RESUMEN
BACKGROUND: People with Down syndrome (DS) develop Alzheimer's disease (AD) at an earlier age of onset than those with sporadic AD. AD neuropathology is typically present in DS by 40 years of age with an onset of dementia approximately 10 years later. This early onset is due to the overexpression of amyloid precursor protein from the third copy of chromosome 21. Cerebrovascular neuropathology is thought to contribute in 40-60% of cases sporadic AD. However, the vascular contribution to dementia in people with DS has been relatively unexplored. We hypothesised that vascular perfusion is compromised in older adults with DS relative to younger individuals and is further exacerbated in those with dementia. METHOD: Cerebral blood flow (CBF) was measured using pulsed arterial spin labelling in 35 cognitively characterised adults with DS (26-65 years). DS participants were also compared with 15 control subjects without DS or dementia (26-65 years). Linear regression evaluated the difference in CBF across groups and diagnosis along with assessing the association between CBF and cognitive measures within the DS cohort. RESULTS: Cerebral blood flow was significantly lower among DS participants with probable AD compared with controls (P = 0.02) and DS participants with no dementia (P = 0.01). Within the DS cohort, CBF was significantly associated with the Severe Impairment Battery (SIB) measure and the Dementia Questionnaire for People with Learning Disabilities (DLD) rating (F3,25 = 5.13; P = 0.007). Both the SIB (ß = 0.74; t = 2.71; P = 0.01) and DLD (ß = -0.96; t = -3.87; P < 0.001) indicated greater impairment as global CBF decreased. Age was significantly associated with CBF among participants with DS. There was a non-linear effect of age, whereby CBF declined more rapidly after 45 years of age. CONCLUSIONS: This preliminary study of CBF in DS indicates that cerebrovascular pathology may be a significant contributor to dementia in DS. CBF was associated with diagnosis, cognition and age. Notably, CBF decreases at a greater rate after age 45 and may represent a significant prodromal event in AD progression.
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Envejecimiento/fisiología , Circulación Cerebrovascular/fisiología , Demencia/epidemiología , Síndrome de Down/epidemiología , Adulto , Anciano , Comorbilidad , Demencia/fisiopatología , Síndrome de Down/fisiopatología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estados Unidos/epidemiologíaRESUMEN
Objective: To explore the effect of anterior circulation transient ischemic attack (TIA) on early neurological deterioration (END) in patients with ipsilateral ischemic stroke and its mechanism. Methods: (1) One hundred and thirteen patients with ipsilateral ischemic stroke and 36 healthy volunteers (healthy control group) in Neurology Department of Tianjin Medical University General Hospital from November 2014 to July 2015 were recruited into this study. According to whether got TIA before ischemic stroke, patients were divided into simple ischemic stroke group (CI group, n=87) and TIA-CI group (n=26). Their END, NIHSS score, 3-month mRS score, infarct size, serum hs-CRP and other risk factors were compared. (2) The peripheral blood mononuclear cells (PBMCs) were extracted from peripheral blood of TIA-CI group and CI group at 24 h, the 3 th day, the 7 th day and 12th day after ischemic stroke onset. At the same time, PBMCs of control group were collected. Western blot was carried out to evaluate the expression of nuclear factor-κB (NF-κB). Immunofluorescence was used to detect the cytoplasmic-to-nuclear shuttling of NF-κB. Results: (1) The incidence of END, NIHSS score at discharge, 3-month mRS score and serum hs-CRP level were significantly lower whereas the infarct size was significantly smaller of TIA-CI group than CI group (11.5% vs 31.0%, 1.9±2.3 vs 3.3±3.7, 0.9±0.8 vs 1.8±1.8, 1.1(0.3, 2.5) cm(3) vs 2.4(0.5, 22.8) cm(3,) (2.5±3.2) mg/L vs (6.2±3.2) mg/L, all P<0.05) . hs-CRP was positively correlated with END (r=0.311, P<0.05). (2) Expression of NF-κB: â Compared with control group, the NF-κB expression increased first and then decreased in both of the two patient groups, and it decreased earlier in TIA-CI group than CI group.â¡In each time point, NF-κB expression of TIA-CI group was lower than CI group(t=1.754, P<0.05; t=1.858, P<0.05; t=0.609, P<0.05; t=0.519, P<0.05). (3) Activity of NF-κB: Most of NF-κB were inactivation and located in cytoplasm of control group. NF-κB of TIA-CI group and CI group was activated and translocated from cytoplasm into nuclear at the 24 h and 3 th day after ischemic stroke. At the 7 th day and 12th day, the accumulation of NF-κB in nuclear decreased and most of them located in cytoplasm in TIA-CI group, whereas most of NF-κB still located in nuclear in CI group. The activated station of NF-κB lasted shorter in TIA-CI group than CI group. Conclusions: TIA can reduce the incidence of END in patients of ipsilateral ischemic stroke. Its protective effect may relate with the inhibition of inflammation which induced by NF-κB.
