Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 27
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
World J Gastroenterol ; 24(44): 5034-5045, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30510378

RESUMO

AIM: To explore the risk factors of developing chronic pancreatitis (CP) in patients with acute pancreatitis (AP) and develop a prediction score for CP. METHODS: Using the National Health Insurance Research Database in Taiwan, we obtained large, population-based data of 5971 eligible patients diagnosed with AP from 2000 to 2013. After excluding patients with obstructive pancreatitis and biliary pancreatitis and those with a follow-up period of less than 1 year, we conducted a multivariate analysis using the data of 3739 patients to identify the risk factors of CP and subsequently develop a scoring system that could predict the development of CP in patients with AP. In addition, we validated the scoring system using a validation cohort. RESULTS: Among the study subjects, 142 patients (12.98%) developed CP among patients with RAP. On the other hand, only 32 patients (1.21%) developed CP among patients with only one episode of AP. The multivariate analysis revealed that the presence of recurrent AP (RAP), alcoholism, smoking habit, and age of onset of < 55 years were the four important risk factors for CP. We developed a scoring system (risk score 1 and risk score 2) from the derivation cohort by classifying the patients into low-risk, moderate-risk, and high-risk categories based on similar magnitudes of hazard and validated the performance using another validation cohort. Using the prediction score model, the area under the curve (AUC) [95% confidence interval (CI)] in predicting the 5-year CP incidence in risk score 1 (without the number of AP episodes) was 0.83 (0.79, 0.87), whereas the AUC (95%CI) in risk score 2 (including the number of AP episodes) was 0.84 (0.80, 0.88). This result demonstrated that the risk score 2 has somewhat better prediction performance than risk score 1. However, both of them had similar performance between the derivation and validation cohorts. CONCLUSION: In the study,we identified the risk factors of CP and developed a prediction score model for CP.


Assuntos
Pancreatite Crônica/epidemiologia , Adulto , Idoso , Área Sob a Curva , Estudos de Coortes , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Programas Nacionais de Saúde/estatística & dados numéricos , Valor Preditivo dos Testes , Fatores de Risco , Taiwan/epidemiologia
2.
Arthritis Rheumatol ; 69(6): 1325-1336, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28118536

RESUMO

OBJECTIVE: To evaluate proinflammatory cytokines and leukocyte subpopulations in the cerebrospinal fluid (CSF) and blood of patients with neonatal-onset multisystem inflammatory disease (NOMID) after treatment, and to compare inflammatory cytokines in the CSF and blood in 6 patients treated with 2 interleukin-1 (IL-1) blockers-anakinra and canakinumab. METHODS: During routine follow-up visits between December 2011 and October 2013, we immunophenotyped the CSF of 17 pediatric NOMID patients who were treated with anakinra, and analyzed CSF cytokine levels in samples obtained at baseline and at 3-5-year follow-up visits and compared them to samples from healthy controls. RESULTS: CSF levels of IL-6, interferon-γ-inducible 10-kd protein (IP-10/CXCL10), and IL-18 and monocyte and granulocyte counts significantly decreased with anakinra treatment but did not normalize to levels in the controls, even in patients fulfilling criteria for clinical remission. CSF IL-6 and IL-18 levels significantly correlated with measures of blood-brain barrier function, specifically CSF protein (r = 0.75 and r = 0.81, respectively) and albumin quotient (r = 0.79 and r = 0.68, respectively). When patients were treated with canakinumab versus anakinra, median CSF white blood cell counts and IL-6 levels were significantly higher with canakinumab treatment (10.2 cells/mm3 versus 3.7 cells/mm3 and 150.7 pg/ml versus 28.5 pg/ml, respectively) despite similar serum cytokine levels. CONCLUSION: CSF leukocyte subpopulations and cytokine levels significantly improve with optimized IL-1 blocking treatment, but do not normalize. The correlation of CSF IL-6, IP-10/CXCL10, and IL-18 levels with clinical laboratory measures of inflammation and blood-brain barrier function suggests that they may have a role as biomarkers in central nervous system (CNS) inflammation. The difference in inhibition of CSF biomarkers between 2 IL-1 blocking agents, anakinra and canakinumab, suggests differences in efficacy in the intrathecal compartment, with anakinra being more effective. Our data indicate that intrathecal immune responses shape CNS inflammation and should be assessed in addition to blood markers.


