RESUMO
Owing to the small number of patients with tyrosine hydroxylase (TH) deficiency, no genotype-phenotype correlations have yet been identified. To investigate the genotype-phenotype correlation of R233H mutation in TH deficiency, we analyzed the clinical manifestations and treatment responses of four patients with the R233H homozygous mutation. Thirty-eight additional patients, available from the literature, known to be homozygous or heterozygous for the R233H mutation, were combined with the four cases from our hospital. Data for a total of 42 patients were retrieved. Our four patients showed clinical presentation consistent with Type A TH deficiency, and responded well to levodopa therapy, with an improvement in clinical symptoms within 1-2 weeks. In the 42 patients, 20 of 42 patients (48%) were homozygous and 22 (52%) were heterozygous for the R233H mutation. Of the 20 patients who were homozygous for the R233H mutation, a majority (80%) suffered from Type A TH deficiency. Of the 8 patients that were heterozygous for the R233H/the mutation located downstream of exon 11, 7 patients (86%) suffered from Type B TH deficiency. Of the 7 patients who were heterozygous for the R233H/nonsense mutation, 6 (86%) suffered from Type B TH deficiency. Genotype-phenotype correlation of R233H mutation was observed in TH deficiency. The homozygous R233H mutation frequently manifests as Type A TH deficiency, whereas R233H/nonsense mutation or any mutation located downstream of exon 11 manifests as Type B TH deficiency.
Assuntos
Distúrbios Distônicos/congênito , Criança , Pré-Escolar , Distúrbios Distônicos/genética , Distúrbios Distônicos/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , FenótipoRESUMO
Severe combined immunodeficiency (SCID), a rare type of genetic associated immune disorder, is poorly characterized in mainland China. We retrospectively reviewed 44 patients with SCID who received treatment from 2004 to 2011 in Shanghai, China, and herein summarize their clinical manifestations and immunological and preliminary genetic features. The male-to-female ratio was 10:1. Twenty five patients presented with X-SCID symptoms. Only one patient was diagnosed before the onset of symptoms due to positive family history. The mean time of delay in the diagnosis of X-SCID was 2.69 months (range, 0.5-8.67). Thirty-seven of the 44 patients died by the end of 2011 with the mean age of death being 7.87 months (range, 1.33-31). Six patients received hematopoietic stem cell transplantation (HSCT); only one of them survived, who was transplanted twice. The time between onset and death was shorter in the HSCT-treated group compared with the untreated group (2.87 ± 1.28 and 3.34 ± 0.59 months, respectively), probably due to active infections during transplantation. Bacillus Calmette-Guérin (BCG) complications occurred in 14 of the 34 patients who received BCG vaccination. Transfusion-induced graft-versus-host disease occurred in 5 patients. Total 20 mutations in interleukin-2 receptor subunit gamma (IL2RG) were identified in 22 patients, including 11 novel mutations. Most patients were misdiagnosed before referred to our SCID Center. Therefore, establishing more diagnostic centers dedicated to the care of PID and accessible by primary immunodeficiency patients will facilitate early, correct diagnosis and better care of SCID in China.
Assuntos
Subunidade gama Comum de Receptores de Interleucina/genética , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Adolescente , Adulto , Idade de Início , Vacina BCG/imunologia , Criança , Pré-Escolar , China , Feminino , Genótipo , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lactente , Recém-Nascido , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Mutação , Imunodeficiência Combinada Severa/terapia , Adulto JovemRESUMO
OBJECTIVE: To study the biotransformation by human intestinal flora, and the absorption and transportation characteristic in a model of human colon adenocarcinoma cell lines (Caco-2 cell) monolayer of d-corydaline (CDL) and tetrahydropalmatine (THP). METHOD: CDL or THP was incubated with crude enzymes of human intestinal flora under the anaerobic environment and 37 degrees C conditions to transform CDL or THP. Caco-2 cell monolayer was used as an intestinal epithelial cell model for determination of the permeability of CDL or THP from apical side (AP side) to basolateral side (BL side) or from BL side to AP side. Transportation parameters and permeability coefficients (P(app)) were then calculated, and P(app) values were compared with the reported values for model compounds, propranolol as a well absorbed drug and atenolol as a poor absorbed drug. The concentration of CDL or THP was measured by HPLC coupled with photodiode array detector. RESULT: CDL or THP in the human intestinal flora incubation system did not happen biotransformation. In the Caco-2 cell monolayer model, the P(app) magnitudes of both CDL and THP were 1 x 10(-5) cm x s(-1) in the bi-directional transport, which were identical with propranolol. And their transports were concentration dependent between 0-180 min. CONCLUSION: Both CDL and THP may be stable in the human intestinal flora incubation system, and their absorption and transportation in the human Caco-2 cell monolayer model are mainly via passive diffusion mechanism.
