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1.
J Neonatal Perinatal Med ; 16(4): 639-647, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38043025

RESUMO

BACKGROUND: Bowel dilation and bowel wall thickness are common prenatal ultrasound measurements for fetuses with gastroschisis. Data regarding antenatal sonographic bowel findings and postnatal outcomes are conflicting. Our objective was to evaluate the impact of in utero bowel measurements on perinatal outcomes in gastroschisis pregnancies. METHODS: Retrospective cohort study of 116 pregnancies complicated by gastroschisis between 2011 and 2020. We reviewed ultrasounds documenting fetal bowel measurements. To evaluate the association of these measurements with antepartum and delivery outcomes, we ran logistic and linear models using generalized estimating equations. RESULTS: Eleven perinatal outcomes reached statistical significance, although with minimal clinical impact given small magnitude of effect. Intra-abdominal bowel dilation was associated with a 0.5 week decrease in delivery gestational age (GA) (95% CI -0.07, -0.03) and a 6.93 g increase in birth weight (95% CI 1.54, 28.73). Intra-abdominal bowel wall thickness was associated with later GA of non-stress test (NST) start of 0.22 weeks (95% CI 0.07, 0.37), increased delivery GA of 0.08 weeks (95% CI 0.02, 0.15), 0.006 decrease in umbilical artery (UA) pH (95% CI -0.009, -0.003), 0.26 increase in UA base deficit (95% CI 0.09, 0.43), and decreased odds of cesarean delivery (OR = 0.83, 95% CI 0.70, 0.99). Extra-abdominal bowel wall thickness was associated with a 0.1 increase in UA base deficit (95% CI 0.02, 0.19) and a 0.05 increase in 5-min APGAR score (95% CI 0.01, 0.09). Stomach cross-section was associated with a 0.01 week decrease in delivery GA (95% CI -0.02, -0.001) and increased odds of receiving betamethasone (OR = 1.02, 95% CI 1.01, 1.04). CONCLUSIONS: In utero bowel characteristics reached statistical significance for several outcomes, but with minimal meaningful clinical differences in outcomes.


Assuntos
Gastrosquise , Feminino , Humanos , Gravidez , Dilatação Patológica/complicações , Gastrosquise/diagnóstico por imagem , Idade Gestacional , Intestinos/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia , Ultrassonografia Pré-Natal
2.
PLoS One ; 18(5): e0284970, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37195937

RESUMO

Child labour is the most common form of child abuse in the world today, with almost half of child workers employed in hazardous industries. The large-scale employment of children during the rapid industrialisation of the late 18th and early 19th centuries in England is well documented. During this period, the removal of pauper children from workhouses in cities to work as apprentices in rural mills in the North of England was commonplace. Whilst the experiences of some of these children have been recorded historically, this study provides the first direct evidence of their lives through bioarchaeological analysis. The excavation of a rural churchyard cemetery in the village of Fewston, North Yorkshire, yielded the skeletal remains of 154 individuals, including an unusually large proportion of children aged between 8 to 20 years. A multi-method approach was undertaken, including osteological and palaeopathological examination, stable isotope and amelogenin peptide analysis. The bioarchaeological results were integrated with historical data regarding a local textile mill in operation during the 18th-19th centuries. The results for the children were compared to those obtained from contemporaneous individuals of known identity (from coffin plates) of comparable date. Most of the children exhibited distinctive 'non-local' isotope signatures and a diet low in animal protein when compared to the named local individuals. These children also showed severe growth delays and pathological lesions indicative of early life adversity, as well as respiratory disease, which is a known occupational hazard of mill work. This study has provided unique insights into the harrowing lives of these children; born into poverty and forced to work long hours in dangerous conditions. This analysis provides a stark testimony of the impacts of industrial labour on the health, growth and mortality risk of children, with implications for the present as well as our understanding of the past.