Assuntos
Barreira Hematoencefálica/metabolismo , Síndromes Periódicas Associadas à Criopirina/líquido cefalorraquidiano , Citocinas/metabolismo , Meningite Asséptica/líquido cefalorraquidiano , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antirreumáticos/uso terapêutico , Biomarcadores/líquido cefalorraquidiano , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Citocinas/líquido cefalorraquidiano , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Meningite Asséptica/tratamento farmacológico , Resultado do Tratamento
3.
BMJ Open ; 7(1): e014215, 2017 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-28115335

RESUMO

OBJECTIVES: Metabolic factors are major risk factors for non-alcoholic fatty liver disease although other factors may also contribute to development of fatty liver disease. We explored the association between exposure to soil heavy metals and prevalence of fatty liver disease. METHODS: We retrospectively analysed data from patients diagnosed with fatty liver disease in 2014 at the Health Evaluation Centre of Chang-Hua Christian Hospital (n=1137). We used residency data provided in the records of the Health Evaluation Centre and data for soil metal concentrations from a nationwide survey conducted by the Environmental Protection Administration of Taiwan. We studied the correlations between the severity of fatty liver disease and concentrations of soil heavy metals (arsenic, mercury, cadmium, chromium, copper, nickel, lead and zinc). RESULTS: The prevalence of moderate to severe fatty liver disease in our study was 26.5%. Using univariate and multivariate analysis, we demonstrated that the presence of soil heavy metals was a significant risk factor for fatty liver disease in men (OR 1.83, 95% CI 1.161 to 2.899, p=0.009). With stratification by body mass index (BMI) and gender, lean men with a BMI <24 kg/m2 were the most susceptible to soil heavy metals (OR 5.059, 95% CI 1.628 to 15.728, p<0.05). CONCLUSIONS: Our study suggested a significant association between exposure to soil heavy metals and fatty liver disease in lean men.


Assuntos
Metais Pesados/toxicidade , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Poluentes do Solo/toxicidade , Adulto , Distribuição por Idade , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Fatores Socioeconômicos , Taiwan/epidemiologia , Adulto Jovem
4.
Clin Infect Dis ; 64(3): 275-283, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28011613

RESUMO

BACKGROUND: Cryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology. METHODS: We describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control. We performed detailed neurological exams, cerebrospinal fluid (CSF) immunophenotyping and biomarker analysis before and after adjunctive immunomodulatory intervention with high dose pulse corticosteroids, affording causal inference into pathophysiology. RESULTS: All 6 exhibited severe lower motor neuron involvement in addition to cognitive changes and gait disturbances from meningoencephalitis. Spinal involvement was associated with asymmetric weakness and urinary retention. Diagnostic specificity was improved by MRI imaging which demonstrated lumbar spinal nerve root enhancement and clumping or lesions. Despite negative fungal cultures, CSF inflammatory biomarkers, sCD27 and sCD21, as well as the neuronal damage biomarker, neurofilament light chain (NFL), were elevated compared to healthy donor (HD) controls. Elevations in these biomarkers were associated with clinical symptoms and showed improvement with adjunctive high dose pulse corticosteroids. CONCLUSIONS: These data suggest that a post-infectious spinal arachnoiditis is an important complication of CM in previously healthy individuals, requiring heightened clinician awareness. Despite microbiological control, this syndrome causes significant pathology likely due to increased inflammation and may be amenable to suppressive therapeutics.


Assuntos
Aracnoidite/congênito , Cryptococcus , Encefalite Infecciosa/complicações , Meningite Criptocócica/complicações , Meningoencefalite/complicações , Adulto , Anti-Inflamatórios/uso terapêutico , Aracnoidite/diagnóstico por imagem , Aracnoidite/tratamento farmacológico , Aracnoidite/imunologia , Aracnoidite/microbiologia , Biomarcadores/líquido cefalorraquidiano , Relação CD4-CD8 , Feminino , Humanos , Imunossupressores/uso terapêutico , Encefalite Infecciosa/líquido cefalorraquidiano , Encefalite Infecciosa/tratamento farmacológico , Encefalite Infecciosa/imunologia , Angiografia por Ressonância Magnética , Masculino , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/imunologia , Meningoencefalite/líquido cefalorraquidiano , Meningoencefalite/tratamento farmacológico , Meningoencefalite/imunologia , Metotrexato/uso terapêutico , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Exame Neurológico , Pulsoterapia , Tacrolimo/uso terapêutico , Adulto Jovem
5.
Ann Clin Transl Neurol ; 3(3): 166-79, 2016 03.
Artigo em Inglês | MEDLINE | ID: mdl-27042677

