RESUMEN
Trisomy 21 (Down Syndrome) may lead to multiple hematological and hepatobiliary manifestations including the development of transient abnormal myelopoiesis. While many cases resolve, transient abnormal myelopoiesis may lead to significant morbidity and mortality in a small percentage of patients. This condition may present a diagnostic challenge for physicians and currently there is only limited data on effective treatments, particularly with low blast percent transient abnormal myelopoiesis. We present a case of a neonate with trisomy 21 and multiple congenital anomalies who consequently developed hepatic failure with evidence of non-cirrhotic portal hypertension likely due to transient abnormal myelopoiesis. This clinical scenario highlights the need for additional evaluation for transient abnormal myelopoiesis associated hepatic disorder and possibly hepatic sinusoidal occlusive syndrome among trisomy 21 neonates particularly with low blast percentage.
Asunto(s)
Síndrome de Down , Enfermedades del Recién Nacido , Reacción Leucemoide , Recién Nacido , Humanos , Síndrome de Down/complicaciones , Reacción Leucemoide/diagnóstico , Resultado del TratamientoAsunto(s)
Vacunas contra la COVID-19 , COVID-19 , Piodermia Gangrenosa , Enfermedades Cutáneas Vesiculoampollosas , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Hemorragia , Humanos , Piodermia Gangrenosa/tratamiento farmacológico , Piodermia Gangrenosa/etiología , VacunaciónRESUMEN
BACKGROUND: There is increasing use of anti-osteoporotic agents (AOA) worldwide for prevention or management of patients with osteoporosis. However, there have been reports of severe cutaneous adverse reactions (SCAR) induced by AOA. A recent study showed weak association between HLA and strontium ranelate (SR)-SCAR. OBJECTIVE: To characterize patients with AOA-SCAR and investigate the HLA association and utility of in vitro diagnostic methods. METHODS: We enrolled 16 cases with AOA-cutaneous adverse drug reactions (cADR), including SCAR (n = 10: 8 with Stevens-Johnson syndrome [SJS] and 2 with drug rash with eosinophilia and systemic symptoms [DRESS]) and maculopapular exanthema (MPE) (n = 6) from Taiwan and Hong Kong. We analysed the clinical characteristics, outcomes, HLA alleles and in vitro testing of AOA-SCAR, and tolerability to alternative drugs. We further performed literature review and meta-analysis on the HLA association of AOA-SCAR. RESULTS: Our data showed strontium ranelate is the most common causality of AOA-SCAR in Asian populations. There was no cross-hypersensitivity of SR-SCAR with other AOA. HLA genotyping showed that SR-SJS was most significantly associated with HLA-A*33:03 (Pc = 5.17 × 10-3 , OR: 25.97, 95% CI: 3.08-219.33). Meta-analysis showed that HLA-A*33:03 was associated with SR-SJS (P = 5.01 × 10-5 ; sensitivity: 85.7%) in Asians. The sensitivity of lymphocyte activation test (LAT) for identifying the culprit drug of SR-SJS was 83.3%. CONCLUSIONS: Strontium ranelate is identified as the most notorious AOA associated with SCAR. The HLA-A*33:03 genetic allele and LAT testing may add benefits to the diagnosis of SR-SCAR in patients whose reaction developed while taking multiple drugs.
