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BACKGROUND: Hyaluronic acid dermal fillers are used for multiple indications including wrinkle correction and restoration of volume/fullness. OBJECTIVES: To compare the efficacy and safety of two hyaluronic acid products for correcting moderate to severe nasolabial folds. METHODS: A prospective randomized double-blind split-face study. Subjects' left and right NLF were randomized for treatment with DKL23 and Juvéderm Volift. Follow-up was conducted at 1, 3, 6, and 9 months. The changes from baseline in wrinkle severity rating scale (WSRS) and Global Aesthetics Improvement Scale (GAIS) were evaluated. Post-treatment adverse events (AEs) were recorded. RESULTS: Forty-eight women (median age, 57.0 years) with skin type I-VI were enrolled. Both treatments showed statistically significant improvement (p<0.0001) in NLFs according to WSRS score from baseline to each of the timepoints assessed. The improvement in NLFs was maintained until the end of the study (9 months). Furthermore, the change from baseline to each of the timepoints assessed was similar between DKL23 and Juvéderm Volift. Investigator- and subject-rated GAIS showed similar rates of improvement (indicated by the sum of responses of improved, much or very much improved) between the 2 products. AEs reported in the study were in line with prior and expected experience after injection of hyaluronic acid dermal fillers. The types of AEs, their rates, intensity and duration were comparable between the 2 products. CONCLUSIONS: DKL23 improved NLF severity from baseline and up to 9 months with comparable improvement to that shown by Juvéderm Volift. Treatment was safe and well tolerated.
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BACKGROUND: Post-traumatic elbow stiffness (PTES) may substantially affect the patient's functional range of motion and quality of life. Open elbow release has been extensively studied, but arthroscopic techniques are limited, particularly in differentiating between post-traumatic and non-traumatic stiffness. The purpose of this study is to assess the clinical outcomes after arthroscopic release of PTES regarding the range of motion (ROM), pain, functional assessment, and complications. METHODS: A prospective cohort was conducted on adult patients who underwent arthroscopic arthrolysis for PTES, with 32 patients included in the final analysis. The ROM was measured using the orthopedic goniometer. Grip strength was measured using the Camry digital hand dynamometer (Camry, CA, USA) and compared to their contralateral side. The functional status of the patients was evaluated using the American Shoulder and Elbow Surgeons Score (ASES)andthe Mayo Elbow Performance Index (MEPI). All measurements were done before surgery and at the last follow-up visit. Pre-operative and post-operative changes in MEPI, ASES, and visual analog (VAS) scores were compared with the paired t-test. RESULTS: After surgery, the ROM significantly improved from 74 ± 11 to 110 ± 15 degrees (p<0.001). Additionally, the ASES score and MEPI index both significantly improved from 69 ± 3.4 to 79 ± 6.3 and from 64 ± 5.7 to 82 ± 8, respectively (p<0.001). VAS scores also significantly improved from 1.1 ± 0.87 to 0.31 ± 0.53 at rest (p<0.001). The complication rate was 12%, including three transient ulnar nerve paresthesia and one superficial infection. Post-traumatic elbow release was more offered in distal humerus fractures (53%), followed by proximal ulna fracture/dislocations (25%). CONCLUSION: We believe that arthroscopic arthrolysis is a safe and reliable treatment of PTES, which improves joint visibility and reduces pain. Patients can be counseled regarding the risk of a secondary surgery following distal humerus or proximal ulna fractures, including the expected recovery and complication rate.
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Aesthetic use of low doses of Botulinum toxin (BoNT) injections into the facial muscles has become a leading non-surgical aesthetic treatment worldwide to reduce facial wrinkles, including glabellar lines, forehead lines, and periorbital wrinkles. Within these aesthetic applications, BoNT injections intend to reduce and prevent wrinkles, and the recommended usage of 2â¯years is often exceeded, which may result in atrophy of the injected muscles. The long-term effects of BoNT injections in the facial muscles and the evidence of diffusion of BoNT to surrounding muscles are obvious pitfalls and challenges for clinical neurophysiologists in differential diagnosing neuromuscular transmission failures. Also, this is further complicated by the risk of developing side effects upon permanent chemical denervation of facial muscles, with less possibility for reinnervation. This review summarizes the known long-term effects of BoNT over time in different facial muscles and the use of objective electrophysiological measures to evaluate these. A better understanding of the long-term effects of BoNT is essential to avoid misdiagnosing other neuromuscular disorders.