RESUMO

OBJECTIVE: Inaccessibility of the inflammation compartmentalized to the central nervous system (CNS) may underlie the lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS). The double blind combination of Rituximab by IntraVenous and IntraThecAl injection versus placebo in patients with Low-Inflammatory SEcondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: (1) Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and (2) If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction? METHODS: Patients aged 18-65 years were randomly assigned to rituximab or placebo. Protocol-stipulated interim analysis quantified the efficacy of B-cell depletion. RESULTS: The efficacy on cerebrospinal fluid (CSF) biomarkers failed to reach criteria for continuation of the trial. B-cell-related CSF biomarkers (sCD21 and B-cell activating factor) changed only in the active-treatment arm. While CSF B cells were killed robustly (median -79.71%, P = 0.0176), B cells in CNS tissue were depleted inadequately (~-10-20%, P < 0.0001). Consequently, the T-cell-specific CSF biomarker sCD27 decreased slightly (-10.97%, P = 0.0005), while axonal damage marker, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement, and paucity of cytotoxic CD56(dim) NK cells contribute to decreased efficacy of rituximab in the CNS. INTERPRETATION: Biomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS, exposed causes for poor efficacy and determined that RIVITALISE trial would be underpowered to measure efficacy on clinical outcomes. Identified mechanisms for poor efficacy are applicable to all CNS-inflammation targeting monoclonal antibodies.

6.
Neurol Neuroimmunol Neuroinflamm ; 3(1): e196, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26848487

RESUMO

OBJECTIVE: The purpose of this study was to assess the potential immunosuppressive role of daclizumab, a humanized monoclonal antibody against the α chain of the interleukin 2 receptor, in vivo, by comparing immune responses to the 2013 seasonal influenza vaccination between patients with multiple sclerosis (MS) on long-term daclizumab therapy and controls. METHODS: Previously defined subpopulations of adaptive immune cells known to correlate with the immune response to the influenza vaccination were evaluated by 12-color flow cytometry in 23 daclizumab-treated patients with MS and 14 MS or healthy controls before (D0) and 1 day (D1) and 7 days (D7) after administration of the 2013 Afluria vaccine. Neutralizing antibody titers and CD4(+), CD8(+) T cell, B cell, and natural killer cell proliferation to 3 strains of virus contained in the Afluria vaccine were assessed at D0, D7, and 180 days postvaccination. RESULTS: Daclizumab-treated patients and controls demonstrated comparable, statistically significant expansions of previously defined subpopulations of activated CD8(+) T cells and B cells that characterize the development of effective immune responses to the influenza vaccine, while proliferation of T cells to influenza and control antigens was diminished in the daclizumab cohort. All participants fulfilled FDA criteria for seroconversion or seroprotection in antibody assays. CONCLUSION: Despite the mild immunosuppressive effects of daclizumab in vivo demonstrated by an increased incidence of infectious complications in clinical trials, patients with MS under daclizumab therapy mount normal antibody responses to influenza vaccinations.