Asunto(s)
Síndrome de Stevens-Johnson , Alelos , Anticonvulsivantes , Pueblo Asiatico , Antígenos HLA-B/genética , Hong Kong , Humanos , TaiwánRESUMEN
OBJECTIVE: To assess the effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on liver regeneration of rats with liver cirrhosis after hepatectomy and antiï¬brosis. MATERIALS AND METHODS: Omega-3 polyunsaturated fatty acids were intravenously injected in n-3 PUFA group 3 days before the operation to 1 day after partial hepatectomy. 70% hepatectomy was performed in rats, which were subsequently divided into 4 groups, namely normal and hepatectomy group (PH); liver cirrhosis and hepatectomy group (LC+PH); liver cirrhosis, n-3 PUFA (1 mL/kg), and hepatectomy group (LC+n-3 PUFA+PH); liver cirrhosis, n-3 PUFA (2 mL/kg) and hepatectomy group (LC+n-3PUFA*+PH). Body/liver weight ratios, serum parameters, histopathological examination, immunostaining, inflammatory cytokine and quantiï¬cation of mRNA expression were also investigated. RESULTS: Liver regeneration was significantly delayed compared with PH group 7 days after hepatectomy (PH) in LC+PH group. Besides, liver regeneration of LC+n-3 PUFA*+PH group increased significantly compared with LC+PH group 7 days after PH. In LC+PH group, liver cirrhotic was significantly higher compared with LC+n-3 PUFA+PH group 7 days after PH. In the meantime, liver cirrhosis of LC+n-3 PUFA*+PH group was significantly reduced compared with LC+n-3 PUFA+PH group 7 days after PH. Anti-inflammatory cytokine IL-10 was increased and pro-inflammatory cytokine IL-6 was decreased in LC+n-3 PUFA*+PH group compared with LC+PH group. N-3 PUFA also suppressed increments in mRNA expression for transforming growth factor-ß and up-regulated the expression of matrix metalloproteinase-9 and matrix metalloproteinase-1 in the liver. CONCLUSIONS: The mentioned results clearly show that n-3 PUFA reduces liver ï¬brosis and promotes liver regeneration, even under cirrhotic conditions. This could be a potentially useful treatment for liver cirrhosis.
Asunto(s)
Ácidos Grasos Omega-3/administración & dosificación , Hepatectomía/efectos adversos , Cirrosis Hepática/dietoterapia , Regeneración Hepática/efectos de los fármacos , Animales , Citocinas/genética , Citocinas/metabolismo , Progresión de la Enfermedad , Ácidos Grasos Omega-3/farmacología , Inyecciones Intravenosas , Cirrosis Hepática/genética , Masculino , Ratas , Resultado del TratamientoAsunto(s)
Azatioprina/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Eritema Nudoso/genética , Inmunosupresores/efectos adversos , Pirofosfatasas/genética , Adulto , Biopsia , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Urticaria Crónica/tratamiento farmacológico , Eritema Nudoso/inducido químicamente , Eritema Nudoso/diagnóstico , Eritema Nudoso/patología , Femenino , Humanos , Pruebas de Función Hepática , Polimorfismo de Nucleótido Simple , Piel/efectos de los fármacos , Piel/patologíaRESUMEN
Background Cutaneous lupus erythematosus (CLE) includes a broad range of dermatologic manifestations. Periorbital involvement, however, is a relatively rare clinical presentation of CLE. Objectives This clinical study aimed to investigate the characteristics of this unique presentation of CLE in tertiary medical centers. Methods We enrolled patients with periorbital erythema and swelling as the presenting sign of lupus erythematosus, from January 2003 to November 2017, using the data of 553 pathologically proven CLE cases from the registration database of the Chang Gung Memorial Hospitals in Taiwan. Results We enrolled a total of 25 patients. The mean age was 46.7 years and 68% of the patients were female. Most of the patients (84.0%) presented with unilateral involvement, with the left orbit involved in 15 patients (60%); the upper eyelid was the most frequently involved (72%). Mean duration between the onset of clinical manifestations and the diagnosis of CLE was approximately 59 weeks. Nineteen patients had been previously misdiagnosed. All patients had features compatible with CLE on histopathological examination. In contrast, laboratory analysis of the autoimmune profile often revealed negative results, including those for antinuclear antibodies (25%). Notably, anti-SSA/SSB (45.5%) showed the highest positive rate. During follow-up, six patients developed systemic lupus erythematosus (SLE) and two patients developed Sjögren syndrome. Conclusions The diagnosis of CLE presenting as periorbital erythema and swelling is often delayed because of clinical mimicry and the high proportion of negative results on autoantibody tests. Increased clinical suspicion and prompt histopathological examination are crucial for early diagnosis. Moreover, one-fourth of the patients ultimately developed SLE, which highlights the importance of clinical awareness.
