RESUMO
BACKGROUND: Acne, a disease of the sebaceous gland with multifactorial pathogenesis, affects more than 85% of adolescents. A better deepening of the mechanisms underlying the disease is needed to define effective and mechanism-targeted treatments. OBJECTIVE: To understand whether the sebocyte differentiation process could be involved in the pathogenesis of the disease. METHODS: Protein expressions were evaluated by Western blot analysis and ELISA; mRNA levels by real-time RT-PCR, lipid analysis and lipid peroxidation were performed by gas chromatography, mass spectrometry and spectrophotometric assay. RESULTS: In vitro, low differentiated SZ95 sebocyte expressed an up-modulation of genes involved in sebogenesis and a higher level of insulin receptor respect to differentiated cells, resulting in an increased response to insulin and in the production of acne-like sebum. The induction of SZ95 sebocyte differentiation by the peroxisome proliferator-activated receptor γ (PPARγ) modulator NAC-GED0507 reduced the response to insulin normalizing the sebum production and decreasing the release of proinflammatory mediators. In vivo treatment of acne patients with NAC-GED0507 1% gel ameliorated clinical manifestations and induced in sebum the expression of PPARγ, associated with the decrease in mammalian target of rapamycin activation and levels of inflammatory molecules, confirming the results obtained in vitro. CONCLUSIONS: The study provides relevant insight into acne pathogenesis, identifying an alteration of sebocyte differentiation as pathogenetic basis of the disease and the induction of the differentiation process as a therapeutic target in acne therapy interfering with all pathogenic mechanisms.
Assuntos
Acne Vulgar , Acne Vulgar/tratamento farmacológico , Adolescente , Diferenciação Celular , Células Epiteliais , Humanos , Glândulas Sebáceas , SeboAssuntos
Diferenciação Celular , Queratinócitos , Pioglitazona , Vitiligo , Vitiligo/tratamento farmacológico , Humanos , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Queratinócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Inflamação/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Células CultivadasRESUMO
BACKGROUND AND AIMS: Alterations in epicardial adipose tissue (EAT) biology (i.e. increased fat thickness and inflammation) have been described in coronary artery disease (CAD) patients. In addition to its classic role in the regulation of calcium-phosphate homeostasis, vitamin D may exert immune-regulatory and anti-inflammatory effects. Whether EAT inflammation may be linked to vitamin D deficiency is still unknown. In the present study we evaluated plasma 25-hydroxycholecalciferol (25OHD) level in CAD patients and its relationship with EAT ability to locally metabolize vitamin D, EAT expression of inflammation-related molecules and EAT thickness. METHODS AND RESULTS: Plasma 25OHD level was quantified by an immunoluminometric assay. EAT expression of inflammation-related molecules (MCP-1, PTX3, TNFα, IL-6, adiponectin), vitamin D receptor (VDR), CYP27B1 (25OHD-activating enzyme) and CYP24A1 (1,25-dihydroxycholecalciferol-metabolizing enzyme) was performed by microarray. EAT thickness was quantified by echocardiography. Median plasma 25OHD level was 10.85 ng/mL and 83% of CAD patients displayed 25OHD level below 20 ng/mL. At decreasing plasma 25OHD concentration, we observed a down-regulation in CYP27B1 and CYP24A1 level and an increased expression of VDR and pro-inflammatory cytokines (MCP-1, PTX3, TNFα, IL-6) at EAT level. No correlation was observed between plasma 25OHD level and EAT thickness. CONCLUSION: Our data suggest an increased activation of inflammatory pathways at EAT level possibly related to systemic and local vitamin D deficiency in CAD patients. Whether maintaining an optimal vitamin D status may be helpful to reduce EAT inflammation and to prevent CAD and its progression needs further investigation.
