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INTRODUCTION: Early identification and initiation of reperfusion therapy is essential for suspected acute ischaemic stroke. A pre-hospital stroke notification (PSN) protocol using FASE (facial drooping, arm weakness, speech difficulties, and eye palsy) was implemented to improve key performance indicators (KPIs) in acute stroke care delivery. We assessed KPIs and clinical outcomes before and after PSN implementation in Hong Kong. METHODS: This prospective cohort study with historical controls was conducted in the Accident and Emergency Departments of four public hospitals in Hong Kong. Patients were screened using the PSN protocol between August 2021 and February 2022. Suspected stroke patients between August 2020 and February 2021 were included as historical controls. Door-to-needle (DTN) and door-to-computed tomography (DTC) times before and after PSN implementation were compared. Clinical outcomes including National Institutes of Health Stroke Scale score at 24 hours and modified Rankin Scale score at 3 months after intravenous recombinant tissue-type plasminogen activator (IV-rtPA) were also assessed. RESULTS: Among the 715 patients (266 PSN and 449 non-PSN) included, 50.8% of PSN patients and 37.7% of non-PSN patients had a DTC time within 25 minutes (P<0.001). For the 58 PSN and 134 non-PSN patients given IV-rtPA, median DTN times were 67 and 75.5 minutes, respectively (P=0.007). The percentage of patients with a DTN time within 60 minutes was higher in the PSN group than in the non-PSN group (37.9% vs 21.6%; P=0.019). No statistically significant differences in clinical outcomes were observed. CONCLUSION: Although the PSN protocol shortened DTC and DTN times, clinical outcomes did not significantly differ.
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In recent years, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been shown to play important roles in tumor biological function. The aim of this study was to investigate the diagnostic and prognostic value of lncRNA H19 and miR-21 expression in non-small-cell lung cancer (NSCLC). H19 and miR-21 expression was measured in tumor tissues and corresponding non-tumor lung tissues from 200 patients by quantitative reverse transcription polymerase chain reaction. Moreover, the in vitro and in vivo effects of H19 knock out in A549 cells were investigated. Expression of both H19 and miR-21 was significantly higher in lung tissues from patients with NSCLC than in normal lung tissues. Increased expression of H19 and miR-21 was positively correlated with advanced tumor-node-metastasis stage and tumor size. miR-21 expression was highest in stage I and II NSCLC, whereas H19 expression was highest in stage III and IV NSCLC. Knockout of H19 significantly inhibited NSCLC cell proliferation both in vitro and in vivo. The results show that H19 may mainly contributes to the progression of NSCLC, and its expression levels can reflect the invasive and metastatic status to some extent. miR-21 expression more likely plays an important role in early stage NSCLC. Moreover, H19 and miR-21 interact in the regulation of NSCLC, and with greater expression of both H19 and miR-21, overall survival decreased. The combination of H19 and miR-21 may have diagnostic value in NSCLC and represent a target for new NSCLC treatments.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , MicroARNs/biosíntesis , ARN Largo no Codificante/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Pronóstico , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
OBJECTIVE: Lung cancer is the most common cause of death in cancer worldwide, and cisplatin plays an important role in its treatment. However, the response to chemotherapy is poorly attributable to drug resistance. Our present study aimed to investigate the relation of the exosomal miR-146a-5p level with the chemosensitivity of NSCLC to cisplatin and the molecular mechanism that miR-146a-5p mediated to effect on chemotherapy response. PATIENTS AND METHODS: The exosomes were isolated by ExoQuick kit. The exosomal morphology and particle size distribution were evaluated by the transmission electron microscopy and nanoSight assay respectively. Cell proliferation was detected using the MTT assay. NSCLC cells were infected with mimics or inhibitor to overexpress or downregulate miR-146a level. Besides, Quantitative real-time PCR, Western blot analysis, and immunohistochemistry were applied to detect the relative miRNA and protein levels. RESULTS: Advanced NSCLC patients with low serum exosomal miR-146a-5p levels had higher recurrence rates than those with high levels. A549/DDP cells and exosomes expressed higher miR-146a-5p than A549. In the process of cisplatin-induced drug resistance, the expression of miR-146a-5p decreased in either NSCLC cell lines or the exosomes gradually. What's more, the overexpression of miR-146a-5p could reverse the resistance of A549/DDP. And the possible mechanism of miR-146a-5p increasing chemosensitivity of NSCLC to cisplatin could be targeting Atg12 to inhibit autophagy. CONCLUSIONS: Serum exosomal miR-146a-5p may be a new biomarker predicting the efficacy of cisplatin for NSCLC patients and real-time monitoring drug resistance.