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Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.
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Autoantígenos/sangue , Síndromes Paraneoplásicas/imunologia , Pênfigo/imunologia , Transglutaminases/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Paraneoplásicas/sangue , Pênfigo/sangue , Adulto JovemRESUMO
Antibiotic-induced microbial imbalance, or dysbiosis, has systemic and long-lasting effects on the host and response to cancer therapies. However, the effects on tumor endothelial cells are largely unknown. Therefore, the goal of the current study was to generate matched B16-F10 melanoma associated endothelial cell lines isolated from mice with and without antibiotic-induced dysbiosis. After validating endothelial cell markers on a genomic and proteomic level, functional angiogenesis assays (i.e., migration and tube formation) also confirmed their vasculature origin. Subsequently, we found that tumor endothelial cells derived from dysbiotic mice (TEC-Dys) were more sensitive to ionizing radiotherapy in the range of clinically-relevant hypofractionated doses, as compared to tumor endothelial cells derived from orthobiotic mice (TEC-Ortho). In order to identify tumor vasculature-associated drug targets during dysbiosis, we used tandem mass tag mass spectroscopy and focused on the statistically significant cellular membrane proteins overexpressed in TEC-Dys. By these criteria c-Met was the most differentially expressed protein, which was validated histologically by comparing tumors with or without dysbiosis. Moreover, in vitro, c-Met inhibitors Foretinib, Crizotinib and Cabozantinib were significantly more effective against TEC-Dys than TEC-Ortho. In vivo, Foretinib inhibited tumor growth to a greater extent during dysbiosis as compared to orthobiotic conditions. Thus, we surmise that tumor response in dysbiotic patients may be greatly improved by targeting dysbiosis-induced pathways, such as c-Met, distinct from the many targets suppressed due to dysbiosis.
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Disbiose , Células Endoteliais/enzimologia , Melanoma Experimental , Neovascularização Patológica , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met , Animais , Disbiose/enzimologia , Disbiose/microbiologia , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/enzimologia , Melanoma Experimental/microbiologia , Melanoma Experimental/terapia , Camundongos , Neovascularização Patológica/enzimologia , Neovascularização Patológica/microbiologia , Neovascularização Patológica/terapia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , RadioterapiaRESUMO
Carbon-based nanomaterials (CBNs) were previously described as regulators of plant cell division. Here, we demonstrated the ability of multi-walled carbon nanotubes (MWCNT) and graphene to enhance biomass production in callus culture of the medicinal plant Catharanthus roseus cultivated in dark conditions. Furthermore, both tested CBNs were able to stimulate biosynthesis of total produced alkaloids in CBN-exposed callus culture of Catharanthus. In one case, total alkaloids in CBN-exposed Catharanthus were double that of unexposed Catharanthus. Analysis of metabolites by HPLC revealed that production of the pharmaceutically active alkaloids vinblastine and vincristine was dramatically enhanced in callus exposed to MWCNT or graphene in both dark and light conditions of callus cultivation. In vitro assays (MTT, flow cytometry) demonstrated that total alkaloid extracts derived from Catharanthus callus treated with CBNs significantly reduced cell proliferation of breast cancer (MCF-7) and lung cancer (A549) cell lines compared to the application of extracts derived from untreated Catharanthus callus.