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Ataque Isquémico Transitorio , Isquemia Encefálica , Humanos , Leucocitos Mononucleares , Factores de Riesgo , Accidente CerebrovascularRESUMEN
To determine if proton magnetic resonance spectroscopy ((1)H-MRS) detect differences in dementia status in adults with Down syndrome (DS), we used (1)H-MRS to measure neuronal and glial metabolites in the posterior cingulate cortex in 22 adults with DS and in 15 age- and gender-matched healthy controls. We evaluated associations between (1)H-MRS results and cognition among DS participants. Neuronal biomarkers, including N-acetylaspartate (NAA) and glutamate-glutamine complex (Glx), were significantly lower in DS patients with Alzheimer's should probably be changed to Alzheimer (without ' or s) through ms as per the new naming standard disease (DSAD) when compared to non-demented DS (DS) and healthy controls (CTL). Neuronal biomarkers therefore appear to reflect dementia status in DS. In contrast, all DS participants had significantly higher myo-inositol (MI), a putative glial biomarker, compared to CTL. Our data indicate that there may be an overall higher glial inflammatory component in DS compared to CTL prior to and possibly independent of developing dementia. When computing the NAA to MI ratio, we found that presence or absence of dementia could be distinguished in DS. NAA, Glx, and NAA/MI in all DS participants were correlated with scores from the Brief Praxis Test and the Severe Impairment Battery. (1)H-MRS may be a useful diagnostic tool in future longitudinal studies to measure AD progression in persons with DS. In particular, NAA and the NAA/MI ratio is sensitive to the functional status of adults with DS, including prior to dementia.
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Ácido Aspártico/análogos & derivados , Demencia/etiología , Demencia/metabolismo , Síndrome de Down/complicaciones , Giro del Cíngulo/metabolismo , Espectroscopía de Protones por Resonancia Magnética , Actividades Cotidianas , Adulto , Análisis de Varianza , Ácido Aspártico/metabolismo , Demencia/psicología , Síndrome de Down/patología , Femenino , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Giro del Cíngulo/patología , Humanos , Inositol/metabolismo , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Encuestas y CuestionariosRESUMEN
Acute ischemic stroke (AIS) has become a serious health problem in many countries because of its poor outcome and worsening epidemic trend. Early identification of genetic risk factors and physiological indicators for stroke occurrence may help to reduce the incidence of stroke. Therefore, we conducted a case-control study including 50 AIS patients and 50 healthy individuals from a Chinese population to explore the association between AIS and patient complete blood profiles and the association between AIS and the genetic polymorphism K469E in intercellular adhesion molecule-1 (ICAM-1). Compared to the control group, AIS patients showed a high percentage of mononuclear cells, low platelet count, low ratio of platelet to lymphocyte count, high frequency of the 469K allele, and low frequency of the 469E allele. White blood cell count, percentage of neutrophils, percentage of lymphatic cells, platelet distribution width, mean platelet volume, and platelet hematocrit levels showed no significant differences between the 2 groups and between different genotypes. Our results suggested an association of elevated levels of mononuclear cells and reduced platelet count with higher AIS risk. Our results also supported the hypothesis that the KK genotype at the K469E locus in ICAM-1 is a risk factor for AIS.
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Predisposición Genética a la Enfermedad , Molécula 1 de Adhesión Intercelular/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/patología , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Sustitución de Aminoácidos , Estudios de Casos y Controles , Índices de Eritrocitos , Femenino , Frecuencia de los Genes , Genotipo , Pruebas Hematológicas , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Análisis de Secuencia de ADN , Accidente Cerebrovascular/sangre , Adulto JovenRESUMEN
Isoproterenol, a ß-adrenergic agonist, has been shown to induce salivary gland hyperplasia. However, the mechanism involved in this pharmacological phenomenon is not well understood. To gain a better understanding of the underlying changes, including genes, networks and pathways altered by isoproterenol, microarray-based gene expression analysis was conducted on rat parotid glands at 10, 30, and 60 min after isoproterenol injection. After isoproterenol treatment, the number of differentially expressed genes was increased in a time-dependent manner. Pathway analysis showed that cell hyperplasia, p38(MAPK), and IGF-1 were the most altered function, network and pathway, respectively. The balanced regulation of up- and down-expression of genes related to cell proliferation/survival may provide a better understanding of the mechanism of isoproterenol-induced parotid gland enlargement without tumor transformation.
