RESUMEN
OBJECTIVE: To improve consumer decision making, the results of risk assessments on food, feed, consumer products or chemicals need to be communicated not only to experts but also to non-expert audiences. The present study draws on evidence from literature reviews and focus groups with diverse stakeholders to identify content to integrate into an existing risk assessment communication (Risk Profile). METHODS: A combination of rapid literature reviews and focus groups with experts (risk assessors (n = 15), risk managers (n = 8)), and non-experts (general public (n = 18)) were used to identify content and strategies for including information about risk assessment results in the "Risk Profile" from the German Federal Institute for Risk Assessment. Feedback from initial focus groups was used to develop communication prototypes that informed subsequent feedback rounds in an iterative process. A final prototype was validated in usability tests with experts. RESULTS: Focus group feedback and suggestions from risk assessors were largely in line with findings from the literature. Risk managers and lay persons offered similar suggestions on how to improve the existing communication of risk assessment results (e.g., including more explanatory detail, reporting probabilities for individual health impairments, and specifying risks for subgroups in additional sections). Risk managers found information about quality of evidence important to communicate, whereas people from the general public found this information less relevant. Participants from lower educational backgrounds had difficulties understanding the purpose of risk assessments. User tests found that the final prototype was appropriate and feasible to implement by risk assessors. CONCLUSION: An iterative and evidence-based process was used to develop content to improve the communication of risk assessments to the general public while being feasible to use by risk assessors. Remaining challenges include how to communicate dose-response relationships and standardise quality of evidence ratings across disciplines.
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Comunicación , Grupos Focales , Humanos , Medición de RiesgoRESUMEN
BACKGROUND: Cannabidiol (CBD) is purported to work for a variety of therapeutic indications. Interest in CBD products has significantly increased as patients with cancer seek ways to improve symptom control and quality of life. OBJECTIVES: The purpose of this study was to explore patients' knowledge of and experience with CBD. METHODS: A panel of oncology nurse practitioners, an oncologist, and oncology pharmacy specialists developed a survey to capture information about patient knowledge and use of CBD. The initial survey was pilot tested and further refined, resulting in the final item survey. The final survey was administered to 100 participants undergoing or having completed cancer treatment and being followed in a supportive oncology care clinic at a large academic medical center. FINDINGS: Most patients learned about CBD through a family member or friend. The majority of patients had never tried CBD. The most common reported indications were pain, anxiety, and nausea. Of those who had not tried CBD, the most common reasons included lack of knowledge about CBD and providers not recommending CBD.
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Cannabidiol , Neoplasias , Cannabidiol/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Dolor , Calidad de Vida , Encuestas y CuestionariosRESUMEN
In recent years, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain have undergone substantial revisions focusing on the appropriate and safe prescription of opioid analgesics, optimization of nonopioid analgesics and adjuvant medications, and integration of nonpharmacologic methods of cancer pain management. This selection highlights some of these changes, covering topics on management of adult cancer pain including pharmacologic interventions, nonpharmacologic interventions, and treatment of specific cancer pain syndromes. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional aspects of this topic, including pathophysiologic classification of cancer pain syndromes, comprehensive pain assessment, management of pain crisis, ongoing care for cancer pain, pain in cancer survivors, and specialty consultations.
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Dolor en Cáncer/diagnóstico , Dolor en Cáncer/terapia , Neoplasias/complicaciones , Manejo del Dolor , Adulto , Factores de Edad , Dolor en Cáncer/etiología , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , HumanosRESUMEN
Leishmania enter macrophages through receptor-mediated phagocytosis and survive the harsh environment of a phagolysosome. Here, we investigated the interaction between mannose receptor (MR), Toll-like receptor 2 (TLR2), and Leishmania, and the subsequent impact on phagosome maturation. Leishmania parasites are able to delay phagosome maturation, not reaching full maturation until 5 hours post-engulfment. Here, maturation of Leishmania major- and Leishmania donovani-containing phagosomes proceeded as expected in the WT macrophages becoming LAMP1 positive by 6 hours. Interestingly, MR-/- macrophages become LAMP1 positive by ~2 hours and ~4 hours post-infection Leishmania-containing phagosomes lost LAMP1 expression and gained the early marker EEA1. LAMP1 expression was again observed by 6 hours. Leishmania LPG was essential for the delay in both WT and MR-/- macrophages but was not essential for the early maturation (2 hours) observed in MR-/- macrophages. Serum opsonization of Leishmania prior to infection induced identical phagosome maturation patterns in WT and MR-/- macrophages. In the absence of MyD88 or TLR2 on macrophages, Leishmania phagosomes matured significantly faster, becoming LAMP1 positive by ~1-2 hours. These studies add to the knowledge that phagosome maturation is influenced by multiple receptor-ligand interactions and signalling pathways.