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Alcaloides/biossíntese , Alcaloides/farmacologia , Catharanthus/química , Catharanthus/crescimento & desenvolvimento , Nanotubos de Carbono/química , Células A549 , Catharanthus/efeitos dos fármacos , Técnicas de Cultura de Células , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Grafite/farmacologia , Humanos , Células MCF-7 , Necrose , Extratos Vegetais/farmacologia , Vimblastina/farmacologiaRESUMO
BACKGROUND: Allergic and non-allergic asthma are viewed as separate entities, despite sharing similarities. The aims of this study were to determine differences in symptoms from the upper airways and the skin in allergic and non-allergic asthma. The secondary aims were to identify childhood risk factors and to compare quality of life in the two asthma groups. METHODS: This cohort (age 17-76 years) consisted of 575 subjects with allergic or non-allergic asthma and 219 controls. The participants participated in an interview, spirometry, FeNO, skin prick test, and responded to the Mini Asthma Quality of Life Questionnaire. RESULTS: Self-reported allergic rhinitis was significantly more common in both allergic and non-allergic asthma (82.3 and 40.7%) groups compared with the controls. The prevalence of chronic rhinosinusitis (CRS) was similar in both asthma groups. Eczema was significantly more common in both asthmatic groups (72.3 and 59.8%) than controls (47.0%) (p < 0.001 and p = 0.012). Severe respiratory infection in childhood and parental allergy were risk factors for both allergic and non-allergic asthma groups. Quality of life was significantly lower in non-allergic than allergic asthma groups (p = 0.01). CONCLUSION: Concomitant symptoms from the upper airways and the skin were significantly more common in both allergic and non-allergic asthma. This indicates that non-allergic asthma has a systemic component with similarities to what is found in allergic asthma. There were similarities in the childhood risk factor pattern between the two types of asthma but asthma-related quality of life was lower in the non-allergic asthma group.
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Asma/epidemiologia , Eczema/epidemiologia , Exantema/epidemiologia , Adulto , Asma/diagnóstico , Asma/metabolismo , Asma/fisiopatologia , Testes Respiratórios , Eczema/diagnóstico , Eczema/metabolismo , Eczema/fisiopatologia , Exantema/diagnóstico , Exantema/metabolismo , Exantema/fisiopatologia , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Pais , Qualidade de Vida , Testes Cutâneos , Espirometria , Inquéritos e Questionários , SuéciaRESUMO
Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1. Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease. Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE. Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure. Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.
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Doença de Addison/diagnóstico , Autoanticorpos/sangue , Biomarcadores/sangue , Citocinas/imunologia , Programas de Rastreamento , Poliendocrinopatias Autoimunes/diagnóstico , Sistema de Registros , Doença de Addison/sangue , Doença de Addison/imunologia , Autoanticorpos/imunologia , Estudos de Casos e Controles , Seguimentos , Humanos , Poliendocrinopatias Autoimunes/sangue , Poliendocrinopatias Autoimunes/imunologia , Prognóstico , SuéciaRESUMO
Botulinum toxin (BoNT) injections into facial and bulbar muscles are widely and increasingly used as medical treatments for cervical and facial dystonia, facial hemispasm, correction of facial palsy, hyperhidrosis, as well as cosmetic treatment of glabellar lines associated with grief and anger. Although BoNT treatment is generally considered safe, the diffusion of the toxin to surrounding muscles may result in complications, including difficulties swallowing, in a dose-dependent manner. The sensitivity of clinical examination for detecting adverse events after BoNT treatment is limited. Few reports have highlighted the potential effects on other muscles in the facial area due to the spreading of the toxin. The possibilities of spreading and thus unknown pharmacological BoNT effects in non-targeted muscles emphasise the importance of correct administration of BoNT in terms of dose selection, injection points, and appropriate effect surveillance. In this review article, we will focus on novel objective measures of efficacy and safety regarding BoNT treatment of facial muscles and the reasons why this is important.
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Toxinas Botulínicas/efeitos adversos , Toxinas Botulínicas/uso terapêutico , Músculos Faciais/efeitos dos fármacos , Animais , Músculos Faciais/anatomia & histologia , Músculos Faciais/fisiologia , Humanos , Resultado do TratamentoRESUMO
Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported. We aimed to isolate and identify specific pituitary autoantigens in patients with APS1. Immunoscreening of a pituitary cDNA expression library identified endothelin-converting enzyme (ECE)-2 as a potential candidate autoantigen. Immunoreactivity against ECE-2 was detected in 46% APS1 patient sera, with no immunoreactivity detectable in patients with other autoimmune disorders or healthy controls. Quantitative-PCR showed ECE-2 mRNA to be most abundantly expressed in the pancreas with high levels also in the pituitary and brain. In the pancreas ECE-2 was co-expressed with insulin or somatostatin, but not glucagon and was widely expressed in GH producing cells in the guinea pig pituitary. The correlation between immunoreactivity against ECE-2 and the major recognized clinical phenotypes of APS1 including hypopituitarism was not apparent. Our results identify ECE-2 as a specific autoantigen in APS1 with a restricted neuroendocrine distribution.
