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1.
J Clin Endocrinol Metab ; 105(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32449514

RESUMO

CONTEXT: Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells. OBJECTIVE: To investigate SOAT1 protein expression as a marker of treatment response to mitotane. PATIENTS: A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens. SETTING: Retrospective study at 12 ACC referral centers. MAIN OUTCOME MEASURE: Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). RESULTS: Sixty-one of 135 patients (45%) with adjuvant mitotane treatment had recurrences and 45/68 patients (66%) with mitotane treatment for advanced disease had progressive disease. After multivariate adjustment for sex, age, hormone secretion, tumor stage, and Ki67 index, RFS (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 0.61-1.85; P = 0.82), and DSS (HR = 1.30; 95% CI, 0.58-2.93; P = 0.53) in adjuvantly treated ACC patients did not differ significantly between tumors with high and low SOAT1 expression. Similarly, in the advanced stage setting, PFS (HR = 1.34; 95% CI, 0.63-2.84; P = 0.45) and DSS (HR = 0.72; 95% CI, 0.31-1.70; P = 0.45) were comparable and response rates not significantly different. CONCLUSIONS: SOAT1 expression was not correlated with clinical endpoints RFS, PFS, and DSS in ACC patients with mitotane monotherapy. Other factors appear to be relevant for mitotane treatment response and ACC patient survival.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32213650

RESUMO

Summary: Pituitary infections, particularly with fungus, are rare disorders that usually occur in immunocompromised patients. Cushing's syndrome predisposes patients to infectious diseases due to their immunosuppression status. We report the case of a 55-year-old woman, working as a poultry farmer, who developed intense headache, palpebral ptosis, anisocoria, prostration and psychomotor agitation 9 months after initial diabetes mellitus diagnosis. Cranioencephalic CT scan showed a pituitary lesion with bleeding, suggesting pituitary apoplexy. Patient underwent transsphenoidal surgery and the neuropathologic study indicated a corticotroph adenoma with apoplexy and fungal infection. Patient had no preoperative Cushing's syndrome diagnosis. She was evaluated by a multidisciplinary team who decided not to administer anti-fungal treatment. The reported case shows a rare association between a corticotroph adenoma and a pituitary fungal infection. The possible contributing factors were hypercortisolism, uncontrolled diabetes and professional activity. Transsphenoidal surgery is advocated in these infections; however, anti-fungal therapy is still controversial. Learning points: Pituitary infections are rare disorders caused by bacterial, viral, fungal and parasitic infections. Pituitary fungal infections usually occur in immunocompromised patients. Cushing's syndrome, as immunosuppression factor, predisposes patients to infectious diseases, including fungal infections. Diagnosis of pituitary fungal infection is often achieved during histopathological investigation. Treatment with systemic anti-fungal drugs is controversial. Endocrine evaluation is recommended at the time of initial presentation of pituitary manifestations.

3.
Eur Neuropsychopharmacol ; 33: 101-116, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32057591

RESUMO

Memory impairment is the main feature of Alzheimer's disease (AD). Initial impairments originate in the temporal lobe area and propagate throughout the brain in a sequential manner. Epigenetic mechanisms, especially histone acetylation, regulate plasticity and memory processes. These may be dismantled during the disease. The aim of this work was to establish changes in the acetylation-associated pathway in two key brain regions affected in AD: the hippocampus and the F2 area of frontal cortex in end-stage AD patients and age-matched controls. We found that the F2 area was more affected than the hippocampus. Indeed, CREB-Binding Protein (CBP), P300/CBP-associated protein (PCAF), Histone Deacetylase 1 (HDAC1) and HDAC2 (but not HDAC3) levels were strongly decreased in F2 area of AD compared to controls patients, whereas only HDAC1 was decreased and CBP showed a downward trend in the hippocampus. At the histone level, we detected a substantial increase in total (H3 and H2B) histone levels in the frontal cortex, but these were decreased in nuclear extracts, pointing to a dysregulation in histone trafficking/catabolism in this brain region. Histone H3 acetylation levels were increased in cell nuclei mainly in the frontal cortex. These findings provide evidence for acetylation dysfunctions at the level of associated enzymes and of histones in AD brains, which may underlie transcriptional dysregulations and AD-related cognitive impairments. They further point to stronger dysregulations in the F2 area of the frontal cortex than in the hippocampus at an end-stage of the disease, suggesting a differential vulnerability and/or compensatory mechanisms efficiency towards epigenetic alterations.