Asunto(s)
Edema/patología , Eritema/patología , Lupus Eritematoso Cutáneo/diagnóstico , Lupus Eritematoso Cutáneo/patología , Piel/patología , Adulto , Anciano , Anticuerpos Antinucleares/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Taiwán , Centros de Atención Terciaria , Adulto JovenRESUMEN
BACKGROUND: Protothecosis is an uncommon infection caused by the achlorophyllic algae found more commonly in tropical areas. Only a limited number of cases have been reported. OBJECTIVE: We aimed to evaluate the clinicopathological features and treatment outcomes of cutaneous protothecosis. METHODS: We retrospectively identified 20 pathology-confirmed cases of cutaneous protothecosis based on skin biopsies in two tertiary medical centres in Taiwan from 1997 to 2015. RESULTS: The age of the patients at the time of diagnosis ranged from 48 to 85 years (mean age of 74 years). All lesions developed on the limbs. Twelve (60%) patients had adrenal insufficiency, but no patients had active malignancy at diagnosis. Interestingly, four (20%) patients had concurrent scabies infestation. Clinically, most lesions were erythematous plaques studded with punctate ulcers. Microscopically, the most common finding was granulomatous inflammation. Nineteen (95%) cases were successfully treated with itraconazole for 14-148 days with only one case of recurrence. Concomitant scabies should be suspected if pruritus is recalcitrant despite itraconazole treatment. CONCLUSION: Despite its rarity, cutaneous protothecosis has become more significant due to an increased prevalence of immunocompromised individuals. Steroid overuse or iatrogenic adrenal insufficiency predisposes individuals to high-risk infections. Neglecting the disease leads to a chronic and incurable state. Protothecosis should be suspected in chronic eczematous and ulcerative plaques on the limbs refractory to conventional antibacterial and antiviral treatments, especially in patients with adrenal insufficiency. Clinical suspicion should be confirmed by skin biopsies, and confirmed cases can be successfully treated with itraconazole.
Asunto(s)
Prototheca , Escabiosis/complicaciones , Enfermedades Cutáneas Infecciosas/complicaciones , Insuficiencia Suprarrenal/inducido químicamente , Insuficiencia Suprarrenal/complicaciones , Anciano , Anciano de 80 o más Años , Antifúngicos/uso terapéutico , Complicaciones de la Diabetes/complicaciones , Eritema/microbiología , Femenino , Humanos , Itraconazol/uso terapéutico , Masculino , Persona de Mediana Edad , Enfermedades Musculoesqueléticas/complicaciones , Prurito/parasitología , Estudios Retrospectivos , Factores de Riesgo , Enfermedades Cutáneas Infecciosas/tratamiento farmacológico , Enfermedades Cutáneas Infecciosas/patología , Úlcera Cutánea/microbiologíaRESUMEN
AIM: To examine the associations between prostate cancer, diabetes and race/ethnicity. METHODS: Using administrative data from British Columbia, Canada for the period 1994 to 2012, we identified men aged ≥50 years with and without diabetes. Validated surname algorithms identified men as Chinese, Indian or of other race/ethnicity. Multivariable Cox regression was used to estimate adjusted risks of prostate cancer according to diabetes status and race/ethnicity. RESULTS: Our cohort of 160 566 men had a mean (sd) age of 64.7 (9.4) years and a median of 9 years' follow-up. The incidence rates of prostate cancer among those with and without diabetes were 177.4 (171.7-183.4) and 216.0 (209.7-222.5) per 1000 person-years, respectively. The incidence among Chinese men was 120.9 (109.2-133.1), among Indian men it was 144.1 (122.8-169.0) and in men of other ethnicity it was 204.8 (200.2-209.5). Diabetes was independently associated with a lower risk of prostate cancer (adjusted hazard ratio 0.82, 95% CI 0.78-0.86), as was Chinese (adjusted hazard ratio 0.54, 95% CI 0.46,0.63) and Indian (adjusted hazard ratio 0.66, 95% CI 0.49,0.89) race/ethnicity; however, there was no statistically significant interaction between diabetes status and race/ethnicity (all P>0.1). CONCLUSION: Diabetes and Chinese and Indian race/ethnicity were each independently associated with a lower risk of prostate cancer.
