RESUMO
Partial tetrasomy of distal 13q has a reported association with a variable phenotype including microphthalmia, ear abnormalities, hypotelorism, facial dysmorphisms, urogenital defects, pigmentation and skin defects, and severe learning difficulties. A wide range of mosaicism has been reported, which may, to some extent, account for the variable spectrum of observed phenotypes. We report here a pregnancy conceived using intrauterine insemination in a 32-year-old female with a history of infertility. Non-invasive prenatal screening (NIPS) was performed in the first trimester which reported an increased risk for trisomy 13. Follow-up cytogenetic workup using chorionic villus sampling (CVS) and amniotic fluid samples showed a mosaic karyotype with a small supernumerary marker chromosome (sSMC). Chromosomal microarray analysis (CMA) identified a mosaic 31.34 Mb terminal gain on chr13q31.1q34 showing the likely origin of the sSMC to distal chromosome 13q. Follow-up metaphase FISH testing suggested an inverted duplication rearrangement involving 13q31q34 in the marker chromosome and the presence of a neocentromere. At 21 months of age, the proband has a history of gross motor delay, hypotonia, left microphthalmia, strabismus, congenital anomaly of the right optic nerve, hemangiomas, and a tethered spinal cord. Postnatal chromosome analyses in buccal, peripheral blood, and spinal cord ligament tissues were consistent with the previous amniocentesis and CVS findings, and the degree of mosaicism varied from 25 to 80%. It is often challenging to pinpoint the chromosomal identity of sSMCs using banding cytogenetics. A combination of low-pass genome sequencing of cell-free DNA, chromosomal microarray, and FISH enabled the identification of the precise chromosomal rearrangement in this patient. This study adds to the growing list of clinically identified neocentric marker chromosomes and is the first described instance of partial tetrasomy 13q31q34 identified in a mosaic state prenatally. Since NIPS is now being routinely performed along with invasive testing for advanced maternal age, an increased prenatal detection rate for mosaic sSMCs in otherwise normal pregnancies is expected. Future studies investigating how neocentromeres mediate gene expression changes could help identify potential epigenetic targets as treatment options to rescue or reverse the phenotypes seen in patients with congenital neocentromeres.
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OBJECTIVE@#MRI-Ultrasound fusion guided targeted biopsy has revolutionized the diagnosis of prostatecancer through accurate identification, localization and characterization of prostatic lesions utilizingthe prostate imaging reporting and data system (PI-RADS) scoring system by multiparametric MRI(MPMRI). The fusion prostate biopsy system on the other hand, enables accurate targeting and easyaccess of the tumor. The study objective is to determine the detection rate of clinically-significantprostate cancer using fusion biopsy, and to establish the correlation between PI-RADS score andGleason's score.@*PATIENTS AND METHODS@#A retrospective cohort study was conducted to determine the correlation betweenPI-RADS score and the presence of prostate cancer using MRI-Ultrasound fusion guided transperinealprostate biopsy. This was carried out from June 2017 to July 2018 in a single institution. One hundredthirty five (135) men were included in this study. They presented with an elevated PSA, abnormalDRE or a previous negative prostate biopsy, but with a persistent rise in PSA. A total of 220 prostatelesions were identified. The following characteristics were measured: patient age; the size, location,the PI-RADS score of each lesion, the maximum PI-RADS score for select patients; and the Gleasonscore of discovered tumors.