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/sangre , Cisplatino/farmacología , Exosomas/genética , Neoplasias Pulmonares/sangre , MicroARNs/sangre , Biomarcadores/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo , Exosomas/patología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , MicroARNs/genética , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
INTRODUCTION: Coagulopathy-associated intracerebral haemorrhage has become increasingly common because of the rising demand in the ageing population for anticoagulation for atrial fibrillation. This study compared the clinical features and neurological outcomes of intracerebral haemorrhage in patients with atrial fibrillation who were prescribed warfarin with those who were not. METHODS: This was a retrospective matched case series of patients with intracerebral haemorrhage from three tertiary hospitals in Hong Kong from 1 January 2006 to 31 December 2011. Patients who developed intracerebral haemorrhage and who were prescribed warfarin for atrial fibrillation (ICH-W group) were compared with those with intracerebral haemorrhage and not prescribed warfarin (ICH-C group); they were matched for age and gender in 1:1 ratio. Clinical features and neurological outcomes were compared, and the impact of coagulopathy on haematoma size was also studied. RESULTS: We identified 114 patients in the ICH-W group with a mean age of 75 years. Both ICH-W and ICH-C groups had a median intracerebral haemorrhage score of 2. There was a non-statistically significant trend of higher intracerebral haemorrhage volume in the ICH-W group (12.9 mL vs 10.5 mL). The median modified Rankin Scale and the proportion with good recovery (modified Rankin Scale score ≤3) at 6 months were comparable. Nonetheless, ICH-W patients had higher hospital mortality (51.8% vs 36.0%; P=0.02) and 6-month mortality (60.5% vs 43.0%; P=0.01) than ICH-C patients. Overall, 60% of ICH-W patients had their admission international normalised ratio within the therapeutic range during intracerebral haemorrhage, and 14% had a subtherapeutic admission international normalised ratio. International normalised ratio at admission was not associated with intracerebral haemorrhage volume or neurological outcome. CONCLUSION: Warfarin-associated intracerebral haemorrhage in patients with atrial fibrillation carried a higher stroke mortality than the non-warfarinised patients.
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Anticoagulantes/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/mortalidad , Warfarina/efectos adversos , Anciano , Estudios de Casos y Controles , Hemorragia Cerebral/diagnóstico por imagen , Femenino , Hong Kong/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos XRESUMEN
Serum prostate-specific antigen (PSA) is a diagnostic biomarker of prostate cancer and is possibly associated with obesity. This study aimed to explore the relationships between obesity indicators [body mass index (BMI) and waist circumference (WC)] with PSA in Chinese men. A cross-sectional study of men aged 30-85 years undergoing prostate cancer screening was conducted from August 2008 to July 2013 in Xi'an, China. Data were obtained from clinical reports, condition was recorded based on self-report including demographics, weight, height, and WC (>90 cm=obese). Fasting blood glucose (FBG) and prostate volume (PV) were assessed clinically. Patients were grouped by BMI (normal=22.9, overweight=23-27.4, obese≥27.5 kg/m2). PSA parameters of density (PSAD), PSA serum level, and PSA increasing rate per year (PSAR) were calculated per BMI and age groups (30-40, 41-59, 60-85 years). Obesity indicators (BMI and WC) and PSA parameter relationships were modeled by age-stratified linear regression. Of 35,632 Chinese men surveyed, 13,084 were analyzed, including 13.44% obese, 57.44% overweight, and 29.12% normal weight, according to BMI; 25.84% were centrally (abdominally) obese according to WC. BMI and WC were negatively associated with all PSA parameters, except PSAD and PSAR [P<0.05, BMI: ß=-0.081 (95%CI=-0.055 to -0.036), WC: ß=-0.101 (-0.021 to -0.015)], and independent of FBG and PV (P<0.05) in an age-adjusted model. In conclusion, obesity was associated with lower PSA in Chinese men. Therefore, an individual's BMI and WC should be considered when PSA is used to screen for prostate cancer.
