RESUMO
BACKGROUND: Aspiration lung disease (ALD) is a common cause of respiratory morbidity in children and adults with severe neurodisability (sND). Recent studies suggest that chronic microaspiration of gastric contents is associated with mild rather than low, airway acidification. We investigated inflammatory responses to infection by airway epithelial cells (AECs) exposed to weakly acidic media. METHODS: Using pH measurements from children with sND at high risk of ALD as a guide, we incubated AECs in weakly acidic (pH5.5-7.4) media alone; in combination with lipopolysaccharide (LPS); or prior to LPS stimulation at normal pH. Interleukin (IL) -6 and IL-8 expression were measured. RESULTS: IL-6/8 expression in AECs simultaneously exposed to weakly acidic media and LPS for 4 h was reduced with no effect on cell viability. Pre-incubation of AECs at weakly acidic pH also reduced subsequent LPS-induced cytokine expression. Suppression of inflammation was greatest at lower pHs (pH 5.5-6.0) for prolonged periods (16/24 h), but this also adversely affected cell viability. CONCLUSION: AEC inflammatory responses to bacterial stimuli is markedly reduced in a mildly acidic environment.
Assuntos
Doenças do Sistema Nervoso Central/complicações , Células Epiteliais/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Pulmão/metabolismo , Aspiração Respiratória de Conteúdos Gástricos/etiologia , Linhagem Celular , Sobrevivência Celular , Doenças do Sistema Nervoso Central/imunologia , Doenças do Sistema Nervoso Central/metabolismo , Regulação para Baixo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Humanos , Concentração de Íons de Hidrogênio , Mediadores da Inflamação/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Aspiração Respiratória de Conteúdos Gástricos/imunologia , Aspiração Respiratória de Conteúdos Gástricos/fisiopatologia , Fatores de TempoRESUMO
Most wastewater treatment processes are not specifically designed to remove micropollutants. Many micropollutants are hydrophobic so they remain in the biosolids and are discharged to the environment through land-application of biosolids. Micropollutants encompass a broad range of organic chemicals, including estrogenic compounds (natural and synthetic) that reside in the environment, a.k.a. environmental estrogens. Public concern over land application of biosolids stemming from the occurrence of micropollutants hampers the value of biosolids which are important to wastewater treatment plants as a valuable by-product. This research evaluated pyrolysis, the partial decomposition of organic material in an oxygen-deprived system under high temperatures, as a biosolids treatment process that could remove estrogenic compounds from solids while producing a less hormonally active biochar for soil amendment. The estrogenicity, measured in estradiol equivalents (EEQ) by the yeast estrogen screen (YES) assay, of pyrolyzed biosolids was compared to primary and anaerobically digested biosolids. The estrogenic responses from primary solids and anaerobically digested solids were not statistically significantly different, but pyrolysis of anaerobically digested solids resulted in a significant reduction in EEQ; increasing pyrolysis temperature from 100°C to 500°C increased the removal of EEQ with greater than 95% removal occurring at or above 400°C. This research demonstrates that biosolids treatment with pyrolysis would substantially decrease (removal>95%) the estrogens associated with this biosolids product. Thus, pyrolysis of biosolids can be used to produce a valuable soil amendment product, biochar, that minimizes discharge of estrogens to the environment.