Asunto(s)
Pueblo Asiatico/estadística & datos numéricos , Diabetes Mellitus/epidemiología , Neoplasias de la Próstata/etnología , Población Blanca/estadística & datos numéricos , Anciano , Colombia Británica/epidemiología , Estudios de Cohortes , Etnicidad/estadística & datos numéricos , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Neoplasias de la Próstata/epidemiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Men with diabetes may have a lower risk of prostate cancer than men without diabetes which may be altered by metformin use or race/ethnicity. METHODS: Using administrative databases, from 1994 to 2012, adult (age⩾50 years) men with diabetes were identified. Metformin exposure was defined as a time-dependent variable, stratified first into any use, and into tertiles of cumulative dose. Surname algorithms identified individuals as Chinese or non-Chinese. Multivariable Cox regression estimated the risk of prostate cancer. RESULTS: The cohort of 80 001 had a mean age of 64 years and median follow-up of 9 years. Chinese users of metformin aged 50-59, 60-69 and ⩾70 had similar risks of prostate cancer as non-users. Non-Chinese users aged 50-59 (adjusted hazards ratio (aHR): 0.86, 0.74 to 1.00) had a decreased risk whereas men aged 60-69 and ⩾70 did not. However, when metformin exposure was stratified into tertiles, there was no association in any strata except non-Chinese men aged 50-59 in the first (aHR: 0.68, 95% confidence interval (CI): 0.55, 0.84), second (aHR: 0.75, 95% CI: 0.61, 0.92) and third (aHR: 0.79, 95% CI: 0.64, 0.96) tertiles of metformin exposure and non-Chinese men aged 60-69 in the first (aHR: 0.81, 95% CI: 0.68, 0.95) tertiles of metformin exposure. CONCLUSIONS: There was no clear association between metformin and risk of prostate cancer in men with diabetes in either race/ethnicity. Our findings suggest a consistent relationship between metformin and prostate cancer across race/ethnicity.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Hipoglucemiantes/efectos adversos , Metformina/efectos adversos , Grupos de Población/estadística & datos numéricos , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/etiología , Anciano , Anciano de 80 o más Años , Colombia Británica/epidemiología , Estudios de Cohortes , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estudios de Seguimiento , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Vigilancia de la Población , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Riesgo , Factores SocioeconómicosRESUMEN
Cerebral edema causes intracranial hypertension (ICH) which leads to severe outcome of patients in the clinical setting. Effective anti-edema therapy may significantly decrease the mortality in a variety of neurological conditions. At present drug treatment is a cornerstone in the management of cerebral edema. Osmotherapy has been the mainstay of pharmacologic therapy. Mannitol and hypertonic saline (HS) are the most commonly used osmotic agents. The relative safety and efficacy of HS and mannitol in the treatment of cerebral edema and reduction of enhanced ICP have been demonstrated in the past decades. Apart from its osmotic force, HS exerts anti-edema effects partly through inhibition of Na(+)-K(+)-2Cl(-) Cotransporter-1 (NKCC1) and aquaporin 4 (AQP4) expression in astrocytes. Melatonin may also reduce brain edema and exert neuroprotective effect on several central nervous system diseases through inhibition of inflammatory response. The inhibitors of Na/H exchanger, NKCC and AQP4 may attenuate brain edema formation through inhibition of excessive transportation of ion and water from blood into the cerebral tissue. In this review we survey some of the most recent findings in the drug treatment of brain edema focusing on the use of osmotherapy, melatonin and inhibitors of ion cotransporters and water channels. A better understanding of the molecular mechanism of these agents would help to improve in the clinical management of patients with brain edema.
Asunto(s)
Edema Encefálico/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Animales , Acuaporina 4/antagonistas & inhibidores , Acuaporina 4/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Edema Encefálico/metabolismo , Edema Encefálico/patología , Fluidoterapia/métodos , Humanos , Manitol/farmacología , Manitol/uso terapéutico , Melatonina/farmacología , Melatonina/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Solución Salina Hipertónica/farmacología , Solución Salina Hipertónica/uso terapéutico , Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , Simportadores/antagonistas & inhibidoresRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Febuxostat is recommended as an alternative drug for gouty patients with a history of allopurinol hypersensitivity or carrying the HLA-B*5801 allele. CASE SUMMARY: An 81-year-old man with the medical history of gout presented to our clinic with generalized rashes for 2 days. After taking febuxostat for 2 days, he developed generalized skin rash with high fever. Laboratory tests showed elevated liver enzymes and acute kidney injury. WHAT IS KNOWN AND OBJECTIVE: This is the first identified case of febuxostat-associated DRESS. Febuxostat should be withdrawn immediately when DRESS is observed to avoid further serious complications.