Assuntos
Tecido Adiposo/fisiopatologia , Doença da Artéria Coronariana/fisiopatologia , Inflamação/fisiopatologia , Pericárdio/fisiopatologia , Deficiência de Vitamina D/fisiopatologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Índice de Massa Corporal , Peso Corporal , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Regulação para Baixo , Humanos , Inflamação/complicações , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Vitamina D3 24-Hidroxilase/genética , Vitamina D3 24-Hidroxilase/metabolismoRESUMO
BACKGROUND AND AIM: Growth Hormone Deficiency (GHD) is characterized by increased visceral fat accumulation. Echocardiographic epicardial fat thickness is a new marker of visceral adiposity. Aim of the present study was to evaluate whether epicardial fat thickness can significantly change and therefore serve as a marker of visceral fat reduction after short-term rhGH replacement therapy in patients with adult-onset GHD. METHODS AND RESULTS: Echocardiographic epicardial fat thickness was measured in 18 patients (10 M, 8 F, age 48 ± 11.8 yrs, BMI 29 ± 5.9 kg/m(2)) with adult-onset GHD, at baseline and after 6 and 12 months of rhGH therapy and in 18 healthy matched controls, at baseline. Echocardiographic epicardial fat thickness, conventional anthropometric and metabolic parameters, body fat percentage and quality of life were also evaluated. Epicardial fat thickness in adult GHD patients was higher than in controls (9.8 ± 2.8 vs 8 ± 3 mm, p < 0.05). Epicardial fat thickness significantly decreased after 6-months of rhGH replacement therapy (from 9.8 ± 2.8 to 7.0 ± 2.3 mm, P < 0.01, i.e. -29% from baseline). After 12 months of rhGH replacement therapy, epicardial fat thickness showed a further significant decrease (from 7.0 ± 2.3 to 5.9 ± 3.1 mm, P < 0.01, i.e. -40% from baseline). No significant changes in BMI or waist circumference after 6 or 12 months of rhGH therapy were observed. CONCLUSIONS: Echocardiographic epicardial fat thickness may represent a valuable and easy marker of visceral fat and visceral fat changes during rhGH replacement treatment in patients with adult-onset growth hormone deficiency.
Assuntos
Nanismo Hipofisário/tratamento farmacológico , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Pericárdio/metabolismo , Adiposidade , Adulto , Índice de Massa Corporal , Nanismo Hipofisário/complicações , Ecocardiografia , Feminino , Humanos , Fator de Crescimento Insulin-Like I/uso terapêutico , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico por imagem , Obesidade/tratamento farmacológico , Obesidade/etiologia , Qualidade de VidaRESUMO
BACKGROUND: Vitiligo skin shows different burning capacity in people with different phototype. In normal skin antioxidant status is correlated to skin phototype, but unexpectedly it appears that there is a gradual decrease in burning susceptibility of depigmented skin of individuals with increasing phototype (IIâVI). OBJECTIVE: To assess if the antioxidant response in the lesional vitiligo skin is involved in those protection mechanisms. Moreover, a possible correlation between cutaneous and systemic endogenous antioxidants in vitiligo patients has been investigated. METHODS: We enrolled in the study 29 patients with active vitiligo, divided into five groups according to skin type (II to VI). We analysed reduced and oxidized glutathione (GSH and GSSG, respectively), ubiquinone (CoQ10), catalase (Cat), superoxide dismutases (Cu/Zn-SOD and Mn-SOD), GSH peroxidase (GSH-Px), as indexes of chemical and enzymatic antioxidants, in suction blister roofs as well as in peripheral blood mononuclear cells (PBMNCs). RESULTS: The vitiligo patients showed an imbalance of antioxidant network, both in depigmented skin and PBMNCs. Interestingly, in vitiligo skin a phototype-related increase of antioxidant enzyme activities (Cat, Mn-SOD and GPx) and GSH amount have been observed. Similarly in PMBNCs Cat and total SOD activities, as well as GSH content progressively increased from skin type II to skin type VI. Endogenous antioxidants in vitiligo skin are correlated to those in PBMNCs, suggesting that systemic and epidermal antioxidant network functionalities are connected. CONCLUSIONS: The correlation between antioxidant levels and clinical phototype confirmed the hypothesis that other factors than melanin determine largely the minimal erythema dose values in vitiligo lesional skin.