Assuntos
Carvão Vegetal/análise , Estrogênios/análise , Temperatura Alta , Eliminação de Resíduos/métodos , Águas Residuárias/análise , Poluentes da Água/análiseRESUMO
OBJECTIVE: The decision to perform patent ductus arteriosus (PDA) ligation is controversial. Patient selection is oftentimes poorly standardized, leading to delays in referral and inappropriate intervention. A system for PDA ligation categorization and triaging process was introduced in 2006 at a quaternary hospital in Canada to streamline referrals and enhance perioperative care. We aimed to evaluate the impact of this dedicated PDA ligation triaging system comparing pre- and postimplementation of this system. STUDY DESIGN: We performed a retrospective chart review. Demographic and cardiorespiratory data of neonates ⩽30 weeks gestation age at birth, who were referred for and/or had a PDA ligation performed during two distinct epochs (EPOCH 1 (2003 to 2005) and EPOCH 2 (2010 to 2012)), were analyzed. All surgeries were performed at The Hospital for Sick Children, the regional referral center for PDA ligation. The primary outcome was incidence of PDA ligation and procedural cancellations. Secondary outcomes included postoperative need for cardiovascular or respiratory support. Subgroup analysis was performed in neonates <1000 vs >1000 g at the time of surgery during both epochs. RESULT: A total of 198 neonates underwent surgery with no difference in baseline demographics between epochs. The incidence of PDA ligation as a proportion of total live births under 30 weeks in Central East Region of Ontario was lower in the second epoch (EPOCH 1: 117/1092 (10.7%) vs EPOCH 2: 81/1520 (5.3%)). During the second epoch, 24% of referrals for surgery were canceled after review by our PDA ligation team. There were no overall differences in the proportion of neonates with oxygenation failure, ventilation failure or Post-Ligation Cardiac Syndrome (PLCS), after surgery, between epochs. The proportion of neonates who developed systemic hypotension was higher in patients <1000 g (n=34 (34%) vs n=17 (17.4%), P=0.01) at the time of surgery. In addition, we identified a reduction in the proportion of neonates <1000 g who developed PLCS in EPOCH 2. On the contrary, there was an increase in the proportion of neonates >1000 g who developed ventilation failure in EPOCH 2. CONCLUSION: The presence of dedicated triaging and management system enhances efficiency of referral process through careful selection of patients for PDA ligation and optimizes perioperative management. We demonstrated a reduction in the incidence of PDA ligation without any negative impact on short-term neonatal morbidity. The use of targeted neonatal echocardiography in the assessment of PDA shunt volume and guiding postoperative decision making is likely to have contributed to these findings.
Assuntos
Permeabilidade do Canal Arterial , Equipe de Assistência ao Paciente/organização & administração , Assistência Perioperatória , Complicações Pós-Operatórias/prevenção & controle , Procedimentos Cirúrgicos Vasculares , Canadá , Permeabilidade do Canal Arterial/diagnóstico , Permeabilidade do Canal Arterial/cirurgia , Feminino , Idade Gestacional , Humanos , Saúde do Lactente/normas , Recém-Nascido , Ligadura , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde , Seleção de Pacientes , Assistência Perioperatória/métodos , Assistência Perioperatória/normas , Melhoria de Qualidade , Tempo para o Tratamento , Triagem/organização & administração , Triagem/normas , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Procedimentos Cirúrgicos Vasculares/métodos , Procedimentos Cirúrgicos Vasculares/estatística & dados numéricosRESUMO
Pneumococcal carriage is common in children that may account for the high incidence of disease in this age group. Recent studies in animals suggest an important role for CD4+ T cells, T helper type 17 (Th17) cells in particular, in pneumococcal clearance. Whether this Th17-mediated mechanism operates in humans and what pneumococcal components activate Th17 are unknown. We investigated the ability of domain 4 pneumolysin (D4Ply) to activate CD4+ T cells including Th17 in human nasopharynx-associated lymphoid tissue (NALT) and peripheral blood. We show that D4Ply elicited a prominent CD4+ T-cell proliferative response. More importantly, D4Ply elicited a significant memory Th17 response in NALT, and a moderate response in peripheral blood mononuclear cells (PBMCs). This D4Ply-elicited memory Th17 response was more marked in carriage- than in carriage+ children in both NALT and PBMCs. In contrast, no difference was shown in D4Ply-induced Th1 response between the two groups. We also show D4Ply activated human monocytes and murine macrophages that was in part dependent on Toll-like receptor 4 (TLR-4). Our results support a protective role of Th17 against pneumococcal carriage in human nasopharynx, and identify a novel property of D4Ply to activate Th17 in NALT that may offer an attractive vaccine candidate in intranasal immunization against pneumococcal infection.
