/fisiologia , Fator de Crescimento Derivado de Plaquetas/genética , Espermatogênese/fisiologia , Animais , Animais Recém-Nascidos , Apoptose/fisiologia , Bromodesoxiuridina/análise , Hibridização In Situ , Marcação In Situ das Extremidades Cortadas , Células Intersticiais do Testículo/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Crescimento Derivado de Plaquetas/análise , RNA Mensageiro/análise , Receptores do Fator de Crescimento Derivado de Plaquetas/análise , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Epitélio Seminífero/química , Epitélio Seminífero/citologia , Epitélio Seminífero/fisiologiaRESUMO
The present study reports the modulation of basement membrane (BM) components, laminin, entactin, and type IV collagen, expression in prepubertal rat Sertoli cell by the thyroid hormone T3. Immunocytochemical studies of permeabilized Sertoli cells in culture showed that T3 treatment (10[-7] M for 24 h) increased the number of cells staining positive for laminin and/or entactin (from 58 +/- 5.3% to 86.4 +/- 6.5%, P < 0.01). In contrast, a strong inhibition of type IV collagen immunopositivity was observed. Western blot analysis of Sertoli cell-conditioned media indicated that T3 treatment significantly (P < 0.01) increased the level of secreted entactin by 60-65% without affecting the levels of laminin A and B1/B2 chains. Moreover, thyroid hormone treatment of Sertoli cells significantly reduced type IV collagen secretion by 62% (P < 0.05). Slot blot analysis of poly-A RNA demonstrated a significant (P < 0.01) increase in the level of entactin messenger RNA (mRNA) by 140% (P < 0.01) and a 50% reduction of type IV collagen alpha1 chain mRNA after thyroid hormone treatment. No effect of the hormone was observed on the accumulation of the laminin B1 and B2 chain mRNAs in Sertoli cell cultures. These effects cannot be ascribed to changes in the degradation of BM components, because no effect of thyroid hormone was observed on plasminogen activators or metalloproteinase secretion by Sertoli cells. These observations indicate the Sertoli cell as a source of entactin within the testis, demonstrate the ability of T3 to differentially regulate the expression of BM components, and can be regarded as a part of the integrated mechanism by which thyroid hormone affects testicular development and differentiation.
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Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Tri-Iodotironina/farmacologia , Animais , Membrana Basal/metabolismo , Colágeno/genética , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Laminina/genética , Laminina/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Células de Sertoli/enzimologiaRESUMO
Platelet-derived growth factors (PDGFs) are growth-regulatory molecules that stimulate chemotaxis, proliferation and metabolism primarily of cells of mesenchymal origin. In this study, we found high levels of PDGFs and PDGFs receptors (PDGFRs) mRNAs, and specific immunostaining for the corresponding proteins in the rat testis. PDGFs and PDGFRs expression was shown to be developmentally regulated and tissue specific. Expression of PDGFs and PDGFRs genes was observed in whole testis RNA 2 d before birth, increased through postnatal day 5 and fell to low levels in adult. The predominant cell population expressing transcripts of the PDGFs and PDGFRs genes during prenatal and early postnatal periods were Sertoli cells and peritubular myoid cells (PMC) or their precursors, respectively, while in adult animals PDGFs and PDGFRs were confined in Leydig cells. We also found that early postnatal Sertoli cells produce PDGF-like substances and that this production is inhibited dose dependently by follicle-stimulating hormone (FSH). The expression of PDGFRs by PMC and of PDGFs by Sertoli cells corresponds in temporal sequence to the developmental period of PMC proliferation and migration from the interstitium to the peritubulum. Moreover, we observed that all the PDGF isoforms and the medium conditioned by early postnatal Sertoli cells show a strong chemotactic activity for PMC which is inhibited by anti-PDGF antibodies. These data indicate that, through the spatiotemporal pattern of PDGF ligands and receptors expression, PDGF may play a role in testicular development and homeostasis.
Assuntos
Fator de Crescimento Derivado de Plaquetas/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Testículo/fisiologia , Animais , Especificidade de Anticorpos , Movimento Celular/fisiologia , Fatores Quimiotáticos/fisiologia , Hormônio Foliculoestimulante/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Imuno-Histoquímica , Células Intersticiais do Testículo/fisiologia , Masculino , Técnicas de Cultura de Órgãos , Fator de Crescimento Derivado de Plaquetas/biossíntese , Fator de Crescimento Derivado de Plaquetas/imunologia , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Crescimento Derivado de Plaquetas/biossíntese , Células de Sertoli/fisiologia , Testículo/citologia , Testículo/crescimento & desenvolvimento , Testosterona/biossínteseRESUMO
The main objective of this study was to determine the effect of daily oral alendronate treatment on bone mass in postmenopausal women affected by osteoporosis. The efficacy of intranasal salmon calcitonin was also examined. Nine centers in Italy enrolled 286 postmenopausal women between the ages of 48 and 76 with spinal bone mineral density > or = 2 SD below adult mean peak in the two-year, double-blind, randomized, placebo-controlled trial. Patients were randomized to one of four treatment arms: double-blind placebo, alendronate 10 mg/day, alendronate 20 mg/day, or open-label intranasal salmon calcitonin 100 IU/day; all patients received 500 mg Ca++ supplements. Bone mass was measured by dual-energy x-ray absorptiometry every six months for two years. Patients who received alendronate 10 or 20 mg experienced significant increases in bone mass at all sites measured. At the end of the second year, the mean percent changes, for alendronate 10 and 20 mg relative to placebo, were 5.2% and 7.3% at the lumbar spine, 3.8% and 4.6% at the femoral neck, and 7.1% and 7.5% at the trochanter, respectively. In contrast, intranasal salmon calcitonin failed to increase bone mineral mass significantly at any site. Both alendronate doses significantly decreased serum alkaline phosphatase, serum osteocalcin, and urinary pyridinolines, markers of bone turnover, whereas placebo and intranasal calcitonin did not. Alendronate was generally well tolerated and no serious adverse events were attributed to its use.(ABSTRACT TRUNCATED AT 250 WORDS)