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1.
Dis Esophagus ; 34(12)2021 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-34155508

RESUMO

Geographic differences in eosinophilic esophagitis (EoE) prevalence suggest the possibility that environmental exposures contribute to EoE pathogenesis. We aimed to examine the association between environmental quality and risk of EoE, using the Environmental Quality Index (EQI), which provides quantification of environmental quality in five domains: air, land, water, built, and sociodemographic for all counties in the United States. To do this, we performed a case-control study in a large pathology database. EoE cases were defined by ≥15 eosinophils per high-power field with other pathologic diagnoses excluded; controls did not have EoE. The pathology data were geocoded and linked with the EQI by county of residence. Logistic regression was used to estimate odds ratio (OR and 95% confidence interval [CI]) of EoE with overall EQI and for each domain, after adjusting for sex, age, and proportion minority race or ethnicity at the county level (higher EQI score indicates worse environmental quality). Of 29,802 EoE cases and 593,329 controls analyzed, odds of EoE were highest in the worst quintile of EQI (OR 1.25; 95% CI: 1.04-1.50), which was largely explained by poor scores in the water domain (OR: 1.33; 1.17-1.50). Conversely, odds of EoE were reduced with higher scores in the air domain (OR: 0.87, 0.74-1.03) and land domain (OR 0.87; 0.76-0.99). Poor EQI, mostly reflected by poor water quality, was associated with increased odds of EoE, while poor air and land quality were inversely associated with EoE. Additional work to identify specific water pollutants that may have an etiologic role in EoE may be warranted.


Assuntos
Esofagite Eosinofílica , Estudos de Casos e Controles , Exposição Ambiental/efeitos adversos , Esofagite Eosinofílica/epidemiologia , Esofagite Eosinofílica/etiologia , Humanos , Razão de Chances , Prevalência , Estados Unidos/epidemiologia
3.
J Thromb Haemost ; 14(11): 2230-2240, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27629384

RESUMO

Essentials Co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. We determined pathogenic variants in a three-generational pedigree with excessive bleeding. Bleeding occurred with concurrent variants in prostaglandin synthase-1 (PTGS-1) and factor VIII. The PTGS-1 variant was associated with functional defects in the arachidonic acid pathway. SUMMARY: Background Inherited human variants that concurrently cause disorders of primary hemostasis and coagulation are uncommon. Nevertheless, rare cases of co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. Objective We prospectively sought to determine pathogenic variants in a three-generational pedigree with excessive bleeding. Patients/methods Platelet number, size and light transmission aggregometry to multiple agonists were evaluated in pedigree members. Transmission electron microscopy determined platelet morphology and granule content. Thromboxane release studies and light transmission aggregometry in the presence or absence of prostaglandin G2 assessed specific functional defects in the arachidonic acid pathway. Whole exome sequencing (WES) and targeted nucleotide sequence analysis identified potentially deleterious variants. Results Pedigree members with excessive bleeding had impaired platelet aggregation with arachidonic acid, epinephrine and low-dose ADP, as well as reduced platelet thromboxane B2 release. Impaired platelet aggregation in response to 2MesADP was rescued with prostaglandin G2 , a prostaglandin intermediate downstream of prostaglandin synthase-1 (PTGS-1) that aids in the production of thromboxane. WES identified a non-synonymous variant in the signal peptide of PTGS-1 (rs3842787; c.50C>T; p.Pro17Leu) that completely co-segregated with disease phenotype. A variant in the F8 gene causing hemophilia A (rs28935203; c.5096A>T; p.Y1699F) was also identified. Individuals with both variants had more severe bleeding manifestations than characteristic of mild hemophilia A alone. Conclusion We provide the first report of co-existing variants in both F8 and PTGS-1 genes in a three-generation pedigree. The PTGS-1 variant was associated with specific functional defects in the arachidonic acid pathway and more severe hemorrhage.


Assuntos
Fator VIII/genética , Hemorragia/genética , Prostaglandina-Endoperóxido Sintases/genética , Adulto , Idoso , Ácido Araquidônico/metabolismo , Criança , Ciclo-Oxigenase 1/genética , Saúde da Família , Feminino , Frequência do Gene , Variação Genética , Hemorragia/sangue , Hemorragia/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Agregação Plaquetária , Contagem de Plaquetas , Estudos Prospectivos , Prostaglandina-Endoperóxido Sintases/sangue , Tromboxano B2/genética , Adulto Jovem
4.
Haemophilia ; 19(5): 720-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23711294

