RESUMO
The physiological role of protein kinase C (PKC) enzymes in the immune system is presented briefly. From earlier publications of others data were collected how the defects of one/two isoenzymes of PKC system suggested their involvement in the pathogenesis of human autoimmune diseases. Our observations on the defects of seven PKC isoenzymes in the peripheral blood mononuclear cells (PBMC) demonstrate that these molecular impairments are not prerequisits of the pathogenesis of systemic lupus erythematosus (SLE), mixed connective tissue disease and Sjögren's syndrome. However, these defects can modulate the disease activity and symptoms especially in SLE by several pathways. The role of PKC system in other forms of autoimmune diseases is also very small. It was of note that we detected decreased expression of PKC isoenzymes in PBMC of a European white family with an X-linked genetic background showing seasonal undulations in the lupus patient and also in her healthy mother.
Assuntos
Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Síndrome de Sjogren , Doenças Autoimunes/etiologia , Feminino , Humanos , Isoenzimas/genética , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Proteína Quinase C , Síndrome de Sjogren/genéticaRESUMO
The present paper is focusing on rare diseases manifesting in late childhood or adulthood. A part of these syndromes are not of genetic origin, such as relatively or absolutely rare infections, autoimmune diseases, tumours, or diseases due to rare environmental toxic agents. In addition, even a large proportion of genetic disorders may develop in adulthood or may have adult forms as well, affecting are almost each medical specialization. Examples are storage disorders (e.g. adult form of Tay-Sachs disease, Gaucher-disease), enzyme deficiencies (e.g. ornithin-transcarbamylase deficiency of the urea cycle disorders), rare thrombophilias (e.g. homozygous factor V. Leiden mutation, antithrombin deficiency), or some rare monogenic disorders such as Huntington-chorea and many others. It is now generally accepted that at least half of the 6-8000 "rare diseases" belong either to the scope of adult-care (e.g. internal medicine, neurology), or to "age-neutral" specialities such as ophtalmology, dermatology etc.).
Assuntos
Idade de Início , Diagnóstico Tardio , Doenças Raras/diagnóstico , Doenças Raras/etiologia , Adolescente , Adulto , Idoso , Doenças Autoimunes/diagnóstico , Criança , Erros de Diagnóstico , Doenças Genéticas Inatas/diagnóstico , Humanos , Hungria/epidemiologia , Infecções/diagnóstico , Doenças por Armazenamento dos Lisossomos/diagnóstico , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Poliarterite Nodosa/diagnóstico , Prevalência , Doenças Raras/epidemiologia , Doenças Raras/genética , Doenças Raras/imunologiaAssuntos
Anti-Hipertensivos/administração & dosagem , Imunossupressores/administração & dosagem , Lúpus Eritematoso Sistêmico , Imageamento por Ressonância Magnética/métodos , Procedimentos Neurocirúrgicos/métodos , Síndrome da Leucoencefalopatia Posterior , Púrpura Trombocitopênica Trombótica , Substância Branca/diagnóstico por imagem , Edema Encefálico/diagnóstico , Edema Encefálico/etiologia , Descompressão Cirúrgica/métodos , Evolução Fatal , Feminino , Hemorragia/diagnóstico , Hemorragia/etiologia , Hemorragia/terapia , Humanos , Testes Imunológicos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Neuroimagem/métodos , Administração dos Cuidados ao Paciente/métodos , Síndrome da Leucoencefalopatia Posterior/sangue , Síndrome da Leucoencefalopatia Posterior/etiologia , Síndrome da Leucoencefalopatia Posterior/fisiopatologia , Síndrome da Leucoencefalopatia Posterior/terapia , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/etiologia , Púrpura Trombocitopênica Trombótica/fisiopatologia , Púrpura Trombocitopênica Trombótica/terapia , Adulto JovemRESUMO
Hereditary hemorrhagic telangiectasia (HHT) is a rare germline vascular malformation syndrome with a prevalence of 1:5000-1:10,000 [...].
RESUMO
Systemic lupus erythematosus is a polysystemic autoimmune disease. One of the most common and serious complication is lupus nephritis. Notification of these complications before organic disorder, prediction of flares, starting aggressive therapy as early as possible, and the follow-up of successful treatment would be desirable. There is an intensive need for identifying the best biomarker for monitoring flare activity. The goal of this review is to present not only the most frequently ordered serologic tests, but the latest, partly experimental biomarkers reflecting flares, which are not used in clinical practice. Biomarkers used specifically in lupus nephritis are also described.
