RESUMO
Objective: Successful rheumatoid arthritis (RA) outcome depends on treatment efficacy in the early stages of the disease and its sustainability. It is thus critical to identify factors predicting treatment persistence with biological agents, such as abatacept. We compared clinical profiles, including early changes in autoantibody titres at 3 months, between patients with RA demonstrating sustained persistence and those discontinuing abatacept treatment.Method: We prospectively enrolled 71 and 78 active RA patients treated with abatacept and tumour necrosis factor inhibitors (TNF-Is), respectively, who had previous disease-modifying anti-rheumatic drug) failure. Clinical characteristics were compared between non-continuation and continuation groups stratified according to abatacept or TNF-I persistence for at least 12 months from treatment initiation.Results: Significantly larger decreases in rheumatoid factor titre and anti-citrullinated protein autoantibody (ACPA) titre were observed in the continuation group of abatacept therapy at 3 months, and early reduction in ACPA titre remained a significant and independent predictor of sustained persistence with abatacept in multivariate analysis. In addition, we obtained the area under the receiver operator characteristics curve of 0.904 from a model including baseline ACPA titre and reduction of ACPA titre at 3 months. Sustained reduction of RA disease activity score at 12 months was significantly and independently associated with reduced ACPA titre at 3 months.Conclusions: Persistence with abatacept and sustained therapeutic response are associated with an early reduction in ACPA titre. Prediction of abatacept continuation and efficacy will facilitate the optimal design of therapy in the early stages of RA.
Assuntos
Abatacepte/administração & dosagem , Anticorpos Antiproteína Citrulinada/sangue , Artrite Reumatoide/imunologia , Idoso , Anticorpos Antiproteína Citrulinada/imunologia , Antirreumáticos/administração & dosagem , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Japão , Masculino , Estudos Prospectivos , Resultado do Tratamento , UltrassonografiaRESUMO
BACKGROUND: Lupus nephritis (LN) is a major determinant of mortality in systemic lupus erythematosus (SLE). Here we evaluated the association between complete renal response (CR) and mortality in LN. METHODS: We retrospectively analyzed the cases of 172 of 201 patients with LN for whom data on the therapeutic response at 6 and 12 months after induction therapy were available. The patients underwent a renal biopsy at Nagasaki University Hospital and community hospitals in Nagasaki between the years 1990 and 2016. We determined the CR rates at 6 and 12 months after induction therapy initiation and evaluated the predictive factors for CR and their relationship with mortality. We performed univariate and multivariable competing risks regression analyses to determine the factors predictive of CR. The patients' survival data were analyzed by the Kaplan-Meier method with a log-rank test. RESULTS: The median follow-up duration after renal biopsy was 120 months (interquartile range: 60.3-191.8 months). The 5-, 10-, 15- and 20-year survival rates of our cohort were 99.3, 94.6, 92.0 and 85.4%, respectively. During follow-up, nine patients (5.2%) died from cardiovascular events, infection, malignancy and other causes. The multivariate analysis revealed that the following factors were predictive of CR. At 6 months: male gender (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.08-0.65, p = 0.0028), proteinuria (g/gCr) (OR 0.83, 95% CI 0.71-0.97, p = 0.0098) and index of activity (0-24) (OR 0.84, 95% CI 0.71-0.99, p = 0.0382). At 12 months: male gender (OR 0.25, 95% CI 0.09-0.67, p = 0.0043) and index of activity (0-24) (OR 0.82, 95% CI 0.69-0.98, p = 0.0236). The Kaplan-Meier analysis showed that compared to not achieving CR at 12 months, achieving CR at 12 months was significantly correlated with the survival rate (OR 0.18, 95% CI 0.04-0.92, p = 0.0339). CONCLUSIONS: Our results suggest that the survival rate of patients with LN is associated with the achievement of CR at 12 months after induction therapy, and that male gender and a higher index of activity (0-24) are the common predictive factors for failure to achieve CR at 6 and 12 months.