Assuntos
Trabalho Infantil , Humanos , História do Século XIX , Inglaterra , Indústrias/história , Isótopos , Pobreza
3.
Chembiochem ; 24(7): e202200802, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36734186

RESUMO

The emergence of drug-resistant pathogens necessitates the development of new countermeasures. In this regard, the introduction of probiotics to directly attack or competitively exclude pathogens presents a useful strategy. Application of this approach requires an understanding of how a probiotic and its target pathogen interact. A key means of probiotic-pathogen interaction involves the production of small molecules called natural products (NPs). Here, we report the use of whole-cell matrix-assisted laser desorption/ionization time-of-flight (MALDI-ToF) mass spectrometry to characterize NP production by candidate probiotics (mouse airway microbiome isolates) when co-cultured with the respiratory pathogen Burkholderia. We found that a Bacillus velezensis strain inhibits growth of and elicits NP production by Burkholderia thailandensis. Dereplication of known NPs detected in the metabolome of this B. velezensis strain suggests that a previously unannotated bioactive compound is involved. Thus, we present the use of whole-cell MALDI as a broadly applicable method for screening the NP composition of microbial co-cultures; this can be combined with other -omics methods to characterize probiotic-pathogen and other microbe-microbe interactions.


Assuntos
Metabolômica , Camundongos , Animais , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
4.
J Am Coll Health ; 71(6): 1670-1675, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-34242137

RESUMO

OBJECTIVES: Sexual Strategies Theory suggests people fall on a continuum between having short-term mating orientation (STMO) and long-term mating orientation. One way STMO individuals signal mating goals is via risky drinking. The current study therefore aims to investigate drinks per week (DPW) as a mediator between STMO and risky sexual behavior (RSB), with gender as a moderator between STMO and DPW. PARTICIPANTS: Undergraduate students (N = 300) from a Midwestern university during Fall 2019. METHOD: Participants completed questionnaires assessing STMO, DPW, and RSB frequency. RESULTS: A moderated-mediation model indicated DPW significantly mediated the relationship between STMO and RSB. Positive associations were found among all three variables. Gender was not a moderator between STMO and DPW. CONCLUSIONS: Mating orientation was a correlate of alcohol use and RSB for women and men, contributing to the literature identifying STMO as an indicator of those in need of substance use and RSB intervention.

5.
J Am Coll Health ; 71(5): 1479-1485, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-34242540

RESUMO

OBJECTIVE: The present study developed a measure assessing the emotional responses, "Displacement Imposition," of cigarette and e-cigarette users on a college campus with a smoking/vaping ban. It also examined the relationship between Displacement Imposition and readiness to quit smoking/vaping, and how this relationship differed between cigarette and e-cigarette users. PARTICIPANTS: Participants (N = 297) were from a large, Midwestern university. METHODS: Participants completed online questionnaires assessing demographics, cigarette and e-cigarette use, Displacement Imposition, and readiness to quit. RESULTS: All six Displacement Imposition items loaded onto a single factor. A significant interaction emerged between Displacement Imposition and product use in predicting readiness to quit. At high levels of Displacement Imposition, cigarette users were less ready to quit than e-cigarette users. CONCLUSIONS: Findings suggest restrictions imposed on cigarette and e-cigarette users were associated with reduced readiness to quit. Findings inform tobacco control policies as tobacco denormalization may increase the burden placed on tobacco users.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Política Antifumo , Abandono do Hábito de Fumar , Produtos do Tabaco , Humanos , Abandono do Hábito de Fumar/psicologia , Universidades , Estudantes
6.
J Stud Alcohol Drugs ; 83(6): 944-948, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36484592