Assuntos
Antioxidantes/metabolismo , Vitiligo/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Superóxido Dismutase/metabolismo , Ubiquinona/metabolismo , Vitiligo/enzimologiaRESUMO
BACKGROUND: Cutaneous pigmentation is regulated by a complex melanogenic network in which both keratinocytes and fibroblasts synthesize growth factors and cytokines. Solar lentigo (SL) is characterized by hyperpigmented lesions occurring on photodamaged skin areas. Despite the association of SL to ultraviolet (UV) exposure, the mechanisms underlying the development of these spots are not completely defined. OBJECTIVES: To analyse the involvement of the fibroblast-derived growth factors, hepatocyte growth factor (HGF), keratinocyte growth factor (KGF) and stem cell factor (SCF) in SL hyperpigmentation; to evaluate whether the photoageing process occurring in fibroblasts could be responsible for the altered expression of these cytokines; and to investigate a new possible role of KGF in regulating pigmentation through the specific induction of melanogenic cytokines by keratinocytes. METHODS: We performed immunohistochemical analysis of HGF, KGF and SCF on SL biopsies. We analysed the mRNA expression of these cytokines using an in vitro model of photoageing induced on fibroblasts. Finally, we evaluated the effects of KGF on the expression of melanogenic cytokines at the mRNA and protein levels on keratinocytes. RESULTS: We found positive staining for HGF, KGF and SCF in the upper dermis of SL lesions and a significant induction of the three cytokines in photoaged fibroblasts. We also demonstrated the contribution of KGF to pigmentation, showing its ability specifically to modulate the expression of SCF in keratinocytes. CONCLUSIONS: Fibroblasts may be persistently activated by UV exposure to release melanogenic growth factors; this inducible cytokine network acts both directly and indirectly through keratinocytes and may contribute to the hyperpigmentation of SL.
Assuntos
Fator 7 de Crescimento de Fibroblastos/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Hiperpigmentação/metabolismo , Lentigo/metabolismo , Fator de Células-Tronco/metabolismo , Luz Solar/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Biópsia , Western Blotting , Feminino , Humanos , Hiperpigmentação/etiologia , Imuno-Histoquímica , Lentigo/etiologia , Masculino , Pessoa de Meia-Idade , Transtornos de Fotossensibilidade/metabolismo , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/metabolismo , Envelhecimento da Pele/fisiologiaRESUMO
OBJECTIVE: Thyroid ultrasound is crucial for clinical decision in the management of thyroid nodules. In this study, we aimed to estimate and compare the performance of ATA, AACE/ACE/AME and ACR TI-RADS ultrasound classifications in discriminating nodules with high-risk cytology. DESIGN: Cross-sectional study. METHODS: 1077 thyroid nodules undergoing fine-needle aspiration were classified according to ATA, AACE/ACE/AME and ACR TI-RADS ultrasound classifications by an automated algorithm. Odds ratios (ORs) and receiver operating characteristic (ROC) curves for high-risk cytology categories (TIR3b, TIR4 and TIR5) were calculated for the different US categories and compared. RESULTS: Cytological categories of risk increased together with all US classifications' sonographic patterns (P < 0.001). The diagnostic performance (C-index) of ACR TI-RADS and AACE/ACE/AME significantly improved when adding clinical data as gender and age in the regression model (P < 0.001). A significant difference in the final model C-index between the three US classification systems was found (P < 0.029), with the ACR TI-RADS showing the highest nominal C-index value, significantly superior to ATA (P = 0.008), but similar to AACE/ACE/AME (P = 0.287). ATA classification was not able to classify 54 nodules, which showed a significant 7 times higher risk of high-risk cytology than the 'very low suspicion' nodules (OR: 7.20 (95% confidence interval: 2.44-21.24), P < 0.001). CONCLUSIONS: The ACR TI-RADS classification system has the highest area under the ROC curve for the identification of cytological high-risk nodules. ATA classification leaves 'unclassified' nodules at relatively high risk of malignancy.