Asunto(s)
Síndrome de Hipersensibilidad a Medicamentos/etiología , Eosinofilia/inducido químicamente , Febuxostat/efectos adversos , Anciano de 80 o más Años , Febuxostat/uso terapéutico , Gota/tratamiento farmacológico , Humanos , MasculinoRESUMEN
The binding interaction of lovastatin with calf thymus DNA (ct-DNA) was studied using UV/Vis absorption spectroscopy, fluorescence emission spectroscopy, circular dichroism (CD), viscosity measurement and molecular docking methods. The experimental results showed that there was an obvious binding interaction of lovastatin with ct-DNA and the binding constant (Kb ) was 5.60 × 10(3) M(-1) at 298 K. In the binding process of lovastatin with ct-DNA, the enthalpy change (ΔH(0)) and entropy change (ΔS(0)) were -24.9 kJ/mol and -12.0 J/mol/K, respectively, indicating that the main binding interaction forces were van der Waal's force and hydrogen bonding. The molecular docking results suggested that lovastatin preferred to bind on the minor groove of different B-DNA fragments and the conformation change of lovastatin in the lovastatin-DNA complex was obviously observed, implying that the flexibility of lovastatin molecule plays an important role in the formation of the stable lovastatin-ct-DNA complex.
Asunto(s)
ADN/química , Lovastatina/química , Simulación del Acoplamiento Molecular , Animales , Bovinos , Dicroismo Circular , Espectrometría de Fluorescencia , Espectrofotometría Ultravioleta , ViscosidadRESUMEN
Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase metabolites of arachidonic acid involved in regulating pathways promoting cellular protection. We have previously shown that EETs trigger a protective response limiting mitochondrial dysfunction and reducing cellular death. Considering it is unknown how EETs regulate cell death processes, the major focus of the current study was to investigate their role in the autophagic response of HL-1 cells and neonatal cardiomyocytes (NCMs) during starvation. We employed a dual-acting synthetic analog UA-8 (13-(3-propylureido)tridec-8-enoic acid), possessing both EET-mimetic and soluble epoxide hydrolase (sEH) inhibitory properties, or 14,15-EET as model EET molecules. We demonstrated that EETs significantly improved viability and recovery of starved cardiac cells, whereas they lowered cellular stress responses such as caspase-3 and proteasome activities. Furthermore, treatment with EETs resulted in preservation of mitochondrial functional activity in starved cells. The protective effects of EETs were abolished by autophagy-related gene 7 (Atg7) short hairpin RNA (shRNA) or pharmacological inhibition of autophagy. Mechanistic evidence demonstrated that sarcolemmal ATP-sensitive potassium channels (pmKATP) and enhanced activation of AMP-activated protein kinase (AMPK) played a crucial role in the EET-mediated effect. Our data suggest that the protective effects of EETs involve regulating the autophagic response, which results in a healthier pool of mitochondria in the starved cardiac cells, thereby representing a novel mechanism of promoting survival of cardiac cells. Thus, we provide new evidence highlighting a central role of the autophagic response in linking EETs with promoting cell survival during deep metabolic stress such as starvation.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Aminoácidos/deficiencia , Autofagia/efectos de los fármacos , Cardiotónicos/farmacología , Citoprotección/efectos de los fármacos , Miocitos Cardíacos/citología , Ácidos Oléicos/farmacología , Ácido 8,11,14-Eicosatrienoico/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina Trifosfato/farmacología , Animales , Animales Recién Nacidos , Benzamidas/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/ultraestructura , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/ultraestructura , Fosforilación/efectos de los fármacos , Canales de Potasio/metabolismo , Ratas , Estrés Fisiológico/efectos de los fármacosRESUMEN
In addition to excretion of metabolic waste products, organic ionic transporters facilitate uptake of specific compounds of physiological importance. In animals, the organic cation transporter, OCTN1 was found to enable the specific uptake of the unique amino acid, ergothioneine (EGT). EGT can accumulate in the body at up to millimolar concentrations and is believed to function as a physiological antioxidant. However the main function of EGT and the reasons for its active accumulation in the body remain obscure. Through bioinformatic approaches, we identified an analogous EGT transporter in the nematode, Caenorhabditis elegans. The present study investigated and characterized deletion mutants of this gene, OCT-1, in the nematodes. Gene deletion mutations of the OCT-1 transporter were shown to decrease overall lifespan of the worms and increase oxidative damage. However the absence of impaired EGT uptake and the inability of excess EGT to rescue the debilitating phenotype indicate that EGT transport does not explain the deleterious effects of the gene deletion.