Assuntos
Portador Sadio , Memória Imunológica , Tecido Linfoide/imunologia , Nasofaringe/imunologia , Nasofaringe/microbiologia , Streptococcus pneumoniae/imunologia , Estreptolisinas/imunologia , Células Th17/imunologia , Animais , Proteínas de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Criança , Pré-Escolar , Colesterol/metabolismo , Feminino , Humanos , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Monócitos/imunologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Early eradication therapy is key to keeping the airways Pseudomonas aeruginosa infection-free and rapid identification is essential. METHODS: We used rapid DNA extraction and qPCR assays to detect bacterial, P. aeruginosa and strain-specific targets in samples using two qPCR chemistries. Using 459 respiratory samples from adult and children CF patients, we compared two qPCR methods to culture-based methods in terms of sensitivity and time to result. RESULTS: For adult samples, there was 100% concordance between methods. There was no clear pattern in fluctuations in P. aeruginosa number during exacerbation. In child samples, qPCR methods identified additional P. aeruginosa positive samples. The time-to-result was reduced by over 24h and copy number and colony forming unit could differ dramatically in some samples. CONCLUSION: If adopted, these methods could significantly improve early P. aeruginosa detection in diagnostic laboratories and therefore play a pivotal role in prolonging infection-free airways in CF patients.
Assuntos
Fibrose Cística/microbiologia , Infecções por Pseudomonas/diagnóstico , Pseudomonas aeruginosa , Reação em Cadeia da Polimerase em Tempo Real , Líquido da Lavagem Broncoalveolar/microbiologia , DNA Bacteriano/análise , Erradicação de Doenças , Progressão da Doença , Humanos , Sensibilidade e Especificidade , Escarro/microbiologiaRESUMO
OBJECTIVES: The objective of this study was to establish the level of awareness of HAND among healthcare providers, the screening tools that are currently used in its detection and factors that limit cognitive assessments. METHODS: We distributed a 12-item questionnaire to doctors and nurses who work in the Department of Genitourinary Medicine and Infectious Disease (GUIDE) service and also to doctors who work in the emergency department (ED) at St James Hospital. RESULTS: 35 surveys were collected, 54% (n = 19) from the GUIDE service and 46% (n = 16) from the ED. 82% (n = 29) of participants were doctors from interns to consultants. There was reasonable appreciation among participants with regards the prevalence of neurocognitive impairment (estimated at 29.1% among patients on HAART, and 39.3% among patients not on HAART). Screening tools were rarely used by GUIDE and ED clinicians (25% vs. 15% of the time). The Mini Mental State Examination (MMSE) was previously used by 37% (n = 13) of the group. Very few people had used the HIV Dementia Scale (HIVDS) 6% (n = 2). 34% of respondents felt that 'Orientation in Person, Place and Time was a sufficient screening tool for cognitive assessment'. Lack of time, exposed environment and lack of availability of screening tool were cited as limitations to cognitive screening in the ED environment. CONCLUSIONS: This study examines awareness of HAND among healthcare providers and also reasons for inadequate assessment. There is a need for consensus on screening guidelines. A quick, easy to use and readily available screening tool may have a role in the acute setting in identifying high-risk patients.
Assuntos
Transtornos Cognitivos/diagnóstico , Equipamentos e Provisões/provisão & distribuição , Soropositividade para HIV , Médicos/psicologia , Conscientização , Transtornos Cognitivos/epidemiologia , Serviço Hospitalar de Emergência/normas , Feminino , Humanos , Masculino , Programas de Rastreamento/instrumentação , Testes Neuropsicológicos , Papel do Médico/psicologia , Médicos/normas , Inquéritos e Questionários , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The mechanisms regulating antibody expression within the human lung during airway infection are largely unknown. In this study, our objectives were to determine if infection with respiratory syncytial virus (RSV) upregulates expression of the B cell differentiation factors A proliferation inducing ligand (APRIL) and B cell activating factor of the TNF family (BAFF), if this is a common feature of viral airway infection, and how this is regulated in human airway epithelial cells. METHODS: We measured BAFF and APRIL protein expression in bronchoalveolar lavage (BAL) fluid from infants with severe RSV disease, and healthy control children, and in nasopharyngeal aspirates from preschool children with other single respiratory viral infections. We also measured mRNA expression in bronchial brushings from RSV-infected infants, and in RSV-infected paediatric primary airway epithelial cell cultures (pAEC). Beas-2B cell cultures were used to examine mechanisms regulating BAFF expression. RESULTS: BAFF protein and mRNA were elevated (in marked contrast with APRIL) in BAL and bronchial brushings, respectively, from RSV-infected infants. BAFF protein was also found in upper airway secretions from children with human metapneumovirus, H1N1, bocavirus, rhinovirus, RSV and Mycoplasma pneumoniae infection. BAFF mRNA and protein were expressed following in vitro RSV infection of both pAEC and Beas-2B cultures, with mRNA expression peaking 12-h postinfection. BAFF induction was blocked by addition of a neutralising anti-interferon-ß antibody or palivizumab. CONCLUSIONS: BAFF, produced through an interferon-ß-dependent process, is a consistent feature of airway infection, and suggests a role for the airway epithelia in supporting protective antibody and B cell responses in the lung.