Assuntos
Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/mortalidade , Prednisolona/uso terapêutico , Adulto , Idade de Início , Estudos de Casos e Controles , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteinúria , Indução de Remissão , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores SexuaisRESUMO
L5/L6 spinal nerve ligation (SNL) in rodents induces behavioral signs similar to the symptoms of neuropathic pain in humans. L5/L6 SNL in rats has been well characterized so far, but there have been few studies using mice. In this study, we established an L5/L6 SNL model in mice and examined the effects of known antinociceptive drugs in the model. We also analyzed the changes in gene expression in dorsal root ganglions with special reference to those which are known to change in a neuropathic pain state to validate the model. Mechanical allodynia in the ipsilateral side paw was observed beginning on day 1 and lasted for at least 2 months following surgery. Diclofenac showed no significant effect on the mechanical allodynia. Gabapentin and pregabalin completely reversed allodynia, but they also caused a decrease in locomotor activity. Duloxetine caused a partial recovery of the threshold. Mexiletine completely reversed allodynia, but it also caused sedation or motor impairment. Morphine caused a partial recovery of the threshold and hyper-locomotion. This mouse L5/L6 SNL model represents a robust mechanical allodynia, which shows a similar pharmacological response to that reported in rats and human patients with neuropathic pain. The pattern changes in gene expression also resembled those reported in rats. This model will therefore be useful for investigation of the effects of novel antinociceptive compounds and the mechanisms of neuropathic pain.
Assuntos
Analgésicos/farmacologia , Dor/genética , Doenças do Sistema Nervoso Periférico/genética , Nervos Espinhais/fisiologia , Analgésicos não Narcóticos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Perfilação da Expressão Gênica , Injeções Espinhais , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Neurológicos , Atividade Motora/efeitos dos fármacos , Fatores de Crescimento Neural/metabolismo , Neuropeptídeos/metabolismo , Dor/etiologia , Doenças do Sistema Nervoso Periférico/complicações , Estimulação Física , Antagonistas do Receptor Purinérgico P2 , Receptores Purinérgicos P2X2 , Receptores Purinérgicos P2X3 , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND AND PURPOSE: Despite the rapid progress made in understanding the significant role played by signalling via extracellular ATP in physiology and pathology, there has been no clear information generated on its involvement in the emetic response. EXPERIMENTAL APPROACH: In the present study, the emetogenic potential of extracellular ATP signalling in mammalian species was examined using ferrets and Suncus murinus (house musk shrews). A slowly degradable ATP analogue, alpha,beta-methyleneATP (alpha,beta-meATP), was used to activate the P2X receptors, and either the non-selective P2 receptor antagonist, pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), or the specific P2X(3) homomer and P2X(2/3) heteromer antagonist, A-317491, were tested against the agonist-induced response. KEY RESULTS: Intraperitoneal injection of alpha,beta-meATP produced significant emetic responses in ferrets (1 - 30 mg kg(-1)) and in Suncus murinus (5 - 50 mg kg(-1)). The responses occurred frequently within the first 10 min after administration, much less frequently from 11 to 60 min and no responses occurred later than 60 min. The emetic responses were completely inhibited by intraperitoneal pre-treatment with PPADS (100 mg kg(-1)) or A-317491 (100 mg kg(-1)). Abdominal surgical vagotomy did not reduce the emetic response in Suncus murinus significantly. CONCLUSIONS AND IMPLICATIONS: These results for the first time indicate that the activation of P2X receptors evokes emetic responses in mammalian species. The P2X(3) homomer and.or P2X(2/3) heteromer in the area postrema could be responsible for the emetic response. This finding contributes to the elucidation of the roles played by extracellular ATP signalling in various emetic symptoms.
Assuntos
Receptores Purinérgicos P2/fisiologia , Vômito/fisiopatologia , Trifosfato de Adenosina/administração & dosagem , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Furões , Injeções Intraperitoneais , Masculino , Modelos Animais , Náusea/fisiopatologia , Náusea/prevenção & controle , Fenóis/administração & dosagem , Fenóis/farmacologia , Compostos Policíclicos/administração & dosagem , Compostos Policíclicos/farmacologia , Agonistas do Receptor Purinérgico P2 , Antagonistas do Receptor Purinérgico P2 , Fosfato de Piridoxal/administração & dosagem , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Musaranhos , Especificidade da Espécie , Fatores de Tempo , Vagotomia/métodos , Vômito/prevenção & controleRESUMO
OBJECTIVE: To test for association of the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) K121Q polymorphism with body mass index (BMI) and diabetes in a large sample of Caucasians and African-Americans by selectively genotyping individuals at the extremes of the phenotypic distribution. SUBJECTS: Subsets comprising the extremes of the BMI distribution (10th-20th and above the 90th BMI percentile for Caucasians and between the 10th-30th and above the 80th percentile for African-Americans) from a group of 10,260 Caucasian and 2268 African-American adults participating in New York Cancer Project were studied. METHODS: Subjects were genotyped for the ENPP1 K121Q polymorphism by pyrosequencing and tested for association with BMI and diabetes by regression analysis. RESULTS: Regression analysis with BMI as the dependent variable demonstrated a significant association (P = 0.02) of genotype at K121Q with BMI, with no significant race-by-genotype interaction (P = 0.30). Compared with Q/Q or Q/K individuals, the K/K individuals had a BMI approximately 1.3 kg/m2 higher, without effects of age, gender or race. By logistic regression analysis, the K121Q alleles had no significant effect on diabetes status (P = 0.37) in obese subjects. CONCLUSION: In both Caucasians and African-Americans, the K121 polymorphism in ENPP1 was associated with increased BMI, but not with diabetes.