RESUMO

OBJECTIVE: Health care providers using brief alcohol-related health messaging is an effective manner of reducing risky drinking; however, research is needed to guide the content of such messages. The present study compared current drinkers' and nondrinkers' perspectives on the value of four different alcohol-related messages and the hypothetical impact of the messages on intentions to reduce drinking. METHOD: Undergraduates (n = 286 current drinkers, n = 101 nondrinkers) from a large, public, Southern Plains university identified primarily as White (82.9%) and female (70%), with a mean age of 19.98 years. They viewed four video recordings containing different alcohol-related messages in random order and were asked to rate how likely they were to change their drinking behaviors after watching each video. RESULTS: All participants generally had a comparably positive appraisal of all four messages. Among current drinkers, one-way analyses of variance revealed significant differences across messages for intention to change drinking frequency, F(3, 260) = 5.69, p = .001, ηp2 = .06, and quantity, F(3, 263) = 4.95, p = .002, ηp2 = .05. Post hoc tests showed that the condition warning students of severe consequences resulted in higher intentions to reduce drinking compared with other conditions describing less severe consequences, drinking norms, or protective behavioral strategies. No significant differences emerged among nondrinkers. CONCLUSIONS: Despite mixed research regarding the effectiveness of fear-based warning messages in reducing high-risk drinking, the message containing severe alcohol-related consequences evoked the greatest hypothetical intentions to reduce quantity and frequency of drinking. Future studies should track actual drinking behaviors longitudinally following each message.


Assuntos
Consumo de Álcool na Faculdade , Estudantes , Feminino , Humanos , Adulto Jovem , Adulto , Universidades , Intenção , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/prevenção & controle , Etanol
7.
Psychiatr Q ; 92(4): 1657-1671, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34169388

RESUMO

Nonsuicidal self-injury (NSSI) is a major public health concern. Web-based personalized feedback interventions (PFIs) may be a cost-effective and efficient way to treat NSSI. In order to develop a PFI, it is imperative to assess descriptive and injunctive norms. The current study examines descriptive and injunctive norms of NSSI within college students and adults in the community, comparing how perceived norms may differ for those who do or do not engage in NSSI. Study 1 calculated percentages of NSSI behavior within the student sample. Study 2 then examined perceived descriptive and injunctive norms between those with and without history of NSSI in both samples. Study 1 indicated that 19% of undergraduate students had histories of NSSI. Additionally, there was a general tendency to overestimate the percentage of people who engage in NSSI and the number of times a typical person engages in NSSI. Finally, those who engaged in NSSI believed that most people do not understand why individuals engage in NSSI; comparatively, the majority of people without history of NSSI still indicated that they understand why others would engage in NSSI. These research findings may be utilized in a PFI to reduce shame and NSSI behavior.


Assuntos
Comportamento Autodestrutivo , Universidades , Adulto , Humanos , Comportamento Autodestrutivo/epidemiologia , Estudantes
8.
Addict Behav ; 118: 106884, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33744620

RESUMO

INTRODUCTION: The prevalence of little cigar and cigarillo (LCC) use among young adults is high. Research shows there are racial/ethnic differences in this prevalence, with Black/African American users more likely to report current LCC use. Given these discrepancies in LCC use, the present study aimed to assess potential differences in reasons for LCC use between White and Black/African American young adult ever and past 30-day users. METHODS: Participants were White (n = 2150), and Black/African American (n = 308) young adults (aged 18 to 24) recruited from Amazon Mechanical Turk who completed an online survey of tobacco use (December 2018-January 2019). LCC users were asked eight reasons for using LCCs. RESULTS: Flavoring was cited as the most popular reason for LCC use among White ever users while affordability was the most popular among Black/African American ever users. Adjusted logistic regressions among ever users revealed that Black/African American respondents (vs White) were more likely to use LCCs because of their affordability, the perception that LCCs are less harmful than cigarettes, and because of LCC advertising appeal. Among past 30-day users, adjusted logistic regression models showed that Black/African American respondents (vs White) were more likely to use LCCs because of their affordability. CONCLUSIONS: Findings align with previous studies showing that LLCs are more heavily marketed in predominantly Black/African American communities. Prevention efforts should account for racial differences in reasons for use in message development.