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Obesidad/sangre , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Glucemia , Índice de Masa Corporal , China , Estudios Transversales , Tacto Rectal , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Sobrepeso/sangre , Próstata/anatomía & histología , Estudios Retrospectivos , Circunferencia de la CinturaRESUMEN
Serum prostate-specific antigen (PSA) is a diagnostic biomarker of prostate cancer and is possibly associated with obesity. This study aimed to explore the relationships between obesity indicators [body mass index (BMI) and waist circumference (WC)] with PSA in Chinese men. A cross-sectional study of men aged 30-85 years undergoing prostate cancer screening was conducted from August 2008 to July 2013 in Xi'an, China. Data were obtained from clinical reports, condition was recorded based on self-report including demographics, weight, height, and WC (>90 cm=obese). Fasting blood glucose (FBG) and prostate volume (PV) were assessed clinically. Patients were grouped by BMI (normal=22.9, overweight=23-27.4, obese≥27.5 kg/m2). PSA parameters of density (PSAD), PSA serum level, and PSA increasing rate per year (PSAR) were calculated per BMI and age groups (30-40, 41-59, 60-85 years). Obesity indicators (BMI and WC) and PSA parameter relationships were modeled by age-stratified linear regression. Of 35,632 Chinese men surveyed, 13,084 were analyzed, including 13.44% obese, 57.44% overweight, and 29.12% normal weight, according to BMI; 25.84% were centrally (abdominally) obese according to WC. BMI and WC were negatively associated with all PSA parameters, except PSAD and PSAR [P<0.05, BMI: β=-0.081 (95%CI=-0.055 to -0.036), WC: β=-0.101 (-0.021 to -0.015)], and independent of FBG and PV (P<0.05) in an age-adjusted model. In conclusion, obesity was associated with lower PSA in Chinese men. Therefore, an individual's BMI and WC should be considered when PSA is used to screen for prostate cancer.
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Humanos , Masculino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Obesidad/sangre , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/diagnóstico , Glucemia , Índice de Masa Corporal , China , Estudios Transversales , Tacto Rectal , Tamizaje Masivo , Sobrepeso/sangre , Próstata/anatomía & histología , Estudios Retrospectivos , Circunferencia de la CinturaRESUMEN
OBJECTIVES: To explore how buccal carcinoma spread, using contrast-enhanced multislice CT (CEMSCT). METHODS: We retrospectively analysed the extent of lesions in 56 patients with primary buccal squamous cell carcinoma (SCCA). Abnormal manifestations on CEMSCT at oral subsites and involved adjacent structures were documented and evaluated, which were compared with the results of surgery and histopathology. RESULTS: Infiltration and spread to oral subsites and/or adjacent structures was confirmed in 33 patients (58.9%). The opening of the Stensen duct was the most commonly invaded oral subsite (72.7%); other sites included the gingivobuccal sulcus (60.6%), pterygomandibular raphe (54.5%), gingiva (24.2%), retromolar trigone (24.2%), orbicularis oris (18.2%) and the floor of mouth (15.2%). Of the involved adjacent structures, the buccal space was the most common site of spread (69.7%), followed by the masticatory muscles and spaces (57.6%), bone (54.5%), skin and subcutaneous fat (39.4%), pharynx (30.3%), investing fascia (15.2%) and the base of the skull (6.1%). CEMSCT manifestations of the involvement in buccal SCCAs had correlations with pathological findings (p < 0.05). The sensitivities, specificities and accuracies of two radiologists' evaluation on buccal carcinoma involvement were 50.00%, 23.21% and 73.21%; and 51.79%, 32.14% and 83.93%, respectively. CONCLUSIONS: Buccal SCCAs could superficially and deeply spread to multiple oral subsites and/or adjacent structures. CEMSCT could delineate their spread pathways and extents.