@*RESULTS@# Two hundred twenty PI-RADS 3, 4 and 5 lesions were detected in 135 patients by MPMRI.131 of the 220 lesions were scored as PI-RADS 3, 61 as PI-RADS 4 and 28 as PI-RADS 5. Theselesions were biopsied using the MRI-Ultrasound fusion guided transperineal prostate biopsy system.Thirty-three out of the 131 PI-RADS 3 lesions (25.2%), 44 out of the 61 PI-RADS 4 lesions (72.1%)and 24 out of the 28 PI-RADS 5 lesions (85.7%) respectively were positive for malignancy. Overall,there were 101 (45.9%) lesions classified as PI-RADS 3 to 5 that were positive for prostate carcinoma.Seventy four (74) of the 135 patients (54.8%) were diagnosed with prostate adenocarcinoma. Nineteenout of 65 patients with a maximum score of PI-RADS 3 (29.2%), 33 of 44 with a maximum of PI-RADS 4 (75%) and 22 of 26 with a maximum of PI-RADS 5 (84.6%) harbored malignancy. In termsof location, 45 of the 101 (44.6%) malignancies were in the peripheral sector, 31 (30.7%) in theanterior sector, and 25 (24.8%) in the central sector of the prostate. The mean Gleason grade of PI-RADS 3, 4 and 5 lesions were 6.61, 7.73, and 7.38, respectively. Using Spearman correlation, the rhocoefficient was 0.3153 (p-value =.00013) which denotes a significant positive relationship betweenGleason and PI-RADS score.@*CONCLUSION@#This is the first comprehensive Philippine study on Multiparametric MRI-Ultrasoundfusion-guided transperineal prostate biopsy. Present data validate the superiority of MPMRI in theidentification, localization and characterization of prostate cancers. The authors also verified thepositive correlation between PI-RADS score and Gleason score. Finally, they demonstrated theaccuracy of the MRI- ultrasound fusion-guided transperineal prostate biopsy system in targetingprostate lesions.
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The Visible and near Infrared Hyperspectral Imager (VIHI) is the VIS-IR spectrometer with imaging capabilities aboard the ESA BepiColombo mission to Mercury. In this second paper, we report the instrument spectral characterization derived by the calibration campaign carried out before spacecraft integration. Complementary measurements concerning radiometric and linearity responses, as well as geometric performances, are described in Paper I [G. Filacchione et al., Rev. Sci. Instrum. 88, 094502 (2017)]. We have verified the VIHI spectral range, spectral dispersion, spectral response function, and spectral uniformity along the whole slit. Instrumental defects and optical aberrations due to smiling and keystone effects have been evaluated, and they are lower than the design requirement (<1/3 pixel). The instrumental response is uniform along the whole slit, while spectral dispersion is well represented by a second order curve, rather than to be constant along the spectral dimension.
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Pre-clinical studies have shown that injection of allogeneic T cells primed against a single minor histocompatibility antigen (MiHA) could cure hematologic cancers (HC) without causing any toxicity to the host. However, translation of this approach in humans has been hampered by the paucity of molecularly defined human MiHAs. Using a novel proteogenomic approach, we have analyzed cells from 13 volunteers and discovered a vast repertoire of MiHAs presented by the most common HLA haplotype in European Americans: HLA-A*02:01;B*44:03. Notably, out of >6000 MiHAs, we have identified a set of 39 MiHAs that share optimal features for immunotherapy of HCs. These 'optimal MiHAs' are coded by common alleles of genes that are preferentially expressed in hematopoietic cells. Bioinformatic modeling based on MiHA allelic frequencies showed that the 39 optimal MiHAs would enable MiHA-targeted immunotherapy of practically all HLA-A*02:01;B*44:03 patients. Further extension of this strategy to a few additional HLA haplotypes would allow treatment of almost all patients.
Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia/métodos , Antígenos de Histocompatibilidade Menor/uso terapêutico , Proteogenômica/métodos , Células Cultivadas , Feminino , Antígeno HLA-A2 , Antígeno HLA-B44 , Haplótipos , Humanos , MasculinoRESUMO
BACKGROUND AND OBJECTIVES: Reticular erythematous mucinosis (REM) and lupus erythematosus tumidus (LET) share similarities. However, to our knowledge no study extensively compared the histological features of these two conditions. The aim of this study is to compare the histological and immunohistochemical features of REM and LET. METHODS: We evaluated epidermal thickness, hyperkeratosis, dermo-epidermal junction changes, interstitial mucin deposition, vessel dilatation and pattern, type and density of the inflammatory infiltrate in 25 cases of REM and LET. Anti-CD3, anti-CD20, anti-CD68, anti-CD4, anti-CD8, anti-CD123, anti-CD2AP, anti-IgG and anti-C3 antibodies were tested in a subset of patients. RESULTS: Both diseases are characterized by perivascular dermal infiltrates of lymphocytes mainly CD4+ positive and increased dermal mucin. However, REM tended to show more scattered and more superficial lymphocytes with more superficial mucin and to have less frequent immunoglobulin and complement depositions along the dermo-epidermal junction. Plasmacytoid dendritic cells (PDCs) were less represented in REM, and were mainly found as single cells differently from LET. CONCLUSIONS: REM and LET present some differences in the infiltrate, including PDCs, the mucin deposition and the immunoreactant deposition at the dermo-epidermal junction that justify the distinction of the two diseases and suggest different pathogenetic mechanisms.
Assuntos
Eritema/patologia , Lúpus Eritematoso Cutâneo/patologia , Mucinoses/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos , Células Dendríticas , Epiderme/patologia , Eritema/complicações , Eritema/metabolismo , Feminino , Humanos , Imunoglobulinas/análise , Imuno-Histoquímica , Ceratose/patologia , Lúpus Eritematoso Cutâneo/metabolismo , Masculino , Pessoa de Meia-Idade , Mucinoses/complicações , Mucinoses/metabolismo , Mucinas/análise , Adulto JovemRESUMO
Enterotoxigenic Escherichia coli (ETEC) is a significant cause of diarrheal disease and death, especially in children in developing countries. ETEC causes disease by colonizing the small intestine and producing heat-labile toxin (LT), heat-stable toxin (ST), or both LT and ST (LT+ST). The majority of ETEC strains produce both ST and LT. Despite the prevalence of LT+ST-producing organisms, few studies have examined the physiologic or immunologic consequences of simultaneous exposure to these two potent enterotoxins. In the current report, we demonstrate that when LT and ST are both present, they increase water movement into the intestinal lumen over and above the levels observed with either toxin alone. As expected, cultured intestinal epithelial cells increased their expression of intracellular cyclic GMP (cGMP) when treated with ST and their expression of intracellular cyclic AMP (cAMP) when treated with LT. When both toxins were present, cGMP levels but not cAMP levels were synergistically elevated compared with the levels of expression caused by the corresponding single-toxin treatment. Our data also demonstrate that the levels of inflammatory cytokines produced by intestinal epithelial cells in response to LT are significantly reduced in animals exposed to both enterotoxins. These findings suggest that there may be complex differences between the epithelial cell intoxication and, potentially, secretory outcomes induced by ETEC strains expressing LT+ST compared with strains that express LT or ST only. Our results also reveal a novel mechanism wherein ST production may reduce the hosts' ability to mount an effective innate or adaptive immune response to infecting organisms.