7.
J Tissue Eng ; 6: 2041731415579215, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26090087

RESUMO

To address the functionality of diabetic adipose-derived stem cells in tissue engineering applications, adipose-derived stem cells isolated from patients with and without type II diabetes mellitus were cultured in bioreactor culture systems. The adipose-derived stem cells were differentiated into adipocytes and maintained as functional adipocytes. The bioreactor system utilizes a hollow fiber-based technology for three-dimensional perfusion of tissues in vitro, creating a model in which long-term culture of adipocytes is feasible, and providing a potential tool useful for drug discovery. Daily metabolic activity of the adipose-derived stem cells was analyzed within the medium recirculating throughout the bioreactor system. At experiment termination, tissues were extracted from bioreactors for immunohistological analyses in addition to gene and protein expression. Type II diabetic adipose-derived stem cells did not exhibit significantly different glucose consumption compared to adipose-derived stem cells from patients without type II diabetes (p > 0.05, N = 3). Expression of mature adipocyte genes was not significantly different between diabetic/non-diabetic groups (p > 0.05, N = 3). Protein expression of adipose tissue grown within all bioreactors was verified by Western blotting.The results from this small-scale study reveal adipose-derived stem cells from patients with type II diabetes when removed from diabetic environments behave metabolically similar to the same cells of non-diabetic patients when cultured in a three-dimensional perfusion bioreactor, suggesting that glucose transport across the adipocyte cell membrane, the hindrance of which being characteristic of type II diabetes, is dependent on environment. The presented observation describes a tissue-engineered tool for long-term cell culture and, following future adjustments to the culture environment and increased sample sizes, potentially for anti-diabetic drug testing.

8.
Ann Clin Transl Neurol ; 2(5): 445-55, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26000318

RESUMO

OBJECTIVE: Novel treatments such as natalizumab and fingolimod achieve their therapeutic efficacy in multiple sclerosis (MS) by blocking access of subsets of immune cells into the central nervous system, thus creating nonphysiological intrathecal immunity. In contrast, daclizumab, a humanized monoclonal antibody against the alpha chain of the IL-2 receptor, has a unique mechanism of action with multiple direct effects on innate immunity. As cellular intrathecal abnormalities corresponding to MS have been well defined, we asked how daclizumab therapy affects these immunological hallmarks of the MS disease process. METHODS: Nineteen subpopulations of immune cells were assessed in a blinded fashion in the blood and 50-fold concentrated cerebrospinal fluid (CSF) cell pellet in 32 patients with untreated relapsing-remitting MS (RRMS), 22 daclizumab-treated RRMS patients, and 11 healthy donors (HDs) using 12-color flow cytometry. RESULTS: Long-term daclizumab therapy normalized all immunophenotyping abnormalities differentiating untreated RRMS patients from HDs. Specifically, strong enrichment of adaptive immune cells (CD4+ and CD8+ T cells and B cells) in the CSF was reversed. Similarly, daclizumab controlled MS-related increases in the innate lymphoid cells (ILCs) and lymphoid tissue inducer cells in the blood and CSF, and reverted the diminished proportion of intrathecal monocytes. The only marker that distinguished daclizumab-treated MS patients from HDs was the expansion of immunoregulatory CD56(bright) NK cells. INTERPRETATION: Normalization of immunological abnormalities associated with MS by long-term daclizumab therapy suggests that this drug's effects on ILCs, NK cells, and dendritic cell-mediated antigen presentation to CD4+ and CD8+ T cells are critical in regulating the MS disease process.

9.
PLoS Pathog ; 11(5): e1004884, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26020932

RESUMO

The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell damage.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Cryptococcus neoformans/imunologia , Células Matadoras Naturais/imunologia , Meningite Criptocócica/imunologia , Células Th1/imunologia , Adulto , Autopsia , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD8-Positivos/microbiologia , Estudos de Coortes , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Células Matadoras Naturais/microbiologia , Ativação Linfocitária , Masculino , Meningite Criptocócica/líquido cefalorraquidiano , Meningite Criptocócica/microbiologia , Pessoa de Meia-Idade , Adulto Jovem
10.
Opt Lett ; 40(9): 1904-7, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25927744

RESUMO

The mid-infrared whispering-gallery-mode disk cavities with InAs0.85Sb0.15/InAs0.53P0.23Sb0.24 multiple quantum wells active medium on a GaSb substrate were fabricated. For this material system in the mid-infrared range, fabrication techniques were developed to form the disk cavity structure. The smooth sidewalls of the disk cavities were achieved by appropriate gas mixture flow ratio of BCl3/Ar in the inductively coupled plasma-reactive ion etching. In addition, selective wet etching technique was used to form the pedestal of the disk cavity using dilute hydrofluoric acid with good selectivity. For efficient confinement of the whispering gallery modes along the radial direction, the extent of the lateral etching was carefully controlled. The processed 30-µm-diameter disk cavities were optically pumped, and the whispering gallery modes with wavelengths around 4.1 µm can be observed up to 90 K.