Assuntos
Nódulo da Glândula Tireoide/classificação , Nódulo da Glândula Tireoide/diagnóstico por imagem , Ultrassonografia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores de Risco , Sensibilidade e Especificidade , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/patologia , Estados UnidosRESUMO
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) controls the expression of genes involved in the regulation of lipid and glucose metabolism, cell proliferation/differentiation as well as inflammatory pathways. Pivotal studies in human sebocytes and isolated sebaceous glands have raised the interesting possibility that compounds acting on PPARγ can modulate sebaceous lipids and inflammation and, as such, may be useful in the treatment of acne. To investigate the role of this receptor in the regulation of lipid synthesis, proliferation and inflammation, we used the SZ95 sebaceous gland cell line stimulated with insulin. In sebocytes, insulin signaling activated the phosphatidylinositide 3-kinase-Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) pathways, which, in turn, induced high protein/lipid synthesis, increased cell growth and proliferation as well as inflammation. As regards lipogenesis, insulin initially stimulated the formation of unsaturated lipids and then the neosynthesis of lipids. The results showed, that the modulation of PPARγ, counteracted the insulin-induced altered lipogenesis, evident through a decrease in gene expression of key enzymes responsible for the synthesis of fatty acids, and through a reduction of lipid species synthesis analyzed by Oil/Nile Red staining and GC-MS. PPARγ modulation also regulated the insulin-induced proliferation, inhibiting the cell cycle progression and p21WAF1/CIP1 (p21) protein reduction. Moreover, the expression of inflammatory cytokines, induced by insulin or lipopolysaccharide (LPS), was down-modulated. In PPARγ-deficient cells or in the presence of GW9662 antagonist, all these observed effects were abolished, indicating that PPARγ activation plays a role in regulating alteration of lipogenesis, cell proliferation and inflammatory signaling. We demonstrated that selective modulation of PPARγ activity is likely to represent a therapeutic strategy for the treatment of acne.
Assuntos
Regulação da Expressão Gênica , Lipogênese , PPAR gama/metabolismo , Glândulas Sebáceas/metabolismo , Sebo/metabolismo , Transdução de Sinais , Acetanilidas/efeitos adversos , Acetanilidas/farmacologia , Anilidas/efeitos adversos , Anilidas/farmacologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/agonistas , Citocinas/metabolismo , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Antagonistas da Insulina/efeitos adversos , Antagonistas da Insulina/farmacologia , Lipogênese/efeitos dos fármacos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , PPAR gama/genética , Fenilpropionatos/efeitos adversos , Fenilpropionatos/farmacologia , Interferência de RNA , Glândulas Sebáceas/citologia , Glândulas Sebáceas/efeitos dos fármacos , Glândulas Sebáceas/imunologia , Sebo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
The oxidation of (5Z,8Z,11Z,13E,15S)-15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-(S)-HETE, 1a) with the Fenton reagent (Fe2+/EDTA/H2O2) was investigated. In phosphate buffer, pH 7.4, the reaction proceeded with 75% substrate consumption after 1 h to give a mixture of products, one of which was identified as (2E,4S)-4-hydroxy-2-nonenal (3a, 18% yield). Methylation of the mixture with diazomethane allowed isolation of another main product which could be identified as methyl (5Z,8Z,13E)-11,12-trans-epoxy-15-hydroxy-5,8,13-eicosatrienoate (2a methyl ester, 8% yield). A similar oxidation carried out on (15-(2)H)-15-HETE (1b) indicated complete retention of the label in 2b methyl ester and 3b, consistent with an oxidation pathway involving as the primary event H-atom abstraction at C-10. Overall, these results support the recently proposed role of 1a as a potential precursor of the cytotoxic gamma-hydroxyalkenal 3a and disclose a hitherto unrecognized interconnection between 1a and the epoxy-alcohol 2a, previously implicated only in the metabolic transformations of the 15-hydroperoxy derivative of arachidonic acid.
Assuntos
Aldeídos/química , Compostos de Epóxi/química , Ácidos Graxos Ômega-3/química , Peróxido de Hidrogênio/química , Ácidos Hidroxieicosatetraenoicos/química , Ferro/química , Aldeídos/toxicidade , Reagentes de Ligações Cruzadas/química , Reagentes de Ligações Cruzadas/toxicidade , Deutério/química , Radicais Livres/química , Concentração de Íons de Hidrogênio , Marcação por Isótopo , Peroxidação de Lipídeos , Espectroscopia de Ressonância Magnética , Metilação , Modelos Químicos , Oxirredução , EstereoisomerismoRESUMO
Several hypotheses have been made about the pathogenesis of vitiligo, and some of them have considered a systemic involvement in the course of the disease. Evidence has been presented on the role of oxidative stress as the initial event in melanocyte degeneration. In accordance with this view, we determined the levels of some antioxidants, i.e., superoxide dismutase, catalase, reduced glutathione, and vitamin E, in erythrocytes and/or peripheral blood mononuclear cells from patients with active or stable vitiligo and from a control group of healthy subjects. In erythrocytes the parameters evaluated were not significantly different. On the contrary, in peripheral blood mononuclear cells, superoxide dismutase activity was increased in both groups of patients, whereas catalase activity, reduced glutathione and vitamin E levels were decreased exclusively in subjects with active disease. The imbalance of antioxidants was associated with hyperproduction of reactive oxygen species due to a mitochondrial impairment as cyclosporin A, an inhibitor of the permeability transition pores opening, significantly reduced the reactive oxygen species production. Moreover an alteration of the mitochondrial transmembrane potential and a higher percentage of apoptotic cells were observed in active vitiligo patients. Based on these results, we suggest that, in vitiligo, mitochondria might be the target of different stimuli, such as reactive oxygen species generation, cytokines production, catecholamine release, alteration of Ca2+ metabolism, all of which capable of inducing melanocyte degeneration.