Assuntos
Biomarcadores Tumorais/sangue , Nefrite Lúpica/metabolismo , Autoanticorpos/sangue , Biomarcadores Tumorais/urina , Quimiocinas/sangue , Humanos , Nefrite Lúpica/complicações , Nefrite Lúpica/imunologia , Proteinúria/etiologia , Proteinúria/metabolismo , Proteoma/metabolismoRESUMO
We aimed to answer the question whether the decreased expression of protein kinase C (PKC) isoenzymes in the peripheral blood mononuclear cells (PBMC) of patients with systemic lupus erythematosus (SLE) is inherited or not. For this reason we examined the expression of PKC isoenzymes in a European white girl with acute SLE and in her healthy mother and father simultaneously in summer and winter during one year using western blotting and densitometry. We found that in the father the expression of PKC isoenzymes did not differ from that of eight healthy controls included women and men. However, in the "SLE-free" mother and in the patient arrived in July with acute symptoms of lupus, the expression of PKC isoenzymes showed a season dependent undulation in parallel. Namely, in summer the expression values were significantly lower, in winter they were significantly higher than those in the controls. Thus, the decreased expression of PKC isoenzymes in the PBMC of SLE patient is not a disease specific marker; it appears also in her lupus free mother. This phenomenon may be due to a season dependent female genetic background. However, the low PKC levels in summer can still decrease further the low production of IL-2 in T cells of lupus patients augmenting the existing AP-1 defects. This is the first report on the season and female dependent inherited changing of PKC expression in a European white patient with SLE and her mother. Further studies are needed to confirm these findings in other populations.
Assuntos
Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/enzimologia , Proteína Quinase C/sangue , Criança , Feminino , Humanos , Isoenzimas/sangue , Leucócitos Mononucleares/enzimologia , Estações do Ano , Adulto JovemRESUMO
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder mainly affecting the cardiovascular, ocular and musculo-skeletal systems. FBN1 gene mutations lead to MFS and related connective tissue disorders. In this work we described clinical and molecular data of 26 unrelated individuals with suspected MFS who were referred for FBN1 mutation analysis. FBN1 gene sequencing was performed by next generation sequencing and Sanger sequencing methods. We identified 23 causal or potentially causal (including variants of uncertain significance) FBN1 variants, seven of them was novel (Ë30%). About 30% of the cases were sporadic. FBN1 mutations were associated with MFS in the majority of the patients, in two cases with severe and early onset manifestation of the syndrome. Missense mutations were detected in 69.6% (16/23), the majority of them were located in one of the cbEGF motifs and Ë70% of them substituted conserved cystein residues. Small deletions/duplications were identified in 13% of the cases (3/23), while splice site variants were detected in 17.4% (4/23). In three unrelated patients a low frequency recurrent silent variant (c.3294Câ¯>â¯T (p.Asp1098=) was identified. FBN1 mRNA analysis showed that the mutation does not lead to aberrant splicing, based on available data the mutation was classified as benign.
Assuntos
Fibrilina-1/genética , Síndrome de Marfan/genética , Mutação/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Cisteína/genética , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Systemic corticosteroids are widely used for the treatment/prevention of chronic lung disease (CLD) in premature infants. The use of the inhalation route for delivering corticosteroids has been widely recognized, however so far pre-term babies continue to be treated with oral glucocorticoids, such as dexamethasone. We hypothesize that the pulmonary administration of sustained release formulations of inhaled corticosteroids to pre-term infants will result in a higher benefit/risk ratio as compared to traditional inhalation therapy. To achieve a slow release formulation budesonide particles were coated with a very thin film of polylactic acid using a pulse laser ablation technique. Coated material was characterized with respect to the dissolution behavior and particle size. Ex vivo receptor binding studies were performed to monitor the cumulative lung, liver and brain receptor occupancies after adminstration in neonatal (10-11 days old) rats after intratracheal instillation of either uncoated budesonide or poly (l-lactic acid) (PLA) coated budesonide. The mean dissolution timed for the uncoated and the polymer coated formulations were 1.2 +/- 0.5 and 4.7 +/- 0.1 h, respectively (p < 0.05). No significant differences in the respirable fraction were found between coated and uncoated formulation (p>0.05). The average receptor occupancies in the lung, liver and brain after administration of uncoated budesonide were 58.4 +/- 12.9, 56.4 +/- 6.8 and 38.3 +/- 6.7%, respectively. However, after administration of PLA coated budesonide, the average AUC estimates in the lung, liver and brain were 75.8 +/- 3.7%, 46.6 +/- 14.5 and 29 +/- 7, respectively. The results from our study suggest sustained receptor occupancy in the lungs of neonatal rats after administration of PLA coated budesonide results in lower systemic exposure (as indicated by low liver receptor occupancy). The data strongly underscore the urgent need to develop sustained release pulmonary-targeted delivery systems of corticosteroids for the treatment of CLD in pre-term infants. The administration of inhaled corticosteroids using targeted drug-delivery systems will potentially result in higher local effects and a reduction in systemic exposure.