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Regulación de la Expresión Génica/efectos de los fármacos , Isoproterenol/farmacología , Glándulas Salivales/metabolismo , Animales , Perfilación de la Expresión Génica , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Glándulas Salivales/efectos de los fármacosRESUMEN
OBJECTIVES: Candida-associated denture stomatitis is a recurrent and debilitating oral mucosal disease. Development of anticandidal denture materials represents a promising strategy to manage this condition. We have previously shown that miconazole incorporated in methacrylic acid (MAA) copolymerized diurethane dimethacrylate (UDMA) denture materials has long-term anticandidal activity. In this study, we examined the ability of culture medium conditioned with drug-free- or miconazole-MAA-UDMA discs to prevent Candida infection in an in vitro oral epithelial cell/Candida albicans coculture system. MATERIALS AND METHODS: Candida albicans (C. albicans)-induced OKF6/TERT-2 cell damage was quantified by the release of lactate dehydrogenase from epithelial cells, cytokine production was quantified using protein cytokine arrays, and the expression of C. albicans genes was measured by RT-qPCR. RESULTS: Candida albicans had limited growth with altered expression levels of secreted aspartyl proteinase-2 and -5 in culture medium conditioned by miconazole-MAA-UDMA discs. Significantly, the ability of C. albicans to induce oral epithelial cell damage and trigger epithelial proinflammatory cytokine production was also inhibited by miconazole disc conditioned media. CONCLUSION: Miconazole released from MAA-UDMA denture materials effectively prevents the development of candidal infection in an in vitro oral epithelial system. Further characterization of this drug-rechargeable denture material is warranted.
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Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Diseño de Prótesis Dental , Dentaduras , Portadores de Fármacos , Miconazol/farmacología , Materiales Biocompatibles , Metacrilatos/farmacología , Uretano/análogos & derivadosRESUMEN
We examined the cellular signaling pathways involved in parotid gland enlargement induced by repeated isoproterenol administration in rats. Immunoblot analysis revealed early (1h) activation of the mitogen activated protein kinase (MAPK) ERK1/2, and progressive activation of epidermal growth factor receptor (EGFR), p38MAPK and p70S6 kinase (p70S6K) during 72h of isoproterenol treatment. Expression of ß-adrenergic receptors (ARs) of the ß2, but not ß1, subtype increased over time in parallel with increases in the proliferation marker PCNA and parotid gland weight. Levels of ß2-AR mRNA, assessed by quantitative RT-PCR and Northern blot analysis, were upregulated in parotid glands of isoproterenol treated rats. cAMP response element binding protein (CREB), a positive regulator of ß2-AR transcription, was activated at 1h after isoproterenol administration, as evidenced by increased nuclear translocation and DNA binding using immunohistochemical staining and electrophoretic mobility shift assay. ELISA of NF-κB, also a ß2-AR transcriptional regulator, revealed an increase in p65 and p50 subunits in nuclear protein extracts from parotid glands of isoproterenol treated rats. Together, these results demonstrate that ß-adrenergic stimulation activates diverse cell survival and progrowth signaling pathways, including cAMP and EGFR linked activation of ERK1/2, p38MAPK, and p70S6K, and also induction of ß2-ARs, possibly mediated by CREB and NF-κB, resulting in salivary gland enlargement. We propose that during isoproterenol treatment activation of the ß1-AR, the predominant ß-AR subtype in unstimulated salivary glands, initiates proliferative signaling cascades, and that upregulation of the ß2-AR plays an essential role in later stages of salivary gland growth.
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Glándula Parótida/crecimiento & desarrollo , Glándula Parótida/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación de la Expresión Génica , Isoproterenol/farmacología , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Masculino , Proteína Quinasa 14 Activada por Mitógenos/genética , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , FN-kappa B/metabolismo , Glándula Parótida/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de SeñalRESUMEN
Dendritic cells (DC) are professional antigen-presenting cells that can actively taken up and present tumour-derived proteins to induce a tumour-specific immune response. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a pivotal role in the generation, sensitization, maturation and survival of DC. We charged the peripheral blood monocyte cell-derived DC with tumour lysate, and then transfected the DC with lentiviral vector-encoding human GM-CSF (hGM-CSF). The antigen-presenting capacity of the hGM-CSF-transfected DC was tested by means of the mixed lymphocyte reaction and cytotoxic T-lymphocyte assay using wild-type DC as the control. The Lenti-hGM-CSF-transfected DC was able to stimulate the proliferation of naive allogeneic T lymphocytes and to generate tumour-specific cytotoxic T lymphocytes more efficiently than the wild-type DC. This data indicates that Lenti-hGM-CSF-transfected DC could potentially be used as an effective clinical approach for cancer immunotherapy.