Assuntos
Negro ou Afro-Americano , Produtos do Tabaco , Adolescente , Adulto , Aromatizantes , Humanos , Fumar , Uso de Tabaco , Adulto Jovem
9.
Seizure ; 81: 332-337, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32883563

RESUMO

PURPOSE: The aim of this study was to review the causes of the epilepsies in our institution, an adult tertiary referral center for neurology and neurosurgery in Dublin, Ireland. Data was obtained from a bespoke epilepsy electronic patient record (EPR). METHODS: Predetermined search parameters of well-established broad categories of epilepsy aetiology were used to identify patients with a diagnosis of epilepsy attending Beaumont Hospital, Dublin. There were 3216 patients that met the inclusion criteria for this study. We included living patients with epilepsy attending our institution. We then excluded patients with a diagnosis of pure non-epileptic attack disorder and patients found to have idiopathic generalised epilepsy (IGE) (n = 382) from our final cohort. We excluded IGE due to the complex polygenic basis underlying this patient group. RESULTS: An aetiology was identified in 54.3 % (n = 1747) of the total number of patients studied. Of the symptomatic epilepsies, 41.08 % (n = 1321) were acquired and 13.3 % (n = 426) were predominantly of genetic or developmental aetiology. The most common causes of the acquired epilepsies were hippocampal sclerosis (n = 380; 28.75 %), cerebral tumor (n = 279; 21.06 %), traumatic brain injury (n = 248; 18.77 %), stroke and cerebrovascular disease (n = 151; 11.43 %) and perinatal causes (n = 138; 10.45 %). The leading causes in the genetic / developmental category included cavernous haemangiomas (n = 62, 22.22 %), arteriovenous malformations (n = 59; 21.15 %) and cortical dysplasia (n = 55; 19.71 %). The aetiology of a patient's epilepsy was undetermined in 45.68 % (n = 1469) of individuals. CONCLUSION: This study emphasizes the clinical utility of the ILAE's 2017 revised classification of the epilepsies and highlights the evolving dynamic nature of attributing causality in epilepsy. This is the largest single centre analysis of the aetiology of the epilepsies described in the literature. It is also the first large scale study examining aetiology utilising a bespoke electronic patient record in epilepsy.


Assuntos
Epilepsia , Neurologia , Adulto , Registros Eletrônicos de Saúde , Epilepsia/epidemiologia , Epilepsia/etiologia , Humanos , Irlanda/epidemiologia , Centros de Atenção Terciária
10.
Acta Biomater ; 70: 84-97, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29447961

RESUMO

3D scaffold-based in vitro cell culturing is a recent technological advancement in cancer research bridging the gap between conventional 2D culture and in vivo tumours. The main challenge in treating neuroblastoma, a paediatric cancer of the sympathetic nervous system, is to combat tumour metastasis and resistance to multiple chemotherapeutic drugs. The aim of this study was to establish a physiologically relevant 3D neuroblastoma tissue-engineered system and explore its therapeutic relevance. Two neuroblastoma cell lines, chemotherapeutic sensitive Kelly and chemotherapeutic resistant KellyCis83 were cultured in a 3D in vitro model on two collagen-based scaffolds containing either glycosaminoglycan (Coll-GAG) or nanohydroxyapatite (Coll-nHA) and compared to 2D cell culture and an orthotopic murine model. Both neuroblastoma cell lines actively infiltrated the scaffolds and proliferated displaying >100-fold increased resistance to cisplatin treatment when compared to 2D cultures, exhibiting chemosensitivity similar to orthotopic xenograft in vivo models. This model demonstrated its applicability to validate miRNA-based gene delivery. The efficacy of liposomes bearing miRNA mimics uptake and gene knockdown was similar in both 2D and 3D in vitro culturing models highlighting the proof-of-principle for the applicability of 3D collagen-based scaffolds cell system for validation of miRNA function. Collectively, this data shows the successful development and characterisation of a physiologically relevant, scaffold-based 3D tissue-engineered neuroblastoma cell model, strongly supporting its value in the evaluation of chemotherapeutics, targeted therapies and investigation of neuroblastoma pathogenesis. While neuroblastoma is the specific disease being focused upon, the platform may have multi-functionality beyond this tumour type. STATEMENT OF SIGNIFICANCE: Traditional 2D cell cultures do not completely capture the 3D architecture of cells and extracellular matrix contributing to a gap in our understanding of mammalian biology at the tissue level and may explain some of the discrepancies between in vitro and in vivo results. Here, we demonstrated the successful development and characterisation of a physiologically relevant, scaffold-based 3D tissue-engineered neuroblastoma cell model, strongly supporting its value in the evaluation of chemotherapeutics, targeted therapies and investigation of neuroblastoma pathogenesis. The ability to test drugs in this reproducible and controllable tissue-engineered model system will help reduce the attrition rate of the drug development process and lead to more effective and tailored therapies. Importantly, such 3D cell models help to reduce and replace animals for pre-clinical research addressing the principles of the 3Rs.