Assuntos
Toxinas Bacterianas/toxicidade , Citocinas/metabolismo , Escherichia coli Enterotoxigênica/fisiologia , Enterotoxinas/toxicidade , Células Epiteliais/efeitos dos fármacos , Proteínas de Escherichia coli/toxicidade , Nucleotídeos Cíclicos/metabolismo , Água/metabolismo , Animais , Linhagem Celular , Escherichia coli Enterotoxigênica/imunologia , Células Epiteliais/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB CRESUMO
OBJECTIVE: To investigate the effect of tumour necrosis factor (TNF) antagonist treatment on workforce participation in patients with rheumatoid arthritis (RA). METHODS: Data from the Stockholm anti-TNFalpha follow-up registry (STURE) were used in this observational study. Patients with RA (n = 594) aged 18-55 years, (mean (SD) 40 (9) years) followed for up to 5 years were included with hours worked/week as the main outcome measure. Analyses were performed unadjusted and adjusted for baseline age, disease duration, Health Assessment Questionnaire (HAQ), 28-joint Disease Activity Score (DAS28) and pain score. RESULTS: At baseline patients worked a mean 20 h/week (SD 18). In unadjusted analyses, significant improvements in hours worked/week could already be observed in patients at 6 months (mean, 95% CI) +2.4 h (1.3 to 3.5), with further increases compared to baseline at 1-year (+4.0 h, 2.4 to 5.6) and 2-year follow-up (+6.3 h, 4.2 to 8.4). The trajectory appeared to stabilise at the 3-year (+6.3 h, 3.6 to 8.9), 4-year (+5.3 h, 2.3 to 8.4) and 5-year follow-up (+6.6 h, 3.3 to 10.0). In a mixed piecewise linear regression model, adjusted for age, sex, baseline disease activity, function and pain, an improvement of +4.2 h/week was estimated for the first year followed by an added improvement of +0.5 h/week annually during the years thereafter. Over 5 years of treatment, the expected indirect cost gain corresponded to 40% of the annual anti-TNF drug cost in patients continuing treatment. CONCLUSION: Data from this population-based registry indicate that biological therapy is associated with increases in workforce participation in a group typically expected to experience progressively deteriorating ability to work. This could result in significant indirect cost benefits to society.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Efeitos Psicossociais da Doença , Emprego/estatística & dados numéricos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Artrite Reumatoide/economia , Artrite Reumatoide/reabilitação , Esquema de Medicação , Eficiência , Métodos Epidemiológicos , Etanercepte , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Infliximab , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Receptores do Fator de Necrose Tumoral/uso terapêutico , Suécia , Carga de Trabalho/estatística & dados numéricos , Adulto JovemRESUMO
Breath-hold divers may experience haemoptysis during diving. Central pooling of blood as well as compression of pulmonary gas content can damage the integrity of the blood-gas barrier, resulting in alveolar hemorrhage. The single-breath carbon monoxide test (DL,CO) was used to investigate the blood-gas barrier following diving. The study population consisted of 30 divers recruited from a training course. DL,CO levels were measured before diving and at 2, 10 and 25 min after the last of a series of four dives to depths of 10, 15, 20 and 30 m. When compared to pre-diving values, DL,CO values increased significantly at 2 min following diving in all subjects except one. Thereafter values progressively decreased toward baseline at 10 and 25 min in all subjects but one, while in four divers DL,CO values decreased below baseline. The early but transient increase in DL,CO levels shortly after diving supports the persistence of capillary pooling of red blood cells following emersion. Persistence at 25 min of high DL,CO values in one subject could be attributed by lung CT to extravasation of blood into the alveoli. Early or late DL,CO values >10% below baseline values suggest the presence of pulmonary edema. The relatively high prevalence of DL,CO alterations found suggests caution on the safety of breath-hold diving activities.