Asunto(s)
Células Dendríticas/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Activación de Linfocitos , Neoplasias , Proliferación Celular , Células Cultivadas , Clonación Molecular , ADN Complementario/genética , Células Dendríticas/citología , Regulación de la Expresión Génica/inmunología , Técnicas de Transferencia de Gen , Vectores Genéticos/genética , Células HEK293 , Células HeLa , Humanos , Inmunoterapia , Activación de Linfocitos/inmunología , Neoplasias/inmunología , Linfocitos T Citotóxicos/inmunologíaRESUMEN
OBJECTIVES: To test whether the submandibular/sublingual (SMSL) salivary secretion, mucin concentration and candida carriage status were altered in human immunodeficiency virus-positive (HIV+) patients. SUBJECTS AND METHODS: SMSL saliva collected from 48 HIV-infected and 31 HIV-negative men were analyzed for flow rates, total protein and mucin concentrations. Salivary cultures were performed for Candida assessment. RESULTS: The salivary flow rate and protein secretion of the HIV+ patients was 37% and 32% less than that of the controls (P < 0.0001, P = 0.0087). The mucin concentrations (MG1 and MG2) were higher in the HIV+ subjects compared with controls (P = 0.0186, P = 0.0014); however, the mucin secretions were not different. The frequency of Candida-positive cultures was higher in the HIV+ subjects than in the controls (61.4%vs 24.1%, P = 0.0018). In the HIV-infected group, the unstimulated SMSL flow rates were lower in Candida-positive than in Candida-negative patients (P = 0.0158). CONCLUSION: The salivary secretion of the SMSL glands was reduced in HIV infection. Although the mucin concentration increased in HIV+ subjects, mucin secretion was not altered. Highly active antiviral therapy had no effect on salivary function. We found an association between the level of candida carriage and salivary flow rate in HIV-infected patients.
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Candida/aislamiento & purificación , Infecciones por VIH/complicaciones , Seropositividad para VIH/complicaciones , Mucinas/metabolismo , Saliva/metabolismo , Salivación/fisiología , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/efectos adversos , Candidiasis/complicaciones , Infecciones por VIH/tratamiento farmacológico , Seropositividad para VIH/tratamiento farmacológico , Humanos , Masculino , Saliva/microbiología , Tasa de Secreción/efectos de los fármacos , Tasa de Secreción/fisiología , Glándula Sublingual/efectos de los fármacos , Glándula Sublingual/metabolismo , Glándula Submandibular/efectos de los fármacos , Glándula Submandibular/metabolismo , Xerostomía/complicaciones , Xerostomía/microbiologíaRESUMEN
The etiology of salivary gland hypofunction in HIV(+) patients is unclear. This study was designed to determine the effect of early-stage HIV(+) infection (CD4(+) > 200 cells/ micro L; n = 139) on salivary gland function and the relationship of this dysfunction to the taking of xerostomic medications. Salivary flow rates and the content of electrolytes and antimicrobial proteins in stimulated parotid and submandibular/sublingual saliva were determined. Compared with healthy controls (n = 50), the HIV(+) group showed significant reductions in flow rates of unstimulated whole (35%), stimulated parotid (47%), unstimulated submandibular/sublingual (23%), and stimulated submandibular/sublingual (39%) saliva. The flow rates for the HIV(+) patients taking xerostomic medications did not differ from those of patients who did not. Concentrations of some salivary gland components were altered in the HIV(+) group. Analysis of these data suggests that salivary gland function is adversely affected early in HIV infection and that these changes do not appear to be compounded by the taking of xerostomic medications.
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Infecciones por VIH/fisiopatología , Saliva/fisiología , Adulto , Albúminas/análisis , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Calcio/análisis , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunoglobulina A Secretora/análisis , Masculino , Glándula Parótida/metabolismo , Saliva/química , Proteínas y Péptidos Salivales/análisis , Tasa de Secreción/fisiología , Sodio/análisis , Estadísticas no Paramétricas , Glándula Sublingual/metabolismo , Glándula Submandibular/metabolismo , Ácido Úrico/análisis , Xerostomía/inducido químicamenteRESUMEN
This study investigated salivary anticandidal activity and salivary composition in stimulated whole saliva of 18 advanced HIV-infected patients and compared these values to healthy controls. Stimulated whole saliva from HIV-infected patients showed decreased anticandidal activity. The flow rate was reduced by 40% as compared with controls. The saliva flow rate for HIV-infected patients who had recoverable yeast in their saliva was reduced as compared to HIV-infected patients without recoverable yeast. For HIV-infected patients, the saliva concentrations of lactoferrin, secretory IgA and Cl- were increased while the secretion rate of lysozyme, total protein and K+ were reduced. There was no difference in any parameter as a function of taking the antifungal drug fluconazole. There was no association between salivary anticandidal activity and any salivary component. This study shows reduced anticandidal activity and salivary flow rate in HIV-infected patients. These alterations may contribute to their increased incidence of oral candidal infections.