4.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31665449

RESUMO

CONTEXT: Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). OBJECTIVE, DESIGN, SETTING: This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. PATIENTS AND METHODS: 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography-mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. RESULTS: Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine "steroid fingerprint" at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). CONCLUSION: Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

5.
BMJ Case Rep ; 12(8)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31439569

RESUMO

Phaeochromocytomas are rare neuroendocrine tumours (NET) with malignant behaviour in about 10% of cases. The median time from the diagnosis of primary tumour and bone metastasis is 3.4 years. We report a case of a 66-year-old woman presenting with a hypertensive crisis and back pain. She has a history of a phaeochromocytoma completely resected 18 years before. MRI showed a neoplastic mass on the 10th thoracic vertebra (T10), with fracture and spinal cord compression. The CT-guided biopsy was consistent with metastasis of a NET. Therefore, she was treated with phenoxybenzamine and external beam radiotherapy. However, clinical (dorsal pain) and biochemical (ie, elevated chromogranin A) signs suggested persistent disease and the patient was treated with iodine-131 metaiodobenzylguanidine and T10 kyphoplasty. After 8 years, she remains clinically stable. This case demonstrates that phaeochromocytomas may reveal malignant behaviour several years after diagnosis, and therefore patients should be maintained under long term surveillance.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias da Coluna Vertebral/diagnóstico , Vértebras Torácicas , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Idoso , Dor nas Costas/etiologia , Diagnóstico Diferencial , Feminino , Humanos , Metástase Neoplásica , Feocromocitoma/secundário , Feocromocitoma/cirurgia , Neoplasias da Coluna Vertebral/complicações , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Coluna Vertebral/cirurgia , Tomografia Computadorizada por Raios X
6.
Glia ; 67(12): 2329-2342, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31328322

RESUMO

Adenosine A2A receptors (A2A R) are modulators of various physiological processes essential for brain homeostasis and fine synaptic tuning. In certain neurodegenerative conditions, notably Alzheimer's disease (AD), A2A Rs are pathologically upregulated in neurons but also in astrocytes. In that context, the use of A2A Rs inhibitors, normalizing impaired receptor function, is seen as a potential therapeutic strategy. However, the impact of A2A R alterations, particularly in astrocytes, is not fully understood. Here, we investigated the effect of A2A R overexpression on transcriptional deregulation in primary astrocytic cultures. By performing whole transcriptome analysis, we found that A2A R overexpression promotes robust transcriptional changes, mostly affecting immune response, angiogenesis, and cell activation-related genes. Importantly, we observed that treatment with SCH58261, a selective A2A R antagonist, restored the expression levels of several inflammatory and astrocytic activation-related genes, such as Interleukin-1beta and vimentin. This supports the notion that A2A R blockade could restore some astrocytic dysfunctions associated with abnormal A2A R expression, further arguing for a potential beneficial impact of receptor antagonists in A2A R-induced transcriptional deregulation, inflammation, and astrogliosis. Overall, our findings provide novel insights into the putative impact of A2A R overexpression on transcriptional deregulation in astrocytes, thereby opening novel avenues for the use of A2A R antagonists as potential therapeutic strategy in neurodegenerative diseases.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Astrócitos/fisiologia , Receptor A2A de Adenosina/genética , Receptor A2A de Adenosina/metabolismo , Transcrição Genética/fisiologia , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Células Cultivadas , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/fisiologia , Camundongos , Transcrição Genética/efeitos dos fármacos
7.
Acta Med Port ; 32(5): 381-387, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31166899