11.
Ann Neurol ; 78(1): 3-20, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25808056

RESUMO

OBJECTIVE: The management of complex patients with neuroimmunological diseases is hindered by an inability to reliably measure intrathecal inflammation. Currently implemented laboratory tests developed >40 years ago either are not dynamic or fail to capture low levels of central nervous system (CNS) inflammation. Therefore, we aimed to identify and validate biomarkers of CNS inflammation in 2 blinded, prospectively acquired cohorts of untreated patients with neuroimmunological diseases and embedded controls, with the ultimate goal of developing clinically useful tools. METHODS: Because biomarkers with maximum utility reflect immune phenotypes, we included an assessment of cell specificity in purified primary immune cells. Biomarkers were quantified by optimized electrochemiluminescent immunoassays. RESULTS: Among markers with cell-specific secretion, soluble CD27 is a validated biomarker of intrathecal T-cell activation, with an area under the receiver operating characteristic curve of 0.97. Comparing the quantities of cerebrospinal fluid (CSF) immune cells and their respective cell-specific soluble biomarkers (released by CSF cells as well as their counterparts in CNS tissue) provided invaluable information about stationary CNS immune responses, previously attainable via brain biopsy only. Unexpectedly, progressive and relapsing-remitting multiple sclerosis (MS) patients have comparable numbers of activated intrathecal T and B cells, which are preferentially embedded in CNS tissue in the former group. INTERPRETATION: The cell-specific biomarkers of intrathecal inflammation may improve diagnosis and management of neuroimmunological diseases and provide pharmacodynamic markers for future therapeutic developments in patients with intrathecal inflammation that is not captured by imaging, such as in progressive MS.


Assuntos
Biomarcadores/líquido cefalorraquidiano , Líquido Cefalorraquidiano/citologia , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Adulto , Idoso , Linfócitos B/citologia , Estudos de Casos e Controles , Líquido Cefalorraquidiano/imunologia , Estudos de Coortes , Feminino , Humanos , Inflamação/líquido cefalorraquidiano , Subunidade p40 da Interleucina-12/líquido cefalorraquidiano , Interleucina-8/líquido cefalorraquidiano , Receptores de Lipopolissacarídeos/líquido cefalorraquidiano , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Estudos Prospectivos , Receptores de Complemento 3d/metabolismo , Linfócitos T/citologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/líquido cefalorraquidiano , Adulto Jovem
12.
Opt Lett ; 39(17): 4998-5001, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25166058

RESUMO

We demonstrate ultrafast all-optical switching in GaAs microdisk resonators using a femtosecond pump-probe technique through tapered-fiber coupling. The temporal tuning of the resonant modes resulted from the refractive index change due to photoexcited carrier density variation inside the GaAs microdisk resonator. Transmission through the GaAs microdisk resonator can be modulated by more than 10 dB with a switching time window of 8 ps in the switch-off operation using pumping pulses with energies as low as 17.5 pJ. The carrier lifetime was fitted to be 42 ps, much shorter than that of the bulk GaAs, typically of the order of nanoseconds. The above observation indicates that the surface recombination plays an important role in increasing the switching speed.

13.
J Immunol ; 192(6): 2551-63, 2014 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-24510966

RESUMO

We performed unbiased, comprehensive immunophenotyping of cerebrospinal fluid (CSF) and blood leukocytes in 221 subjects referred for the diagnostic work-up of neuroimmunological disorders to obtain insight about disease-specific phenotypes of intrathecal immune responses. Quantification of 14 different immune cell subsets, coupled with the assessment of their activation status, revealed physiological differences between intrathecal and systemic immunity, irrespective of final diagnosis. Our data are consistent with a model where the CNS shapes intrathecal immune responses to provide effective protection against persistent viral infections, especially by memory T cells, plasmacytoid dendritic cells, and CD56(bright) NK cells. Our data also argue that CSF immune cells do not simply reflect cells recruited from the periphery. Instead, they represent a mixture of cells that are recruited from the blood, have been activated intrathecally and leave the CNS after performing effector functions. Diagnosis-specific differences provide mechanistic insight into the disease process in the defined subtypes of multiple sclerosis (MS), neonatal onset multisystem inflammatory disease, and Aicardi-Goutières syndrome. This analysis also determined that secondary-progressive MS patients are immunologically closer to relapsing-remitting patients as compared with patients with primary-progressive MS. Because CSF immunophenotyping captures the biology of the intrathecal inflammatory processes, it has the potential to guide optimal selection of immunomodulatory therapies in individual patients and monitor their efficacy. Our study adds to the increasing number of publications that demonstrate poor correlation between systemic and intrathecal inflammatory biomarkers in patients with neuroimmunological diseases and stresses the importance of studying immune responses directly in the intrathecal compartment.