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Lectinas Tipo C/metabolismo , Leishmania donovani/inmunología , Leishmania major/inmunología , Leishmaniasis/inmunología , Leishmaniasis/patología , Proteínas de Membrana de los Lisosomas/metabolismo , Lectinas de Unión a Manosa/metabolismo , Receptores de Superficie Celular/metabolismo , Receptor Toll-Like 2/metabolismo , Animales , Células Cultivadas , Femenino , Lectinas Tipo C/genética , Leishmaniasis/parasitología , Macrófagos/inmunología , Macrófagos/parasitología , Receptor de Manosa , Lectinas de Unión a Manosa/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Fagocitosis/inmunología , Fagosomas/inmunología , Receptores de Superficie Celular/genética , Receptor Toll-Like 2/genéticaRESUMEN
Case notification rates of tuberculosis (TB) in Bangladesh remain poor despite a high burden of disease. Peer sputum collection among underserved populations was implemented to expand case notification and to provide socially empowering roles in society for often excluded members of marginalized populations. Over the 55 months of the evaluation, 32 587 members of key populations were screened for TB, with 1587 smear-positive TB cases detected. Broadening TB services at human immunodeficiency virus drop-in centers using peer sputum collection to target high-risk populations for TB may be an effective way to increase TB case notification among key populations in Bangladesh.
Le taux de déclaration des cas de tuberculose (TB) au Bangladesh reste médiocre en dépit du lourd fardeau de la maladie. Le recueil de crachats par les pairs au sein des populations vulnérables a été mis en Åuvre pour augmenter la déclaration des cas et également fournir des rôles socialement valorisants à des membres des populations marginales souvent exclus. Pendant 55 mois d'évaluation, 32 587 membres de ces populations ont bénéficié d'un dépistage de la TB, qui a permis de détecter 1587 cas de TB à frottis positif. L'expansion des services de TB dans les centres pour le virus d'immunodéficience humaine sans rendez-vous, utilisant le recueil de crachats par les pairs pour cibler les populations à haut risque de TB, peut être une façon efficace d'augmenter la déclaration des cas de TB parmi les populations les plus touchées au Bangladesh.
Las tasas de notificación de la tuberculosis (TB) en Bangladesh siguen siendo bajas pese a la alta carga de morbilidad por esta enfermedad. Se introdujo una medida de recogida de esputo por los pares en las poblaciones desatendidas, con el objeto de aumentar la notificación de casos y al mismo tiempo crear funciones de empoderamiento social en poblaciones marginadas, dirigidas a miembros de la comunidad que con frecuencia están excluidos. Durante los 55 meses de la evaluación, se investigó la TB en 32 587 miembros de poblaciones clave y se detectaron 1587 casos de TB con baciloscopia positiva. Una ampliación de los servicios de atención de la TB a los centros de encuentro y consulta de la infección por el virus de la inmunodeficiencia humana con aplicación de una estrategia de recogida de esputo por los pares y destinada a llegar a las poblaciones de alto riesgo de contraer la TB, sería una medida efectiva en aras de mejorar la notificación de los casos en las poblaciones clave de Bangladesh.
RESUMEN
Leishmania are intracellular protozoa that influence host immune responses eliciting parasite species-specific pathologies. MicroRNAs (miRNAs) are short single-stranded ribonucleic acids that complement gene transcripts to block protein translation and have been shown to regulate immune system molecular mechanisms. Human monocyte-derived dendritic cells (DC) and macrophages (MP) were infected in vitro with Leishmania major or Leishmania donovani parasites. Small RNAs were isolated from total RNA and sequenced to identify mature miRNAs associated with leishmanial infections. Normalized sequence read count profiles revealed a global downregulation in miRNA expression among host cells following infection. Most identified miRNAs were expressed at higher levels in L. donovani-infected cells relative to L. major-infected cells. Pathway enrichments using in silico-predicted gene targets of differentially expressed miRNAs showed evidence of potentially universal MAP kinase signalling pathway effects. Whereas JAK-STAT and TGF-ß signalling pathways were more highly enriched using targets of miRNAs upregulated in L. donovani-infected cells, these data provide evidence in support of a selective influence on host cell miRNA expression and regulation in response to differential Leishmania infections.