Assuntos
Fator Ativador de Células B/genética , Bronquiolite/virologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Bronquiolite/fisiopatologia , Lavagem Broncoalveolar , Estudos de Casos e Controles , Células Cultivadas , Criança , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Regulação da Expressão Gênica , Humanos , Técnicas In Vitro , Lactente , Recém-Nascido , Interferon gama/genética , Interferon gama/metabolismo , Masculino , RNA Mensageiro/metabolismo , Infecções por Vírus Respiratório Sincicial/diagnóstico , Vírus Sinciciais Respiratórios/metabolismo , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Regulação para CimaRESUMO
A retrospective chart review was carried out at the HIV clinic in St. James's Hospital, Dublin to examine the rate of cognitive impairment through the use of surrogate markers for cognitive impairment. 500 consecutive hospital charts were reviewed. There were 306 men and 194 women. Median age was 37. The most common mode of transmission was heterosexual. 45% had a nadir CD4 < 200. 78.6% were on antiretroviral therapy and 72.26% were virally suppressed. 69/500 patients (13.8%) had one or more positive surrogate markers for cognitive impairment. The surrogate markers used were subjective complaints, a new onset of a psychiatric diagnosis post diagnosis with HIV, neurological complications and radiological evidence of atrophy. Multivariate analysis using logistic regression showed significant relationships only with gender and year of diagnosis. This figure is lower than reported international prevalence rates of cognitive impairment and demonstrates that surrogate markers are no match for structured cognitive screening. We have since commenced structured prospective screening to obtain a true prevalence of cognitive impairment in this population.
Assuntos
Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Infecções por HIV/psicologia , Programas de Rastreamento/métodos , Adolescente , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/etiologia , Radiografia , Adulto JovemRESUMO
The presence of micropollutants can be a concern for land application of biosolids. Of particular interest are nonylphenol diethoxylate (NP(2)EO), nonylphenol monoethoxylate (NP(1)EO), and nonylphenol (NP), collectively referred to as NPE, which accumulate in anaerobically digested biosolids and are subject to regulation based on the environmental risks associated with them. Because biosolids are a valuable nutrient resource, it is essential that we understand how various treatment processes impact the fate of NPE in biosolids. Thermal hydrolysis (TH) coupled with mesophilic anaerobic digestion (MAD) is an advanced digestion process that destroys pathogens in biosolids and increases methane yields and volatile solids destruction. We investigated the impact of thermal hydrolysis pretreatment on the subsequent biodegradation of NPE in digested biosolids. Biosolids were treated with TH, anaerobic digestion, and aerobic digestion in laboratory-scale reactors, and NPE were analyzed in the influent and effluent of the digesters. NP(2)EO and NP(1)EO have been observed to degrade to the more estrogenic NP under anaerobic conditions; therefore, changes in the ratio of NP:NPE were of interest. The increase in NP:NPE following MAD was 56%; the average increase of this ratio in four sets of TH-MAD samples, however, was only 24.6 ± 3.1%. In addition, TH experiments performed in pure water verified that, during TH, the high temperature and pressure alone did not directly destroy NPE; TH experiments with NP added to sludge also showed that NP was not destroyed by the high temperature and pressure of TH when in a more complex sludge matrix. The post-aerobic digestion phases removed NPE, regardless of whether TH pretreatment occurred. This research indicates that changes in biosolids processing can have impacts beyond just gas production and solids destruction.