Assuntos
Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Imunofenotipagem/métodos , Inflamação/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Malformações do Sistema Nervoso/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Doenças Autoimunes do Sistema Nervoso/sangue , Doenças Autoimunes do Sistema Nervoso/imunologia , Antígeno CD56/imunologia , Antígeno CD56/metabolismo , Contagem de Células , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Citometria de Fluxo , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Memória Imunológica/imunologia , Inflamação/sangue , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Crônica Progressiva/imunologia , Malformações do Sistema Nervoso/sangue , Malformações do Sistema Nervoso/imunologia , Estudos Prospectivos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem
14.
Plast Reconstr Surg ; 132(2): 251e-262e, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23897353

RESUMO

BACKGROUND: Restoring peripheral nerve function after long gap peripheral nerve damage is challenging. Lithium chloride has demonstrated neuroprotective qualities and therefore shows great potential therapeutic benefit for some neurodegenerative diseases. This study examined the synergistic combination of glial cell line-derived neurotrophic factor and lithium chloride and its effect on peripheral nerve regeneration in a rat sciatic nerve injury model. METHODS: Polycaprolactone conduits with glial cell line-derived neurotrophic factor-loaded double-walled microspheres and local injections of lithium chloride, 1.5 or 2.5 mEq/kg body weight, were examined in a 15-mm rat sciatic nerve defect model. Eighteen Lewis male rats were divided randomly into control, 1.5-, and 2.5-mEq/kg lithium chloride injection groups. As an indicator of recovery, nerve sections were stained with S100, protein gene product 9.5 antibody, and toluidine blue. RESULTS: Nerves stained with S100 and protein gene product 9.5 antibody demonstrated a significantly increased density of Schwann cells and axons in the 2.5-mEq/kg lithium chloride injection-treated groups compared with both the control and 1.5-mEq/kg lithium chloride injection-treated groups (p<0.05). At 6 weeks, histomorphometry revealed a significantly higher fiber density in the middle of the conduit for the 2.5-mEq/kg groups compared with the 1.5-mEq/kg group or the control group. CONCLUSION: Polycaprolactone nerve guides with glial cell line-derived neurotrophic factor-loaded double-walled microspheres and local injections of lithium chloride, 2.5-mEq/kg, represent a potentially viable guiding material for Schwann cell and axon migration and proliferation for the treatment of peripheral nerve regeneration.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Cloreto de Lítio/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Nervo Isquiático/efeitos dos fármacos , Animais , Biópsia por Agulha , Modelos Animais de Doenças , Sinergismo Farmacológico , Imuno-Histoquímica , Masculino , Condução Nervosa/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/patologia , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Valores de Referência , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Resultado do Tratamento
15.
Acta Biomater ; 9(2): 5243-50, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23022891

RESUMO

Cell sheet technology has been studied for applications such as bone, ligament and skin regeneration. There has been limited examination of adipose-derived stem cells (ASCs) for cell sheet applications. The specific aim of this study was to evaluate ASC sheet technology for wound healing. ASCs were isolated from discarded human abdominal subcutaneous adipose tissue, and ASC cell sheets were created on the surface of fibrin-grafted culture dishes. In vitro examination consisted of the histochemical characterization of the ASC sheets. In vivo experiments consisted of implanting single-layer cell sheets, triple-layer cell sheets or non-treated control onto a full-thickness wound defect (including epidermis, dermis, and subcutaneous fat) in nude mice for 3 weeks. Cell sheets were easily peeled off from the culture dishes using forceps. The single- and triple-layer ASC sheets showed complete extracellular structure via hematoxylin & eosin staining. In vivo, the injury area was measured 7, 10, 14 and 21 days post-treatment to assess wound recovery. The ASC sheet-treated groups' injury area was significantly smaller than that of the non-treated control group at all time points except day 21. The triple-layer ASC sheet treatment significantly enhanced wound healing compared to the single-layer ASC sheet at 7, 10 and 14 days. The density of blood vessels showed that ASC cell sheet treatment slightly enhanced total vessel proliferation compared to the empty wound injury treatment. Our studies indicate that ASC sheets present a potentially viable matrix for full-thickness defect wound healing in a mouse model. Consequently, our ASC sheet technology represents a substantial advance in developing various types of three-dimensional tissues.