Assuntos
Mitocôndrias/fisiologia , Monócitos/fisiologia , Vitiligo/fisiopatologia , Adulto , Apoptose , Feminino , Humanos , Masculino , Potenciais da Membrana , Pessoa de Meia-Idade , Oxirredutases/sangue , Espécies Reativas de Oxigênio/sangue , Vitiligo/sangueRESUMO
OBJECTIVE: To evaluate the clinical significance of a second-trimester elevated maternal serum hCG in women carrying singleton, chromosomally normal fetuses. METHODS: The results of second-trimester maternal serum screening (alpha-fetoprotein [MSAFP], hCG, and unconjugated estriol) for 25,438 women were reviewed, and those with hCG values exceeding 3.0 multiples of the median (MoM) were identified. A control population was selected only on the basis of samples accessioned by the laboratory at the same time as the study group. Follow-up information was collected from physicians' offices for both groups. Incidence of fetal or neonatal loss (spontaneous abortion, fetal death, and neonatal death combined), preterm birth (before 37 weeks' gestation), small for gestational age, and preeclampsia were compared. RESULTS: Three hundred twenty-two women (1.3%) had hCG levels exceeding 3.0 MoM. In addition to chromosomal abnormalities and fetal death at the time of testing, this group showed a significantly higher incidence of fetal or neonatal death, preterm birth, low birth weight, and preeclampsia than did controls. For patients with elevated second-trimester hCG, many of the preterm deliveries occurred before 34 weeks' gestation. Logistic regression analysis indicated that hCG, MSAFP, and race were significant independent factors in predicting risk for adverse outcome. CONCLUSIONS: Similar to elevated AFP, elevated hCG is associated with poor pregnancy outcome. By combining the results of the two tests, it may be possible to improve substantially the identification of patients at very high risk for adverse outcomes.
Assuntos
Gonadotropina Coriônica/sangue , Resultado da Gravidez , alfa-Fetoproteínas/análise , Adulto , Feminino , Seguimentos , Humanos , Modelos Logísticos , Gravidez , Complicações na Gravidez/sangue , Segundo Trimestre da GravidezRESUMO
About 10 patients admitted with acute pancreatitis were also, found to have Fredrikson type V hyperlipoproteinaemia. Eight were males aged less than 45 yr. Awareness of the aetiopathogenetic and metabolic aspects of this increasingly common association and its clinical identification form the sine qua non in the prevention of recurrences via marked dietary restriction of fats.