RESUMO

INTRODUCTION: Diagnosis of Cushing's syndrome remains a challenge in clinical endocrinology. Even though late-night salivary cortisol is used as screening tool, individualized cut-off levels for each population must be defined. MATERIAL AND METHODS: Three groups of subjects were studied: normal subjects, suspected and proven Cushing's syndrome. Salivary cortisol was measured using an automated electrochemiluminescence assay. The functional sensitivity of the assay is 0.018 µg/dL. The diagnostic cut-off level was defined by Receiver Operating Characteristic curve and Youden's J index. RESULTS: We studied 127 subjects: 57 healthy volunteers, 39 patients with suspected and 31 with proven Cushing's syndrome. 2.5th - 97.5th percentile of the late-night salivary cortisol concentrations in normal subjects was 0.054 to 0.1827 µg/dL. Receiver Operating Characteristic curve analysis showed an area under the curve of 0.9881 (p < 0.0001). A cut-off point of 0.1 µg/dL provided a sensitivity of 96.77% (95% CI 83.3 - 99.92%) and specificity of 91.23% (95% CI 80.7 - 97.09%). There was a significant correlation between latenight salivary cortisol and late-night serum cortisol (R = 0.6977; p < 0.0001) and urinary free cortisol (R = 0.5404; p = 0.0025) in proven Cushing's syndrome group. DISCUSSION: The mean ± SD late-night salivary cortisol concentration in patients with proven Cushing's syndrome (0.6798 ± 0.52 µg/ dL) was significantly higher (p < 0.0001). In our population, the late-night salivary cortisol cut-off was 0.1 µg/dL with high sensitivity and specificity. CONCLUSION: Late-night salivary cortisol has excellent diagnostic accuracy, making it a highly reliable, noninvasive, screening tool for outpatient assessment. Given its convenience and diagnostic accuracy, late-night salivary cortisol may be added to other traditional screening tests on hypercortisolism.


Assuntos
Síndrome de Cushing/diagnóstico , Hidrocortisona/análise , Saliva/química , Adulto , Idoso , Área Sob a Curva , Biomarcadores/análise , Feminino , Voluntários Saudáveis , Humanos , Medições Luminescentes/métodos , Masculino , Pessoa de Meia-Idade , Curva ROC , Valores de Referência , Sensibilidade e Especificidade , Fatores de Tempo
8.
Arch Ital Urol Androl ; 91(1): 1-4, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30932420

RESUMO

OBJECTIVES: Standard multi-port laparoscopic adrenalectomy (LA) is considered the gold standard for benign adrenal tumors. Single-site LA has been proposed as a feasible and safe alternative because of lower invasiveness, improved cosmetics, less pain and shorter hospital stay. The objective was to evaluate and compare results of single-site transumbilical laparoendoscopic adrenalectomy with standard LA for adrenal tumors. MATERIALS AND METHODS: One hundred consecutive adrenalectomies from 93 patients, performed between March 2009 and June 2017, were laparoscopically excised: 59 by standard multi-port LA (group 1) and 41 by transumbilical laparoendoscopic single-site adrenalectomy (group 2). Data gathered included demographics, comorbidities, preoperative imaging, tumor characteristics, perioperative data, surgical complications, pathology and follow-up. IBM SPSS Statistics 23 software was used and p value < 0.05 was considered significant. RESULTS: Patients of group 2 were younger (48.7 ± 13.9 versus 59.7 ± 15.1 years; p < 0.001) and had fewer comorbidities (p < 0.05). Mean tumor diameter in group 2 was lower than those of group 1 (27.52 ± 14.3 versus 47.9 ± 30.6 mm; p < 0.001). Tumor laterality did not influence the choice of technique nor the surgical morbidity. All procedures were successfully completed, although one standard LA needed conversion to open surgery. Mean operative time, hemorrhagic losses, postoperative opioid analgesic requirement and hospital stay were not statistically different between groups. Most patients in group 2 (31 patients, 85.4%) did not require drainage, compared to 14 (25.4%) patients of group 1 (p < 0.001). Patients who underwent single-site LA resumed normal diet earlier (1.0 ± 0.2 versus 1.6 ± 0.7 days; p < 0.001). There were no reoperations and no perioperative mortality. Overall mean follow-up time was 94.9 ± 3.1 months, not statiscally different between groups (p = 0.7). CONCLUSIONS: Our results revealed that transumbilical approach for laparoendoscopic single-site adrenalectomy for adrenal tumors is a feasible and safe alternative to standard laparoscopic adrenalectomy.