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Barreira Alveolocapilar/fisiologia , Monóxido de Carbono/metabolismo , Mergulho/fisiologia , Capacidade de Difusão Pulmonar/fisiologia , Adulto , Resistência das Vias Respiratórias/fisiologia , Barreira Alveolocapilar/metabolismo , Mergulho/efeitos adversos , Feminino , Hemoptise/etiologia , Humanos , Masculino , Alvéolos Pulmonares/fisiologia , Ventilação Pulmonar/fisiologia , Espirometria , Fatores de TempoRESUMO
OBJECTIVE: To identify temporal trends in the prescription of disease-modifying antirheumatic drugs (DMARDs) in patients with early rheumatoid arthritis (RA). METHODS: Using data from the Swedish RA register (n = 2,584), we analysed the proportion of RA patients prescribed DMARDs at their first consultation between 1997 and 2001. Statistical process control (SPC) was used to chart and analyse major changes in prescription behaviour, while more traditional time series analysis methods (i.e. regression) were used to corroborate the nature of any trend. RESULTS: The SPC method identified an upward shift in the prescription of DMARDs in July 1998 and a change in the process by October 1998. Time series analysis confirmed an increasing trend in DMARD prescription over the period as a whole and the trend was statistically significant (pAssuntos
Antirreumáticos/uso terapêutico
, Artrite Reumatoide/tratamento farmacológico
, Padrões de Prática Médica/tendências
, Guias como Assunto
, Política de Saúde
, Humanos
, Estudos Prospectivos
, Sistema de Registros
, Suécia
, Resultado do Tratamento
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Side-to-side, functional end-to-end stapled anastomosis (SS-EESA) is a frequently employed technique to re-establish continuity following bowel resection. We describe, for the first time in children, two cases of an important complication of this form of bowel anastomosis. Patient 1 had resection of a jejunal lymphangioma and formation of an SS-EESA at the age of 3 years. By the age of 7 years he was demonstrating symptoms consistent with malabsorption, which was confirmed by hydrogen breath testing. An upper GI contrast study indicated a segmental dilatation of the distal small bowel. Elective laparotomy revealed partial volvulus of a greatly dilated SS-EESA. Patient 2 had undergone bowel resection as a neonate for ileal atresia, with end-to-end anastomosis. An anastomotic stricture developed at two months of age that was resected with formation of an SS-EESA. Multiple ensuing episodes of partial small bowel obstruction were managed non-operatively until, at 5 years of age, she presented with complete bowel obstruction. At operation, volvulus of a hugely dilated SS-EESA was found. Intraoperative cultures of the succus entericus were consistent with bacterial overgrowth. Both patients were successfully treated with resection of the SS-EESA and primary anastomosis. SS-EESA can be complicated by bacterial overgrowth, massive dilatation and volvulus. In patients with SS-EESA who present with recurrent obstructive symptoms, this complication should be considered.
Assuntos
Íleo/anormalidades , Atresia Intestinal/cirurgia , Volvo Intestinal/etiologia , Neoplasias do Jejuno/cirurgia , Linfangioma/cirurgia , Técnicas de Sutura/efeitos adversos , Anastomose Cirúrgica/efeitos adversos , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Volvo Intestinal/diagnóstico , Volvo Intestinal/diagnóstico por imagem , Laparotomia/métodos , Masculino , Radiografia Abdominal , Reoperação , Técnicas de Sutura/instrumentação , Suturas , Fatores de TempoRESUMO
PURPOSE: The most important diagnostic features of Hirschsprung's disease (HD) are the combination of aganglionosis and hypertrophic nerve bundles. Acetylcholinesterase staining is widely used for diagnosis of HD as it identifies hypertrophic nerves in both diagnostic and intraoperative biopsies. The main drawback of this method is in the identification of ganglia. It has been suggested that the combination of this method together with another histochemical marker would be a superior diagnostic tool. Hematoxylin and eosin is still the diagnostic measure of choice for identifying ganglia in many centers, although it presents a persistent diagnostic challenge for pathologists trying to rapidly and accurately interpret the frozen biopsies that guide intraoperative decision making. METHODS: Therefore, we sought to develop a fast, intraoperative immunohistochemical protocol for visualization of ganglia and nerves in HD specimens that can be used in conjunction with these other tools. RESULTS: With the use of acetone fixation and immunofluorescence staining with antibodies to neurofilament 68 and tubulin, ganglia in sections of full thickness and suction biopsies could be visualized in only 10 minutes. This protocol facilitated the identification of ganglia in hematoxylin and eosin-stained adjacent sections and also identified hypertrophic nerve trunks. CONCLUSION: This method should significantly enable the identification of ganglia in suction and full thickness biopsies.