Assuntos
Tecido Adiposo/citologia , Transplante de Células-Tronco , Células-Tronco/citologia , Cicatrização , Adulto , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Pessoa de Meia-Idade
16.
Biomed Mater ; 7(2): 024102, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22456722

RESUMO

Acute sensory problems following peripheral nerve injury include pain and loss of sensation. Approximately 360,000 people in the United States suffer from upper extremity paralytic syndromes every year. Restoration of sufficient functional recovery after long-gap peripheral nerve damage remains a clinical challenge. Potential nerve repair therapies have increased in the past decade as the field of tissue engineering expands. The following review describes the use of biomaterials in nerve tissue engineering. Namely, the use of both synthetic and natural biomaterials, including non-degradable and degradable nerve grafts, is addressed. The enhancement of axonal regeneration can be achieved by further modification of the nerve guides. These approaches include injectable hydrogel fillers, controlled drug delivery systems, and cell incorporation. Hydrogels are a class of liquid-gel biomaterials with high water content. Injectable and gelling hydrogels can serve as growth factor delivery vehicles and cell carriers for tissue engineering applications. While natural hydrogels and polymers are suitable for short gap nerve repair, the use of polymers for relatively long gaps remains a clinical challenge.


Assuntos
Géis/administração & dosagem , Regeneração Tecidual Guiada/métodos , Regeneração Tecidual Guiada/tendências , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/terapia , Engenharia Tecidual/tendências , Tecidos Suporte , Materiais Biocompatíveis/administração & dosagem , Humanos , Injeções
17.
Tissue Eng Part C Methods ; 18(1): 54-61, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21902468

RESUMO

To further differentiate adipose-derived stem cells (ASCs) into mature adipocytes and create three-dimensional (3D) adipose tissue in vitro, we applied multicompartment hollow fiber-based bioreactor technology with decentral mass exchange for more physiological substrate gradients and integral oxygenation. We hypothesize that a dynamic 3D perfusion in such a bioreactor will result in longer-term culture of human adipocytes in vitro, thus providing metabolically active tissue serving as a diagnostic model for screening drugs to treat diabetes. ASCs were isolated from discarded human abdominal subcutaneous adipose tissue and then inoculated into dynamic 3D culture bioreactors to undergo adipogenic differentiation. Insulin-stimulated glucose uptake from the medium was assessed with and without TNF-alpha. 3D adipose tissue was generated in the 3D-bioreactors. Immunohistochemical staining indicated that 3D-bioreactor culture displayed multiple mature adipocyte markers with more unilocular morphologies as compared with two-dimensional (2D) cultures. Results of real-time polymerase chain reaction showed 3D-bioreactor treatment had more efficient differentiation in fatty acid-binding protein 4 expression. Repeated insulin stimulation resulted in increased glucose uptake, with a return to baseline between testing. Importantly, TNF-alpha inhibited glucose uptake, an indication of the metabolic activity of the tissue. 3D bioreactors allow more mature adipocyte differentiation of ASCs compared with traditional 2D culture and generate adipose tissue in vitro for up to 2 months. Reproducible metabolic activity of the adipose tissue in the bioreactor was demonstrated, which is potentially useful for drug discovery. We present here, to the best of our knowledge for the first time, the development of a coherent 3D high density fat-like tissue consisting of unilocular structure from primary adipose stem cells in vitro.