Assuntos
Negro ou Afro-Americano/genética , Obesidade Mórbida/genética , Diester Fosfórico Hidrolases/genética , Polimorfismo Genético , Pirofosfatases/genética , População Branca/genética , Adulto , Alelos , Índice de Massa Corporal , Distribuição de Qui-Quadrado , Diabetes Mellitus/etnologia , Diabetes Mellitus/genética , Feminino , Frequência do Gene , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , New York , Obesidade Mórbida/etnologia , Reação em Cadeia da Polimerase/métodos , Estudos ProspectivosRESUMO
BACKGROUND AND OBJECTIVE: Phosphodiesterase-III inhibitors and dobutamine effectively improve cardiac function in patients with cardiac failure, but they are limited by possible hypotensive effects. We tested the hypothesis that dopamine contributes to stabilizing milrinone-induced haemodynamic changes. METHODS: Nine patients undergoing major surgery were anaesthetized using nitrous oxide and oxygen supplemented with isoflurane 1-2%. After baseline haemodynamics were recorded, milrinone (25 or 50 microg kg(-1)) was administered over 10min, followed by a continuous infusion (0.5 microg kg(-1) min(-1). The second set of haemodynamic values was measured 50 min after beginning the continuous infusion of milrinone. Dopamine (4 microg kg(-1) min(-1)) was then administered with milrinone. RESULTS: Milrinone significantly increased the heart rate from 81 +/- 8 to 102 +/- 16beats min(-1), but it decreased the mean arterial pressure from 83 +/- 10 to 66 +/- 10 mmHg and systemic vascular resistance (P < 0.05 for each). The pulmonary capillary wedge pressure, cardiac index and pulmonary vascular resistance did not change significantly. The addition of dopamine to the milrinone infusion significantly decreased the heart rate (94 +/- 12 beats min(-1)) and increased the mean arterial pressure (82 +/- 11 mmHg). Dopamine and milrinone, but not milrinone alone, significantly increased the cardiac index and the rate-pressure product. CONCLUSIONS: The combination regimen of milrinone and dopamine improved cardiac function, and changes in heart rate and mean arterial pressure induced by milrinone were attenuated by dopamine. The results suggest that a combination regimen of milrinone and dopamine rather than milrinone alone should be used to maintain arterial pressure.
Assuntos
Anestesia Geral , Anestésicos Inalatórios/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/farmacologia , Neoplasias do Sistema Digestório/cirurgia , Dopamina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Isoflurano/uso terapêutico , Milrinona/farmacologia , Análise de Variância , Quimioterapia Combinada , Humanos , MasculinoRESUMO
To evaluate the transgenic mouse carrying a human prototype c-Ha-ras gene (rasH2 mouse) as a model for 26-week carcinogenicity tests, Di(2-ethylhexyl)phthalate (DEHP), a peroxisome proliferator, was administered to 15 rasH2 mice/sex/group at concentrations of 1,500, 3,000 or 6,000 ppm, and to 15 wild-type (non-Tg) mice/sex/group at a concentration of 6,000 ppm in their diets for 26 weeks. Survival rates and food consumption in the groups treated with DEHP and in the control group were similar. Body weight gain in rasH2 and non-Tg mice at 6,000 ppm in the terminal week decreased about 10% as compared to the control group. Common findings related to treatment with DEHP in rasH2 and non-Tg mice included hypertrophy with coarse granules and deposit of pigment in the liver, hydronephrosis and tubular regeneration in the kidney, focal atrophy in the testis, and increased eosinophilic body in the nasal cavity. Hepatocellular adenoma was induced by treatment with DEHP, and was confined to male rasH2; mice the incidence being 7%(1/15), 13%(2/15), and 27%(4/15) in the 1,500-, 3,000-, and 6,000-ppm group, respectively. Point mutation was not detected in codon 12 and 61 of human c-Ha-ras transgene upon DNA analyses on frozen samples taken from these hepatocellular adenomas. From the results obtained in this 26-week carcinogenicity study, it is concluded that DEHP is a hepato-carcinogen for transgenic mouse carrying a human prototype c-Ha-ras gene.