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Células Dendríticas/parasitología , Leishmania donovani/fisiología , Leishmania major/fisiología , Macrófagos/parasitología , MicroARNs/metabolismo , Adulto , Células Cultivadas , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Leishmania donovani/inmunología , Leishmania major/inmunología , Leishmaniasis/inmunología , Leishmaniasis/parasitología , Leishmaniasis Visceral/inmunología , Leishmaniasis Visceral/parasitología , Sistema de Señalización de MAP Quinasas/genética , Macrófagos/inmunología , Macrófagos/metabolismo , MicroARNs/genética , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Leishmania major is an aetiological agent of cutaneous leishmaniasis. The parasite primarily infects immune sentinel cells, specifically macrophages and dendritic cells, in the mammalian host. Infection is receptor mediated and is known to involve parasite binding to cell surface protein complement receptor 3 (CR3, Mac-1, CD11b/CD18). Engagement of CR3 by various ligands inhibits production of interleukin-12 (IL-12), the cytokine that drives antileishmanial T helper 1-type immune responses. Likewise, L. major infection inhibits IL-12 production and activation of host macrophages. Our data indicate that in the absence of CR3, L. major-infected bone marrow-derived macrophages produce more IL-12 and nitric oxide compared with WT cells upon lipopolysaccharide (LPS) stimulation. We therefore investigated multiple signalling pathways by which L. major may inhibit IL-12 transcription through CR3 ligation. We demonstrate that L. major infection does not elicit significant NFκB p65, MAPK, IRF-1 or IRF-8 activation in WT or CD11b-deficient macrophages. Furthermore, infection neither inhibits LPS-induced MAPK or NFκB activation nor blocks IFN-γ-activated IRF-1 and IRF-8. ETS-mediated transcription, however, is inhibited by L. major infection independently of CR3. Our data indicate that L. major-mediated inhibition of IL-12 occurs through CR3 engagement; however, the mechanism of inhibition is independent of NFκB, MAPK, IRF and ETS.
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Interleucina-12/genética , Leishmania major/inmunología , Leishmania major/fisiología , Leishmaniasis Cutánea/inmunología , Antígeno de Macrófago-1/metabolismo , Macrófagos/inmunología , Macrófagos/parasitología , Transcripción Genética , Animales , Regulación hacia Abajo , Regulación de la Expresión Génica , Factor 1 Regulador del Interferón/metabolismo , Factores Reguladores del Interferón/metabolismo , Interleucina-12/biosíntesis , Interleucina-12/inmunología , Leishmania major/genética , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/metabolismo , Leishmaniasis Cutánea/parasitología , Lipopolisacáridos/inmunología , Antígeno de Macrófago-1/genética , Antígeno de Macrófago-1/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVE: To examine prevalence and predictors of cancer-specific distress in undiagnosed men with and without a family history of prostate cancer, and to examine the contribution of perceptions of an affected relative's cancer experience on the distress of unaffected male relatives. METHODS: Men with a first degree relative with prostate cancer (n = 207) and men without a family history (n = 239) from Australia completed a Computer Assisted Telephone Interview. Participants completed the Prostate Cancer Anxiety Subscale of the Memorial Anxiety Scale for Prostate Cancer, measures of perceived risk, and socio-demographic information. Men with a family history provided details about their family history (number of relatives diagnosed with and dead from prostate cancer, relationship to affected relative, months since diagnosis) and reported their perceptions of their affected relative's prostate cancer experience including perceptions of threat related to the relative's diagnosis and perceived treatment phase and prognosis. RESULTS: Cancer-specific distress was low for all men and there was no significant difference in the distress experienced by men with and without a family history. Regression analyses showed that for all men, cancer-specific distress increased with urinary symptoms and decreased in those with higher education and in older participants. For men with a family history, having a relative who died from prostate cancer and perceiving greater threat from a relative's diagnosis was associated with greater cancer-specific distress. CONCLUSIONS: Interventions would benefit from examining appraisals of familial risk and examining prospective assessments of distress in the unaffected male relatives of men with prostate cancer over the course of the cancer trajectory.