Assuntos
Fenóis/química , Esgotos , Anaerobiose , Cromatografia Líquida de Alta Pressão , Estrogênios/química , Hidrólise , Espectrometria de Massas por Ionização por Electrospray , Poluentes da Água/químicaRESUMO
Monitoring respiratory status in cystic fibrosis (CF) is challenging, particularly in young children. We aimed to test whether the Liverpool Respiratory Symptom Questionnaire (LRSQ) could distinguish well, pre-school and older children with and without CF, whether it could distinguish well and unwell children with CF and, finally, whether LRSQ scores in older children with CF correlated with established measures of disease severity. 20 stable pre-school children with CF had significantly higher total LRSQ scores than 51 pre-school controls, and higher scores in two out of eight domains. Similarly, 21 stable 6- to 12-yr-old children with CF had higher total scores than 97 6- to 12-yr-old controls, and higher scores in seven out of eight domains. In older children with CF, LRSQ scores correlated negatively with Shwachman score and forced expiratory volume in 1 s (r = -0.58, p < 0.001, n = 31; and r = -0.46, p < 0.010, n = 34, respectively). Within the CF group, patients who cultured Pseudomonas aeruginosa, who used more "back-up" antibiotics or whose school attendance was lower also had higher LRSQ scores. The LRSQ differentiates well children from those with CF in both pre-school and the 6- to 12-yr-old age group, even at a point of stability. It also differentiates stable from unwell children with CF, and scores correlate with other measures of respiratory disease, highlighting its potential as a clinical monitoring tool in paediatric CF.
Assuntos
Fibrose Cística/fisiopatologia , Dispneia/fisiopatologia , Pneumonia/fisiopatologia , Infecções por Pseudomonas/fisiopatologia , Inquéritos e Questionários/normas , Distribuição por Idade , Criança , Pré-Escolar , Estudos Transversais , Fibrose Cística/mortalidade , Dispneia/mortalidade , Feminino , Humanos , Lactente , Masculino , Avaliação de Resultados em Cuidados de Saúde , Pneumonia/microbiologia , Pneumonia/mortalidade , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/mortalidade , Pseudomonas aeruginosa , Reprodutibilidade dos Testes , Licença Médica/estatística & dados numéricosRESUMO
BACKGROUND: Metatarsophalangeal joint arthroplasty is an accepted treatment for hallux rigidus. There are few reports of the long-term results of this procedure. METHODS: A series of 15 consecutive bio-action first metatarsophalangeal total joint replacements were retrospectively reviewed after a minimum follow-up of 5 years. The patients were assessed using the American Orthopaedic Foot and Ankle Society Score. Patient satisfaction and standard radiographs were also examined. RESULTS: Subjectively, just over half the patients were satisfied with the results of the surgery. Objectively, however mechanical failure of the implant was universal, as determined radiographically. DISCUSSION: Despite some success in relieving symptoms in patients, we have abandoned this procedure because of the high and increasing rate of failure, as demonstrated both clinically and radiologically.
Assuntos
Artroplastia de Substituição/métodos , Hallux Rigidus/cirurgia , Articulação Metatarsofalângica/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Airway epithelial cells (AECs) are important in asthma as they are the first cells to encounter pathogens/allergens. In children, AECs can be obtained using a "blind" nonbronchoscopic technique through an endotracheal tube. However, due to the increasing use of laryngeal masks the number of children in whom this technique is applicable has become limited. Recently, the present authors began to use a portable "bronchoscope-directed" technique to sample AECs. The current study compares both techniques in both asthmatic and nonasthmatic children. A total of 81 children undergoing elective surgery, were grouped according to atopic status and respiratory symptoms. Cellular yield of blind and bronchoscope-directed brushings were compared and immunocytochemistry performed. AECs were cultured and cytokine analysis of culture supernatant undertaken. Both techniques were equally well-tolerated, with the only adverse effect being a cough in 10% of the subjects. The mean+/-SD cell yield was higher in bronchoscope-directed than blind brushings (5.1+/-2.4 versus 3.1+/-1.4x10(6) cells). Immunocytochemistry confirmed an epithelial cell lineage. Culture supernatant cytokine concentrations were similar regardless of sampling technique with patterns preserved between asthmatic and healthy nonatopic phenotypes. Compared with blind brushing portable bronchoscope-directed brushing is well-tolerated, yields significantly more cells and is a potentially quick and useful technique for obtaining airway epithelial cells for research into childhood respiratory disease, specifically asthma.