RESUMO

Utilization of the synthetic vasopressin analogue (1-deamino-8-D-arginine-vasopressin, DDAVP) in treatment of mild haemophilia A (MHA, specific clotting factor VIII activity level 0.05-0.4 IU mL(-1) ) is convenient and effective for many but not all patients. Genetic testing for patients with MHA is increasingly recognized as providing valuable information for patient care beyond informing reproductive decisions, and as more patients are genotyped, mutation data can be utilized to individualize treatment decisions. To determine if genetic information informs response to DDAVP, a retrospective chart review was performed under Institutional Review Board approval to extract patient data with MHA, genetic mutation results, and response to DDAVP challenge. 62 patients met inclusion criteria. Complete responses (C) presented in mean value IU mL(-1) (range), were recorded for 32 of 62(52%) subjects: pre 0.19(0.04-0.45) and post 0.78(0.5-1.95); partial responses (P) were recorded for 15 of 62(24%) subjects: pre 0.1(0.06-0.15) and post 0.4(0.3-0.47); responses that were not clinically significant (N) were recorded for 15 of 62(24%) subjects: pre 0.17(0.02-0.34) and post 0.25(0.03-0.44). Subjects (related and unrelated) with the same mutation showed a trend towards a similar response to DDAVP. Eight genotypes were common to two or more subjects (n = 26). Two genotypes were concordant in all subjects [p.Ser2192Ile n = 3(C), p.Ala2220Pro n = 2(P)]. Of mutations in the C1 or C2 domains, 13 of 15(87%) subjects responded to DDAVP [C = 9(60%); P = 4(27%); n = 2(13%)]. Baseline FVIII:C did not predict magnitude of response to DDAVP. Genetic mutation results can assist with predicting DDAVP responsiveness, but baseline FVIII:C may not.


Assuntos
Desamino Arginina Vasopressina/uso terapêutico , Fator VIII/metabolismo , Hemofilia A/tratamento farmacológico , Desamino Arginina Vasopressina/administração & dosagem , Fator VIII/genética , Hemofilia A/genética , Humanos , Mutação , Estudos Retrospectivos
5.
Haemophilia ; 18(3): e277-85, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22151249

RESUMO

Women with factor X deficiency (FXD) who want to become pregnant face uncertain risks to themselves and to an unborn infant from haemorrhagic complications during pregnancy and at parturition. Women with FXD may also experience difficulty achieving pregnancy secondary to haemorrhagic symptoms of the reproductive organs. Case reports describe differences in bleeding phenotypes and pregnancy outcomes that are not easily correlated with prepregnancy bleeding symptoms or factor X levels. The aim of this article is to identify factors for consideration and information to assist the physician in counselling women with FXD who want to become pregnant, and to offer guidelines for management where appropriate. We identified cases of pregnancy among women with FXD and their outcomes from the literature; 15 women with 24 pregnancies were identified and 18 were successful. The women in this small cohort did not have an increased rate of spontaneous abortion, (8.3% vs. 13.5% in the general US population) but did have a 2.5-fold increased risk of preterm labour (37.5% vs. 12.2% in the general US population). The role of prophylaxis to control reproductive haemorrhagic symptoms, including haemorrhagic complications of pregnancy has not yet been defined, but use of prophylaxis may allow more women to be able to attempt pregnancy. Women who had access to a tertiary care centre with a multidisciplinary team including an obstetrician with high-risk obstetric training, a haematologist, a perinatologist, and access to a reference laboratory and blood bank were able in most cases to successfully deliver healthy, term infants.


Assuntos
Coagulantes/administração & dosagem , Deficiência do Fator X/tratamento farmacológico , Fator X/administração & dosagem , Educação de Pacientes como Assunto/métodos , Cuidado Pré-Concepcional , Complicações Hematológicas na Gravidez/prevenção & controle , Adulto , Aconselhamento/métodos , Gerenciamento Clínico , Feminino , Humanos , Gravidez
6.
Haemophilia ; 17 Suppl 1: 6-13, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21692922