Assuntos
Adenoma de Células Hepáticas/genética , Dietilexilftalato/toxicidade , Genes ras , Neoplasias Hepáticas Experimentais/genética , Proliferadores de Peroxissomos/toxicidade , Adenoma de Células Hepáticas/induzido quimicamente , Adenoma de Células Hepáticas/patologia , Administração Oral , Animais , Testes de Carcinogenicidade/métodos , Dietilexilftalato/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Transgênicos , Cavidade Nasal/efeitos dos fármacos , Cavidade Nasal/patologia , Proliferadores de Peroxissomos/administração & dosagem , Polimorfismo Conformacional de Fita Simples , Fatores Sexuais , Taxa de Sobrevida , Testículo/efeitos dos fármacos , Testículo/patologia , Fatores de TempoRESUMO
We have recently reported the accumulation of oligoclonal activated T cells in the spontaneously developed autoimmune pancreatitis in aly/aly mouse. In this study, we examined the effects of FK506 in this mouse model in preventing autoimmune pancreatitis and investigated its action on calcium signalling apoptosis of alymphoplasia (aly) lymphocytes in vitro. Mice were treated with FK506 from 8 to 25 weeks of age. At the age of 15 weeks, minimal mononuclear cell infiltration was observed in the pancreas in both the FK506 treated group and the control group. Furthermore, a marked cell infiltration associated with destruction of acini and partial fatty changes were observed in 25-week-old control mice. In contrast, FK506 treated mice showed almost no tissue destruction or mononuclear cell infiltration at the age of 25 weeks. Furthermore, at 15 weeks of age, most mononuclear cells in FK506-treated mice were TUNEL positive, whereas only a few were positive in control mice. This augmentation of T cell apoptosis by FK506 was confirmed using naive splenocytes activated by PMA and ionomycin in vitro. Finally, a suppressive effect of FK506 on Bcl-2 production but not on Bax production was confirmed by Western blotting. This unique effect of FK506 on the augmentation of T cell apoptosis is probably one of the mechanisms explaining its beneficial effect on aly autoimmune pancreatitis.
Assuntos
Apoptose , Sinalização do Cálcio , Imunossupressores/farmacologia , Linfócitos T/efeitos dos fármacos , Tacrolimo/farmacologia , Animais , Doenças Autoimunes/tratamento farmacológico , Células Cultivadas , Imunossupressores/uso terapêutico , Camundongos , Pancreatite/tratamento farmacológico , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Receptores de Antígenos de Linfócitos T/biossíntese , Linfócitos T/citologia , Linfócitos T/imunologia , Tacrolimo/uso terapêutico , Proteína X Associada a bcl-2RESUMO
According to the results of to a survey conducted by the Japanese Society of Nuclear Medicine Technology in 1995, the mean monthly exposure dose to the trunk of nuclear medicine technicians was less than 0.2 mSv at more than 75% of the institutions, whereas the exposure dose to the fingers exceeded 0.5 mSv at 30% of the institutions. Many recent radiopharmaceuticals are being supplied as the syringe type, and while the syringe is surrounded by a tungsten or lead-glass shield, there is no shielding of the syringe needle or the plungers. The plastic plunger provides little shielding effect, and even when a tungsten plunger is used, calculating back from the leakage rate, the shielding effect for 99mTc is approximately 75%. We therefore trial-manufactured a plunger devised in such a manner as to considerably reduce exposure of the fingers and evaluated its shielding effect from leakage rate obtained with a dual-detector scintillation camera when the radionuclides 99mTc, 67Ga, 201Tl, and 123I were used. Its performance was satisfactory, with shielding effects (99mTc, 99%; 67Ga, 95%, 201Tl, 95%; 123I, 73%) about the same or better than back-calculated from the leakage rates.