Assuntos
Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia/métodos , Laparoscopia/métodos , Dor Pós-Operatória/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/patologia , Adrenalectomia/efeitos adversos , Adulto , Idoso , Analgésicos Opioides/administração & dosagem , Feminino , Seguimentos , Humanos , Laparoscopia/efeitos adversos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Estudos Retrospectivos , Umbigo
9.
Case Rep Endocrinol ; 2019: 7906272, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019814

RESUMO

Systemic inflammatory response syndrome (SIRS) can be a rare manifestation of pheochromocytoma, since this adrenal tumor may produce cytokines and other hormones or neuropeptides besides catecholamines. We report the case of a 53-year-old female patient with a pheochromocytoma that presented with fever and weight loss of 5% in one month along with normocytic anemia, thrombocytosis, leukocytosis, and elevated C-reactive protein. In this setting, interleukin-6 (IL-6) was requested and was elevated [26.7ng/L (<7.0)]. She also presented biochemical evidence of ACTH-independent cortisol production without overt Cushing syndrome. After adrenalectomy, the inflammatory syndrome resolved and all biochemical parameters normalized, including IL-6 and ACTH. To our knowledge, this is the first case report of IL6-producing pheochromocytoma along with autonomous cortisol production.

10.
Chemosphere ; 223: 171-179, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30776762

RESUMO

Old mine tailings from Northern and Central Portugal were studied in order to perform a radiological and chemical characterization. The evaluation of massic activity of natural radionuclides and concentrations in tailings of polymetallic and Ra/U mines was performed by gamma spectrometry and neutron activation analysis. Iron speciation was carried out by Mössbauer spectroscopy. In polymetallic tailings with physical ore processing (Cumieira and Verdes - exploited for Sn, Nb-Ta) higher contents of Th, 228Ra and 226Ra in the coarser materials occur, probably due to their presence in host rock and ore fragments. In finer tailings, washing may explain the lower 226Ra and 210Pb massic activity. In tailings with physical/chemical ore processing (Covas - exploited for W and Sn) high U contents and a tendency for higher 226Ra and 210Pb massic activity in the fine materials is observed, probably due to their incorporation in nano-sized particles of iron oxides. A high variation of the 210Pb/226Ra ratio occurs in polymetallic tailings; a deficit of 210Pb can be observed particularly in deposits of settling tanks drained from dumps of chemically treated ore. In Ervideira-Mestras tailings (Ra/U exploitation) where no ore process in situ was performed, a near equilibrium between 210Pb and 226Ra occurs. Dose risk assessment was carried out by calculating external outdoor Annual Effective Dose Rate; the dose rates in air due to terrestrial gamma radiation are low for the polymetallic tailings (<47 nGy/h), and higher for tailings of Ra/U (up to 4130 nGy/h), in the worst scenario.


Assuntos
Mineração , Radioisótopos/análise , Poluentes Radioativos do Solo/análise , Raios gama , Radioisótopos de Chumbo/análise , Portugal , Rádio (Elemento)/análise , Medição de Risco , Espectrometria gama , Urânio/análise
11.
Artigo em Inglês | MEDLINE | ID: mdl-30738016