Assuntos
Asma , Biópsia/métodos , Broncoscopia/métodos , Células Epiteliais , Adolescente , Brônquios/citologia , Contagem de Células , Células Cultivadas , Criança , Pré-Escolar , Humanos , MasculinoRESUMO
Mammalian sleep is composed of two distinct states - rapid-eye-movement (REM) and non-REM (NREM) sleep - that alternate in cycles over a sleep bout. The duration of these cycles varies extensively across mammalian species. Because the end of a sleep cycle is often followed by brief arousals to waking, a shorter sleep cycle has been proposed to function as an anti-predator strategy. Similarly, higher predation risk could explain why many species exhibit a polyphasic sleep pattern (division of sleep into several bouts per day), as having multiple sleep bouts avoids long periods of unconsciousness, potentially reducing vulnerability.Using phylogenetic comparative methods, we tested these predictions in mammals, and also investigated the relationships among sleep phasing, sleep-cycle length, sleep durations and body mass.Neither sleep-cycle length nor phasing of sleep was significantly associated with three different measures of predation risk, undermining the idea that they represent anti-predator adaptations.Polyphasic sleep was associated with small body size, shorter sleep cycles and longer sleep durations. The correlation with size may reflect energetic constraints: small animals need to feed more frequently, preventing them from consolidating sleep into a single bout. The reduced daily sleep quotas in monophasic species suggests that the consolidation of sleep into one bout per day may deliver the benefits of sleep more efficiently and, since early mammals were small-bodied and polyphasic, a more efficient monophasic sleep pattern could be a hitherto unrecognized advantage of larger size.
RESUMO
Respiratory syncytial virus (RSV) bronchiolitis is an important cause of severe respiratory disease in infants. This study aimed to characterise changes in pulmonary pro- and anti-inflammatory responses in infants with RSV bronchiolitis over the course of the illness. On the day of intubation (Day 1) and the day of extubation (Day X), nonbronchoscopic bronchoalveolar lavage was performed on term and preterm infants ventilated for RSV bronchiolitis and on control infants on Day 1. Tumour necrosis factor (TNF)-alpha, soluble TNF receptor (sTNFR) and interleukin (IL)-6 messenger ribonucleic acid (mRNA) and protein were measured. Twenty-four infants, born at term and 23 infants born preterm with RSV bronchiolitis and 10 controls were recruited. TNF-alpha and IL-6 mRNA and protein in infants with bronchiolitis were greater than the control group on Day 1. In preterm infants, who were ventilated for longer than term infants, TNF-alpha and IL-6 proteins decreased between Day 1 and Day X. Concentrations of sTNFRs differed between groups on Day 1, but levels did not change between Day 1 and Day X. Large amounts of tumour necrosis factor-alpha and interleukin-6 in the respiratory syncytial virus-infected lung suggest important roles for these cytokines in the pathogenesis of respiratory syncytial virus bronchiolitis. The decrease in tumour necrosis factor-alpha and interleukin-6 protein in preterm infants may reflect the prolonged clinical course seen in these infants.