Assuntos
Dedos/efeitos da radiação , Exposição Ocupacional/prevenção & controle , Equipamentos de Proteção/normas , Proteção Radiológica/instrumentação , Humanos , Proteção Radiológica/normas , Contagem de Cintilação , Seringas , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
AIMS: Extended lymphadenectomy for rectal cancer has been superseded by autonomic nerve-sparing surgery, but it still has historical significance. It is useful to document the long-term outcome of urinary function in cases who had resection of the inferior hypogastric nerve plexus (pelvic nerve plexus). METHODS: The long-term urinary function following extended lymphadenectomy was studied retrospectively through the medical records of 83 patients who had been followed-up for more than 5 years after surgery. RESULTS: Forty-four per cent of the male patients and 17% of the female patients had to perform clean intermittent self-catheterization (CIC) for more than 1 year; these rates were almost the same at 3 years after the procedure. Urinary incontinence was reported in 34% of the male patients and 45% of the female patients. Complicated cystitis (eight patients), complicated pyelonephritis (two patients), bladder stones (five patients) that required surgical treatment, and chronic renal failure (two patients) were considered as adverse outcomes of extended surgery. In particular, one case needed to undergo urinary diversion. CONCLUSIONS: A surprisingly large proportion of patients suffered various urinary tract problems due to extended lymphadenectomy. The findings demonstrate the importance of selection of well-balanced operations that can encompass both radicality and quality of life. The extent of resection should be decided by the extent of the cancer and routine excision of the inferior hypogastric nerve plexus should not be performed.
Assuntos
Denervação Autônoma/efeitos adversos , Excisão de Linfonodo , Neoplasias Retais/cirurgia , Transtornos Urinários/etiologia , Adulto , Idoso , Feminino , Humanos , Plexo Hipogástrico/cirurgia , Masculino , Pessoa de Meia-Idade , Pelve/inervação , Estudos Retrospectivos , Resultado do Tratamento , Doenças Urológicas/etiologiaRESUMO
A 61-year-old woman had repeated episodes of muscle weakness of face, neck and limbs for 18 years. She was diagnosed as having myasthenia gravis (MG) by the positive anti-acetylcholine receptor antibody and findings of electromyogram. Simultaneously, she was noticed to have diabetes mellitus with high titers of anti-glutamic acid decarboxylase (GAD) antibody. Magnetic resonance imaging showed a large thymoma. In spite of the improvement of MG after thymectomy, the insulin secretion slowly exacerbated during next two years. The clinical course of her disease was characteristic as slowly progressive insulin dependent diabetes mellitus (SPIDDM). She continued to have positive autoantibody against beta-cell of pancreas. Recently, anti-GAD antibody is detected in patients with SPIDDM and stiffman syndrome (SS) in high rate, and it is closely associated with the cause of these syndromes. The patient did not reveal the symptoms of SS. From the clinical course, MG and SPIDDM in this patient may be caused by a common underlying autoimmune abnormality resulting from the long presence of the thymoma. MG and SPIDDM may be derived from organ-specific autoimmunopathy from the defect of self-tolerance.
Assuntos
Autoanticorpos/sangue , Glutamato Descarboxilase/imunologia , Miastenia Gravis/complicações , Timoma/complicações , Neoplasias do Timo/complicações , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
A novel rat model of hereditary renal cell carcinoma (RC) was found in a rat colony of the Sprague-Dawley strain in Japan, and named the rising "Nihon" rat. In this strain, RCs develop from early preneoplastic lesions, which begin to appear at 4 weeks of age, forming adenomas by the age of 16 weeks. The RCs are predominantly of clear cell type. Southern blot, northern blot and SSCP analyses revealed no change in the Tsc1, Tsc2, VHL, and c-Met genes. Thus, the Nihon rat should be a valuable experimental model for understanding renal carcinogenesis, especially clear cell type, which is common among human RCs.
Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Ligases , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Animais , Northern Blotting , Southern Blotting , Carcinoma de Células Renais/patologia , Cruzamentos Genéticos , Modelos Animais de Doenças , Feminino , Genes Dominantes/genética , Genes Supressores de Tumor , Neoplasias Renais/patologia , Masculino , Mutação , Linhagem , Fenótipo , Polimorfismo Conformacional de Fita Simples , Proteínas/genética , Proteínas Proto-Oncogênicas c-met/genética , Ratos , Ratos Sprague-Dawley , Proteínas Repressoras/genética , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteína Supressora de Tumor Von Hippel-LindauRESUMO
We constructed two replication-deficient recombinant adenovirus vectors coding human basic fibroblast growth factor (bFGF), one with and one without the interleukin-2 (IL-2) secretory signal sequence and examined their neurotrophic effects on primary neuronal cells in vitro. The primary neuronal cells were successfully infected at a high efficiency with the adenovirus vectors. bFGF protein was detected in the culture medium of the neurons infected with both these vectors. The cells infected with the bFGF-expressing adenovirus containing the IL-2 signal sequence showed 2- to 10-fold higher levels of secretion levels than cells infected with the native bFGF-expressing adenovirus alone. Both bFGF-expressing vectors augmented the survival of primary neuronal cells in an in vitro culture, compared with a mock infection or control virus infection. Notably, the cells infected with the bFGF-expressing adenovirus containing the IL-2 signal sequence were markedly enhanced cell survival in the early phase of the culture, compared with the control cells and even those infected with the bFGF-expressing adenovirus without the IL-2 signal sequence. However, in the late phase of neuronal culture, neither viral vector could support the cell survival. In contrast the co-infection of the bFGF-expressing vector with a Bcl-xL-expressing vector was extremely effective on neuronal survival.