Assuntos
Colágeno/química , Técnicas de Transferência de Genes , Neuroblastoma , Alicerces Teciduais/química , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neuroblastoma/terapia
11.
Clin Pharmacol Ther ; 99(2): 146-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26517013

RESUMO

The direct-to-consumer genetic testing debate reached a fever pitch in November 2013 when the US Food and Drug Administration (FDA) instructed 23andMe to discontinue marketing and sale of their Personal Genome Service. In 2015, 23andMe emerged with FDA approval to market a carrier test for Bloom syndrome only, and plans to release additional reports. The dust has settled and it is time to ask: What have we learned, and where do we go from here?


Assuntos
Atenção à Saúde/tendências , Triagem e Testes Direto ao Consumidor/tendências , Testes Genéticos/tendências , Acesso à Informação , Síndrome de Bloom/diagnóstico , Síndrome de Bloom/genética , Genoma , Humanos , Estados Unidos , United States Food and Drug Administration
12.
Br J Cancer ; 109(9): 2356-67, 2013 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-24071597

RESUMO

BACKGROUND: Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy. METHODS: We generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy. RESULTS: We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å(2)) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively. CONCLUSION: We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/genética , Ciclina D1/genética , Quinases Ciclina-Dependentes/metabolismo , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Fase G2/efeitos dos fármacos , Fase G2/genética , Células HCT116 , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas de Neoplasias/genética , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Eur J Surg Oncol ; 36(7): 604-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20541352

RESUMO

OBJECTIVE: Lobular intra-epithelial neoplasia (LIN) is a rare breast disease that has been regarded alternately as a risk factor for invasive breast cancer in both breasts or a true breast cancer precursor. The controversy is largely dependent on the estimation of the IBC (Invasive Breast Cancer) risk after LIN; however a systematic review of the published data has not been previously performed. We aimed to review the IBC after LIN and the characteristics of those cancers. METHODS: A PubMed search was performed to identify the published articles in English addressing the breast cancer risk after LIN. RESULTS: There was a wide range in the figures estimating the risk of the breast cancer among the 22 studies that form the basis of this review. The cumulative average risk of invasive breast cancer (IBC) was 8.7% (range 0-33). It was 4.7% (range 0-25) for the ipsilateral and 4.2% (range 0-16) for the contralateral breast. 52% of the breast cancers occurred more than 10 years after the initial LIN. A lobular histotype was present in 30% (range 0-67%) of all IBC. CONCLUSIONS: LIN should be considered both as a risk factor (low and similar level of IBC risk for both breasts, long delay between LIN and IBC) and a precursor for IBC (over-representation of lobular histotype).


Assuntos
Neoplasias da Mama/complicações , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Intraductal não Infiltrante/complicações , Carcinoma Lobular/complicações , Segunda Neoplasia Primária/epidemiologia , Carcinoma Ductal de Mama/patologia , Feminino , França/epidemiologia , Humanos , Invasividade Neoplásica , Segunda Neoplasia Primária/patologia , PubMed , Medição de Risco , Fatores de Risco
14.
Brain Behav Immun ; 24(4): 569-76, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20035858