Assuntos
Hiperlipidemias/etiologia , Pancreatite/complicações , Doença Aguda , Adulto , Feminino , Humanos , Hiperlipidemias/prevenção & controle , Masculino , Pessoa de Meia-IdadeRESUMO
New topical immunomodulators have been reported to cause repigmentation of vitiligo lesions. However, time-kinetics of such repigmentation in different anatomic locations is not well known. We performed a randomized double-blind placebo control study with tacrolimus versus the vehicle and a nonrandomized control study with pimecrolimus to evaluate the time to reach significant pigmentation, its duration and extent in treated areas. Antioxidant status of serum was also assessed. Twenty patients, in the tacrolimus study, had one pair of lesions on different localizations, and 20 on face and/or upper limbs for pimecrolimus. The extent of repigmentation was evaluated by slides and mapmakings at baseline and every 4 weeks during 7 months. Adverse events were recorded. The derivatives of oxygen metabolites, the ferric reducing ability of serum and vitamin E were assessed. Three groups of patients were identified with the tacrolimus study. Eight had no significant change in response characterized by a parallel increase of repigmentation or none in treated and control areas. Nine had a better repigmentation to tacrolimus at fifth month of treatment. Three had a marked repigmentation in control areas at the end of treatment. Repigmentation was significant on the face compared to upper-limbs with pimecrolimus from fourth to seventh month. A significant reduction of oxidative stress and an increase in antioxidant capacity in serum of patients treated with topical tacrolimus was observed, while those treated with pimecrolimus did not show any significant changes but an increase in vitamin E. Our work defines three periods in repigmentation, triggering during the first 4 months, increase in pigmentation with tacrolimus and a plateau or a sustained repigmentation. The continuity of the treatment seems necessary to ensure a prolonged repigmenting effect and even an enhanced one, such as the one we observed on the face with pimecrolimus. The extent of repigmentation was more significant on the face compared to other locations probably due to differences in melanocyte density. Furthermore, we did not find any relationship between repigmentation and the duration of vitiligo. Tacrolimus was able to reduce the systemic oxidative stress independently from its repigmenting capacity. Both drugs were well tolerated.
Assuntos
Pigmentação da Pele/efeitos dos fármacos , Tacrolimo/análogos & derivados , Tacrolimo/uso terapêutico , Vitiligo/tratamento farmacológico , Adolescente , Adulto , Idoso , Antioxidantes/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Tacrolimo/efeitos adversos , Vitiligo/metabolismoRESUMO
Due to its interface function between the body and the environment, the skin is chronically exposed to both endogenous and environmental pro-oxidant agents, leading to the harmful generation of reactive oxygen species (ROS). There is compelling evidence that oxidative stress is involved in the damage of cellular constituents, such as DNA, cell membrane lipids or proteins. To protect the skin against the over-load of oxidant species, it contains a well-organised system of both chemical and enzymatic antioxidant which are able to work in a synergistic manner. Skin antioxidant network protects cells against oxidative injury and prevent the production of oxidation products, such as 4-hydroxy-2-nonenal or malonaldehyde, which are able to induce protein damage, apoptosis or release of pro-inflammatory mediators, such as cytokines. When oxidative stress overwhelms the skin antioxidant capacity the subsequent modification of cellular redox apparatus leads to an alteration of cell homeostasis and a generation of degenerative processes. Topical application or oral administration of antioxidants has been recently suggested as preventive therapy for skin photoaging and UV-induced cancer. The recognition that ROS can act as second messengers in the induction of several biological responses, such as the activation of NF-kB or AP-1, the generation of cytokines, the modulation of signalling pathways, etc., has led many researchers to focus on the possible effects of antioxidants in many pathological processes. The recent demonstration that the peroxisome proliferators-activated receptors, whose natural ligands are polyunsaturated fatty acids and theirs oxidation products, have a central role in the induction of some skin diseases, such as psoriasis or acne, has indicated new links between free radicals and skin inflammation. Based on these findings, the review summarises the possible correlations between antioxidant imbalance, lipid oxidative breakage and skin diseases, from both a pathological and therapeutic points of view.