Assuntos
Adenoviridae/genética , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/fisiologia , Técnicas de Transferência de Genes , Neurônios/fisiologia , Adenoviridae/metabolismo , Infecções por Adenoviridae/metabolismo , Animais , Sobrevivência Celular/fisiologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Humanos , Interleucina-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Proteína bcl-XRESUMO
Damage to the paraspinal muscle after various lumbar back surgery procedures was evaluated by measuring the paraspinal muscle thickness preoperatively and postoperatively in 89 patients, 61 males and 28 females. There were 42 single interlaminar level procedures (SL group), 13 multiple interlaminar level procedures (ML group), and 34 posterolateral fusion procedures (PLF group). Changes in paraspinal muscle thickness were evaluated at more than 10 months after surgery, because muscle swelling continued as long as 10 months after surgery, and then reduced as the edema subsided. Postoperative serum creatine phosphokinase (CPK) level on postoperative day 2 was also measured. The decrease of paraspinal muscle thickness was significantly larger in the PLF group than in the SL group (-12.9% and -2.7%, respectively, p < 0.02). There was no significant correlation between postoperative serum CPK level and decrease of paraspinal muscle thickness. However, the postoperative elevation of serum CPK level was significantly higher in the PLF group than in the SL and ML groups (979 +/- 114 vs. 292 +/- 45 and 410 +/- 44 IU/l, respectively, p < 0.001). In conclusion, posterolateral fusion is the most invasive procedure of the paraspinal muscles in various lumbar back surgery procedures. Paraspinal muscle damage during lumbar back surgery may be one of the most important factors that causes atrophy of the muscles.
Assuntos
Laminectomia , Vértebras Lombares/cirurgia , Atrofia Muscular/patologia , Complicações Pós-Operatórias/patologia , Fusão Vertebral , Adulto , Idoso , Idoso de 80 Anos ou mais , Creatina Quinase/sangue , Edema/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologiaRESUMO
Cerebral ischemic disease often causes morbidity and mortality, while the induction of new blood vessels is expected to provide a therapeutic effect in this occlusive cerebrovascular disease. In this study, we utilized two replication-deficient adenoviral vectors containing cDNA from basic fibroblast growth factor (bFGF), a well-known angiogenic factor, and examined whether biological angiogenic activity of adenovirally gene-transferred bFGF could be observed in the rat brain. One vector contained native cDNA from bFGF without the secretory signal sequence and the other contained the same cDNA fused with an interleukin-2 secretory signal sequence. After ventricular administration of these viral vectors, gene-transferred cells demonstrated a high immunoreactivity against the anti-bFGF antibody and a remarkably high concentration of bFGF was detected in the cerebrospinal fluid. A semiquantitative analysis of angiogenic activity revealed that bFGF gene transfer induced angiogenesis in normal rat brains, with a more pronounced angiogenic effect seen with the vector of a secreted form than with the vector without a secretory signal sequence. These results suggest that bFGF gene transfer using these adenoviral vectors might be useful for the treatment of ischemic cerebrovascular disease.
Assuntos
Adenoviridae/genética , Encéfalo/irrigação sanguínea , Fator 2 de Crescimento de Fibroblastos/genética , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Neovascularização Fisiológica/genética , Animais , Encéfalo/metabolismo , Ensaio de Imunoadsorção Enzimática/métodos , Fator 2 de Crescimento de Fibroblastos/análise , Expressão Gênica , Imuno-Histoquímica , Masculino , Ratos , Ratos Wistar , Transfecção/métodosRESUMO
STUDY DESIGN: A case report. OBJECTIVES: To understand a rare case of ligamentum flavum progressive hematoma. SUMMARY OF BACKGROUND DATA: Previously there were only two reports about ligamentum flavum hematoma. METHODS: A patient was surgically treated for ligamentum flavum hematoma causing progressive L5 radiculopathy. Clinical and neuroradiologic features were reported, and the literature was reviewed. RESULTS: The etiology of this case could not be defined except by minor back injury. In spite of conservative therapy, the symptoms were progressive for 7 months. Magnetic resonance imaging demonstrated the epidural mass lesion at L4-L5 that was continuous with the ligamentum flavum. The mass was hypointense in T1-weighted images and central hyperintense and marginal hypointense in T2-weighted images. The margin was well enhanced by Gd-DTPA administration. After removal of the mass lesion, the patient's symptoms completely resolved. Before surgery, accurate diagnosis was difficult even based on magnetic resonance imaging and was achieved after histologic examinations. CONCLUSIONS: Surgery could be a choice of the treatment modality to resolve symptoms in ligamentum flavum hematoma.