RESUMO

Intracranial germinomas are rare tumors affecting mostly patients at young age. Therefore, molecular data on its etiopathogenesis are scarce. We present a clinical case of a male patient of 25 years with an intracranial germinoma and a 16p11.2 microdeletion. His initial complaints were related to obesity, loss of facial hair and polydipsia. He also had a history of social-interaction difficulties during childhood. His blood tests were consistent with hypogonadotropic hypogonadism and secondary adrenal insufficiency, and he had been previously diagnosed with hypothyroidism. He also presented with polyuria and polydipsia and the water deprivation test confirmed the diagnosis of diabetes insipidus. His sellar magnetic resonance imaging (MRI) showed two lesions: one located in the pineal gland and other in the suprasellar region, both with characteristics suggestive of germinoma. Chromosomal microarray analysis was performed due to the association of obesity with social disability, and the result identified a 604 kb 16p11.2 microdeletion. The surgical biopsy confirmed the histological diagnosis of a germinoma. Pharmacological treatment with testosterone, hydrocortisone and desmopressin was started, and the patient underwent radiotherapy (40 Gy divided in 25 fractions). Three months after radiotherapy, a significant decrease in suprasellar and pineal lesions without improvement in pituitary hormonal deficiencies was observed. The patient is currently under follow-up. To the best of our knowledge, we describe the first germinoma in a patient with a 16p11.2 deletion syndrome, raising the question about the impact of this genetic alteration on tumorigenesis and highlighting the need of molecular analysis of germ cell tumors as only little is known about their genetic background. Learning points: Central nervous system germ cell tumors (CNSGTs) are rare intracranial tumors that affect mainly young male patients. They are typically located in the pineal and suprasellar regions and patients frequently present with symptoms of hypopituitarism. The molecular pathology of CNSGTs is unknown, but it has been associated with gain of function of the KIT gene, isochromosome 12p amplification and a low DNA methylation. Germinoma is a radiosensitive tumor whose diagnosis depends on imaging, tumor marker detection, surgical biopsy and cerebrospinal fluid cytology. 16p11.2 microdeletion syndrome is phenotypically characterized by developmental delay, intellectual disability and autism spectrum disorders. Seminoma, cholesteatoma, desmoid tumor, leiomyoma and Wilms tumor have been described in a few patients with 16p11.2 deletion. Bifocal germinoma was identified in this patient with a 16p11.2 microdeletion syndrome, which represents a putative new association not previously reported in the literature.

12.
Hum Mol Genet ; 28(1): 31-50, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30219847

RESUMO

Alpha-synuclein (aSyn) is a central player in Parkinson's disease (PD) but the precise molecular mechanisms underlying its pathogenicity remain unclear. It has recently been suggested that nuclear aSyn may modulate gene expression, possibly via interactions with DNA. However, the biological behavior of aSyn in the nucleus and the factors affecting its transcriptional role are not known. Here, we investigated the mechanisms underlying aSyn-mediated transcription deregulation by assessing its effects in the nucleus and the impact of phosphorylation in these dynamics. We found that aSyn induced severe transcriptional deregulation, including the downregulation of important cell cycle-related genes. Importantly, transcriptional deregulation was concomitant with reduced binding of aSyn to DNA. By forcing the nuclear presence of aSyn in the nucleus (aSyn-NLS), we found the accumulation of high molecular weight aSyn species altered gene expression and reduced toxicity when compared with the wild-type or exclusively cytosolic protein. Interestingly, nuclear localization of aSyn, and the effect on gene expression and cytotoxicity, was also modulated by phosphorylation on serine 129. Thus, we hypothesize that the role of aSyn on gene expression and, ultimately, toxicity, may be modulated by the phosphorylation status and nuclear presence of different aSyn species. Our findings shed new light onto the subcellular dynamics of aSyn and unveil an intricate interplay between subcellular location, phosphorylation and toxicity, opening novel avenues for the design of future strategies for therapeutic intervention in PD and other synucleinopathies.


Assuntos
alfa-Sinucleína/metabolismo , alfa-Sinucleína/fisiologia , Animais , Linhagem Celular , Núcleo Celular , Proteínas de Ligação a DNA , Regulação para Baixo , Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Humanos , Camundongos , Sinais de Localização Nuclear/fisiologia , Doença de Parkinson/patologia , Fosforilação , Cultura Primária de Células , Ratos
13.
Neurobiol Dis ; 119: 121-135, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30092270

RESUMO

Alpha-synuclein (aSyn) is the major protein component of Lewy bodies and Lewy neurites, the typical pathological hallmarks in Parkinson's disease (PD) and Dementia with Lewy bodies. aSyn is capable of inducing transcriptional deregulation, but the precise effect of specific aSyn mutants associated with familial forms of PD, remains unclear. Here, we used transgenic mice overexpressing human wild-type (WT) or A30P aSyn to compare the transcriptional profiles of the two animal models. We found that A30P aSyn promotes strong transcriptional deregulation and increases DNA binding. Interestingly, COL4A2, a major component of basement membranes, was found to be upregulated in both A30P aSyn transgenic mice and in dopaminergic neurons expressing A30P aSyn, suggesting a crucial role for collagen related genes in aSyn-induced toxicity. Finally, we observed that A30P aSyn alters Golgi morphology and increases the susceptibility to endoplasmic reticulum (ER) stress in dopaminergic cells. In total, our findings provide novel insight into the putative role of aSyn on transcription and on the molecular mechanisms involved, thereby opening novel avenues for future therapeutic interventions in PD and other synucleinopathies.