Assuntos
Infecções por Vírus Respiratório Sincicial/fisiopatologia , Bronquiolite Viral/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Doenças do Prematuro/fisiopatologia , Interleucina-6/análise , Pulmão/fisiopatologia , Masculino , RNA Mensageiro/análise , Receptores do Fator de Necrose Tumoral/análise , Fator de Necrose Tumoral alfa/análiseRESUMO
Transporter-mediated processes in the lactating mammary gland may explain the significant accumulation of certain drugs in breast milk. The purpose of this study was to identify potential candidate drug transport proteins involved in drug accumulation in milk. Quantitative reverse transcription-polymerase chain reaction methods were developed to determine the relative RNA levels of 30 different drug transporter genes. Transporter gene RNA levels in lactating mammary epithelial cells (MEC) purified from pooled fresh breast milk samples were compared with levels in nonlactating MEC, liver, and kidney tissue. Transcripts were detected in lactating MEC for OCT1, OCT3, OCTN1, OCTN2, OATP-A, OATP-B, OATP-D, OATP-E, MRP1, MRP2, MRP5, MDR1, CNT1, CNT3, ENT1, ENT3, NCBT1, PEPT1, and PEPT2. No transcripts were detected for OCT2, OAT1, OAT2, OAT3, OAT4, OATP-C, MRP3, MRP4, CNT2, ENT2, and NCBT2. Lactating MEC demonstrated more than 4-fold higher RNA levels of OCT1, OCTN1, PEPT2, CNT1, CNT3, and ENT3, and more than 4-fold lower RNA levels of MDR1 and OCTN2 relative to nonlactating MEC. Lactating MEC showed significantly higher RNA levels of CNT3 relative to liver and kidney, increased PEPT2 RNA levels relative to liver, and increased OATP-A RNA levels relative to kidney. These data imply CNT3 may play a specialized role in nucleoside accumulation in milk and may identify an important role for PEPT2 and OATP-A transporters at the lactating mammary epithelium. Furthermore, transporters expressed in lactating MEC identify a potential role for these transporters in drug disposition at the mammary gland.
Assuntos
Mama/metabolismo , Proteínas de Transporte/biossíntese , Células Epiteliais/metabolismo , Lactação/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Calibragem , Proteínas de Transporte/genética , Separação Celular , Primers do DNA/síntese química , Feminino , Humanos , Imuno-Histoquímica , Rim/metabolismo , Fígado/metabolismo , Leite Humano/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , TemperaturaRESUMO
The objectives of our study were to estimate the percentage of aluminum (Al) that enters the brain, the half-life of brain Al, and the ability of an Al chelator to reduce brain Al. Rats received an iv infusion of Al transferrin, the primary Al species in plasma, or Al citrate, the predominant small molecular weight Al species in plasma. The infusion contained approximately 0.2-0.3 nCi (0.4-0.6 nmol) (26)Al, enabling the study of Al distribution into and retention by the brain at physiological Al concentrations. Some Al transferrin-infused rats received ip injections of the Al chelator desferrioxamine (DFO), 0.15 mmol/kg, three times weekly. The others received saline injections. The rats were euthanized from 4 hr to 4 days (Al citrate) or 256 days (Al transferrin) later. Brain (26)Al was determined by accelerator mass spectrometry. Peak brain (26)Al concentration was approximately 0.005% of the (26)Al dose in each gram of brain, irrespective of Al species administered. In the absence of DFO treatments, brain (26)Al concentration decreased with a half-life of approximately 150 days. The brain Al half-life in the DFO-treated rats was approximately 55 days. The results show a small fraction of Al in blood enters the brain, where it persists for a long time. The ability of repeated DFO treatments to modestly accelerate the reduction of brain Al is consistent with the necessity of prolonged DFO therapy to significantly reduce Al-induced dialysis encephalopathy.