RESUMO

Spinal release of cytokines may play a critical role in the maladapted nociceptive signaling underlying chronic pain states. In order to investigate this biology, we have developed a novel 'high flux' intrathecal microdialysis approach in combination with multiplex bead-based immunoassay technology to concurrently monitor the spinal release of interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF)alpha in rats with unilateral sciatic nerve chronic constriction injury (CCI). Intrathecal microdialysis was performed under isoflurane/N(2)O anaesthesia in rats with confirmed mechanical hypersensitivity. In a first study, C-fiber strength electrical stimulation of the operated nerve in neuropathic rats was found to evoke a dramatic increase in IL-1beta efflux ( approximately 15-fold) that was significantly greater than that observed in the sham-operated group. Spinal IL-6 efflux was also responsive to primary afferent stimulation, whereas TNFalpha was not. In a second study, treatment with the glial inhibitor propentofylline for 7days normalized CCI-induced mechanical hypersensitivity. In the same animals, this treatment also significantly reduced intrathecal IL-1beta, IL-6 and TNFalpha and prevented afferent stimulation-evoked cytokine release of both IL-1beta and IL-6. These results provide support for glia as the source of the majority of intrathecal IL-1beta, IL-6 and TNFalpha that accompanies mechanical hypersensitivity in the CCI rat. Moreover, our studies demonstrate the ability of a neurone-glia signaling mechanism to dynamically modulate this release and support a role of spinal IL-1beta in the phasic transmission of abnormal pain signals.


Assuntos
Citocinas/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Medula Espinal/imunologia , Traumatismos do Sistema Nervoso/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Vias Aferentes , Animais , Modelos Animais de Doenças , Estimulação Elétrica/métodos , Masculino , Microdiálise/métodos , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Medula Espinal/efeitos dos fármacos , Xantinas/farmacologia
15.
Osteoarthritis Cartilage ; 17(6): 790-7, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19010066

RESUMO

OBJECTIVE: Interleukin-1beta (IL-1beta) plays a key role in the pathogenesis of chronic joint diseases, including osteoarthritis (OA), and drives a cascade of inflammatory and destructive responses within the synovial joint. Animal models of arthritis support the role of IL-1beta in joint pathology, however, the molecular changes downstream of IL-1beta are poorly understood in vivo. This study aimed to evaluate the intra-articular (i.a.) injection of IL-1beta in the rat joint as an acute model of joint disease and associate gene and mediator expression with clinical endpoints and pathological changes. METHODS: The effects of i.a. administration of a pathologically relevant dose of IL-1beta on joint swelling, mechanical hyperalgesia, histopathology, gene expression and biochemical changes were measured from 2 to 24h. RESULTS: IL-1beta-induced joint swelling and mechanical hyperalgesia. Gene expression analysis of joint tissue and biochemical analysis of joint lavage fluid identified pro-inflammatory and destructive mediators induced by IL-1beta. Histopathology of joint tissues showed evidence of synovitis and connective tissue inflammation, but not cartilage destruction. However, biochemical analysis of glucosaminoglycan levels in joint lavage fluids indicated cartilage breakdown and might be a sensitive marker of cartilage pathology. CONCLUSIONS: Intra-articular injection of IL-1beta is a reproducible acute model of joint pathology that is potentially useful to evaluate IL-1 pathway inhibitors. The correlation of molecular events with clinical and pathological changes in this model has enhanced the understanding of the role of IL-1beta in joint disease. Methods developed for gene expression analysis using multi-gene microfluidics cards and for biochemical analysis of joint lavage fluid might have utility for characterisation of other arthritis models and corresponding human disease.


Assuntos
Articulação do Tornozelo/patologia , Artrite Experimental/patologia , Cartilagem Articular/patologia , Interleucina-1beta/metabolismo , Osteoartrite/patologia , Animais , Articulação do Tornozelo/efeitos dos fármacos , Artrite Experimental/genética , Cartilagem Articular/efeitos dos fármacos , Feminino , Expressão Gênica , Humanos , Injeções Intra-Articulares , Interleucina-1beta/genética , Osteoartrite/genética , Ratos , Reprodutibilidade dos Testes
16.
Br J Dermatol ; 157(3): 474-81, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17596156