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Antifúngicos , Candida albicans , Candidiasis Bucal/inmunología , Infecciones por VIH/inmunología , Saliva/fisiología , Adulto , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Candida albicans/inmunología , Candidiasis Bucal/complicaciones , Estudios de Casos y Controles , Estudios de Cohortes , Recuento de Colonia Microbiana , Electrólitos/análisis , Femenino , Fluconazol/farmacología , Estructuras Fúngicas , Infecciones por VIH/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Saliva/química , Saliva/metabolismo , Saliva/microbiología , Proteínas y Péptidos Salivales/análisis , Tasa de SecreciónRESUMEN
A restraining device was designed specifically for the collection of whole saliva from mice without using anesthesia. As the procedure does not involve surgical cannulation of the salivary glands, saliva can be collected from the same mouse at different times. The time between the injection of a secretory stimulant (pilocarpine) and the appearance of saliva in the mouth (lag time) was 100.5 +/-8.5 s (mean+/-S.E.M., n=10) for control mice. The volume of saliva collected in the first 5 min was three times greater than that collected between 15 and 20 min. The average flow rate for a collection period of 15 min was 16.7 +/-1.8 microl/min (n=10). The flow rate was decreased 50% (P<0.005) whereas the lag time was increased more than 300% (P<0.05) at 24 h after irradiation. The concentrations of a 23.5-kDa protein and a mucin were decreased after irradiation whereas there was no significant effect on the concentration of amylase or peroxidase.
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Rayos gamma , Restricción Física/instrumentación , Glándulas Salivales/efectos de la radiación , Amilasas/efectos de la radiación , Análisis de Varianza , Animales , Diseño de Equipo , Masculino , Ratones , Ratones Endogámicos C57BL , Mucinas/efectos de la radiación , Agonistas Muscarínicos/farmacología , Peroxidasas/efectos de la radiación , Pilocarpina/farmacología , Saliva/metabolismo , Saliva/efectos de la radiación , Glándulas Salivales/efectos de los fármacos , Glándulas Salivales/metabolismo , Proteínas y Péptidos Salivales/efectos de la radiación , Tasa de Secreción/efectos de los fármacos , Tasa de Secreción/efectos de la radiación , Estadística como Asunto , Factores de Tiempo , Irradiación Corporal TotalRESUMEN
Salivary anticandidal activities play an important role in oral candidal infection. R. P. Santarpia et al. (Oral Microbiol. Immunol. 7:38-43, 1992) developed in vitro anticandidal assays to measure the ability of saliva to inhibit the viability of Candida albicans blastoconidia and the formation of germ tubes by C. albicans. In this report, we describe modifications of these assays for use with small volumes of saliva (50 to 100 microl). For healthy subjects, there is strong inhibition of blastoconidial viability in stimulated parotid (75%), submandibular-sublingual (74%), and whole (97%) saliva, as well as strong inhibition of germ tube formation (>80%) for all three saliva types. The susceptibility of several Candida isolates to inhibition of viability by saliva collected from healthy subjects is independent of body source of Candida isolation (blood, oral cavity, or vagina) or the susceptibility of the isolate to the antifungal drug fluconazole. Salivary anticandidal activities in human immunodeficiency virus (HIV)-infected patients were significantly lower than those in healthy controls for inhibition of blastoconidial viability (P < 0.05) and germ tube formation (P < 0. 001). Stimulated whole-saliva flow rates were also significantly lower (P < 0.05) for HIV-infected patients. These results show that saliva of healthy individuals has anticandidal activity and that this activity is reduced in the saliva of HIV-infected patients. These findings may help explain the greater incidence of oral candidal infections for individuals with AIDS.
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Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Candidiasis Bucal/inmunología , Saliva/inmunología , Saliva/microbiología , Adulto , Antifúngicos , Candida albicans/efectos de los fármacos , Candida albicans/crecimiento & desarrollo , Candida albicans/inmunología , Candidiasis Bucal/virología , Estudios de Cohortes , Farmacorresistencia Microbiana , Fluconazol , Humanos , Masculino , Persona de Mediana Edad , Glándula Sublingual/inmunología , Glándula Sublingual/microbiología , Glándula Submandibular/inmunología , Glándula Submandibular/microbiologíaRESUMEN
Strongyloidiasis is caused by the nematode Strongyloides stercoralis. The parasite has a unique life cycle that enables it to cause a hyperinfection syndrome in which pulmonary involvement is characteristic. We describe the case of a 68-yr-old Hispanic male from Puerto Rico with disseminated strongyloidiasis who developed intense granulomatous reaction in the lung associated with interlobular septal fibrosis. Granulomatous lung disease leading to fibrosis within the lung has been well demonstrated in schistosomiasis, another parasitic disease. This case represents the first report, as far as we are aware, of fibrosis within the lung and restrictive pulmonary disease in association with Strongyloides stercoralis.