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Autoantígenos/imunologia , Enzimas Conversoras de Endotelina/imunologia , Poliendocrinopatias Autoimunes/imunologia , Adolescente , Processamento Alternativo , Autoanticorpos/imunologia , Autoantígenos/genética , Autoimunidade , Criança , Enzimas Conversoras de Endotelina/genética , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Loci Gênicos , Humanos , Imuno-Histoquímica , Masculino , Fenótipo , Hipófise/imunologia , Hipófise/metabolismo , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/genéticaRESUMO
In recent years, by extensive achievements in understanding the mechanisms and the pathways affected by cancer, the focus of cancer research is shifting from developing new chemotherapy methods to using natural compounds with therapeutic properties to reduce the adverse effects of synthetic drugs on human health. We used fruit extracts from previously generated human type I InsP 5-ptase gene expressing transgenic tomato plants for assessment of the anti-cancer activity of established genetically modified tomato lines. Cellular assays (MTT, Fluorescent microscopy, Flow Cytometry analysis) were used to confirm that InsP 5-ptase fruit extract was more effective for reducing the proliferation of breast cancer cells compared to wild-type tomato fruit extract. Metabolome analysis of InsP 5-ptase expressing tomato fruits performed by LC-MS identified tomato metabolites that may play a key role in the increased anti-cancer activity observed for the transgenic fruits. Total transcriptome analysis of cancer cells (MCF-7 line) exposed to an extract of transgenic fruits revealed a number of differently regulated genes in the cells treated with transgenic extract compared to untreated cells or cells treated with wild-type tomato extract. Together, this data demonstrate the potential role of the plant derived metabolites in suppressing cell viability of cancer cells and further prove the potential application of plant genetic engineering in the cancer research and drug discovery.
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Proliferação de Células/efeitos dos fármacos , Inositol 1,4,5-Trifosfato/metabolismo , Extratos Vegetais/química , Proteínas de Plantas/metabolismo , Polifenóis/toxicidade , Solanum lycopersicum/química , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Flavonoides/análise , Flavonoides/metabolismo , Citometria de Fluxo , Frutas/química , Frutas/metabolismo , Humanos , Solanum lycopersicum/metabolismo , Células MCF-7 , Espectrometria de Massas , Metaboloma , Microscopia de Fluorescência , Análise de Sequência com Séries de Oligonucleotídeos , Plantas Geneticamente Modificadas/química , Plantas Geneticamente Modificadas/metabolismo , Polifenóis/química , Polifenóis/isolamento & purificação , Transcriptoma/efeitos dos fármacosRESUMO
BACKGROUND: Different volumes of 0.9% NaCl may be used to reconstitute abobotulinumtoxinA yielding an injection volume that ranges from 0.05 to 0.1 mL per injection point for treatment of glabellar lines. OBJECTIVE: To evaluate the efficacy, safety, and subject satisfaction of 2 different injection volumes to deliver the same unit dose of abobotulinumtoxinA for treatment of glabellar lines. MATERIALS AND METHODS: This randomized comparative study was conducted using 2 different reconstitution volumes to deliver a fixed unit dose of 10 Speywood units (sU) of abobotulinumtoxinA in either 0.05 mL (labeled volume) or 0.1 mL (twofold volume) per injection point. Evaluations included wrinkle severity, neurophysiological assessment by compound muscle action potential (CMAP), and subject satisfaction. RESULTS: Use of either injection volume of abobotulinumtoxinA resulted in the early onset of effect, high effectiveness, and long duration of effect. The safety profile and injection pain levels were similar in both groups. The twofold injection volume was shown to be noninferior to the labeled injection volume based on CMAP results. CONCLUSION: A twofold increase in injection volume to 0.1 mL per injection point to deliver 10 sU of abobotulinumtoxinA is effective and safe.