Assuntos
Adipogenia , Tecido Adiposo/citologia , Reatores Biológicos , Células-Tronco/citologia , Adipócitos/citologia , Adulto , Técnicas de Cultura de Células , Diferenciação Celular , Feminino , Humanos , Imuno-Histoquímica/métodos , Pessoa de Meia-Idade , Oxigênio/química , Perfusão , Fator de Necrose Tumoral alfa/metabolismo
18.
Plast Reconstr Surg ; 129(1): 67-78, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22186500

RESUMO

BACKGROUND: Restoration with sufficient functional recovery after long-gap peripheral nerve damage remains a clinical challenge. In vitro, keratins, which are derived from human hair, enhance activity and gene expression of Schwann cells. The specific aim of the authors' study was to examine keratin gel as conduit filler for peripheral nerve regeneration in a rat sciatic nerve injury model. METHODS: Incorporation of glial cell line-derived, neurotrophic factor, double-walled microspheres into polycaprolactone nerve guides has demonstrated an off-the-shelf product alternative to promote nerve regeneration, and this conduit was filled with keratin gel and examined in a rat 15-mm sciatic nerve defect model. As an indicator of recovery, nerve sections were stained with S100 and protein gene product 9.5 antibody. RESULTS: The keratin-treated groups, compared with both saline and empty polycaprolactone (control) groups (p < 0.05), demonstrated a significantly increased density of Schwann cells and axons. Polycaprolactone-based nerve conduits possess optimal mechanical and degradative properties, rendering the biocompatible conduits potentially useful in peripheral nerve repair. CONCLUSION: From their studies, the authors conclude that polycaprolactone nerve guides with glial cell line-derived, neurotrophic factor-loaded, double-walled microspheres filled with keratin gel represent a potentially viable guiding material for Schwann cell and axon migration and proliferation in the treatment of peripheral nerve regeneration.


Assuntos
Regeneração Nervosa , Traumatismos dos Nervos Periféricos/cirurgia , Nervo Isquiático/lesões , Engenharia Tecidual/métodos , Tecidos Suporte , Géis , Humanos , Queratinas , Modelos Animais , Músculo Esquelético/patologia , Tamanho do Órgão , Poliésteres , Células de Schwann , Cicatrização/fisiologia
20.
Ann Plast Surg ; 67(2): 147-55, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21712696

RESUMO

Restoration with sufficient functional recovery after long-gap peripheral nerve damage remains a clinical challenge. Silk has shown clinical promise for numerous tissue engineering applications due to its biocompatibility, impressive mechanical properties, and Food and Drug Administration approval. The aim of this study was to evaluate the efficacy of silk fibroin--based nerve guides containing glial cell line-derived neurotrophic factor (GDNF) in a long-gap sized (15 mm) rat sciatic nerve defect model. Four groups of nerve conduits were prepared: (1) silk conduits with empty silk microspheres, (2) silk conduits with GDNF-loaded silk microspheres uniformly distributed in the conduit wall, (3) silk conduits with GDNF-loaded silk microspheres in a controlled manner with the highest GDNF concentration at the distal end, and (4) isograft. After 6 weeks, the nerve grafts were explanted, harvested, and fixed for histologic analysis. Nerve tissue stained with the S-100, and neuroendocrine marker PGP 9.5 antibodies demonstrated a significantly increased density of nerve tissue in the GDNF-treated groups compared with the empty microsphere (control) group (P < 0.05). GDNF-treated animals with a higher concentration of GDNF in the distal portion possessed a significantly higher density of PGP 9.5 protein middle conduit part than comparison to GDNF uniform-treated animals (P < 0.05). Silk-based nerve conduits possess optimal mechanical and degradative properties, rendering them potentially useful in peripheral nerve repair. This study demonstrates that novel, porous silk fibroin--based nerve conduits, infused with GDNF in a controlled manner, represent a potentially viable conduit for Schwann cell migration and proliferation in the regeneration of peripheral nerves.


Assuntos
Fibroínas , Fator Neurotrófico Derivado de Linhagem de Célula Glial/administração & dosagem , Regeneração Tecidual Guiada/métodos , Regeneração Nervosa , Nervo Isquiático/cirurgia , Tecidos Suporte , Animais , Fibroínas/química , Microesferas , Músculo Esquelético/inervação , Distribuição Aleatória , Ratos , Células de Schwann/fisiologia , Nervo Isquiático/lesões , Nervo Isquiático/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...