RESUMO

BACKGROUND: Patients with papulopustular rosacea have a higher density of Demodex folliculorum mites on their faces than normal subjects but the role, if any, of their mites in initiating inflammation is disputed. Selective antibiotics are effective in reducing the inflammatory changes of papulopustular rosacea, but their mode of action is unknown. OBJECTIVES: To investigate whether a D. folliculorum-related bacterium was capable of expressing antigens that could stimulate an inflammatory immune response in patients with rosacea. METHODS: A bacterium (Bacillus oleronius) was isolated from a D. folliculorum mite extracted from the face of a patient with papulopustular rosacea, and was investigated further. RESULTS: This bacterium produced antigens capable of stimulating peripheral blood mononuclear cells proliferation in 16 of 22 (73%) patients with rosacea but only five of 17 (29%) control subjects (P = 0.0105). This antigenic preparation was fractionated into 70 subfractions and the proteins in each fraction were visualized by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Western blot analysis revealed the presence of two antigenic proteins of size 62 and 83 kDa in fractions when probing with sera from patients with rosacea. No immunoreactivity to these proteins was recorded when probing with sera from control patients. Two-dimensional electrophoretic separation was used to isolate these proteins and matrix-assisted laser desorption/ionization time-of-flight analysis was employed to identify the relevant peptides. The 62-kDa immunoreactive protein shared amino acid sequence homology with an enzyme involved in carbohydrate metabolism and signal transduction while the 83-kDa protein was similar to bacterial heat shock proteins. CONCLUSIONS: Antigenic proteins related to a bacterium (B. oleronius), isolated from a D. folliculorum mite, have the potential to stimulate an inflammatory response in patients with papulopustular rosacea.


Assuntos
Antígenos de Bactérias/fisiologia , Bacillus/imunologia , Infestações por Ácaros/imunologia , Ácaros/imunologia , Rosácea/imunologia , Adulto , Animais , Formação de Anticorpos , Western Blotting , Eletroforese em Gel Bidimensional , Dermatoses Faciais/imunologia , Dermatoses Faciais/microbiologia , Dermatoses Faciais/parasitologia , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Ácaros/microbiologia
17.
Diabet Med ; 24(4): 359-63, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17298587

RESUMO

AIMS: Integrated Care Pathways (ICPs) are management plans that indicate the sequence and timing of the optimal treatment for individuals with a given disorder. The treatment of diabetic ketoacidosis (DKA) before and after the implementation of an ICP in a teaching hospital was examined. METHODS: Twenty-seven episodes of DKA were identified during the 13-month control period and 22 in the 13 months following implementation of the ICP. Case notes were reviewed and relevant clinical data extracted. RESULTS: The introduction of the ICP was associated with a reduction in the time taken to initiate intravenous fluid [45.0 (5-225) min to 37.5 (0-135) min; P = 0.01]. Time taken to initiate insulin infusion was also reduced [60.0 (5-755) min to 37.5 (0-175) min; P = 0.02]. The proportion of patients commenced on intravenous insulin within 60 min increased from 48 to 77% (P = 0.04). In addition, there was a reduction in the prescription of antibiotics (48-18%; P = 0.028) and low molecular weight heparin (59-5%; P < 0.001). Length of stay was not affected. CONCLUSION: The ICP significantly improved key areas in the management of DKA, although there remains room for further improvements.


Assuntos
Procedimentos Clínicos/organização & administração , Diabetes Mellitus Tipo 1/terapia , Cetoacidose Diabética/terapia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Adolescente , Adulto , Feminino , Hospitalização , Hospitais de Ensino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Fatores de Tempo , Resultado do Tratamento
18.
Biochem Soc Trans ; 34(Pt 2): 313-6, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16545102

RESUMO

The discipline of molecular biology has become increasingly important in recent times for the process of drug discovery. We describe the impact of molecular biology across the whole process of drug discovery and development, including (i) the identification and validation of new drug targets, (ii) the development of molecular screens to find new candidate drugs, and (iii) the generation of safety data and competences leading to enhanced clinical efficacy. We also speculate on emerging developments in drug discovery where it seems likely that molecular biology will play an even more vital role in the generation of future therapies.