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Ansiedad/epidemiología , Depresión/epidemiología , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/psicología , Estrés Psicológico/epidemiología , Adulto , Anciano , Ansiedad/psicología , Australia/epidemiología , Depresión/psicología , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Percepción , Prevalencia , Estudios Prospectivos , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Calidad de Vida , Análisis de Regresión , Factores Socioeconómicos , Estrés Psicológico/psicologíaRESUMEN
As important vectors of human disease, phlebotomine sand flies are of global significance to human health, transmitting several emerging and re-emerging infectious diseases. The most devastating of the sand fly transmitted infections are the leishmaniases, causing significant mortality and morbidity in both the Old and New World. Here we present the first global transcriptome analysis of the Old World vector of cutaneous leishmaniasis, Phlebotomus papatasi (Scopoli) and compare this transcriptome to that of the New World vector of visceral leishmaniasis, Lutzomyia longipalpis. A normalized cDNA library was constructed using pooled mRNA from Phlebotomus papatasi larvae, pupae, adult males and females fed sugar, blood, or blood infected with Leishmania major. A total of 47 615 generated sequences was cleaned and assembled into 17 120 unique transcripts. Of the assembled sequences, 50% (8837 sequences) were classified using Gene Ontology (GO) terms. This collection of transcripts is comprehensive, as demonstrated by the high number of different GO categories. An in-depth analysis revealed 245 sequences with putative homology to proteins involved in blood and sugar digestion, immune response and peritrophic matrix formation. Twelve of the novel genes, including one trypsin, two peptidoglycan recognition proteins (PGRP) and nine chymotrypsins, have a higher expression level during larval stages. Two novel chymotrypsins and one novel PGRP are abundantly expressed upon blood feeding. This study will greatly improve the available genomic resources for P. papatasi and will provide essential information for annotation of the full genome.
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Perfilación de la Expresión Génica , Proteínas de Insectos/genética , Phlebotomus/genética , Secuencia de Aminoácidos , Animales , Sangre/parasitología , Quimotripsina/genética , Quimotripsina/metabolismo , Etiquetas de Secuencia Expresada , Femenino , Biblioteca de Genes , Insectos Vectores/genética , Leishmania major , Masculino , Datos de Secuencia Molecular , Filogenia , Polimorfismo de Nucleótido Simple , Psychodidae/genética , Homología de Secuencia de Aminoácido , Tripsina/genética , Tripsina/metabolismoRESUMEN
Dendritic cells (DC) play a pivotal role in regulating immunity, establishing immunologically privileged tissue microenvironments and maintaining homoeostasis. It is becoming increasingly clear that one key mechanism that mediates many DC functions is production of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). For pathogens that cause chronic infection, exploitation of host DCs is a solution to establish and persist within a host. Leishmania parasites cause a range of clinical manifestations, all involving chronic infection, and are proficient at avoiding immune responses. We demonstrate here that infection of human myeloid-derived DC with L. major and L. donovani induces IDO expression using a mechanism that involves autocrine or paracrine stimulation with a DC-secreted factor. Leishmania-induced IDO suppresses allogeneic and tetanus toxoid-specific lymphocyte proliferation, an inhibition that is reversed with the IDO inhibitor, 1-methyl tryptophan (1-MT). Furthermore, IDO expression by human DC does not require live Leishmania infection, as parasite lysates also up-regulate IDO mRNA production. Our data suggest that one mechanism Leishmania parasites utilize to circumvent immune clearance may be to promote the induction of IDO among host DC within the infection microenvironment.