Asunto(s)
Caenorhabditis elegans/metabolismo , Ergotioneína/metabolismo , Transportador 1 de Catión Orgánico/metabolismo , Animales , Transporte Biológico , Caenorhabditis elegans/genética , Eliminación de Gen , Técnicas de Silenciamiento del Gen , Humanos , Longevidad , Proteínas de Transporte de Catión Orgánico/genética , Transportador 1 de Catión Orgánico/deficiencia , Transportador 1 de Catión Orgánico/genética , Oxidación-Reducción , Estrés Oxidativo/genética , Estrés Oxidativo/fisiología , SimportadoresRESUMEN
α-Galactosylceramide (α-GalCer)-activated natural killer T (NKT) cells have antiviral properties against hepatitis B virus (HBV). However, α-GalCer activation of NKT cells can induce anergy. We hypothesized that this effect may be overcome by a treatment strategy that includes manipulation of CD28/CD80 costimulatory and PD-1/PDL1 coinhibitory signals of NKT cells, thereby enhancing the anti-HBV effect of α-GalCer. We established a transgenic mouse model of chronic HBV infection and investigated hepatic NKT cell frequencies, functions and expression of immunomodulatory factors. Our results showed that compared with uninfected control mice, hepatic NKT cells from HBV transgenic mice displayed lower frequencies (7.91% vs 16.74%, P < 0.05), impaired capabilities to produce interferon (IFN)-γ (5.6% vs 1.4%, P < 0.05) and interleukin (IL)-4 (6.8% vs 0.3%, P < 0.05), higher expression of PD-1 (9.64% vs 6.36%, P < 0.05) and lower expression of CD28 (5.05% vs 28.88%, P < 0.05). However, when hepatic mononuclear cells (MNCs) were isolated from HBV transgenic mice, α-GalCer exposure in culture remarkably upregulated both PD-1(+) NKT cells (P < 0.05) and CD28(+) NKT cells (P < 0.05). Furthermore, when HBV transgenic mice were treated with combination therapies consisting of α-GalCer and anti-PDL1 monoclonal antibody (mAb) and/or anti-CD80/anti-CD28 mAbs, IFN-γ(+) NKT cell frequency was selectively increased (P < 0.05) and HBV replication was suppressed; these effects were accompanied by varying degrees and types of liver damage. Surprisingly, activating CD28/CD80 signal in HBV transgenic mice was more effective but caused less liver injury than blocking PD-1/PDL1 signal in modulating αGalCer-activated NKT cell function to inhibit HBV infection. Our findings also show that combined therapy with blocking PD-1/PDL1 and activating CD28/CD80 signal in the presence of aGalCer cannot superimpose the effect of antivirus. α-GalCer combination therapy that modulates the CD28/CD80 pathways of NKT cells may represent a promising approach to inhibit HBV replication in chronically infected patients.
Asunto(s)
Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/inmunología , Células T Asesinas Naturales/inmunología , Receptores Inmunológicos/inmunología , Replicación Viral/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Antígeno B7-1/inmunología , Antígeno B7-1/metabolismo , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , China , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Galactosilceramidas/administración & dosificación , Galactosilceramidas/inmunología , Galactosilceramidas/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Humanos , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células T Asesinas Naturales/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Receptores Inmunológicos/metabolismo , Resultado del TratamientoRESUMEN
iNKT cells are relatively abundant in the liver, which suggests that they may play important roles in the clearance of invading foreign pathogens such as hepatitis B virus. In this study, we investigated the frequencies, functions and PD-1 expression of peripheral iNKT cells from HBeAg-positive chronic hepatitis B (CHB) patients during antiviral treatment with Telbivudine. Results demonstrated that as compared with the healthy donors, the peripheral iNKT cells from these patients existed at lower frequencies, displayed impaired capabilities to produce IFN-γ and expressed higher PD-1. Antiviral treatment with Telbivudine significantly increased IFN-γ production by iNKT cells, which may be associated with the decreased PD-1 expression as manifested by blocking experiments. Our study suggested that iNKT cells played an important role in the chronicity of HBV infection and antiviral therapy with Telbivudine could restore at least in part the impaired host immune response in the HBeAg-positive CHB patients.