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Carcinoma de Células Escamosas/diagnóstico por imagen , Neoplasias de la Boca/diagnóstico por imagen , Invasividad Neoplásica/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , China , Medios de Contraste , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Neoplasias de la Boca/cirugía , Invasividad Neoplásica/patología , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
GB virus C (GBV-C) is frequently identified in patients co-infected with human immunodeficiency virus type 1 (HIV-1) due to the similar transmission routes. However, it remains unclear how these two viruses interact with each other and how one virus affects the replication of the other in the human body. In this study, we performed a case-control study to determine whether GBV-C viraemia could prevent the acquisition of HIV-1 infection, and a cohort study to determine the prevalence, genotypic characteristics and incidence of GBV-C infection in men who have sex with men (MSM) populations in Beijing, China. The prevalence of GBV-C infection in HIV-1-negative subjects was similar to that in HIV-1-positive subjects. Before HIV-1 acquisition, the prevalence of GBV-C was 17·7%, which increased to 27·2% at the acute stage and to 34% at the chronic stage. Genotype 3 was the major genotype of GBV-C in both groups. A significantly positive correlation was observed between the CD4+ T-cell counts and GBV-C viral loads at the acute stage of HIV infection. At the chronic stage (12 months later), this correlation was no longer significant, although it was still positive. Overall, this study demonstrated that pre-existing GBV-C viraemia could not prevent the acquisition of HIV-1 infection and transmission of HIV-1 significantly increased the prevalence of GBV-C viraemia.
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Infecciones por Flaviviridae/epidemiología , Virus GB-C , Infecciones por VIH/epidemiología , VIH-1 , Hepatitis Viral Humana/epidemiología , Viremia/epidemiología , Enfermedad Aguda , Adulto , Recuento de Linfocito CD4 , Estudios de Casos y Controles , China/epidemiología , Enfermedad Crónica , Estudios de Cohortes , Coinfección , Intervalos de Confianza , Infecciones por Flaviviridae/virología , Virus GB-C/genética , Genotipo , Infecciones por VIH/transmisión , Infecciones por VIH/virología , Hepatitis B/epidemiología , Hepatitis C/epidemiología , Homosexualidad Masculina/estadística & datos numéricos , Humanos , Masculino , Oportunidad Relativa , Prevalencia , Sífilis/epidemiología , Carga Viral , Viremia/virología , Adulto JovenRESUMEN
The Predicted No-Effect Concentration (PNEC) is a key for ecological risk assessment. In this paper, the aquatic species existing widely in the Taihu Lake were selected, and their toxicity data to 2,4-dichlorophenol (2,4-DCP), 2,4,6-trichlorophenol (2,4,6-TCP) and pentachlorophenol (PCP) were collected. The PNECs of 2,4-DCP; 2,4,6-TCP; and PCP were derived using three different approaches, i.e., the assessment factor (AF), species sensitivity distribution (SSD) as well as an eco-toxicological model (AQUATOX). As the results, PNEC(AF)s were 2.18 µg L(-1), 2.53 µg L(-1) and 0.26 µg L(-1), and PNEC(SSD)s were 77 µg L(-1), 197 µg L(-1) and 10 µg L(-1), respectively for 2,4-DCP; 2,4,6-TCP; and PCP respectively. Based on the aquatic conditions of the Taihu Lake, the derived site-specific PNEC(AQUATOX)s were 15 µg L(-1), 67 µg L(-1) and 4 µg L(-1), respectively. In general, the PNECs for three chlorophenols derived from different approaches followed the declined order of PNEC(SSD) > PNEC(AQUATOX) > PNEC(AF). The ratios of PNEC(AF) to PNEC(SSD) and PNEC(AQUATOX) to PNEC(SSD) for three chlorophenols were 0.013-0.028 and 0.19-0.4, respectively. It indicated that PNECs obtained using different approaches may vary and the one based on the AF was the lowest. Therefore, PNEC(AF) can be seen as overprotective. The PNEC(AQUATOX) values for three chlorophenols were less than the corresponding PNEC(SSD) values, mostly because the indirect effects were considered in the ecological model.