Assuntos
Hematoma/cirurgia , Ligamento Amarelo/cirurgia , Traumatismos da Medula Espinal/cirurgia , Hematoma/diagnóstico por imagem , Humanos , Ligamento Amarelo/diagnóstico por imagem , Ligamento Amarelo/lesões , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/lesões , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Radiografia , Traumatismos da Medula Espinal/diagnóstico por imagemRESUMO
The accumulation of activated CD4+ T cells and antigen (Ag)-dependent cellular interactions between thyrocytes and CD4+ T cells have been determined in thyroid gland from patients with Graves' disease. The Fas/Fas ligand (FasL) interaction between antigen-presenting cells and T cells regulates the apoptosis of the former cells triggered by the latter cells. The inhibition of Fas-mediated apoptosis in thyrocytes could be a underlying mechanism of hyperplasia of thyrocytes in patients with Graves' disease. We investigated the potential role of Fas/FasL interaction between thyrocytes and CD4+ T cells in the induction of Fas-mediated apoptosis of the former cells induced by the latter cells. The presence of only a few specific T cells responsive to a putative autoantigen has hampered the investigation of specific T cell activation toward antigen-presenting cells (APCs). Therefore, we used a superantigen, staphylococcal enterotoxin B (SEB), to examine specific T cell activation toward thyrocytes in vitro since it stimulates a large proportion of T cells with particular Vbeta elements. Spontaneous apoptosis of thyrocytes in culture was not found even in the presence of various kinds of cytokines. In contrast, a clear induction of Fas-mediated apoptosis by anti-Fas IgM was determined in interferon-gamma (IFN-gamma)-stimulated thyrocytes. In addition, a significant cytotoxicity of purified CD4+ T cells toward IFN-gamma-stimulated thyrocytes in the presence of SEB was induced, and the addition of anti-HLA-DR and -DQ monoclonal antibodies (mAbs) or blockade of the Fas/FasL interaction reduced this cytotoxicity. FasL expression of CD4+ T cells cocultured with IFN-gamma-stimulated thyrocytes in the presence of SEB was clearly induced. Furthermore, the addition of mAbs against CD54 and CD58 inhibited both cytotoxicity and FasL expression of CD4+ T cells. The cytotoxicity of CD4+ T cells toward IFN-gamma-stimulated, SEB-pulsed thyrocytes was markedly inhibited when we used thyrocytes cultured with IFN-gamma in the presence of thyroid-stimulating hormone (TSH) as target cells. Our results suggest that 1) CD4+ T cells were activated by thyrocytes expressing MHC class II molecules in an SEB-dependent manner and then expressed FasL. 2) These activated FasL+ CD4+ T cells killed thyrocytes by interacting with Fas on thyrocytes and FasL on activated CD4+ T cells. The presence of costimulating molecules such as CD54 and CD58 on thyrocytes was also necessary to generate activated FasL+ CD4+ T cells. 3) Since the actions of thyroid stimulating antibody (TSAb) toward thyrocytes are similar to those of TSH, one goitrogenic activity of TSAb may, in part, be due to the inhibitory effect on Fas-mediated apoptosis of thyrocytes triggered by activated CD4+ T cells.