Assuntos
Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/tendências , Biologia Molecular/tendências , Animais , Humanos , Biologia Molecular/métodos , Segurança
19.
Br J Sports Med ; 37(6): 516-20, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14665591

RESUMO

OBJECTIVE: To examine venous partial pressure of oxygen (PvO(2)), transcutaneous oxygen tension (tcPO(2)), and VO(2)MAX in a normobaric environment after a single hyperbaric oxygen (HBO(2)) treatment. METHODS: This was a prospective study of conditions after the intervention compared with baseline. The participants were 10 moderately trained (VO(2)MAX = 57.6 ml/kg/min) men. Two HBO(2) treatments consisting of breathing 95% oxygen at 2.5 atmospheres absolute (ATA) for 90 minutes were administered on non-consecutive days. Baseline testing included measures of VO(2)MAX, tcPO(2), and anthropometry. At 6.0 (1.0) minutes after the first HBO(2) treatment, a VO(2)MAX test was performed. After the second HBO(2) treatment, leg and chest tcPO(2) and PvO(2) were monitored for 60 minutes. RESULTS: VO(2)MAX, running time, and peak blood lactate were not altered after the HBO(2) treatment. Leg tcPO(2) was lower (p = 0.003) and chest tcPO(2) was unchanged after the HBO(2) treatment compared with baseline values. PvO(2) was significantly (p<0.001) lower in the first three minutes after treatment than subsequent values, but no other differences were found. CONCLUSIONS: A single HBO(2) treatment at 2.5 ATA for 90 minutes does not raise PvO(2), tcPO(2), or VO(2)MAX in a normobaric, normoxic environment.


Assuntos
Oxigenoterapia , Oxigênio/sangue , Educação Física e Treinamento , Adulto , Monitorização Transcutânea dos Gases Sanguíneos , Teste de Esforço , Humanos , Ácido Láctico/sangue , Masculino , Consumo de Oxigênio , Estudos Prospectivos
20.
J Anim Physiol Anim Nutr (Berl) ; 87(5-6): 236-44, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12752830

RESUMO

The objective of the present study was to examine the effect of signalment, body size and diet on plasma taurine and whole blood taurine concentrations. A total of 131 normal dogs consuming commercially prepared dog food had blood drawn 3-5 h post-prandially to be analysed for plasma amino acids and whole blood taurine. Body weight and morphometric measurements of each dog were taken. Plasma and whole blood taurine concentrations were 77 +/- 2.1 nmol/ml (mean +/- SEM) and 266 +/- 5.1 nmol/ml (mean +/- SEM), respectively. No effect of age, sex, body weight, body size, or diet was seen on plasma and whole blood taurine concentrations. Mean whole blood taurine concentrations were lower in dogs fed diets containing whole grain rice, rice bran or barley. The lowest whole blood concentrations were seen in dogs fed lamb or lamb meal and rice diets. Plasma methionine and cysteine concentrations were lower in dogs fed diets with animal meals or turkey, and whole grain rice, rice bran or barley. Fifteen of 131 dogs had plasma taurine concentrations lower than, or equal, to the previously reported lowest mean food-deprived plasma taurine concentration in normal dogs of 49 +/- 5 nmol/ml (mean +/- SEM) (Elliott et al., 2000). These findings support the theory that taurine deficiency in dogs may be related to the consumption of certain dietary ingredients. Scientific and clinical evidence supports the hypothesis that dilated cardiomyopathy is associated with low blood taurine concentration in dogs; therefore, further work is indicated to determine the mechanism by which diet can affect taurine status in dogs.


Assuntos
Ração Animal , Constituição Corporal/fisiologia , Cães/sangue , Taurina/sangue , Aminoácidos/sangue , Fenômenos Fisiológicos da Nutrição Animal , Animais , Peso Corporal , Cães/anatomia & histologia , Feminino , Masculino , Estado Nutricional , Estudos Soroepidemiológicos
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