RESUMO

Inherited bleeding disorders are especially problematic for affected girls and women due to the monthly occurrence of menstrual periods and the effects on reproductive health. Although heavy menstrual bleeding (HMB) is the most common manifestation, females with inherited bleeding disorders (FBD) experience other bleeding symptoms throughout the lifespan that can lead to increased morbidity and impairment of daily activities. The purpose of this article is to describe the utility of a female-focused surveillance effort [female Universal Data Collection (UDC) project] in the United States Haemophilia Treatment Centres (HTCs) and to describe the baseline frequency and spectrum of diagnoses and outcomes. All FBD aged 2 years and older receiving care at selected HTCs were eligible for enrollment. Demographic data, diagnoses and historical data regarding bleeding symptoms, treatments, gynaecological abnormalities and obstetrical outcomes were analysed. Analyses represent data collected from 2009 to 2010. The most frequent diagnoses were type 1 von Willebrand's disease (VWD) (195/319; 61.1%), VWD type unknown (49/319; 15.4%) and factor VIII deficiency (40/319; 12.5%). HMB was the most common bleeding symptom (198/253; 78.3%); however, 157 (49.2%) participants reported greater than four symptoms. Oral contraceptives were used most frequently to treat HMB (90/165; 54.5%), followed by desmopressin [1-8 deamino-D-arginine vasopressin (DDAVP)] (56/165; 33.9%). Various pregnancy and childbirth complications were reported, including bleeding during miscarriage (33/43; 76.7%) and postpartum haemorrhage (PPH) (41/109; 37.6%). FBD experience multiple bleeding symptoms and obstetrical-gynaecological morbidity. The female UDC is the first prospective, longitudinal surveillance in the US focusing on FBD and has the potential to further identify complications and reduce adverse outcomes in this population.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Herdados da Coagulação Sanguínea/terapia , Criança , Pré-Escolar , Anticoncepcionais Femininos/uso terapêutico , Feminino , Humanos , Estudos Longitudinais , Menorragia/tratamento farmacológico , Pessoa de Meia-Idade , Vigilância da População , Hemorragia Pós-Parto/epidemiologia , Gravidez , Complicações Hematológicas na Gravidez/epidemiologia , Estudos Prospectivos , Estados Unidos/epidemiologia , Adulto Jovem
7.
Eur J Cancer ; 38(9): 1261-70, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12044514

RESUMO

We have previously shown that circulating intravascular cells generally arrest by mechanical restriction in the hepatic sinusoids, causing rapid release of nitric oxide (NO) which is cytotoxic to these cells and inhibits their growth into metastatic tumours. Here, we present evidence that these NO-dependent cytotoxic mechanisms are susceptible to upregulation by lipopolysaccharide (LPS). Five x 10(5) fluorescently labelled melanoma cells were injected into the mesenteric vein of C57BL/6 mice to effect their localisation in the hepatic microvasculature. Test mice were then given 1 mg/kg LPS intraperitoneally (i.p.) to activate the microvascular cells. By electron paramagnetic resonance (EPR) spectroscopy, the expression of NO in the liver was significantly increased by 8 h in the LPS-treated mice. The non-selective NO synthase inhibitor L-NAME inhibited the induction of NO by LPS, while its inactive enantiomer D-NAME had no significant effect. Using immunohistochemistry (IHC), iNOS-positive microvascular cells were detected in the terminal portal venule (TPV) region of the liver 8 h after LPS stimulation. LPS treatment also increased the retention of melanoma cells in the liver between 8 and 24 h, especially in the TPV region. Eight hours after cell injection, local expression of VCAM-1 and ICAM-1 was detected by double-label immunohistochemistry at the sites of tumour cell arrest. Expression of these adhesion molecules was enhanced in mice treated with LPS. Using flow cytometry, 98% of the B16F1 melanoma cells expressed VLA-4, the counter receptor of VCAM-1, and approximately 1.5% expressed LFA-1, the counter receptor of ICAM-1. LPS did not significantly alter the expression of either counter receptor on melanoma cells in vitro or in vivo. By DNA end-labelling, the rates of melanoma cell apoptosis were significantly increased from 8 to 24 h in the TPV region (but not in the sinusoids) of LPS-treated mice. Fourteen days after tumour cell injection, the LPS-treated mice had a significantly smaller hepatic metastatic tumour burden than the control mice. These data suggest that LPS can inhibit the metastasis of melanoma cells in the liver by inducing the expression of NO and adhesion molecules by the hepatic endothelium. The induction of iNOS and the inducible cytotoxic effect of LPS appear to be primarily located within the TPV region of the liver acinus.


Assuntos
Neoplasias Hepáticas/secundário , Melanoma Experimental/secundário , Animais , Moléculas de Adesão Celular/metabolismo , Feminino , Lipopolissacarídeos/farmacologia , Fígado/metabolismo , Neoplasias Hepáticas/irrigação sanguínea , Melanoma Experimental/irrigação sanguínea , Camundongos , Camundongos Endogâmicos C57BL , Microcirculação , Proteínas de Neoplasias/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Células Tumorais Cultivadas
8.
Cancer Res ; 60(20): 5862-9, 2000 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11059784