Assuntos
Broncodilatadores/administração & dosagem , Budesonida/administração & dosagem , Pulmão/metabolismo , Animais , Animais Recém-Nascidos , Área Sob a Curva , Encéfalo/metabolismo , Broncodilatadores/farmacocinética , Budesonida/farmacocinética , Excipientes , Ácido Láctico , Fígado/metabolismo , Poliésteres , Polímeros , Pós , Ratos , Receptores de Glucocorticoides/metabolismo , Solubilidade , Suspensões , Distribuição TecidualRESUMO
Interleukin-1 receptor antagonist (IL-1Ra) is a good indicator of disease activity in patients with systemic lupus erythematosus (SLE). Glucocorticosteroids are the most frequently used drugs in SLE. Our goal was to compare IL-1Ra activity in SLE patients with and without renal involvement and to determine the effect of different dosage of glucocorticosteroids used in 17 patients with active SLE without nephritis, 7 patients with inactive lupus nephritis (LN), and 8 patients with active LN, along with 10 healthy controls. IL-1Ra levels were measured in the serum of SLE patients by Human Luminex [100] analyzer. Both in patients with active SLE without nephritis and in patients with LN, serum levels of IL-1Ra (p<0.001) were significantly higher compared with those in the controls. IL-1Ra was significantly higher in patients with active LN than in patients with inactive LN (p = 0.028). The use of methylprednisolone was significantly higher in the active LN group compared with the inactive LN group (p = 0.013). SLE patients with higher IL-1Ra are at lower risk for developing nephritis. The higher doses of glucocorticosteroids needed in active LN could be due to steroid resistance and IL-1Ra polymorphism. Measurement of IL-1Ra levels in SLE patients could help to predict future renal involvement.
Assuntos
Proteína Antagonista do Receptor de Interleucina 1/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/fisiopatologia , Nefrite Lúpica/sangue , Nefrite Lúpica/fisiopatologia , Adulto , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Creatinina/sangue , Ciclofosfamida/uso terapêutico , Ciclosporina/uso terapêutico , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Masculino , Taxa de Depuração Metabólica/fisiologia , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Proteinúria/urina , Índice de Gravidade de Doença , Adulto Jovem , beta 2-Glicoproteína I/sangueRESUMO
PURPOSE: Modulatory actions on morphine-induced effects, such as tolerance and withdrawal, have been noted for dynorphin A(1-13) [Dyn A(1-13)] and similar peptides. These are currently of limited therapeutic potential due to extensive metabolism by human metabolic enzymes resulting in a half-life of less than 1 min in human plasma. The purpose of this study was to identify stabilized dynorphin A (Dyn A) derivatives, to determine their metabolic routes in human plasma, and to assess whether the pharmacodynamic activity is retained. METHODS: The stability of peptides in human plasma was tested using in vitro metabolism studies with and without enzyme inhibitors. Identification of the generated metabolites was performed by mass spectrometry after high performance liquid chromatography (HPLC) separation. The in vivo activity of a stabilized dynorphin was tested by tail-flick assay in morphine-tolerant rats. RESULTS: Though amidation of the Dyn A(1-13) was able to stop the majority of C-terminal degradation, metabolism of Dyn A(1-10) amide continued by captopril sensitive enzymes, suggesting that Dyn A(1-13) amide is a better candidate for additional stabilization. Two Dyn A(1-13) amide derivatives further stabilized at the N-terminal end, [D-Tyr1]-Dyn A(1-13) amide and [N-Met-Tyr1]-Dyn A(1-13) amide, showed half-lives in plasma of 70 and 130 min, respectively. The most stable derivative [N-Met-Tyr1]-Dyn A(1-13) amide was tested successfully for retention of the pharmacological activity in modulating antinociceptive activity. CONCLUSIONS: [N-Met-Tyr1]-Dyn A(1-13) amide showed significant stability and antinociceptive activity in the tail-flick test, thus pointing to the clinical potential of this derivative in the management of pain as well as its potential activity in suppressing opiate tolerance and withdrawal.