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Inibidores da Liberação da Acetilcolina/administração & dosagem , Toxinas Botulínicas Tipo A/administração & dosagem , Músculo Esquelético/efeitos dos fármacos , Satisfação do Paciente , Envelhecimento da Pele/efeitos dos fármacos , Inibidores da Liberação da Acetilcolina/efeitos adversos , Potenciais de Ação , Adulto , Toxinas Botulínicas Tipo A/efeitos adversos , Feminino , Testa , Humanos , Pessoa de Meia-Idade , Músculo Esquelético/fisiologia , Dor/etiologiaAssuntos
Neoplasias Ósseas/metabolismo , Calcâneo/diagnóstico por imagem , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndromes Paraneoplásicas Oculares/genética , Doenças Retinianas/genética , Adolescente , Biomarcadores Tumorais/metabolismo , Biópsia , Neoplasias Ósseas/complicações , Neoplasias Ósseas/diagnóstico , Eletrorretinografia , Feminino , Seguimentos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Imageamento por Ressonância Magnética , Síndromes Paraneoplásicas Oculares/diagnóstico , Síndromes Paraneoplásicas Oculares/metabolismo , Glândula Pineal/metabolismo , RNA Neoplásico/genética , Retina/metabolismo , Doenças Retinianas/diagnóstico , Doenças Retinianas/metabolismo , Fatores de TempoRESUMO
Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIRE gene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patient sera to assess the autoimmune response against the male reproductive organs. By screening human protein arrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identified transglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule with critical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients but were absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies first presented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, the Aire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Aire-deficient mice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. In the mouse, we further link TGM4 immunity with a destructive prostatitis and compromised secretion of TGM4. Collectively, our findings in APS1 patients and Aire-deficient mice reveal prostate autoimmunity as a major manifestation of APS1 with potential role in male subfertility.
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Autoantígenos/metabolismo , Infertilidade Masculina/enzimologia , Infertilidade Masculina/imunologia , Próstata/enzimologia , Transglutaminases/metabolismo , Animais , Autoanticorpos/metabolismo , Células Epiteliais/enzimologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Poliendocrinopatias Autoimunes/enzimologia , Poliendocrinopatias Autoimunes/imunologia , Prostatite/patologia , Proteoma/metabolismo , Proteômica , Puberdade , Timo/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismo , Proteína AIRERESUMO
PURPOSE: Reliable biological markers for patients with the autoimmune neuromuscular disorder myasthenia gravis (MG) are lacking. We determined whether levels of the circulating immuno-microRNAs miR-150-5p and miR-21-5p were elevated in sera from clinically heterogeneous MG patients, with and without immunosuppression, as compared to healthy controls and patients with other autoimmune disorders. METHODS: Sera from 71 MG patients and 55 healthy controls (HC) were analyzed for the expression levels of miR-150-5p and miR-21-5p with qRT-PCR. Sera were also assayed from 23 patients with other autoimmune disorders (AID; psoriasis, Addison's and Crohn's diseases). RESULTS: 34 MG patients had no immunosuppressive drug treatment (MG-0) and 37 patients were under stable immunosuppressive drug treatment since ≥ 6 months (MG+IMM). Serum levels of miR-150-5p and miR-21-5p were higher in the MG-0 patients compared to HC (p<0.0001). Further, miR-150-5p levels were 41% lower and miR-21-5p levels were 25% lower in the MG+IMM compared to MG-0 (p=0.0051 and 0.0419). In the AID patients, mean miR-150-5p and miR-21-5p were comparable with healthy controls (p=0.66). CONCLUSIONS: The immuno-microRNAs miR-150-5p and miR-21-5p show a disease specific signature, which suggests these microRNAs as possible biological autoimmune markers of MG.