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Enfermedades Pulmonares Parasitarias/etiología , Fibrosis Pulmonar/etiología , Strongyloides stercoralis , Estrongiloidiasis/complicaciones , Anciano , Animales , Resultado Fatal , Granuloma/diagnóstico , Granuloma/etiología , Granuloma/patología , Humanos , Pulmón/patología , Enfermedades Pulmonares Obstructivas/diagnóstico , Enfermedades Pulmonares Obstructivas/etiología , Enfermedades Pulmonares Obstructivas/patología , Enfermedades Pulmonares Parasitarias/diagnóstico , Enfermedades Pulmonares Parasitarias/patología , Masculino , Fibrosis Pulmonar/diagnóstico , Fibrosis Pulmonar/patología , Estrongiloidiasis/diagnóstico , Estrongiloidiasis/patologíaRESUMEN
Using monolayer cultures of clonally isolated C3 and T5 rat prostate cancer cells, we determined that acidic (aFGF) and basic (bFGF) fibroblast growth factors profoundly enhanced T5 cell thymidine incorporation with half-maximum stimulation at 0.53 and 0.35 ng/ml, respectively. In contrast, aFGF or bFGF enhancement of C3 cell thymidine incorporation was about 5% of that of T5 cells, and effects were principally mitogen concentration independent. Saturation analyses and cross-linking studies established that both C3 and T5 cells contained high-affinity FGF receptors of 120 and 145 kilodaltons and that receptor content and Kd of C3 and T5 cells were comparable. aFGF or bFGF stimulation of T5 cell thymidine incorporation profoundly decreased as cell plating density was reduced from 1.5 x 10(5) to 1.0 x 10(4) cells/well. The modest response of C3 cells to either aFGF or bFGF also decreased as cell plating density was reduced. Because heparin preserves FGF biological activity and enhances bFGF binding to high-affinity FGF receptors, we examined the effect of heparin on FGF stimulation of C3 cell thymidine incorporation. We found that changes in cell plating density and/or medium heparin concentration had variable, inconsistent effects. These were C3 cell plating density associated and included inhibition or modest enhancement of FGF effects. Binding analyses established that high-affinity bFGF binding of C3 and T5 cells immediately prior to assessing FGF-stimulated thymidine incorporation was comparable and independent of cell plating density, implying that C3 cell FGF insensitivity was not attributable to differences in C3 and T5 cell FGF receptor content at the time of mitogen stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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Factores de Crecimiento de Fibroblastos/farmacología , Neoplasias de la Próstata/patología , Transducción de Señal , Animales , Inhibición de Contacto , Replicación del ADN/efectos de los fármacos , Regulación hacia Abajo , Resistencia a Medicamentos , Heparina/farmacología , Masculino , Ratas , Receptores de Factores de Crecimiento de Fibroblastos/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Using biochemical methods we established that estrogen receptor content and distribution and progesterone receptor content in female and male baboon myocardium did not differ between sexes. In contrast, myocardial androgen receptor distribution between cytosolic and nuclear compartments was sexually dimorphic. Female baboon myocardial androgen receptors were restricted to the cytosolic compartment, whereas male myocardial androgen receptors were distributed between the cytosolic and nuclear compartments. Using human estrogen receptor cDNA we showed that baboon aorta, myocardium and uterus contain a 6.3 kb estrogen receptor transcript. Analyses performed with human progesterone receptor cDNA established that baboon aorta and uterus contain an 8 kb progesterone receptor transcript; however, progesterone receptor transcripts were not demonstrable in baboon myocardial RNA preparations. Because relative hybridization signal intensity reflected known uterine and aortic progesterone receptor content, failure to detect progesterone receptor transcripts in myocardial preparations may reflect sensitivity limitations and the fact that aortic progesterone receptor content is 5-fold greater than that of myocardium. Immunocytochemical analyses demonstrated that baboon myocardial progesterone receptors were present in greater than 25% of myocytes and generally absent from other myocardial cells. Our studies establish that: (1) gonadal steroid hormone receptor gene transcription occurs in cells of the baboon cardiovasculature, (2) these steroid hormone receptors may be physiologically functional, and (3) gonadal steroid hormone receptors may be restricted to specialized cells of the cardiovasculature.