RESUMO

The formation of liver metastases involves interactions between intravascular cancer cells and the hepatic microvasculature. Here we provide evidence that the arrest of intravascular B16F1 melanoma cells in the liver induces a rapid local release of nitric oxide (NO) that causes apoptosis of the melanoma cells and inhibits their subsequent development into hepatic metastases. B16F1 melanoma cells (5 x 10(5)) labeled with fluorescent microspheres were injected into the portal circulation of C57BL/6 mice. The production of NO in vivo was detected by electron paramagnetic resonance spectroscopy ex vivo using an exogenous NO-trapping agent. A burst of NO was observed in liver samples examined immediately after tumor cell injection. The relative electron paramagnetic resonance signal intensity was 667 +/- 143 units in mice injected with tumor cells versus 28 +/- 5 units after saline injection (P < 0.001). Two-thirds of cells arrested in the sinusoids compared with the terminal portal venules (TPVs). By double labeling of B16F1 cells with fluorescent microspheres and a TdT-mediated UTP end labeling assay, we determined that the melanoma cells underwent apoptosis from 4-24 h after arrest. The mean rate of apoptosis was 2-fold greater in the sinusoids than in the TPVs at 4, 8, and 24 h after injection (P < 0.05-0.01). Apoptotic cells accounted for 15.9 +/- 0.8% of tumor cells located in the sinusoids and 7.1 +/- 0.9% of tumor cells in the TPVs. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester completely blocked the NO burst (P < 0.001) and inhibited the apoptosis of B16F1 cells in the sinusoids by 77%. However, the rate of tumor cell apoptosis in the TPVs was not changed. There were 5-fold more metastatic nodules in the livers of N(G)-nitro-L-arginine methyl ester-treated mice (P < 0.05). The inactive enantiomer N(G)-nitro-D-arginine methyl ester had no effect on the initial NO burst or on apoptosis of tumor cells in vivo. Both annexin V phosphatidylserine plasma membrane labeling and DNA end labeling of apoptotic cells were demonstrated after a 5-min exposure (a time equivalent to the initial transient NO induction in vivo) of B16F1 cells to a NO donor in vitro. These results identify the existence of a natural defense mechanism against cancer metastasis whereby the arrest of tumor cells in the liver induces endogenous NO release, leading to sinusoidal tumor cell killing and reduced hepatic metastasis formation.


Assuntos
Neoplasias Hepáticas Experimentais/secundário , Fígado/irrigação sanguínea , Melanoma Experimental/secundário , Óxido Nítrico/fisiologia , Penicilamina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Neoplasias Hepáticas Experimentais/irrigação sanguínea , Neoplasias Hepáticas Experimentais/prevenção & controle , Melanoma Experimental/patologia , Veias Mesentéricas/patologia , Camundongos , Camundongos Endogâmicos C57BL , NG-Nitroarginina Metil Éster/farmacologia , Metástase Neoplásica , Transplante de Neoplasias , Células Neoplásicas Circulantes/patologia , Óxido Nítrico/biossíntese , Óxido Nítrico/metabolismo , Óxido Nítrico/toxicidade , Doadores de Óxido Nítrico/farmacologia , Penicilamina/toxicidade , Veia Porta/metabolismo , Veia Porta/patologia , S-Nitroso-N-Acetilpenicilamina , Células Tumorais Cultivadas
9.
Am J Physiol Regul Integr Comp Physiol ; 278(5): R1321-8, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10801303

RESUMO

The impact of plasma corticosterone levels on the sympathetic nervous system (SNS) response to intravenous lipopolysaccharide (LPS) or intracerebroventricular injections of PG was studied in anesthetized (urethan-chloralose) male Sprague-Dawley rats. For this, electrophysiological recordings of splenic and renal nerves were completed in control or adrenalectomized (ADX) rats. LPS (10 microgram iv) similarly increased splenic and renal nerve activity in control rats with a shorter onset latency for the splenic nerve. Acute ADX enhanced the response of both nerves to LPS (P < 0.005) and reduced the onset latency of the renal nerve (P < 0.05). PGE(2) (2 microgram icv) rapidly increased the activity of both nerves but preferentially (magnitude and onset latency) stimulated the renal nerve (P < 0.05). The magnitude of the splenic nerve response to PGE(2) was unaffected by ADX. Unexpectedly, PGE(2) was less effective at stimulating renal nerve activity in ADX animals relative to intact controls (P < 0.05). Pretreatment of ADX rats with a CRF antagonist ([D-Phe(12), Nle(21,38), Calpha-MeLeu(37)]CRF-(12-41)) reversed this effect such that the renal nerve responded to central PGE(2) to a greater extent than the splenic nerve (P < 0.05), as was the case in non-ADX rats. These data indicate that enhanced sensitivity of central sympathetic pathways does not account for the enhanced SNS responses to LPS in ADX rats. Also, a CRF-related process appears to diminish renal sympathetic outflow in ADX rats.


Assuntos
Adrenalectomia , Dinoprostona/farmacologia , Lipopolissacarídeos/farmacologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Corticosterona/sangue , Hormônio Liberador da Corticotropina/fisiologia , Dinoprostona/administração & dosagem , Injeções Intravenosas , Injeções Intraventriculares , Rim/inervação , Lipopolissacarídeos/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Baço/inervação
10.
J Pathol ; 190(3): 310-29, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10685065

RESUMO

The haematogenous phase of cancer metastasis facilitates the transport of metastatic cells within the blood and incorporates a sequence of interactions between circulating intravascular cancer cells and the endothelium of blood vessels at the sites of tumour cell arrest. Initial interactions involve mechanical contact and transient adhesion, mediated by endothelial selectins and their ligands on the neoplastic cells. This contact initiates a sequence of activation pathways that involves cytokines, growth factors, bioactive lipids, and reactive oxygen species produced by either the cancer cell or the endothelium. These molecules elicit expression of integrin adhesion molecules in cancer cells and the endothelium, matrix metalloproteinases, and chemotactic factors that promote the attachment of tumour cells to the vessel wall and/or transvascular penetration. Induction of endothelial free radicals can be cytotoxic to cancer cells. Collectively, the sum of these interactions constitutes an interdependent relationship, the outcome of which determines the fate of the metastatic process.