Assuntos
Colágeno Tipo IV/biossíntese , Retículo Endoplasmático/fisiologia , Complexo de Golgi/fisiologia , Fragmentos de Peptídeos/biossíntese , alfa-Sinucleína/biossíntese , Animais , Células Cultivadas , Colágeno Tipo IV/genética , Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/genética , alfa-Sinucleína/genética
14.
Clin Endocrinol (Oxf) ; 88(6): 787-798, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29574994

RESUMO

OBJECTIVE: Hypercortisolism in Cushing's syndrome (CS) is associated with impaired health-related quality of life (HRQoL), which may persist despite remission. We used the data entered into the European Registry on Cushing's syndrome (ERCUSYN) to evaluate if patients with CS of pituitary origin (PIT-CS) have worse HRQoL, both before and after treatment than patients with adrenal causes (ADR-CS). METHODS: Data from 595 patients (492 women; 83%) who completed the CushingQoL and/or EQ-5D questionnaires at baseline and/or following treatment were analysed. RESULTS: At baseline, HRQoL did not differ between PIT-CS (n = 293) and ADR-CS (n = 120) on both EuroQoL and CushingQoL. Total CushingQoL score in PIT-CS and ADR-CS was 41 ± 18 and 44 ± 20, respectively (P = .7). At long-time follow-up (>1 year after treatment) total CushingQoL score was however lower in PIT-CS than ADR-CS (56 ± 20 vs 62 ± 23; P = .045). In a regression analysis, after adjustment for baseline age, gender, remission status, duration of active CS, glucocorticoid dependency and follow-up time, no association was observed between aetiology and HRQoL. Remission was associated with better total CushingQoL score (P < .001), and older age at diagnosis with worse total score (P = .01). Depression at diagnosis was associated with worse total CushingQoL score at the last follow-up (P < .001). CONCLUSION: PIT-CS patients had poorer HRQoL than ADR-CS at long-term follow-up, despite similar baseline scoring. After adjusting for remission status, no interaetiology differences in HRQoL scoring were found. Age and presence of depression at diagnosis of CS may be potential predictors of worse HRQoL regardless of CS aetiology.


Assuntos
Adenoma/fisiopatologia , Hidrocortisona/metabolismo , Hipersecreção Hipofisária de ACTH/metabolismo , Hipersecreção Hipofisária de ACTH/fisiopatologia , Adenoma/tratamento farmacológico , Adenoma/metabolismo , Adulto , Feminino , Glucocorticoides/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários
15.
Mol Neurobiol ; 55(6): 5269-5281, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28884318

RESUMO

Among the familial forms of amyotrophic lateral sclerosis (fALS), 20% are associated with the Cu,Zn-superoxide dismutase (Sod1). fALS is characterized by the accumulation of aggregated proteins and the increase in oxidative stress markers. Here, we used the non-invasive bimolecular fluorescence complementation (BiFC) assay in human H4 cells to investigate the kinetics of aggregation and subcellular localization of Sod1 mutants. We also studied the effect of the different Sod1 mutants to respond against oxidative stress by following the levels of reactive oxygen species (ROS) after treatment with hydrogen peroxide. Our results showed that only 30% of cells transfected with A4VSod1 showed no inclusions while for the other Sod1 mutants tested (L38V, G93A and G93C), this percentage was at least 70%. In addition, we found that 10% of cells transfected with A4VSod1 displayed more than five inclusions per cell and that A4V and G93A Sod1 formed inclusions more rapidly than L38V and G93C Sod1. Expression of WTSod1 significantly decreased the intracellular oxidation levels in comparison with expression of fALS Sod1 mutants, suggesting the mutations induce a functional impairment. All fALS mutations impaired nuclear localization of Sod1, which is important for maintaining genomic stability. Consistently, expression of WTSod1, but not of fALS Sod1 mutants, reduced DNA damage, as measured by the comet assay. Altogether, our study sheds light into the effects of fALS Sod1 mutations on inclusion formation, dynamics, and localization as well as on antioxidant response, opening novel avenues for investigating the role of fALS Sod1 mutations in pathogenesis.