Assuntos
Biópsia por Agulha/métodos , Gânglios/patologia , Doença de Hirschsprung/patologia , Doença de Hirschsprung/cirurgia , Fixação de Tecidos/métodos , Anus Imperfurado/patologia , Apendicite/patologia , Pré-Escolar , Colite Ulcerativa/patologia , Feminino , Humanos , Imuno-Histoquímica , Lactente , Mucosa Intestinal/patologia , Cuidados Intraoperatórios/métodos , Masculino , Valores de Referência , Estudos de Amostragem , Sensibilidade e Especificidade , Manejo de Espécimes , Fatores de TempoAssuntos
Antieméticos/uso terapêutico , Vômito/tratamento farmacológico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Aprepitanto , Área Sob a Curva , Protocolos Clínicos , Interações Medicamentosas , Humanos , Oncologia/normas , Morfolinas/efeitos adversos , Morfolinas/uso terapêutico , Náusea/prevenção & controle , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Antagonistas dos Receptores de Neurocinina-1 , Radioterapia/efeitos adversos , Antagonistas do Receptor 5-HT3 de Serotonina , Vômito/induzido quimicamente , Vômito/fisiopatologia , Vômito/prevenção & controleRESUMO
OBJECTIVE: To characterise temporal trends and factors associated with the prescription of disease modifying antirheumatic drugs (DMARDs) at the initial consultation in early rheumatoid arthritis (RA). METHODS: Data from 2584 patients with early RA at 19 hospitals were extracted from the Swedish Rheumatoid Arthritis Register for the period 1997-2001. Disease characteristics and DMARD prescription at first consultation with the rheumatologist were investigated using cross tabulation and logistic regression. RESULTS: DMARD prescriptions, particularly for methotrexate, increased from 1997 to 2001 independently of patient characteristics. Stratification by hospital type showed that patients in district hospitals were less likely to be prescribed DMARDs than those in university hospitals (adjusted odds ratio (OR) = 0.53 (95% confidence interval (CI) 0.40 to 0.69), p<0.001), independently of confounding factors. Association of the DAS28 with the likelihood of DMARD prescription was greater among patients attending district hospitals (OR = 1.65 (1.34 to 2.02), p<0.001) than those at university hospitals (OR = 1.23 (1.07 to 1.41), p = 0.003) and county hospitals (OR = 1.34 (1.01 to 1.63), p = 0.003). Interaction testing indicated that the difference was significant (p = 0.007). CONCLUSIONS: Temporal trends in DMARD prescription indicate an increasingly aggressive approach to disease management among Swedish rheumatologists. However, the association of hospital type with DMARD prescription suggests that the adoption of research findings in clinical care varies considerably.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Hospitais , Padrões de Prática Médica , Reumatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hospitais de Distrito , Hospitais Universitários , Humanos , Modelos Logísticos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Razão de Chances , Ambulatório HospitalarRESUMO
Mitochondrial Ca2+ uptake controls cellular functions as diverse as aerobic metabolism, cytosolic Ca2+signalling and mitochondrial participation in apoptosis. Modulatory inputs converging on the organelle can regulate this process, determining the final outcome of Ca2+-mediated cell stimulation. We investigated in HeLa cells and primary skeletal myotubes the effect on Ca2+ signalling of the transcriptional peroxisome-proliferator-activated-receptor-gamma-coactivator-1alpha (PGC-1alpha), which triggers organelle biogenesis and modifies the mitochondrial proteome. PGC-1alpha selectively reduced mitochondrial Ca2+ responses to cell stimulation by reducing the efficacy of mitochondrial Ca2+ uptake sites and increasing organelle volume. In turn, this affected ER Ca2+ release and cytosolic responses in HeLa cells. Most importantly, the modulation of mitochondrial Ca2+ uptake significantly reduced cellular sensitivity to the Ca2+-mediated proapoptotic effect of C2 ceramide. These results reveal a primary role of PGC-1alpha in shaping mitochondrial participation in calcium signalling, that underlies its protective role against stress and proapoptotic stimuli in pathophysiological conditions.