Assuntos
Apoptose/imunologia , Linfócitos T CD4-Positivos/imunologia , Citotoxicidade Imunológica , Glicoproteínas de Membrana/imunologia , Glândula Tireoide/imunologia , Tireotropina/imunologia , Receptor fas/imunologia , Linfócitos T CD4-Positivos/patologia , Proteína Ligante Fas , Doença de Graves/imunologia , Doença de Graves/patologia , Humanos , Glândula Tireoide/patologia , Tireotropina/farmacologiaRESUMO
Our recent work demonstrated functional Fas expression on human osteoblasts, and the histologic examination of the periarticular osteoporosis region in patients with rheumatoid arthritis (RA) showed apoptosis in osteoblasts. High concentrations of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and IL-6--which are thought to increase bone resorption--have been determined in RA synovium. We investigated the effect of these cytokines on the Fas-mediated apoptosis of human osteoblasts. The human osteoblastic cell line MG63 and human primary osteoblast-like cells from bone biopsy specimens were used as human osteoblasts. Fas expression on these cells was examined by flow cytometry, and Fas-mediated apoptosis induced by anti-Fas immunoglobulin M (IgM) was determined by a chromium 51 release assay, the presence of cells with hypodiploid DNA, staining with Hoechst 33258 dye, and the detection of DNA fragmentation on agarose gel electrophoresis. The proliferation of osteoblasts was analyzed by a tritiated thymidine incorporation assay. Spontaneous apoptosis was not found on cultured osteoblasts. The apoptosis of human osteoblasts was not induced by TNF-alpha, IL-1beta, or IL-6 alone in the absence of anti-Fas IgM. In addition, proliferation of the cells was not affected by these cytokines. Fas was constitutively expressed on unstimulated osteoblasts, and treatment of these cells with IL-1beta or TNF-alpha significantly augmented Fas expression. Human osteoblasts were committed to apoptosis with anti-Fas IgM, and the treatment of both IL-1beta and TNF-alpha markedly increased Fas-mediated apoptosis. TNF-alpha augmented both Fas expression and Fas-mediated apoptosis more efficiently than did IL-1beta. In addition, an additive effect on both Fas expression and Fas-mediated apoptosis was demonstrated when TNF-alpha and IL-1beta were added to osteoblasts. IL-6 influenced neither Fas expression nor the Fas-mediated apoptosis of osteoblasts. Furthermore, no synergistic effect of IL-6 with IL-1beta or TNF-alpha was observed. IL-1beta, TNF-alpha, or IL-6 did not change Bcl-2 expression. Our results suggest that IL-1beta and TNF-alpha regulate osteoblast cell number by up-regulating the Fas-mediated apoptosis of osteoblasts, one of the putative mechanisms inducing periarticular osteoporosis in patients with RA.
Assuntos
Apoptose/efeitos dos fármacos , Apoptose/imunologia , Interleucina-1/farmacologia , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Receptor fas/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Fragmentação do DNA/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Imunoglobulina M/administração & dosagem , Interleucina-1/administração & dosagem , Interleucina-6/farmacologia , Osteoblastos/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Necrose Tumoral alfa/administração & dosagemRESUMO
Bcl-xL is a Bcl-2-related gene that regulates programmed cell death in a bcl-2-independent fashion. It is expressed in tissues containing long-surviving postmitotic cells, such as neurons in adult brains. To investigate the possibility of gene therapy for transferring this anti-apoptotic gene into the neuron for the treatment of vascular occlusive or neurodegenerative diseases, we examined the effect of a replication-deficient recombinant adenovirus vector coding human Bcl-xL gene on the augmentation of the survival of primarily-cultured rat neuronal cells in vitro. Immunoblot analysis revealed that primarily-cultured neuronal cells were successfully infected and transferred with this gene by recombinant adenovirus vector with high transduction efficiency. Bcl-xL gene transfer to the primarily-cultured neurons could prevent these cells from cell death.
Assuntos
Adenoviridae/genética , Técnicas de Transferência de Genes , Vetores Genéticos , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Animais , Apoptose/fisiologia , Sobrevivência Celular/fisiologia , Células Cultivadas , Humanos , Ratos , Ratos Wistar , Proteína bcl-XRESUMO
A 26-year-old woman was admitted for the evaluation of edema and massive proteinuria. She had a history of purpura of the lower extremities, abdominal pain and melena. Laboratory investigations showed hypoalbuminemia, hypercholesterolemia and proteinuria of over 10 g/day. Renal biopsy showed moderate proliferative glomerulonephritis with mesangial immunoglobulin A (IgA) deposition. She was diagnosed as having Henoch-Schonlein purpura nephritis. Oral prednisolone, dipyridamole and intravenous heparin treatment were not effective. Steroid pulse therapy induced a partial improvement of proteinuria to 2-3 g/day. High-dose intravenous immunoglobulin (i.v.-IG) treatment was introduced and a dramatic improvement of proteinuria was noted. I.v.-IG should be fully considered in patients with steroid-resistant Henoch-Schonlein purpura nephritis.