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Organismos Acuáticos/efectos de los fármacos , Clorofenoles/análisis , Monitoreo del Ambiente/métodos , Agua Dulce/análisis , Contaminantes Químicos del Agua/análisis , Animales , Organismos Acuáticos/crecimiento & desarrollo , China , Clorofenoles/química , Clorofenoles/toxicidad , Ecotoxicología , Monitoreo del Ambiente/estadística & datos numéricos , Modelos Biológicos , Método de Montecarlo , Nivel sin Efectos Adversos Observados , Valor Predictivo de las Pruebas , Medición de Riesgo , Especificidad de la Especie , Contaminantes Químicos del Agua/química , Contaminantes Químicos del Agua/toxicidadAsunto(s)
Antihipertensivos/uso terapéutico , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Tronco Encefálico/patología , Hipertensión/complicaciones , Edema Encefálico/fisiopatología , Tronco Encefálico/diagnóstico por imagen , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos XAsunto(s)
Encéfalo/patología , Encefalomielitis Aguda Diseminada/inmunología , Mieloma Múltiple/complicaciones , Fibras Nerviosas Mielínicas/patología , Síndromes Paraneoplásicos/inmunología , Antiinflamatorios/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Afasia/etiología , Afasia/fisiopatología , Ganglios Basales/patología , Ganglios Basales/fisiopatología , Encéfalo/fisiopatología , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/fisiopatología , Dexametasona/uso terapéutico , Encefalomielitis Aguda Diseminada/diagnóstico , Encefalomielitis Aguda Diseminada/fisiopatología , Lóbulo Frontal/patología , Lóbulo Frontal/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/fisiopatología , Fibras Nerviosas Mielínicas/inmunología , Síndromes Paraneoplásicos/fisiopatologíaRESUMEN
We report a 39-year-old woman with spinocerebellar ataxia type 6. She presented with ataxia and a 3-year history of progressive ataxia and recurrent falls. There was no relevant family history. Genetic tests revealed an expanded allele of 24 CAG repeats at the spinocerebellar ataxia type 6 locus. This appears to be the first case reported in Hong Kong. As genetic testing becomes more widely available and clinical awareness increases, more such patients are expected to be diagnosed.
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Canales de Calcio/genética , Ataxias Espinocerebelosas/genética , Repeticiones de Trinucleótidos , Adulto , Femenino , HumanosRESUMEN
BACKGROUND: A prospective observational study of the presentation, diagnosis, treatment and outcome of tuberculous meningitis (TBM). METHODS: Demographic characteristics, clinical information, treatment and progress of TBM patients were followed. Their outcomes were ascertained every 6 months for 3 years after diagnosis. Prognostic factors associated with death or full recovery were examined using multivariate Cox's and logistic regression models, respectively. RESULTS: Between 1993 and 2000, 166 TBM patients were recruited. Their mean age was 42.9, 153 were Chinese and 81 were males; 92% received HRZS (H = isoniazid; R = rifampicin; Z = pyrazinamide; S = streptomycin), HRZE (E = ethambutol) or HRZES. Steroids were given to 105 patients, with no significant effect on outcome. After 3 years of follow-up, 110 patients had completely recovered, 20 survived with disability and 26 died. Death was significantly associated with older age, lower cerebrospinal fluid (CSF) lymphocyte and poorer consciousness levels at the time of presentation, while full recovery was associated with younger age, being female and absence of complications. CONCLUSIONS: Relatively good outcomes of TBM cases were documented in this Hong Kong study with a case-fatality ratio of 15.7% (26/166) up to 3 years. Early recognition, diagnosis and administration of effective treatment regimens were probably the most important factors in reducing mortality and morbidity.