Assuntos
Apoptose , Sinalização do Cálcio , Cálcio/metabolismo , Proteínas de Choque Térmico/metabolismo , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fatores de Transcrição/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Albuterol/farmacologia , Animais , Canais de Cálcio/metabolismo , Inibidores Enzimáticos/farmacologia , Células HeLa , Proteínas de Choque Térmico/genética , Histamina/farmacologia , Homeostase , Humanos , Receptores de Inositol 1,4,5-Trifosfato , Canais Iônicos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Dilatação Mitocondrial , Fibras Musculares Esqueléticas/patologia , Fator 1 Nuclear Respiratório/genética , Fator 1 Nuclear Respiratório/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Fatores de Transcrição/genética , Transfecção , Proteína Desacopladora 2RESUMO
Plantas têm contribuído no tratamento da maioria das doenças. Considerando a importância terapêutica das plantas medicinais, foi avaliada a atividade imunológica dos extratos metanólico e etanólico de Davilla elliptica. Macrófagos estão envolvidos em todos estágios da resposta imune, podendo liberar componentes como: peróxido de hidrogênio (H2O2), óxido nítrico (NO) e fator de necrose tumoral-alfa (TNF-alfa). A estimulação dos macrófagos foi avaliada pela determinação de H2O2, NO e TNF-alfa em culturas de macrófagos peritoneais de camundongos na presença dos extratos da D. elliptica. IC50 foi determinado através de ensaio utilizando MTT. Os estudos fitoquímicos realizados mostraram a presença de flavonóides derivados da quercetina e miricetina entre outros compostos. A produção de H2O2 não foi muito expressiva em ambos extratos, contudo a de NO foi significativa. Os dois extratos induziram a produção de TNF-alfa, sendo que a liberação dessa citocina pelo extrato metanólico foi quase cinco vezes maior do que pelo extrato etanólico. Uma relação entre as sínteses de NO e TNF-alfa foi observada. O aumento na produção de NO está relacionado com a indução de citocinas pró-inflamatórias como TNF-alfa. Analisando os resultados, sugere-se que os extratos metanólico e etanólico de D. elliptica podem modular a ativação de macrófagos.
Plants have contributed in a significant way to the treatment of most of the diseases. Considering the therapeutic importance of the medicinal plants, the immunological activity of the methanolic and ethanolic extract of Davilla elliptica was evaluated. In every stage of the immune response macrophages are involved and they can release many compounds such as hydrogen peroxide (H2O2), nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha). Macrophages stimulation was evaluated by the determination of H2O2, NO and TNF-alpha in peritoneal macrophages cultures of mice in the presence of the D. elliptica extracts. IC50 was determined by MTT assay. The phytochemical study showed flavonoids derived from quercetin and myricetin and other compounds. The production of H2O2 was not very expressive in both extracts, but they presented a significant effect on NO production. The two extracts induced TNF-alpha production, although the methanolic liberated almost five times more TNF-alpha than the ethanolic one. A relationship among the synthesis of NO and TNF-alpha was observed. The increase of NO production is related with the induction of proinflammatory cytokines like TNF-alpha. Analyzing the results, it is suggested that methanolic and ethanolic extract of D. elliptica can modulate macrophage activation.
RESUMO
PURPOSE: Reports conflict on the relation of glucose metabolism to hippocampal volume in temporal lobe foci. Previous studies usually have used side-side ratios rather than regional metabolic rates. METHODS: We measured hippocampal volume and glucose metabolism in 37 patients with temporal epileptogenic zones identified by ictal video-EEG telemetry. Metabolic rates were normalized to global brain mean. RESULTS: Both 18-fluoro-2-deoxyglucose-PET and volumetric MRI lateralized the epileptic focus determined by ictal video-EEG. There were significant correlations between left-right metabolic asymmetry and hippocampal formation volume left-right ratios. Comparisons between normalized metabolism and hippocampal formation volume, ignoring the side of the epileptic focus, showed significant relations between left hippocampal volume and left inferior lateral temporal metabolism, right hippocampus and right inferior mesial temporal, and left hippocampus and left inferior mesial temporal metabolism. In contrast, when normalized metabolism was compared with hippocampal volume in the epileptic focus, no relation was found. CONCLUSIONS: Our study suggests that the relation between hippocampal volume and glucose metabolism breaks down in epileptic foci and that hypometabolism is not dependent on neuronal loss. It is consistent with data suggesting that hypometabolism is an independent predictor of surgical outcome.