Assuntos
Endotélio Vascular/fisiopatologia , Células Neoplásicas Circulantes , Animais , Permeabilidade Capilar/fisiologia , Adesão Celular/fisiologia , Citocinas/fisiologia , Citotoxicidade Imunológica/fisiologia , Humanos , Invasividade Neoplásica , Neovascularização Patológica/fisiopatologia , Espécies Reativas de Oxigênio
11.
Clin Exp Metastasis ; 17(2): 149-55, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10411107

RESUMO

The structural and functional heterogeneity of hepatocytes and non-parenchymal cells across the liver lobule or acinus has been well documented. The geographic distribution and potential for induced expression of adhesion molecules on murine hepatic microvascular cells has not been reported, although these molecules are able to influence the metastatic outcome of intravascular cancer cells. We have postulated that the expression of adhesion molecules on these cells is susceptible to regulation by environmental factors and that these molecules have a zonal distribution across the acinus. To test this hypothesis, we injected C57BL/6 mice with bacterial lipopolysaccharide, 1 microg/g body weight, i.p. At various time points (0-48 h) after stimulation, liver tissue sections were prepared for immunohistochemistry. Confocal microscopy was used to detect the expression of vascular cell adhesion molecule-1 (VCAM-1), E-selectin, intercellular adhesion molecule-1 (ICAM-1) and alpha v integrin. The expression patterns were quantitatively measured by histomorphometry. Under basal conditions, ICAM-1 was weakly expressed in terminal portal veins while minimal VCAM-1 and no E-selectin were detected. Following stimulation with lipopolysaccharide, VCAM-1 and E-selectin were expressed on the endothelium of terminal portal veins and on sinusoidal lining cells with significantly stronger expression in the periportal zone than midzone. VCAM-1 expression peaked at 4 h and decreased gradually by 48 h. E-selectin peaked at 2 h and disappeared by 12 h after stimulation. ICAM-1 expression showed a much stronger and more uniform expression across the acinus with the peak reached by 4 h and sustained for longer than 48 h after lipopolysaccharide administration. The alpha v integrin was not detected under basal conditions or after lipopolysaccharide stimulation. Expression of all these adhesion molecules (ICAM-1, VCAM-1, E-selectin and alpha v integrin) was induced by growth of B16F1 melanoma cells in the peritoneal cavity of the mouse. These results support the hypotheses that expression of microvascular adhesion molecules in the mouse liver is susceptible to regulation by environmental stimuli and has a zonal heterogeneity across the acinus.


Assuntos
Fígado/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Selectina E/metabolismo , Endotélio Vascular/metabolismo , Feminino , Imunoquímica , Integrinas/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Transplante de Neoplasias , Peritônio , Polissacarídeos Bacterianos/farmacologia , Fatores de Tempo , Células Tumorais Cultivadas
12.
Orthop Nurs ; 18(1): 21-7; quiz 28-9, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10223001

RESUMO

Spondylolisthesis in children and adolescents can present in various ways and have a wide range of treatment options. Children are not "little adults." They require special interview, evaluation, and treatment considerations. This article addresses the characteristics of spondylolisthesis in children and reviews some of the treatment options and related nursing considerations.


Assuntos
Espondilolistese , Adolescente , Adulto , Criança , Feminino , Humanos , Cuidados Intraoperatórios , Dor Lombar/etiologia , Masculino , Avaliação em Enfermagem , Enfermagem Ortopédica , Educação de Pacientes como Assunto/métodos , Postura , Radiografia , Espondilolistese/complicações , Espondilolistese/diagnóstico por imagem , Espondilolistese/cirurgia , Resultado do Tratamento
13.
Brain Res ; 811(1-2): 111-21, 1998 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-9804916