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Células Dendríticas/enzimología , Células Dendríticas/parasitología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Leishmania donovani/inmunología , Leishmania major/inmunología , Adulto , Proliferación Celular , Células Cultivadas , Células Dendríticas/inmunología , Humanos , Linfocitos/inmunologíaRESUMEN
Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy. Previous research has demonstrated several trends in human tissue that, undoubtedly, contribute to the development and progression of TLE. In this study we examined resected human hippocampus tissue for a variety of changes including gliosis that might contribute to the development and presentation of TLE. The study subjects consisted of six TLE patients and three sudden-death controls. Clinicopathological characteristics were evaluated by H&E staining. Immunohistological staining and Western blotting methods were used to analyze the samples. Neuronal hypertrophy was observed in resected epileptic tissue. Immunohistological staining demonstrated that activation of astrocytes was significantly increased in epileptic tissue as compared to corresponding regions of the control group. The Western blot data also showed increased CX43 and AQP4 in the hippocampus and downregulation of Kir4.1, α-syntrophin, and dystrophin, the key constituents of AQP4 multi-molecular complex. These tissues also demonstrated changes in inflammatory factors (COX-2, TGF-ß, NF-κB) suggesting that these molecules may play an important role in TLE pathogenesis. In addition we detected increases in metabotropic glutamate receptor (mGluR) 2/3, mGluR5 and kainic acid receptor subunits KA1 (Grik4) and KA2 (Grik5) in patients' hippocampi. We noted increased expression of the α1c subunit comprising class C L-type Ca(2+) channels and calpain expression in these tissues, suggesting that these subunits might have an integral role in TLE pathogenesis. These changes found in the resected tissue suggest that they may contribute to TLE and that the kainic acid receptor (KAR) and deregulation of GluR2 receptor may play an important role in TLE development and disease course. This study identifies alterations in number of commonly studied molecular targets associated with astrogliosis, cellular hypertrophy, water homeostasis, inflammation, and modulation of excitatory neurotransmission in hippocampal tissues from TLE patients.
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Epilepsia del Lóbulo Temporal/metabolismo , Epilepsia del Lóbulo Temporal/patología , Hipocampo/metabolismo , Hipocampo/patología , Transcriptoma , Adulto , Astrocitos/metabolismo , Western Blotting , Femenino , Humanos , Inmunohistoquímica , Inflamación/metabolismo , Inflamación/patología , MasculinoRESUMEN
PURPOSE: Good cancer pain control requires appropriate assessment and treatment. The purpose of this study was to examine the relationships among physician, nurse practitioner, and nurse knowledge, documentation of assessment, treatment, and pain reduction in cancer patients seen in ambulatory settings. METHOD: The study method included an assessment of pain knowledge of providers (physicians, nurse practitioners, and nurses) who worked in cancer clinics and a retrospective review of patients' records treated for cancer-related pain in their clinics. Fifty-eight providers from eight cancer clinics completed the knowledge questionnaire; 56 patient records were reviewed for assessment, treatment, and outcome data. Pain relief, the outcome, was obtained from documentation at the next clinic visit. RESULTS: Of the 54 patient records that documented pain relief at the next clinic visit, 61.9% reported no relief. Chi square analysis revealed clinics with a higher level of pain knowledge documented a greater number of elements of an ideal pain assessment (p = 0.03) but was unrelated to treatment and pain relief reported. Assessment and treatment were unrelated to reported pain relief at the next clinic visit. CONCLUSION: These data suggest that providers' pain knowledge is related to pain assessment but not treatment or outcome. In addition, these data showed no relationship between assessment, treatment prescribed, and pain relief in these ambulatory settings.
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Atención Ambulatoria/métodos , Conocimientos, Actitudes y Práctica en Salud , Neoplasias/complicaciones , Manejo del Dolor/métodos , Humanos , Enfermeras Practicantes/normas , Enfermeras y Enfermeros/normas , Evaluación de Resultado en la Atención de Salud , Dolor/diagnóstico , Dolor/etiología , Dimensión del Dolor/métodos , Médicos/normas , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: Patient Reported Outcome (PRO) assessments can assist health professionals to tailor their health practices to the individual needs of patients and improve patient care over time. The present study assessed prospective predictors of unmet supportive care needs in cancer patients over a six-month period. METHODS: Participants were recruited from a regional cancer treatment centre in Australia and completed the Supportive Care Needs Survey (SCNS) at recruitment (n=439; 61.4% response rate) and six months follow-up (n=396). Hierarchical logistic regression was used to identify predictors of change in unmet needs across each supportive care domain. Predictor variables were socio-demographic, treatment and psychosocial factors including depression, anxiety, social support, and patient satisfaction. RESULTS: Unmet needs were reported by approximately two-thirds of patients at baseline and half of patients at six months follow-up. Having unmet needs at baseline was the strongest predictor of unmet needs at six months. Longer time since diagnosis was a consistent predictor of greater unmet needs, associated with change in physical/daily living, psychological and health system and information unmet needs over time. By contrast, a complex relationship was found in that patient satisfaction, psychosocial and treatment characteristics predicted higher needs in some domains and lower needs in others. CONCLUSIONS: Unmet supportive care needs persist over time and psychological needs may emerge later in the illness continuum. Interventions to meet the needs of longer term cancer survivors are needed and should closely articulate with reported supportive care needs.