Assuntos
Alcaloides de Berberina/farmacocinética , Corydalis/química , Medicamentos de Ervas Chinesas/farmacocinética , Mucosa Intestinal/metabolismo , Bactérias/metabolismo , Alcaloides de Berberina/metabolismo , Transporte Biológico , Biotransformação , Células CACO-2 , Medicamentos de Ervas Chinesas/metabolismo , Humanos , Absorção Intestinal , Intestinos/microbiologia , Modelos BiológicosRESUMO
Four new triterpene saponins, ginsenosides Rh(14)-Rh(17)(1- 4), along with two known compounds, 20(S)-ginsenoside Rg2 and dammar-(E)-20(22),24-diene-3 ß,6 α,12 ß-triol, were isolated from the stems and leaves of Panax ginseng. The structures of the new compounds were elucidated as 3 ß,6 α,12 ß,24 ξ-tetrahydroxy-dammar-(E)-20(22),25-diene 6- O- α- L-rhamnopyranosyl-(1 â 2)- ß-D-glucopyranoside (1), 3 ß,12 ß,24 ξ-trihydroxy-dammar-(E)-20(22),25-diene 3- O- ß- D-glucopyranosyl-(1 â 2)- ß-D-glucopyranoside (2), 3 ß,6 α,12 ß-trihydroxy-dammar-(E)-20(22),24-diene 3-O-ß-D-glucopyranoside (3), and 3-oxo-6 α,12 ß,20(S)-trihydroxy-dammar-24-ene 6-O-α-L-rhamnopyranosyl-(1 â 2)-ß-D-glucopyranoside (4) by means of extensive spectroscopic and chemical methods, respectively. The isolated compounds were tested for IN VITRO cytotoxicity against HL-60 cells.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Panax/química , Fitoterapia , Extratos Vegetais/uso terapêutico , Saponinas/uso terapêutico , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Células HL-60 , Humanos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta , Caules de Planta , Saponinas/isolamento & purificação , Saponinas/farmacologiaRESUMO
Two hundred and one patients have been diagnosed with primary immunodeficiency diseases (PIDs) in our center from January 2004 to December 2009. The male-to-female ratio was 5.29:1. Spectrums of PIDs were as follows: predominantly antibody deficiency disease was the most common category (94 patients, 48.2%), followed by other well-defined immunodeficiency syndromes (40 patients, 20.5%), combined T and B cell immunodeficiencies (33 patients, 16.9%), congenital defects of phagocyte number and/or function (21 patients, 10.8%), and diseases of immune dysregulation (six patients, 3.1%). Agammaglobulinemia was the most frequent disease type. The median of diagnosis lag was 18.0 months. Pneumonia was the most common manifestation of PID patients. Some manifestations were prone to concentrate in certain diseases. As for therapy, 99 patients (50.8%) received intravenous immunoglobulin replacement therapy; 13 patients received hematopoietic stem cell transplantation and nine of them were still alive. In this study, we sought to describe and analyze the distribution, clinical features, and therapy methods of PIDs among children diagnosed in our country and to compare with reports from other countries and regions.
Assuntos
Agamaglobulinemia/imunologia , Imunodeficiência de Variável Comum/imunologia , Imunoglobulinas/farmacologia , Disfunção de Fagócito Bactericida/imunologia , Imunodeficiência Combinada Severa/imunologia , Adolescente , Agamaglobulinemia/epidemiologia , Agamaglobulinemia/mortalidade , Agamaglobulinemia/patologia , Agamaglobulinemia/terapia , Antibacterianos/farmacologia , Povo Asiático , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/epidemiologia , Imunodeficiência de Variável Comum/mortalidade , Imunodeficiência de Variável Comum/patologia , Imunodeficiência de Variável Comum/terapia , Consanguinidade , Família , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Isotipos de Imunoglobulinas/análise , Imunoglobulinas/imunologia , Incidência , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Disfunção de Fagócito Bactericida/epidemiologia , Disfunção de Fagócito Bactericida/mortalidade , Disfunção de Fagócito Bactericida/patologia , Disfunção de Fagócito Bactericida/terapia , Estudos Retrospectivos , Imunodeficiência Combinada Severa/epidemiologia , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/patologia , Imunodeficiência Combinada Severa/terapia , Taxa de SobrevidaRESUMO
Chronic active Epstein-Barr virus infection (CAEBV) represents a new subtype of lymphoproliferative disorders characterized by high morbidity and mortality rates and often leads to malignant transformation of infected cells. Efficient therapeutic strategies are presently unavailable; therefore, the development of therapies to prevent CAEBV-mediated transformation and disease progression is crucial. Here, we used microarray analysis and luciferase reporter assays to reveal the potential role of activated nuclear factor kappa B (NF-kB) in T cell type of-CAEBV infection. Using a series of cellular and molecular experiments, we demonstrated that dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-kB inhibitor, can selectively induce apoptosis in SNT-16 cells infected with CAEBV. Mechanistic studies suggested that DHMEQ induces SNT-16 cell apoptosis through NF-kB inhibition coupled with oxidative stress generation. Thus, activated NF-kB could be a new target for CAEBV therapeutics. Owing to its selective targeting ability, DHMEQ may be a candidate for a novel therapeutic regimen to control the progression of CAEBV infections.