RESUMO

Interleukin (IL)-1, IL-2 and IL-6 influence central monoamine activity in a cytokine-specific manner. We demonstrated that whereas IL-2 increased hypothalamic and hippocampal norepinephrine (NE) utilization, and DA turnover in the prefrontal cortex, IL-6 induced profound elevations of serotonin (5-HT) and mesocortical dopamine (DA) activity in the hippocampus and prefrontal cortex [S. Zalcman, J.M. Green-Johnson, L. Murray, D.M. Nance, D.G. Dyck, H. Anisman, A. H. Greenberg, Cytokine-specific central monoamine alterations following IL-1, -2 and -6 administration, Brain Res. 643 (1994) 40-49]. IL-1, in contrast, induced a wide range of central monoamine alterations. We presently report that these cytokines also differentially influence behavior. Profound reductions in non-ambulatory and ambulatory exploration were induced in BALB/c mice following IL-1 administration. In contrast, IL-2-treated mice displayed significant increases in the time spent engaged in non-ambulatory exploration, digging, rearing (particularly the number of free rears), and in the investigation of a novel stimulus (i.e., increased number and duration of stimulus contacts). IL-6-treated mice, moreover, exhibited significant increases in the time spent engaged in ambulatory exploration, digging and rearing (particularly the number of free rears, which tended to be of short duration). Modest increases in locomotion and grooming were also observed in IL-6-treated animals. Plasma corticosterone levels did not vary significantly as a function of IL-6 treatment. Hence, cytokine-specific behavioral-activating effects were induced following administration of IL-2 and IL-6. We suggest that these effects have adaptive significance and relevance to sickness behavior; however, pathological outcomes (e.g., schizophrenia, anxious-like states, anxious depression, motor abnormalities) could develop should these cytokines be overproduced or dysregulated.


Assuntos
Comportamento Animal/efeitos dos fármacos , Interleucina-2/farmacologia , Interleucina-6/farmacologia , Adaptação Fisiológica , Animais , Corticosterona/sangue , Comportamento Exploratório/efeitos dos fármacos , Masculino , Transtornos Mentais/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Atividade Motora/efeitos dos fármacos
14.
Electrophoresis ; 19(8-9): 1351-5, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9694280

RESUMO

The application of nonradioactive RNA probes for Northern blotting offers the advantage of a rapid turn-around time for results without the loss of sensitivity for target mRNA detection. However, a problem that has impeded the widespread use of nonradioactive RNA probes for use in Northern blotting is the difficulty in stripping these probes from nylon membranes after hybridization. In this report we describe two protocols for stripping digoxigenin (Dig)-labeled RNA probes from nylon membranes. One protocol utilizes a phosphate-buffered formamide stripping solution to remove nonchemically modified (regular) RNA probes while the other method utilizes strippable probes that were produced with a chemically modified nucleotide (CTP) and removed by a specific stripping solution. This latter method was developed by Ambion Inc. and is called Strip-EZ. We also describe a protocol for the detection of two separate rat mRNAs using both biotin and digoxigenin-labeled RNA probes that does not require stripping the membrane after hybridization. Finally, we describe the use of another new labeling technology, called Chem-Link, that quickly and conveniently labels RNA for use in Northern blotting.


Assuntos
Biotina , Northern Blotting/métodos , Digoxigenina , Indicadores e Reagentes , Sondas RNA , Animais , Masculino , Ratos , Ratos Sprague-Dawley
15.
Brain Res Brain Res Protoc ; 2(4): 339-51, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9630715

RESUMO

Non-radioactive in situ hybridization is a sensitive method for determining the site of production for secretory molecules such as cytokines. We report here on the central and peripheral induction of proinflammatory cytokines by endotoxin, and outline procedures for the generation and application of rat-specific digoxigenin (Dig)-labelled RNA probes for the localization of mRNA by in situ hybridization. Rats were injected either intravenously (i.v.) or intracerebroventricularly (i.c.v.) with vehicle or lipopolysaccharide (LPS) and sacrificed at various time intervals post-injection. Rats were then perfused with 4% paraformaldehyde and the spleens and brains were removed and cryoprotected in 30% sucrose. Dig-labelled, rat-specific, antisense and sense RNA probes were generated by in vitro transcription from PCR-derived templates. Positive staining with all the antisense probes was cytoplasmic, whereas the sense probes showed no staining. Numerous tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) mRNA positive cells were observed in the marginal zone and in the red pulp of the spleen after iv LPS injections, whereas sections from saline-treated animals showed minimal cytokine mRNA expression. Cells positive for TNF-alpha and IL-1beta mRNA were detectable in the brain after i.c.v. injections of LPS, but not after icv injection of vehicle. An antisense probe for c-fos was utilized in these studies as a positive control for our procedure due to its anatomically specific expression in the rat brain after LPS. In conclusion we have demonstrated that in situ hybridization with Dig-labelled RNA probes is an efficient, sensitive and reliable tool to localize cytokine mRNA production in rat tissue.