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Necesidades y Demandas de Servicios de Salud , Neoplasias/psicología , Neoplasias/terapia , Atención al Paciente/normas , Apoyo Social , Actividades Cotidianas , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Estudios Prospectivos , Psicología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
First-degree relatives of men with prostate cancer have a higher risk of being diagnosed with prostate cancer than men without a family history. The present review examines the prevalence and predictors of testing in first-degree relatives, perceptions of risk, prostate cancer knowledge and psychological consequences of screening. Medline, PsycInfo and Cinahl databases were searched for articles examining risk perceptions or screening practices of first-degree relatives of men with prostate cancer for the period of 1990 to August 2007. Eighteen studies were eligible for inclusion. First-degree relatives participated in prostate-specific antigen (PSA) testing more and perceived their risk of prostate cancer to be higher than men without a family history. Family history factors (e.g. being an unaffected son rather than an unaffected brother) were consistent predictors of PSA testing. Studies were characterized by sampling biases and a lack of longitudinal assessments. Prospective, longitudinal assessments with well-validated and comprehensive measures are needed to identify factors that cue the uptake of screening and from this develop an evidence base for decision support. Men with a family history may benefit from targeted communication about the risks and benefits of prostate cancer testing that responds to the implications of their heightened risk.
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Actitud Frente a la Salud , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/diagnóstico , Ansiedad/etiología , Conductas Relacionadas con la Salud , Humanos , Masculino , Tamizaje Masivo/psicología , Tamizaje Masivo/estadística & datos numéricos , Linaje , Percepción , Neoplasias de la Próstata/psicología , Calidad de Vida , Medición de RiesgoRESUMEN
REASONS FOR PERFORMING STUDY: Absorption of endotoxin across ischaemic-injured mucosa is a major cause of mortality after colic surgery. Recent studies have shown that flunixin meglumine retards mucosal repair. Systemic lidocaine has been used to treat post operative ileus, but it also has novel anti-inflammatory effects that could improve mucosal recovery after ischaemic injury. HYPOTHESIS: Systemic lidocaine ameliorates the deleterious negative effects of flunixin meglumine on recovery of mucosal barrier function. METHODS: Horses were treated i.v. immediately before anaesthesia with either 0.9% saline 1 ml/50 kg bwt, flunixin meglumine 1 mg/kg bwt every 12 h or lidocaine 1.3 mg/kg bwt loading dose followed by 0.05 mg/kg bwt/min constant rate infusion, or both flunixin meglumine and lidocaine, with 6 horses allocated randomly to each group. Two sections of jejunum were subjected to 2 h of ischaemia by temporary occlusion of the local blood supply, via a midline celiotomy. Horses were monitored with a behavioural pain score and were subjected to euthanasia 18 h after reversal of ischaemia. Ischaemic-injured and control jejunum was mounted in Ussing chambers for measurement of transepithelial electrical resistance (TER) and permeability to lipopolysaccharide (LPS). RESULTS: In ischaemic-injured jejunum TER was significantly higher in horses treated with saline, lidocaine or lidocaine and flunixin meglumine combined, compared to horses treated with flunixin meglumine. In ischaemic-injured jejunum LPS permeability was significantly increased in horses treated with flunixin meglumine alone. Behavioural pain scores did not increase significantly after surgery in horses treated with flunixin meglumine. CONCLUSIONS: Treatment with systemic lidocaine ameliorated the inhibitory effects of flunixin meglumine on recovery of the mucosal barrier from ischaemic injury, when the 2 treatments were combined. The mechanism of lidocaine in improving mucosal repair has not yet been elucidated.