Assuntos
Alumínio/farmacocinética , Encéfalo/metabolismo , Quelantes/farmacologia , Desferroxamina/farmacologia , Alumínio/administração & dosagem , Alumínio/sangue , Animais , Meia-Vida , Humanos , Masculino , Espectrometria de Massas , Radioisótopos/administração & dosagem , Radioisótopos/metabolismo , Radioisótopos/farmacocinética , Ratos , Transferrina/administração & dosagem , Transferrina/farmacocinéticaAssuntos
Fumar/efeitos adversos , Doenças Vasculares/etiologia , Animais , Antioxidantes/uso terapêutico , Arteriosclerose/etiologia , Arteriosclerose/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Ensaios Clínicos como Assunto , Sistema Enzimático do Citocromo P-450/metabolismo , Suscetibilidade a Doenças , Eicosanoides/metabolismo , Sequências Hélice-Alça-Hélice , Humanos , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Prostaglandinas/metabolismo , Estrutura Terciária de Proteína , Receptores de Hidrocarboneto Arílico/metabolismo , Fatores de Transcrição/metabolismo , Doenças Vasculares/metabolismoRESUMO
The objectives were to estimate aluminum (Al) oral bioavailability under conditions that model its consumption in drinking water, and to test the hypotheses that stomach contents and co-administration of the major components of hard water affect Al absorption. Rats received intragastric 26Al in the absence and presence of food in the stomach and with or without concomitant calcium (Ca) and magnesium (Mg) at concentrations found in hard drinking water. The use of 26Al enables the study of Al pharmacokinetics at physiological Al concentrations without interference from 27Al in the environment or the subject. 27Al was intravenously administered throughout the study. Repeated blood withdrawal enabled determination of oral 26Al bioavailability from the area under its serum concentrationxtime curve compared to serum 27Al concentration in relation to its infusion rate. Oral Al bioavailability averaged 0.28%. The presence of food in the stomach and Ca and Mg in the water that contained the orally dosed 26Al appeared to delay but not significantly alter the extent of 26Al absorption. The present and published results suggest oral bioavailability of Al from drinking water is very low, about 0.3%. The present results suggest it is independent of stomach contents and water hardness.
Assuntos
Alumínio/farmacocinética , Mucosa Gástrica/metabolismo , Água/química , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Ingestão de Líquidos , Alimentos , Masculino , Ratos , Ratos Endogâmicos F344 , Espectrofotometria AtômicaRESUMO
Acetylation of histones by p300/CBP and PCAF is considered to be a critical step in transcriptional regulation. In order to understand the role of cellular activities that modulate histone acetylation and transcription, we have purified and characterized a multiprotein cellular complex that potently inhibits the histone acetyltransferase activity of p300/CBP and PCAF. We have mapped a novel acetyltransferase-inhibitory domain of this INHAT (inhibitor of acetyltransferases) complex that binds to histones and masks them from being acetyltransferase substrates. Endogenous INHAT subunits, which include the Set/TAF-Ibeta oncoprotein, associate with chromatin in vivo and can block coactivatormediated transcription when transfected in cells. We propose that histone masking by INHAT plays a regulatory role in chromatin modification and serves as a novel mechanism of transcriptional regulation.
Assuntos
Acetiltransferases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Histonas/genética , Histonas/metabolismo , Proteínas de Saccharomyces cerevisiae , Fatores de Transcrição , Acetilação , Acetiltransferases/química , Acetiltransferases/genética , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Cromatina/genética , Cromatina/metabolismo , Mapeamento Cromossômico , Proteínas de Ligação a DNA , Células HeLa , Histona Acetiltransferases , Chaperonas de Histonas , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Ligação Proteica/genética , Estrutura Terciária de Proteína , Proteínas/genética , Proteínas/metabolismo , Receptores do Ácido Retinoico/fisiologia , Transdução de Sinais/fisiologia , Transcrição Gênica/fisiologia , Fatores de Transcrição de p300-CBPRESUMO
A 3-yr-old bearded dragon (Acanthodraco vitticeps) presented with lethargy, a swollen right elbow joint, inability to move its rear limbs normally, and marked leukocytosis. The majority of leukocytes were an abnormal mononuclear lymphoid-type cell with a high nuclear to cytoplasmic ratio, a slightly blue cytoplasm, nuclei with coarsely granular chromatin, and some nuclear clefts. Acute leukemia of lymphoid or myeloid origin was tentatively diagnosed. The abnormal mononuclear leukocyte cell population stained positively for the myeloid cytochemical stains: peroxidase, chloroacetate esterase, and L1-calprotectin. The abnormal cell population of the peripheral blood did not stain with the lymphoid cytochemical stains: alpha-naphthyl butyrate esterase, CD3, and CD79a.