Asunto(s)
Aorta/ultraestructura , Miocardio/ultraestructura , Receptores de Estrógenos/ultraestructura , Receptores de Progesterona/ultraestructura , Caracteres Sexuales , Animales , Citosol/metabolismo , Citosol/ultraestructura , ADN , Femenino , Masculino , Especificidad de Órganos , Papio , Receptores de Estrógenos/genética , Receptores de Progesterona/genéticaRESUMEN
Clonally derived C-, D-, and T-family AXC/SSh rat prostate cancer cell lines contain transforming growth factor-beta (TGF beta) receptors. The content in C3, D1, T1, and T5 cells, respectively, was 8,560 +/- 1,450, 13,160 +/- 1,240, 2,425 +/- 490, and 10,540 +/- 1,025 sites/cell (mean +/- SEM). Respective Kd values were 160 +/- 48, 200 +/- 53, 24 +/- 3, and 115 +/- 15 pM (mean +/- SEM). T1 cell TGF beta receptor site content and Kd differed significantly from those of other prostate cancer cell lines (P less than 0.05). TGF beta is a bifunctional concentration-dependent modulator of T1 and T5 cell thymidine incorporation. At low concentrations, thymidine incorporation was inhibited, whereas as the medium TGF beta content was increased, T1 and T5 cell thymidine incorporation was stimulated. The concentrations of TGF beta causing half-maximum inhibition of T1 or T5 cell thymidine incorporation, respectively, were 0.11 and 0.24 pM, whereas the respective TGF beta concentrations causing half-maximum stimulation of thymidine incorporation were 14.4 and 134 pM. These findings establish that rat prostate cancer cell sensitivity to TGF beta inhibition of function is at least 2 orders of magnitude greater than that of most other mammalian cells. In contrast, the sensitivity of rat prostate cancer cells to TGF beta enhancement of function is comparable to that of other mammalian cells. TGF beta inhibited basic fibroblast growth factor (bFGF) stimulation of T1 and T5 cell thymidine incorporation. Because the concentration of bFGF required for half-maximum increase of T5 cell thymidine incorporation was independent of medium TGF beta content, the effect of TGF beta is distal to the T5 cell bFGF receptor. In contrast, the concentration of bFGF required for half-maximum increase in T1 cell thymidine incorporation increased 5-fold as the medium TGF beta content was increased; suggesting that the effect of TGF beta in T1 cells is proximal to the T1 cell bFGF receptor. Our studies establish that rat prostate cancer cells contain functional TGF beta receptors, imply the presence of functional bFGF receptors, and demonstrate that mitogen modulation of prostate cancer cell function is multifactorial. The finding that TGF beta is a bifunctional effector of prostate cancer cell DNA synthesis provides some insight into the potential complexity of mitogen modulation of prostate cancer cell proliferation. The mechanism by which these mitogens interact is unknown; however, our studies suggest that some interactive effects may be cell line specific.
Asunto(s)
Neoplasias de la Próstata/metabolismo , Receptores de Superficie Celular/metabolismo , Marcadores de Afinidad , Andrógenos/farmacología , Animales , ADN/biosíntesis , Factores de Crecimiento de Fibroblastos/farmacología , Masculino , Ratas , Receptores de Factores de Crecimiento Transformadores beta , Factores de Crecimiento Transformadores/metabolismo , Factores de Crecimiento Transformadores/farmacología , Células Tumorales CultivadasRESUMEN
Using methods for cell lysis and fractionation which yield essentially quantitative recovery of rat prostate cancer cell cytosolic and nuclear androgen receptors, we examined androgen modulation of androgen receptor content of clonally derived prostate cancer cell lines. We showed that testosterone elicited a concentration-dependent 2.3-fold increase in T5 cell androgen receptor content which was maximum after 48 h and was maintained through at least 72 h of culture. Testosterone caused only a 1.4-fold elevation in D2 cell androgen receptor content which was maximum between 6 and 12 h of culture and was maintained through at least 72 h culture. In contrast, testosterone did not cause a change in C3 cell androgen receptor content. Cycloheximide inhibition showed that both the testosterone-mediated increase in and maintenance of basal prostate cancer cell androgen receptor content required protein synthesis. Because testosterone and the nonmetabolizable androgen R1881 were essentially equipotent as effectors of the increase in T5 cell androgen receptor content, findings using testosterone appear to represent maximum effects. RU 23908 antagonized both R1881 and testosterone promoted elevations of prostate cancer cell androgen receptor content. Effectiveness of RU 23908 was comparable to the relative binding affinity of R1881, testosterone and RU 23908 for androgen receptors. This implies that at least part of the androgen-promoted increase in prostate cancer cell androgen receptor content is mediated through the action of androgen receptors and suggests that androgen receptors may act as both cis and trans regulatory elements. The mechanisms which determine basal or androgen-modulated prostate cancer cell androgen receptor content remain to be elucidated.