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MicroRNAs/sangue , Miastenia Gravis/sangue , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/genética , Miastenia Gravis/imunologiaRESUMO
MAIN CONCLUSION: We demonstrate here that the reduction of InsP 3 , the key component of the phosphoinositol pathway, results in changes in ROS-scavenging machinery and, subsequently, increases the tolerance of tomato plants to light stress. Different plant stress signaling pathways share similar elements and, therefore, 'cross-talk' between the various pathways can exist. Links between the phosphoinositol signaling pathway and light signaling were recently found. Tomato plants expressing InsP 5-ptase and exhibiting reduction in the level of inositol 1,4,5-triphosphate (InsP3) demonstrated enhanced tolerance to stress caused by continuous light exposure. To understand the molecular basis of observed stress tolerance in tomato lines with decreased amount of InsP3, we monitored the expression of enzymatic antioxidants as well as important factors in light signaling associated with non-enzymatic antioxidants (secondary metabolites). Here, we demonstrated that InsP 5-ptase transgenic plants accumulate less hydroxide peroxide and maintain higher chlorophyll content during stress caused by continuous light exposure. This observation can be explained by documented activation of multiple enzymatic antioxidants (LeAPX1, SICAT2, LeSOD) at levels of gene expression and enzymatic activities during continuous light exposure. In addition, we noticed the up-regulation of photoreceptors LePHYB and LeCHS1, key enzymes in flavonoid biosynthesis pathway, transcription factors LeHY5, SIMYB12, and early light-inducible protein (LeELIP) genes in transgenic tomato seedlings exposed to blue or red light. Our study confirmed the existence of a correlation between phosphoinositol signaling pathway modification, increased tolerance to stress caused by continuous light exposure, activation of ROS-scavenging enzymes, and up-regulation of molecular activators of non-enzymatic antioxidants in InsP 5-ptase expressing tomato lines.
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Adaptação Fisiológica , Inositol 1,4,5-Trifosfato/metabolismo , Estresse Oxidativo , Solanum lycopersicum/genética , Solanum lycopersicum/fisiologia , Adaptação Fisiológica/efeitos da radiação , Antioxidantes/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Peróxido de Hidrogênio/metabolismo , Inositol Polifosfato 5-Fosfatases , Luz , Transdução de Sinal Luminoso/efeitos da radiação , Solanum lycopersicum/enzimologia , Solanum lycopersicum/efeitos da radiação , Modelos Biológicos , Análise de Sequência com Séries de Oligonucleotídeos , Estresse Oxidativo/efeitos da radiação , Monoéster Fosfórico Hidrolases/metabolismo , Plantas Geneticamente Modificadas , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
CONTEXT: NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) is an autoantigen in hypoparathyroidism associated with autoimmune polyendocrine syndrome type 1 (APS1) but is also expressed in the ovary. Mater is an autoantigen in experimental autoimmune oophoritis. OBJECTIVES: The objectives of the study were to determine the frequency of NALP5/MATER autoantibodies (NALP5/MATER-Ab) in women with premature ovarian insufficiency (POI) and in patients with autoimmune Addison's disease (AAD) and to evaluate whether inhibin chains are a target for autoantibodies in POI. METHODS: Autoantibodies against NALP5/MATER and inhibin chains-α and -ßA were determined by radiobinding assays in 172 patients with AAD without clinical signs of gonadal insufficiency, 41 women with both AAD and autoimmune POI [steroidogenic cell autoimmune POI (SCA-POI)], 119 women with idiopathic POI, 19 patients with APS1, and 211 healthy control subjects. RESULTS: NALP5/MATER-Ab were detected in 11 of 19 (58%) sera from APS1 patients, 12 of 172 (7%) AAD sera, 5 of 41 (12%) SCA-POI sera, 0 of 119 idiopathic POI sera and 1 of 211 healthy control sera (P < .001). None of 160 POI sera, including 41 sera from women with SCA-POI and 119 women with idiopathic POI, and none of 211 healthy control sera were positive for inhibin chain-α/ßA autoantibodies. CONCLUSIONS: NALP5/MATER-Ab are associated with hypoparathyroidism in APS1 but are present also in patients with AAD and in women with SCA-POI without hypoparathyroidism. Inhibin chains do not appear to be likely candidate targets of autoantibodies in human POI.