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Antituberculosos/administración & dosificación , Sistema de Registros , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/terapia , Adolescente , Corticoesteroides/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Áreas de Influencia de Salud , Niño , Preescolar , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Hong Kong/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Tuberculosis Meníngea/mortalidadRESUMEN
OBJECTIVE: To assess the frequency and clinical features of different types of hereditary spinocerebellar ataxia in Hong Kong. DESIGN: Cross-sectional study using a questionnaire and clinical examination, with the majority of the information retrospectively collected. SETTING: Three regional hospitals, Hong Kong. PARTICIPANTS: All patients with spinocerebellar ataxia that was confirmed by molecular genetic tests between January 2001 and October 2003. MAIN OUTCOME MEASURES: History, latest physical examination results, clinical investigation results, and genetic profiles. RESULTS: A total of 16 Chinese patients had received diagnoses of spinocerebellar ataxia. These patients had spinocerebellar ataxia type 1 (n=3), spinocerebellar ataxia type 3 (Machado-Joseph disease; n=12), and dentatorubro-pallidoluysian atrophy (n=1). The most common manifestation was ataxia (15/16), followed by pyramidal signs (12/16). Other features such as bulbar dysfunction, ophthalmoplegia, neuropathy, and cognitive impairment were present but variable. CONCLUSIONS: The clinical manifestations of different types of spinocerebellar ataxia overlap, and genetic study is necessary to confirm the diagnosis. The frequency of spinocerebellar ataxia type 3 is greater than that of other types among these Chinese patients. The age of onset of this type may correlate inversely with the number of CAG repeats.
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Enfermedad de Machado-Joseph/diagnóstico , Ataxias Espinocerebelosas/diagnóstico , Adulto , Estudios Transversales , Femenino , Hong Kong , Humanos , Enfermedad de Machado-Joseph/genética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Ataxias Espinocerebelosas/genética , Repeticiones de Trinucleótidos/genéticaRESUMEN
Kennedy's disease is an X-linked, neurodegenerative disorder, characterised by lower motor neuron syndrome. This report gives the clinical details of six male patients with Kennedy's disease diagnosed at Princess Margaret Hospital. Three were initially diagnosed with other neurological diseases, with the diagnosis of Kennedy's disease made after genetic testing. This hereditary disease should be considered in male patients with muscle weakness, particularly those with a presentation suggesting atypical motor neuron disease.
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Atrofia Muscular Espinal/diagnóstico , Adulto , Asesoramiento Genético , Humanos , Masculino , Persona de Mediana Edad , Atrofia Muscular Espinal/genéticaRESUMEN
BACKGROUND: In most experimental systems examined, "professional" antigen-presenting cells (APCs), such as dendritic cells, have been found to activate T cells, whereas "nonprofessional" antigen-bearing cells (nonAPC) may induce tolerance. Some recent studies have suggested that nonAPCs may under certain conditions prime a T-cell immune response. We have attempted to separate the roles of transplanted T cells and monocytic/dendritic cells in activating or tolerizing antigen-specific T cells in vivo, by examining the consequences of parenteral exposure to male antigen in anti-male TCR transgenic female mice. METHODS: Qualitative and quantitative changes in the large population of male-reactive transgenic T cells to various male donor cell populations in transgenic female mice were followed after injections of highly purified male lymphoid cells. Changes in male-reactive T cells with time and the long-term outcome of male skin grafts were measured. RESULTS: When a nonAPC population consisting of highly purified male T cells alone was injected intravenously into H-Y antigen-specific TCR transgenic female mice, the number of host transgenic T cells was sustainably increased, and male graft rejection was accelerated. Injection of a combination of purified T cells and purified Mac-l+ cells induced massive and permanent deletion of the host male-reactive T-cell population and permanent graft tolerance. Mac-l+ cells alone gave no appreciable change in responsive T cells or graft rejection times. CONCLUSIONS: The data indicate that highly purified T cells engrafted alone induce rapid sensitization toward the male antigen. They also show that both male donor T cells and a population of male monocytic/ dendritic cells are required to induce peripheral tolerance toward this antigen and that this tolerance is related to permanent peripheral deletion of male-reactive T cells.