Assuntos
Química Encefálica/fisiologia , Citocinas/genética , Digoxigenina/química , Sondas RNA , RNA Mensageiro/análise , Baço/química , Actinas/genética , Animais , Hibridização In Situ , Injeções Intraventriculares , Interleucina-1/genética , Lipopolissacarídeos/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética
16.
Neurosci Lett ; 242(3): 151-4, 1998 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-9530928

RESUMO

MK801 induces Fos-like immunoreactivity (FLI) in the paraventricular nucleus (PVN) in a sex, age, hormone and dosage dependent manner. MK801 (1.0 mg/kg) elicited greater behavioural disruption, but less FLI in the PVN of cycling and lactating female rats, compared to like-treated males. Results from gonadectomized rats with or without acute steroid replacement resembled those seen in intact rats but sex differences were extinguished. At a lower dose (0.1 mg/kg), behavioural effects were diminished but females exhibited more behavioural disruption. At this dose however, more FLI was seen in the PVN of females compared to males, but only male-lactating female differences were significant. Taken together, the data suggest that the action of MK801 on the PVN is influenced by gonadal steroids.


Assuntos
Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Núcleo Hipotalâmico Paraventricular/química , Proteínas Proto-Oncogênicas c-fos/análise , Caracteres Sexuais , Animais , Antineoplásicos Hormonais/farmacologia , Comportamento Animal/fisiologia , Estradiol/farmacologia , Feminino , Imuno-Histoquímica , Lactação/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Testosterona/farmacologia
17.
Exp Brain Res ; 119(3): 297-306, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9551830

RESUMO

Micturition in the decerebrate cat is characterized by a coordinated bladder contraction and a simultaneous decrease in external urethral sphincter (EUS) efferent activity. Without the suppression of EUS activity, voiding is significantly impaired, resulting in a state sometimes referred to as bladder-sphincter dyssynergia. The aim of the present study was to determine whether glycinergic inhibition contributes to the suppression of EUS activity during micturition evoked by bladder distension or electrical stimulation of the pontine micturition center (PMC) in decerebrate cats. Using subconvulsive intravenous doses of strychnine (0.1-0.24 mg/kg), we examined changes in bladder and EUS electroneurographic (ENG) activity during micturition. Following subconvulsive doses of strychnine, tonic EUS ENG activity increased during bladder filling in five of six animals. In the presence of strychnine, it was possible to evoke reflex bladder contractions of similar duration and peak pressure to those observed before strychnine administration. However, there was an absence of suppression of EUS ENG activity during the bladder contractions in all the animals. To determine whether the changes in sphincter activity could be due to strychnine acting at glycine receptors on EUS motoneurons, sacral spinal tissue was processed for a structural protein (gephyrin) associated with the glycine receptor. Motoneurons in Onufs nucleus in S1 were identified using choline acetyltransferase immunohistochemistry and subsequently processed with a gephyrin monoclonal antibody. Abundant gephyrin labeling was evident throughout Onufs nucleus. Since Onufs nucleus is made up of EUS and other motoneuron populations, a sample of antidromically identified urethral and anal sphincter motoneurons were intracellularly labeled with tetramethylrhodamine dextran (TMR-D) and then processed with the gephyrin antibody. Using dual-beam confocal microscopy, gephyrin immunoreactivity was observed on the soma and proximal processes of individual EUS motoneurons in both male and female animals. It was concluded that a strychnine-sensitive mechanism contributes to the suppression of sphincter activity normally observed during voiding. Although glycinergic inhibition may affect several components of the circuitry responsible for micturition, it appears that the suppression of EUS motoneurons during micturition may be partly due to a direct glycinergic inhibition of the EUS motoneurons.


Assuntos
Glicinérgicos/farmacologia , Receptores de Glicina/fisiologia , Estricnina/farmacologia , Uretra/fisiologia , Micção/fisiologia , Animais , Proteínas de Transporte/análise , Gatos , Estado de Descerebração , Estimulação Elétrica , Eletrofisiologia , Feminino , Masculino , Proteínas de Membrana/análise , Neurônios Motores/química , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/fisiologia , Inibição Neural/fisiologia , Receptores de Glicina/antagonistas & inibidores , Medula Espinal/anatomia & histologia , Medula Espinal/química , Medula Espinal/citologia , Uretra/química , Uretra/inervação , Bexiga Urinária/fisiologia
18.
J Exp Med ; 187(4): 487-96, 1998 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-9463399

RESUMO

We report that chlamydiae, which are obligate intracellular bacterial pathogens, possess a novel antiapoptotic mechanism. Chlamydia-infected host cells are profoundly resistant to apoptosis induced by a wide spectrum of proapoptotic stimuli including the kinase inhibitor staurosporine, the DNA-damaging agent etoposide, and several immunological apoptosis-inducing molecules such as tumor necrosis factor-alpha, Fas antibody, and granzyme B/perforin. The antiapoptotic activity was dependent on chlamydial but not host protein synthesis. These observations suggest that chlamydia may encode factors that interrupt many different host cell apoptotic pathways. We found that activation of the downstream caspase 3 and cleavage of poly (ADP-ribose) polymerase were inhibited in chlamydia-infected cells. Mitochondrial cytochrome c release into the cytosol induced by proapoptotic factors was also prevented by chlamydial infection. These observations suggest that chlamydial proteins may interrupt diverse apoptotic pathways by blocking mitochondrial cytochrome c release, a central step proposed to convert the upstream private pathways into an effector apoptotic pathway for amplification of downstream caspases. Thus, we have identified a chlamydial antiapoptosis mechanism(s) that will help define chlamydial pathogenesis and may also provide information about the central mechanisms regulating host cell apoptosis.