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Doença de Addison/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Insuficiência Ovariana Primária/imunologia , Doença de Addison/sangue , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Inibinas/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais , Proteínas Nucleares , Insuficiência Ovariana Primária/sangue , Adulto JovemRESUMO
Despite the extensive use of botulinum toxin A (BoNTA) in medical and cosmetic treatments, the potential spreading of BoNTA to surrounding tissues remains unknown. A patient with hemifacial paralysis upon blepharospasm treatment with low dose of BoNTA, prompted us to investigate the spreading effect. A randomised, double-blind study was conducted in which 5 healthy women (33-52 years) were treated with different doses of onabotulinum toxin unilaterally in the corrugator muscle. Parameters of efficacy and diffusion (CMAP; EMG and jitter analysis) in both glabellar and frontalis muscles were assessed at baseline, 2 and 4 weeks following BoNTA injection. CMAP of the treated glabellar muscles was reduced to approximately 40% in all dose groups. Additionally, contralateral CMAP reduction was observed in 3 of 5 subjects. These data confirm regional diffusion of BoNTA in facial muscle application, which raises question on the reliability of split-face models in BoNTA studies.
Assuntos
Inibidores da Liberação da Acetilcolina/farmacocinética , Toxinas Botulínicas Tipo A/farmacocinética , Músculos Faciais/metabolismo , Inibidores da Liberação da Acetilcolina/administração & dosagem , Inibidores da Liberação da Acetilcolina/efeitos adversos , Potenciais de Ação/efeitos dos fármacos , Adulto , Idoso de 80 Anos ou mais , Blefarospasmo/tratamento farmacológico , Toxinas Botulínicas Tipo A/administração & dosagem , Toxinas Botulínicas Tipo A/efeitos adversos , Ensaios Clínicos Controlados como Assunto/métodos , Difusão , Método Duplo-Cego , Eletromiografia , Músculos Faciais/efeitos dos fármacos , Paralisia Facial/induzido quimicamente , Feminino , Testa , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Projetos de PesquisaRESUMO
The mechanisms behind destruction of the adrenal glands in autoimmune Addison's disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in >90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase-specific T cells detectable in 20 patients with Addison's disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8(+) and CD4(+) T cell responses in a large proportion of Addison's patients both ex vivo and after in vitro culture of PBLs ≤20 y after diagnosis. In a large proportion of patients, CD8(+) and CD4(+) 21-hydroxylase-specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer-guided isolation of 21-hydroxylase-specific CD8(+) T cells showed their ability to lyse 21-hydroxylase-positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.
Assuntos
Doença de Addison/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Imunidade Celular , Peptídeos/imunologia , Esteroide 21-Hidroxilase/imunologia , Doença de Addison/patologia , Adolescente , Neoplasias do Córtex Suprarrenal/imunologia , Neoplasias do Córtex Suprarrenal/patologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Humanos , Pessoa de Meia-IdadeRESUMO
Despite the extensive use of botulinum toxin type A (BoNT-A) in treatments for glabellar frown lines, the dose-response effect in the glabellar muscles remains unknown. The aim of this randomized, double-blind, placebo-controlled prospective study was to characterize the neurophysiological parameters that correlate with the effect of BoNT-A in the glabellar muscles and its diffusion to surrounding ocular muscles. Sixteen healthy women were recruited and randomized to 3 different dose-groups of onabotulinumtoxin A (Vistabel®) or placebo and followed 24 weeks by neuro-physiological examinations. Efficacy of treatment on corrugator supercilii muscles was measured by compound motor action potential (CMAP) and electromyography (EMG). Photographs were used to score glabellar frown lines. Diffusion of the drug to surrounding muscles was assessed by CMAP of the nasalis muscle, EMG and concentric needle electrode jitter analysis (CNE) of the orbicularis oculi muscle. CMAP reduction correlated well with intramuscular BoNT-A dose. Muscle paralysis, measured by EMG, began from 2 weeks and was not entirely reversed at 24 weeks in individuals who received high dose of onabotulinumtoxin. Limited diffusion of orbicularis oculi was detected with CNE. In conclusion, we developed a novel neurophysiological strategy for effect evaluation of BoNT-A in glabellar muscles. CMAP and EMG correlated with given BoNT-A dose and are more defined effect measures than clinical glabellar photo scales.