Assuntos
Epilepsia do Lobo Temporal/diagnóstico , Glucose/metabolismo , Hipocampo/anatomia & histologia , Hipocampo/metabolismo , Lobo Temporal/fisiopatologia , Encéfalo/metabolismo , Eletroencefalografia/estatística & dados numéricos , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/fisiopatologia , Fluordesoxiglucose F18 , Lateralidade Funcional , Humanos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Probabilidade , Telemetria , Lobo Temporal/anatomia & histologia , Lobo Temporal/metabolismo , Tomografia Computadorizada de Emissão/estatística & dados numéricos , Resultado do Tratamento , Gravação de VideoteipeRESUMO
The presence of the 4977 bp deletion ('common deletion') in the mitochondrial DNA (mtDNA) is associated with defects in the metabolic machinery acquired during ageing as a hallmark of a degenerative phenotype. We analysed 27 samples (18 from surgical patients and nine from autopsy cases) of DNA extracted from smooth muscle cells of abdominal aorta fragments affected by atherosclerotic lesions. The deletion was detected by PCR amplification gel electrophoresis and characterized by sequencing of the PCR product. The mtDNA 'common deletion' was detected in all analysed samples. However, its levels were not particularly high, which may be ascribed to the fact that smooth muscle cells in atherosclerotic lesions have a lower energy requirement and an appreciable proliferation rate, as compared for instance with cardiac myocytes. When the subjects were divided into two numerically equivalent age classes (60-72 years plus a 45-year-old subject versus 73-95 years), the deletion had significantly higher levels in the older subjects. Conversely, its presence did not correlate with source (surgical or autoptic), sex, cigarettes consumption, other clinical and anamnestic parameters or with the levels of adducts and 8-hydroxy-2'-deoxyguanosine measured in the nuclear DNA of the same samples. A previously unreported deletion of 5111 bp was additionally found in the mtDNA from a 45-year-old woman. The origin of this lesion seems to be compatible with the slipped mispairing model proposed for the 'common deletion'.
Assuntos
Arteriosclerose/genética , DNA Mitocondrial/genética , Deleção de Sequência/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/química , Composição de Bases , DNA Mitocondrial/isolamento & purificação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores SexuaisRESUMO
Gerstmann-Sträussler-Scheinker disease (GSS), a cerebello-pyramidal syndrome associated with dementia and caused by mutations in the prion protein gene (PRNP), is phenotypically heterogeneous. The molecular mechanisms responsible for such heterogeneity are unknown. Since we hypothesize that prion protein (PrP) heterogeneity may be associated with clinico-pathologic heterogeneity, the aim of this study was to analyze PrP in several GSS variants. Among the pathologic phenotypes of GSS, we recognize those without and with marked spongiform degeneration. In the latter (i.e. a subset of GSS P102L patients) we observed 3 major proteinase-K resistant PrP (PrPres) isoforms of ca. 21-30 kDa, similar to those seen in Creutzfeldt-Jakob disease. In contrast, the 21-30 kDa isoforms were not prominent in GSS variants without spongiform changes, including GSS A117V, GSS D202N, GSS Q212P, GSS Q217R, and 2 cases of GSS P102L. This suggests that spongiform changes in GSS are related to the presence of high levels of these distinct 21-30 kDa isoforms. Variable amounts of smaller, distinct PrPres isoforms of ca. 7-15 kDa were seen in all GSS variants. This suggests that GSS is characterized by the presence PrP isoforms that can be partially cleaved to low molecular weight PrPres peptides.