Asunto(s)
Antivirales/administración & dosificación , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/inmunología , Células T Asesinas Naturales/efectos de los fármacos , Células T Asesinas Naturales/inmunología , Nucleósidos/administración & dosificación , Pirimidinonas/administración & dosificación , Adulto , Femenino , Perfilación de la Expresión Génica , Humanos , Factores Inmunológicos/administración & dosificación , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/biosíntesis , Receptor de Muerte Celular Programada 1/genética , Telbivudina , Timidina/análogos & derivadosRESUMEN
From 25 June to 11 July 2008, a total of 177 adult patients hospitalised in an intensive care unit (ICU) (94 in medical ICUs and 83 in surgical ICUs) at a tertiary care hospital were screened for nasal carriage of meticillin-resistant Staphylococcus aureus (MRSA) by polymerase chain reaction. The overall prevalence of S. aureus and MRSA nasal carriage among the patients was 42% and 32%, respectively. MRSA carriage rate of the patients hospitalised in medical ICUs was significantly higher than that of those hospitalised in surgical ICUs (47% vs 16%, P<0.001). Multivariate logistic regression analysis revealed that pneumonia, chronic obstructive pulmonary disease, current MRSA infection, and medical ICU admission were independent predictors for nasal carriage of MRSA. Of the 38 MRSA isolates available for molecular analysis, a total of six pulsed-field gel electrophoresis (PFGE) patterns with two major patterns (F, 42%; A, 37%) were identified. Most MRSA isolates belonged to one of two major clones characterised as sequence type 5/PFGE F/staphylococcal cassette chromosome mec (SCCmec) II/Panton-Valentine leucocidin (PVL) genes negative (34%) and ST239/PFGE A/SCCmec III/PVL negative (26%), both clones being associated with healthcare-associated (HA) clones in Taiwan. Six isolates (16%) were characterised as ST59/SCCmec IV or V(T) and were associated with community strains in Taiwan. In conclusion, 32% of ICU hospitalised adult patients in a Taiwanese tertiary care teaching hospital between June and July 2008 were colonised with MRSA in their nares. Though most isolates were HA-MRSA, community strains accounted for a proportion of the isolates.
Asunto(s)
Portador Sano/epidemiología , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Mucosa Nasal/microbiología , Infecciones Estafilocócicas/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Toxinas Bacterianas/genética , Técnicas de Tipificación Bacteriana , Portador Sano/microbiología , Análisis por Conglomerados , Dermatoglifia del ADN , ADN Bacteriano/genética , Electroforesis en Gel de Campo Pulsado , Exotoxinas/genética , Femenino , Genotipo , Humanos , Unidades de Cuidados Intensivos , Leucocidinas/genética , Masculino , Staphylococcus aureus Resistente a Meticilina/clasificación , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Infecciones Estafilocócicas/microbiología , Taiwán/epidemiologíaRESUMEN
Osmotherapy with 10% hypertonic saline (HS) alleviates cerebral edema through osmotic force. Aquaporin-4 (AQP4) has been reported to be implicated in the pathogenesis of cerebral edema resulting from a variety of brain injury. This study aimed to determine if 10% hypertonic saline ameliorates cerebral edema through downregulation of AQP4 expression in the perivascular astrocytes in the ischemic cerebral edema. Adult male Sprague-Dawley (SD) rats were subjected to permanent right-sided middle cerebral artery occlusion (MCAO) and treated with a continuous i.v. infusion of 10% HS. Brain water content (BWC) analyzed by wet-to-dry ratios in the ischemic hemisphere of SD rats was attenuated after 10% HS treatment. This was coupled with the reduction of neuronal apoptosis in the peri-ischemic brain tissue. Concomitantly, downregulated expression of AQP4 in the perivascular astrocytes after 10% HS treatment was observed. Our results suggest that in addition to its osmotic force, 10% HS exerts anti-edema effects possibly through downregulation of AQP4 expression in the perivascular astrocytes. The reduction of brain edema after 10% HS administration can prevent ischemic brain damage.