Assuntos
Esclerose Amiotrófica Lateral/enzimologia , Esclerose Amiotrófica Lateral/genética , Modelos Biológicos , Mutação/genética , Multimerização Proteica , Superóxido Dismutase/genética , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Dano ao DNA , Humanos , Transporte Proteico , Espécies Reativas de Oxigênio/metabolismo
16.
J Gerontol A Biol Sci Med Sci ; 73(4): 459-467, 2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-28645186

RESUMO

In rats, learning and memory performance decline during normal aging, which makes this rodent species a suitable model to evaluate therapeutic strategies. In aging rats, insulin-like growth factor-I (IGF-I), is known to significantly improve spatial memory accuracy as compared to control counterparts. A constellation of gene expression changes underlie the hippocampal phenotype of aging but no studies on the effects of IGF-I on the hippocampal transcriptome of old rodents have been documented. Here, we assessed the effects of IGF-I gene therapy on spatial memory performance in old female rats and compared them with changes in the hippocampal transcriptome. In the Barnes maze test, experimental rats showed a significantly higher exploratory frequency of the goal hole than controls. Hippocampal RNA-sequencing showed that 219 genes are differentially expressed in 28-month-old rats intracerebroventricularly injected with an adenovector expressing rat IGF-I as compared with placebo adenovector-injected counterparts. From the differentially expressed genes, 81 were down and 138 upregulated. From those genes, a list of functionally relevant genes, concerning hippocampal IGF-I expression, synaptic plasticity as well as neuronal function was identified. Our results provide an initial glimpse at the molecular mechanisms underlying the neuroprotective actions of IGF-I in the aging brain.


Assuntos
Envelhecimento/genética , Terapia Genética/métodos , Hipocampo/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/farmacologia , Transtornos da Memória/genética , Memória Espacial/fisiologia , Fatores Etários , Animais , Feminino , Aprendizagem em Labirinto/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma
17.
Endocr Connect ; 6(8): 935-942, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29089364

RESUMO

INTRODUCTION: Primary adrenal insufficiency (PAI) is a rare but severe and potentially life-threatening condition. No previous studies have characterized Portuguese patients with PAI. AIMS: To characterize the clinical presentation, diagnostic workup, treatment and follow-up of Portuguese patients with confirmed PAI. METHODS: This multicentre retrospective study examined PAI patients in 12 Portuguese hospitals. RESULTS: We investigated 278 patients with PAI (55.8% were females), with a mean age of 33.6 ± 19.3 years at diagnosis. The most frequent presenting clinical features were asthenia (60.1%), mucocutaneous hyperpigmentation (55.0%) and weight loss (43.2%); 29.1% of the patients presented with adrenal crisis. Diagnosis was established by high plasma ACTH and low serum cortisol in most patients (43.9%). The most common aetiology of PAI was autoimmune adrenalitis (61.0%). There were 38 idiopathic cases. Autoimmune comorbidities were found in 70% of the patients, the most frequent being autoimmune thyroiditis (60.7%) and type 1 diabetes mellitus (17.3%). Seventy-nine percent were treated with hydrocortisone (mean dose 26.3 ± 8.3 mg/day) mostly in three (57.5%) or two (37.4%) daily doses. The remaining patients were treated with prednisolone (10.1%), dexamethasone (6.2%) and methylprednisolone (0.7%); 66.2% were also on fludrocortisone (median dose of 100 µg/day). Since diagnosis, 33.5% of patients were hospitalized for disease decompensation. In the last appointment, 17.2% of patients had complaints (7.6% asthenia and 6.5% depression) and 9.7% had electrolyte disturbances. CONCLUSION: This is the first multicentre Portuguese study regarding PAI. The results emphasize the need for standardization in diagnostic tests and etiological investigation and provide a framework for improving treatment.