Assuntos
Apoptose , Caspases , Infecções por Chlamydia/patologia , Cisteína Endopeptidases/metabolismo , Grupo dos Citocromos c/metabolismo , Mitocôndrias/enzimologia , Animais , Caspase 3 , Infecções por Chlamydia/enzimologia , Ativação Enzimática , Células HeLa , Humanos , Hidrólise , Camundongos , Microscopia Confocal , Microscopia de Fluorescência , Poli(ADP-Ribose) Polimerases/metabolismo
19.
J Pediatr Oncol Nurs ; 14(4): 194-201, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9322393

RESUMO

Epstein-Barr virus lymphoproliferative disease (EBV LPD) is a well-recognized, life-threatening complication of bone marrow transplantation (BMT). The incidence of EBV LPD is increasing as more transplants are performed from mismatched and unrelated donors. Significant strides have been made in the diagnosis, prevention, and treatment of EBV LPD in marrow transplant recipients. Immunovirological assays can provide early identification of patients at risk for developing EBV LPD. Prophylaxis and treatment by the adoptive transfer of EBV-specific T cells and the subsequent long-term restoration of immunity against EBV-associated lymphoproliferation have provided positive outcomes in the management of this uniformly fatal complication of BMT. The purpose of this article is to provide a review of EBV LPD and to present a newly developed strategy for EBV LPD prophylaxis in pediatric BMT recipients.


Assuntos
Transferência Adotiva/enfermagem , Transplante de Medula Óssea/efeitos adversos , Infecções por Herpesviridae/prevenção & controle , Herpesvirus Humano 4 , Transtornos Linfoproliferativos/prevenção & controle , Linfócitos T Citotóxicos/transplante , Infecções Tumorais por Vírus/prevenção & controle , Transferência Adotiva/métodos , Criança , Infecções por Herpesviridae/etiologia , Humanos , Transtornos Linfoproliferativos/virologia , Planejamento de Assistência ao Paciente , Infecções Tumorais por Vírus/etiologia
20.
Am J Physiol ; 273(2 Pt 2): R609-14, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9277545

RESUMO

We tested whether prostaglandin synthesis mediates the lipopolysaccharide (LPS)-induced increase in splenic sympathetic nerve activity. Sprague-Dawley rats were pretreated with intravenous or intracerebroventricular injections of indomethacin, and splenic nerve activity was recorded after intravenous injections of LPS. In vehicle-pretreated rats, 100 micrograms LPS induced a 62.8 +/- 5.6% increase in splenic nerve activity beginning 22.7 +/- 2.7 min postinjection. All vehicle-pretreated animals responded to high (100 micrograms, 5 of 5 animals) and low (10 micrograms, 8 of 8 animals) doses of LPS. Both intravenous (15 mg/kg) and intracerebroventricular (50 micrograms) pretreatments with indomethacin delayed (F1.19 = 30.66, P < 0.001) the increase in nerve activity after 100 micrograms LPS. When given intravenously, 50 micrograms indomethacin (the intracerebroventricular dose) did not delay the response to intravenous LPS, indicating that the effects of intracerebroventricular indomethacin pretreatment were restricted to the central nervous system. Importantly, intracerebroventricular indomethacin reduced (2 of 7 animals) or completely blocked (5 of 7 animals) the splenic nerve response to the low dose of LPS (10 micrograms, iv). The indomethacin effects could not be accounted for by central release of vasopressin because intracerebroventricular injection of indomethacin did not alter baseline nerve activity or blood pressure, whereas intracerebroventricular injection of vasopressin rapidly increased both measures. Additionally, central injection of LPS did not elevate splenic nerve activity, whereas intracerebroventricular injection of prostaglandin E2 induced a rapid (2.2 +/- 2.7 min) increase in splenic nerve activity. These data indicate that central prostaglandin synthesis is an intermediate step whereby systemic LPS elicits an increase in sympathetic outflow to an immune organ.


Assuntos
Encéfalo/metabolismo , Endotoxinas/farmacologia , Prostaglandinas/biossíntese , Baço/inervação , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Animais , Eletrofisiologia , Indometacina/farmacologia , Injeções Intravenosas , Injeções Intraventriculares , Lipopolissacarídeos/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
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