Assuntos
Benzamidas/farmacologia , Cicloexanonas/farmacologia , Infecções por Vírus Epstein-Barr/patologia , Apoptose/efeitos dos fármacos , Sequência de Bases , Células Cultivadas , Doença Crônica , Primers do DNA , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Citometria de Fluxo , Expressão Gênica , Humanos , NF-kappa B/metabolismo , Estresse Oxidativo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Atractylodes macrocephala (Compositae) is one of the most well-known traditional Chinese medicine in China, Japan and Korea, which has a long history of use for the treatment of splenic asthenia, edema, anorexia, and excessive perspiration, etc. As active compounds of anti-inflammatory activity of this medicinal plant have not been fully elucidated, the aim of this study was to isolate and identify the active constituents inhibiting nitric oxide (NO) production from the rhizomes of A. macrocephala. MATERIALS AND METHODS: Inhibitory activity against NO production in lipopolysaccharide-activated RAW264.7 macrophages was evaluated by Griess reaction. Fifteen polyacetylenes were isolated from the active ethyl acetate extract using activity-guided screening. The structures of all compounds were elucidated by spectroscopic methods and comparison with published data. The compounds were further tested for their inhibitory activity against NO production. RESULTS: Seven new polyacetylenes, named atractylodemaynes A-G (1-7), along with eight known ones (8-15) were isolated. Compound 14 was isolated for the first time from the rhizomes of A. macrocephala. The study showed that the tested compounds exhibited inhibitory activity against NO production in a dose-dependent manner. Among them, compounds 10, 11 and 12 had relatively stronger inhibitory effect with IC50 values of 28, 23 and 19µM, respectively. CONCLUSION: The results demonstrated that the polyacetylenes might greatly contribute to the anti-inflammatory activity of the rhizomes of A. macrocephala.
Assuntos
Anti-Inflamatórios/farmacologia , Atractylodes , Macrófagos/efeitos dos fármacos , Óxido Nítrico/antagonistas & inibidores , Poli-Inos/farmacologia , Rizoma/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Extratos Vegetais/químicaRESUMO
OBJECTIVE: To explore the therapeutic mechanisms of interferon-beta (IFN-beta) and intravenous immunoglobulin (IVIG) for experimental peripheral neuropathy induced by Campilobacter jejuni (Cj) lipopolysaccharide (LPS). METHOD: Forty healthy Wistar rats weighing 205 - 230 g were divided into IFN-beta, IVIG, IFN-beta plus IVIG and control groups. After the immune neuropathy was induced in the rats by Cj LPS, IFN-beta (1.3 microg/kg) was given by subcutaneous injection to the rats every other day for 6 weeks; IVIG [400 mg/(kg x d)] was given to the rats for five days, every other week for two times and IFN-beta [1.3 microg/(kg x d)] and IVIG [400 mg/(kg x d)] were given to the rats on the same days. Meanwhile, the control group was given PBS. The sera were collected in the 2nd, 4th and 6th week after therapy, the titers of anti-GM(1) IgG, MMP-9 and TNF-alpha in sera of immunized rats were measured by ELISA; histological study of sciatic nerve was performed and IgG on sciatic nerve was detected by immunohistochemistry in the 6th week. RESULTS: (1) There were no significant differences in titers of anti-GM(1) IgG, MMP-9 and TNF-alpha among the 3 therapeutic groups and control group after therapy for 2 weeks (P > 0.05). (2) The titers of anti- GM(1) IgG, MMP-9 or TNF-alpha in the control group were much higher than those of the IFN-beta group, the IVIG group or the IFN-beta and IVIG group after therapy for 4 weeks (P > 0.01) and there were no significant differences in titers of antibody among the 3 therapeutic groups (P > 0.05); the titers of MMP-9 or TNF-alpha in the IFN-beta and IVIG group were lower than those of the IFN-beta group or the IVIG group (P < 0.05). (3) The titers of anti-GM(1) IgG, MMP-9 or TNF-alpha in the control group were much higher than those of the IFN-beta group, the IVIG group or the IFN-beta with IVIG group after therapy for 6 weeks (P > 0.01); the IFN-beta with IVIG group had much lower levels of all indexes than the IFN-beta group or the IVIG group (P < 0.01). CONCLUSION: IFN-beta and IVIG showed therapeutic effects on immune peripheral neuropathy through inhibiting the humoral and cellular immunity simultaneously in the peripheral neuropathy induced by CJ LPS, treatment with combined IFN-beta and IVIG was more effective.