Assuntos
Antioxidantes/uso terapêutico , Peroxidação de Lipídeos/fisiologia , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/efeitos adversos , Dermatopatias/tratamento farmacológico , Dermatopatias/etiologia , Acne Vulgar/tratamento farmacológico , Acne Vulgar/etiologia , Acne Vulgar/patologia , Doença Crônica , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/etiologia , Dermatite Atópica/patologia , Feminino , Humanos , Masculino , Prognóstico , Psoríase/tratamento farmacológico , Psoríase/etiologia , Psoríase/patologia , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Dermatopatias/patologiaRESUMO
OBJECTIVE: Our goal was to determine whether gestational age should be based on ultrasonographic evaluation or last menstrual period data in the interpretation of second-trimester maternal serum screening for Down syndrome and open neural tube defects. STUDY DESIGN: Initial and revised screen-positive rates and detection rates were reviewed for women undergoing triple-marker testing (maternal serum alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol). The study population consisted of > 24,000 women at 15.0 to 21.9 weeks' gestation with approximately 60% of test interpretations based on ultrasonographic evaluation of gestational age. Gestational age and screening results were compared for 24 Down syndrome pregnancies in which both ultrasonography and last menstrual period dating were available. RESULTS: Both initial and revised screen-positive rates for Down syndrome were significantly lower when ultrasonographic data were used compared with last menstrual period dating. The detection rate for Down syndrome appeared to be higher with ultrasonographic dating (approximately 76% vs 60% for last menstrual period dating). Down syndrome fetuses had a significantly shorter gestational age when evaluated by ultrasonography (relative to last menstrual period dating), but a similar trend was also seen in control pregnancies. Initial and revised screen-positive rates for open neural tube defects were higher for women who had received an ultrasonographic examination compared with the rates for those women referred with only last menstrual period data. The detection rates for open neural tube defects were similar for both methods of pregnancy dating. CONCLUSION: By use of ultrasonographic measurement of gestational age, the number of amniocenteses performed to detect Down syndrome can be substantially reduced while detection rates are maintained or improved.
Assuntos
Síndrome de Down/diagnóstico , Idade Gestacional , Defeitos do Tubo Neural/diagnóstico , Diagnóstico Pré-Natal , Ultrassonografia Pré-Natal , Adulto , Gonadotropina Coriônica/sangue , Síndrome de Down/sangue , Estriol/sangue , Feminino , Humanos , Programas de Rastreamento , Menstruação , Defeitos do Tubo Neural/sangue , Gravidez , alfa-Fetoproteínas/análiseRESUMO
We developed a sensitive and specific liquid chromatography-electrospray mass spectrometric (HPLC-ESI-MS) assay for the simultaneous determination of reduced and oxidized glutathione (GSH and GSSG) in peripheral blood mononuclear cells (PBMC). Following derivatization with N-ethylmaleimide to prevent GSH auto-oxidation, addition of thiosalicylic acid as internal standard, and protein precipitation with cold acetonitrile, the samples were injected into a diol column, eluted with acetonitrile-1% aqueous acetic acid (25:75) and detected by the ESI-MS system. The optimized method exhibited a good detection limit for both analytes (0.01 and 0.05 microM for GSH and GSSG, respectively). Good linearity was reached in the 0.01-20 microM range for GSH and 0.05-20 microM for GSSG. The mean recoveries of GSH and GSSG were 98.5-100.6% and 105.8-111.5%, respectively. The run-to-run repeatability for retention time and peak area was RSD% 0.06 and 1.75 for GSH and 0.18 and 2.50 for GSSG. The optimized method was applied to GSH and GSSG assay in PBMC analyzing 20 healthy individuals.
Assuntos
Cromatografia Líquida/métodos , Glutationa/sangue , Monócitos/metabolismo , Espectrometria de Massas por Ionização por Electrospray/métodos , Etilmaleimida/química , Glutationa/química , Humanos , Oxirredução , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Our purpose was to determine the incidence of all types of chromosome abnormalities (i.e., trisomy 21 and other abnormalities) in women receiving prenatal chromosome analysis after a Down syndrome screen-positive result by maternal serum triple-marker testing (alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol analyses). STUDY DESIGN: A total of 11,434 patients between 15.0 and 21.9 weeks' gestation received second-trimester Down syndrome risk evaluation by triple-marker testing. By use of a 1:270 midtrimester Down syndrome risk cutoff value, and after ultrasonographic confirmation of gestational age, 677 patients were screen positive for Down syndrome (corrected screen-positive rate 5.92%). Karyotypes were reviewed for 468 (69%) of these patients who received prenatal chromosome analysis. RESULTS: In addition to 12 cases of Down syndrome, 12 other fetal chromosome abnormalities were found (i.e., 5.13% had a chromosome abnormality of some type). Expressed as a proportion of all patients with a corrected Down syndrome screen-positive result, at least 3.69% had a chromosome abnormality. The overall spectrum of abnormal karyotypes (approximately 50% autosomal trisomy, 25% structural and 25% sex chromosome abnormality) appears to be comparable to that seen in patients undergoing amniocentesis because of advanced maternal age. CONCLUSIONS: As is the case for women of advanced maternal age, preamniocentesis counseling for patients with positive triple-marker testing results should reflect the relatively high probability that an abnormality other than Down syndrome may be identified.