Asunto(s)
Andrógenos/fisiología , Neoplasias de la Próstata/ultraestructura , Receptores Androgénicos/ultraestructura , Andrógenos/inmunología , Animales , Anticuerpos/inmunología , Anticuerpos/farmacología , Línea Celular , Citosol/análisis , Citosol/metabolismo , Citosol/ultraestructura , Estrenos/metabolismo , Masculino , Metribolona , Neoplasias de la Próstata/análisis , Neoplasias de la Próstata/metabolismo , Ratas , Receptores Androgénicos/análisis , Receptores Androgénicos/metabolismo , Congéneres de la Testosterona/metabolismo , Células Tumorales CultivadasRESUMEN
Digestion of the rat liver glucocorticoid receptor with chymotrypsin results in the generation of a 42-kDa fragment which contains the steroid-binding and DNA-binding domains and the antigenic site for the BuGR anti-glucocorticoid receptor monoclonal antibody, while digestion with trypsin generates a 15-kDa receptor fragment containing only the DNA-binding function and the BuGR epitope (Eisen, L.P., Reichman, M.E., Thompson, E.B., Gametchu, B., Harrison, R. W., and Eisen, H.J. (1985) J. Biol. Chem. 260, 11805-11810). In this paper, glucocorticoid receptor of mouse L cells that were grown in the presence of [32P]orthophosphate was digested with trypsin or chymotrypsin (either before or after immune purification with BuGR antibody) and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, autoradiography, and Western blotting. The receptor is endogenously phosphorylated only on serine residues. Chymotrypsin digestion results in a 32P-labeled 42-kDa receptor fragment which contains steroid-binding, DNA-binding, and BuGR-reactive sites. Trypsin digestion generates a 27-kDa steroid-bound fragment (meroreceptor) which is not labeled with 32P and a 32P-labeled 15-kDa fragment which contains both the DNA-binding domain and the BuGR epitope. We have calculated that there are 4 times as many phosphate residues in the intact receptor than in the 42-kDa chymotrypsin fragment. From examination of 32P-labeled receptor fragments, we have deduced that one phosphate is located between amino acids 398 and 447, a region containing the BuGR epitope and about one-third of the DNA-binding domain, and the remaining three phosphates appear to be clustered just to the amino-terminal side of the BuGR epitope in a region defined by amino acids 313 to 369. Treatment of intact 32P-labeled receptor in cytosol with alkaline phosphatase removes these three phosphates, but it does not remove the phosphate from the DNA-binding-BuGR-reactive fragment and it does not affect the ability of the transformed receptor to bind to DNA-cellulose.
Asunto(s)
Fosfatos/metabolismo , Receptores de Glucocorticoides/metabolismo , Animales , Anticuerpos Monoclonales , Cromatografía Líquida de Alta Presión , Quimotripsina/metabolismo , ADN/metabolismo , Electroforesis en Gel de Poliacrilamida , Técnicas para Inmunoenzimas , Técnicas de Inmunoadsorción , Células L , Ratones , Fragmentos de Péptidos/aislamiento & purificación , Fragmentos de Péptidos/metabolismo , Fosforilación , Fosfoserina/metabolismo , Tripsina/metabolismoRESUMEN
To examine the potential of steroid hormones to serve as putative regulators of aortic cell function, we defined hormone receptor content and distribution in intact baboons. Total androgen receptor content in baboon aortic arch, thoracic arch, and abdominal aorta of young mature males was indistinguishable from that of proestrus females. However, 30% to 40% of male aortic androgen receptors were in the nuclear fraction, whereas all aortic androgen receptors of proestrus females were in the cytoplasmic fraction. Cytoplasmic fraction estrogen receptor content of aortic arch and thoracic aorta of intact males was indistinguishable from that of proestrus females. However, cytoplasmic fraction estrogen receptor content of abdominal aorta of proestrus females was significantly greater than that of males. Nuclear fraction estrogen receptors were not detectable in either male or proestrus female baboon aortas. To assess effects of endogenous estrogen on aortic progesterone receptor content, we quantified cytoplasmic fraction progesterone receptors and found that content of proestrus female aortic arch was not significantly different from that of males. However, cytoplasmic fraction progesterone receptor content of thoracic and abdominal aorta of proestrus females was significantly higher than that of males. To determine whether differences in aortic receptor content or distribution were associated with changes in aortic cell function, we quantified the activity of two enzymes of glycosaminoglycan metabolism. Aortic beta-glucuronidase activity was not different in male or proestrus female baboons.(ABSTRACT TRUNCATED AT 250 WORDS)