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Antígeno H-Y/inmunología , Tolerancia Inmunológica/inmunología , Antígeno de Macrófago-1/inmunología , Trasplante de Piel/inmunología , Linfocitos T/inmunología , Linfocitos T/trasplante , Animales , Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Femenino , Rechazo de Injerto/inmunología , Activación de Linfocitos/inmunología , Macrófagos/inmunología , Macrófagos/trasplante , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunologíaRESUMEN
In in vivo tolerance induction, the dose of tolerogen injected is generally linearly correlated to the length of tolerance induced. Small, medium and large doses are related to no, partial and long-term tolerance, respectively. However, even with injection of substantially large doses of tolerogen, the length of tolerance induced varies over a wide range. Most of the recipients can still reject donor grafts. In this study, it is shown that the linear dose-response can be altered into an all or nothing response in a H-Y antigen-specific TCR transgenic (Tg) mouse model. In thymectomized female Tg mice, injection of 3, 30 and 100 x 10(6) male spleen cells was correlated to no, partial and massive deletion of Tg (alpha T beta T) CD8 cells, respectively. When the thymectomized Tg mice were injected with 9 x 10(6) T cell-enriched (T+) male cells, one half of the recipients showed no deletion of alpha T beta T cells, and in the other half massive deletion occurred. In complete correlation with deletion, all male skin grafts were rejected in the undeleted group as PBS-injected controls, whereas with massive deletion they were indefinitely tolerized. Thus, partial deletion and partial tolerance can be avoided. Injection of 18 x 10(6) male T+ cells induced long-term tolerance in all the recipients. The all or none T cell deletion and long-term tolerance induction has not only significant implications in understanding the mechanism of peripheral tolerance induction, but also in tolerance induction in transplantation, gene therapy and the prevention and treatment of autoimmune diseases.
Asunto(s)
Epítopos de Linfocito T/inmunología , Antígeno H-Y/inmunología , Tolerancia Inmunológica/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Trasplante de Piel/inmunología , Bazo/citología , Bazo/inmunología , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Mice carrying a rearranged TCR Vbeta 8.2 transgene express the Vbeta protein on the vast majority of peripheral T-cells. The bone marrow and peripheral blood, as well as other lymphoid organs of both untreated animals and animals depleted of T-cells by neonatal thymectomy and/or injection from birth of monoclonal anti-TCR antibodies, contain a small population of cells that express low levels of the Vbeta transgene product, but no T-cell or other detectable lineage-specific phenotypic markers. When such TG-bearing BM cells are purified and injected directly into the non-TG thymus, they show the phenotypic maturation sequences of intrathymic T-cell development and, subsequently, mature TG-bearing peripheral T-cells. However, this population failed to support long-term recovery from lethal irradiation. Both Vbeta 8.2 TG and CD3delta mRNA transcripts are strongly expressed in the cell population, but no CD3gamma, CD3epsilon, CD3zeta, CD4, CD8beta, pre-Talpha, or RAG-1 transcript was detected. The transgene-encoded TCR component is not bound to the cell membrane exclusively by a phosphatidylinositol linkage. The data show that the fully rearranged TCR transgene and transcripts for at least one of the associated CD3 components, CD3delta, can be expressed on a subpopulation of BM and PBL cells that has not passed through the thymus. The phenotypic characteristics of this cell population resemble those described for the earliest thymocyte described by others. The TG protein molecule in this model may provide a specific developmental marker for a prothymocyte lineage subset that lacks pluripotential properties.