18.
Artigo em Inglês | MEDLINE | ID: mdl-28458908

RESUMO

SUMMARY: Insulinomas are the most frequent cause of hyperinsulinaemic hypoglycaemia. Although surgical enucleation is the standard treatment, a few other options are available to high-risk patients who are elderly or present with co-morbidities. We present a case report of an 89-year-old female patient who was admitted to the emergency department due to recurrent hypoglycaemia, especially during fasting. Laboratory work-up raised the suspicion of hyperinsulinaemic hypoglycaemia, and abdominal CT scan revealed a 12 mm nodular hypervascular lesion of the pancreatic body suggestive of neuroendocrine tumour. The patient was not considered a suitable candidate for surgery, and medical therapy with diazoxide was poorly tolerated. Endoscopic ultrasound-guided ethanol ablation therapy was performed and a total of 0.6 mL of 95% ethanol was injected into the lesion by a transgastric approach; no complications were reported after the procedure. At 5 months of follow-up, no episodes of hypoglycaemia were reported, no diazoxide therapy was necessary, and revaluation abdominal CT scan revealed a pancreatic nodular lesion with a size involution of about half of its original volume. The patient is regularly followed-up at the endocrinology clinic and shows a significant improvement in her wellbeing and quality of life. LEARNING POINTS: Insulinomas are the most frequent cause of hyperinsulinaemic hypoglycaemia.Surgical enucleation is the standard treatment with a few other options available to high-risk patients.Endoscopic ultrasound-guided ethanol ablation therapy is one feasible option in high-risk patients with satisfactory clinical outcomes, significant positive impact on quality of life and low complication rates related to the procedure.

19.
Hum Mol Genet ; 26(12): 2231-2246, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28369321

RESUMO

Alpha-synuclein (aSyn) is considered a major culprit in Parkinson's disease (PD) pathophysiology. However, the precise molecular function of the protein remains elusive. Recent evidence suggests that aSyn may play a role on transcription regulation, possibly by modulating the acetylation status of histones. Our study aimed at evaluating the impact of wild-type (WT) and mutant A30P aSyn on gene expression, in a dopaminergic neuronal cell model, and decipher potential mechanisms underlying aSyn-mediated transcriptional deregulation. We performed gene expression analysis using RNA-sequencing in Lund Human Mesencephalic (LUHMES) cells expressing endogenous (control) or increased levels of WT or A30P aSyn. Compared to control cells, cells expressing both aSyn variants exhibited robust changes in the expression of several genes, including downregulation of major genes involved in DNA repair. WT aSyn, unlike A30P aSyn, promoted DNA damage and increased levels of phosphorylated p53. In dopaminergic neuronal cells, increased aSyn expression led to reduced levels of acetylated histone 3. Importantly, treatment with sodium butyrate, a histone deacetylase inhibitor (HDACi), rescued WT aSyn-induced DNA damage, possibly via upregulation of genes involved in DNA repair. Overall, our findings provide novel and compelling insight into the mechanisms associated with aSyn neurotoxicity in dopaminergic cells, which could be ameliorated with an HDACi. Future studies will be crucial to further validate these findings and to define novel possible targets for intervention in PD.


Assuntos
alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Ácido Butírico/metabolismo , Técnicas de Cultura de Células , Dano ao DNA , Neurônios Dopaminérgicos/metabolismo , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Humanos , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia
20.
Brain ; 140(4): 878-886, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27585855

RESUMO

Parkinson's disease is the second most prevalent neurodegenerative disorder. The main neuropathological hallmarks of the disease are the degeneration of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of protein inclusions known as Lewy bodies. Recently, great attention has been given to the study of genes associated with both familial and sporadic forms of Parkinson's disease. Among them, the α-synuclein gene is believed to play a central role in the disease and is, therefore, one of the most studied genes. Parkinson's disease is a complex disorder and, as such, derives from the interaction between genetic and environmental factors. Here, we offer an update on the landscape of epigenetic-mediated regulation of gene expression that has been linked with α-synuclein and associated with Parkinson's disease. We also provide an overview of how epigenetic modifications can influence the transcription and/or translation of the α-synuclein gene and, on the other hand, how α-synuclein function/dysfunction can, per se, affect the epigenetic landscape. Finally, we discuss how a deeper understanding of the epigenetic profile of α-synuclein may enable the development of novel therapeutic approaches for Parkinson's disease and other synucleinopathies.


Assuntos
Epigenômica , Doença de Parkinson/genética , alfa-Sinucleína/genética , Meio Ambiente , Humanos , Yin-Yang
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