Assuntos
Aberrações Cromossômicas/diagnóstico , Síndrome de Down/diagnóstico , Diagnóstico Pré-Natal , Adulto , Gonadotropina Coriônica/sangue , Transtornos Cromossômicos , Estriol/sangue , Feminino , Doenças Fetais/diagnóstico , Idade Gestacional , Humanos , Cariotipagem , Idade Materna , Gravidez , Segundo Trimestre da Gravidez , Fatores de Risco , Ultrassonografia Pré-Natal , alfa-Fetoproteínas/análiseRESUMO
One of the goals of antifungal therapy is to combine an anti-inflammatory activity with antimycotic properties, and therefore it is interesting to evaluate the capacity of active antifungal drugs to interfere with different phases of the inflammatory reaction. In order to identify a possible scavenger property of free radical species of the antifungal agent terbinafine, we studied its activity on the reduction of nitrotetrazolium blue chloride (NTB), induced by superoxide anions with the ultraviolet (UV)- and chemical-induced peroxidation of unsaturated lipid targets. NTB reduction was followed by spectrophotometer and the decomposition of squalene or methyl arachidonate by gas chromatography-mass spectrometry. Terbinafine (20 microgram and over) was capable of significantly inhibiting NTB reduction, indicating that the drug scavenges superoxide anion radicals. In these conditions no modifications of the concentration of the drug, as evaluated by high performance liquid chromatography, were observed. The UV- or chemically induced peroxidation of squalene and arachidonic acid was significantly reduced in the presence of 50 microgram of terbinafine, suggesting that the substance interferes with the chemical properties of peroxyl radicals. In all the tests used the degree of inhibition was proportional to the amount of free radicals generated. In conclusion our results indicate that terbinafine, at therapeutic concentrations, can be considered to be a free radical interceptor in vitro and could exert a mild anti-inflammatory activity in vivo.
Assuntos
Alilamina/farmacologia , Antifúngicos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Naftalenos/farmacologia , Nitroazul de Tetrazólio/química , Superóxidos/química , Anti-Inflamatórios/farmacologia , Relação Dose-Resposta a Droga , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos da radiação , Oxirredução , TerbinafinaRESUMO
The pathogenesis of the physical urticarias has not been completely defined. Indeed, different stimuli can induce similar clinical manifestations, some of which are capable of generating reactive oxygen species. In order to evaluate whether the generation of an oxidative stress response could be a common pathogenetic mechanism of the disease, we have determined the profile of a number of chemical and enzymatic antioxidants in blood samples from a group of patients with physical urticarias. Compared with controls, a systemic imbalance of the antioxidants was detected in the patient group with a decrease of both plasma vitamin E and cellular catalase and glutathione peroxidase activities along with an increase of superoxide dismutase activity. Moreover, an increase in the percentage of plasma polyunsaturated fatty acids, as a target for peroxidative damage, was also observed. These alterations may lead to an increased percentage of peroxidable compounds in skin and to the intracellular generation of reactive oxygen species and could therefore provide one possible explanation for the patients' urticarial response to stimuli. Even if the alteration of the antioxidant status is secondary to changes in cytokine or complement activation, our results suggest a common biochemical profile in patients with different forms of physical urticaria.
Assuntos
Estresse Oxidativo/fisiologia , Urticária/fisiopatologia , Adulto , Antioxidantes/análise , Eritrócitos/enzimologia , Feminino , Humanos , Leucócitos Mononucleares/enzimologia , Masculino , Urticária/sangueRESUMO
In a series of 39 subjects previous results for serum folate levels were confirmed while intraglobular folate did not differ from those in a control group. To verify the hypothesis that SASP administration could be responsible for serum folate deficiency three different sub-groups were considered. 11 patients had never taken SASP (sub-group I), 16 patients had taken SASP in the past but the treatment had been withheld at least 2 months before (sub-group II), 12 patients were still taking the drug at the time of the study (sub-group III). Differences in serum folate levels between each one of the three sub-groups and the control group were significant. The same was not true for the differences between each one of the three sub-groups and the other. These findings seem to confirm that SASP treatment is not the major cause of serum folate deficiency, but a multifactorial pathogenesis might account for it.