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Anestésicos Locales/uso terapéutico , Enfermedades de los Caballos/tratamiento farmacológico , Mucosa Intestinal/efectos de los fármacos , Isquemia/veterinaria , Yeyuno/irrigación sanguínea , Lidocaína/uso terapéutico , Anestésicos Locales/sangre , Animales , Clonixina/análogos & derivados , Clonixina/farmacología , Impedancia Eléctrica , Femenino , Enfermedades de los Caballos/prevención & control , Caballos , Infusiones Intravenosas/veterinaria , Mucosa Intestinal/irrigación sanguínea , Isquemia/tratamiento farmacológico , Isquemia/prevención & control , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Lidocaína/sangre , Lipopolisacáridos/farmacología , Masculino , Dimensión del Dolor/veterinaria , Permeabilidad/efectos de los fármacos , Reperfusión/veterinaria , Factores de Tiempo , Técnicas de Cultivo de Tejidos/veterinariaRESUMEN
Dendritic cells are potent immune-activating cells, which traditionally are thought of as presenters of protein antigen to lymphocytes to initiate an immune response. Recently, another mechanism of immune surveillance, the detection of lipid antigens, has been found to be mediated by the nonpolymorphic family of CD1 molecules. There are two different CD1 families, Group 1 consisting of CD1a, CD1b and CD1c, and Group 2 consisting only of CD1d. Leishmania donovani-infected dendritic cells have previously been demonstrated to exhibit decreased surface levels of Group 1 CD1 molecules and are no longer able to initiate a CD1b-restricted T cell response. In contrast to L. donovani, which disseminates to the visceral organs, L. major remains localized, forming a cutaneous lesion. We investigate here whether L. major, the aetiological agent of cutaneous leishmaniasis, also inhibits CD1 expression. We demonstrate that infection of human monocyte-derived dendritic cells with either L. major or L. donovani results in transcriptional down-regulation of both Groups 1 and 2 CD1 molecules. Furthermore, infection of monocytes during differentiation results in a cell phenotype similar to undifferentiated monocytes. Finally, we demonstrate that this down-regulation is not mediated by lipophosphoglycan or other phosphoglycans.
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Antígenos CD1/inmunología , Antígenos CD1/metabolismo , Células Dendríticas/inmunología , Leishmania donovani/patogenicidad , Leishmania major/patogenicidad , Monocitos/inmunología , Animales , Células Dendríticas/parasitología , Regulación hacia Abajo , Glicoesfingolípidos/inmunología , Glicoesfingolípidos/metabolismo , Humanos , Monocitos/parasitología , Polisacáridos/inmunología , Polisacáridos/metabolismoRESUMEN
Severe acute respiratory syndrome (SARS) is an emerging infectious disease associated with a high rate of mortality. The SARS-associated coronavirus (SARS-CoV) has been identified as the etiological agent of the disease. Although public health procedures have been effective in combating the spread of SARS, concern remains about the possibility of a recurrence. Various approaches are being pursued for the development of efficacious therapeutics. One promising approach is to develop small molecule inhibitors of the essential major polyprotein processing protease 3Clpro. Here we report a complete description of the tetrapeptide substrate specificity of 3Clpro using fully degenerate peptide libraries consisting of all 160,000 possible naturally occurring tetrapeptides. The substrate specificity data show the expected P1-Gln P2-Leu specificity and elucidate a novel preference for P1-His containing substrates equal to the expected preference for P1-Gln. These data were then used to develop optimal substrates for a high-throughput screen of a 2000 compound small-molecule inhibitor library consisting of known cysteine protease inhibitor scaffolds. We also report the 1.8 A X-ray crystal structure of 3Clpro bound to an irreversible inhibitor. This inhibitor, an alpha,beta-epoxyketone, inhibits 3Clpro with a k3/Ki of 0.002 microM(-1) s(-1) in a mode consistent with the substrate specificity data. Finally, we report the successful rational improvement of this scaffold with second generation inhibitors. These data provide the foundation for a rational small-molecule inhibitor design effort based upon the inhibitor scaffold identified, the crystal structure of the complex, and a more complete understanding of P1-P4 substrate specificity.
Asunto(s)
Antivirales/aislamiento & purificación , Antivirales/farmacología , Inhibidores de Cisteína Proteinasa/farmacología , Dipéptidos/farmacología , Compuestos Epoxi/farmacología , Oligopéptidos/farmacología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/enzimología , Proteínas Virales/antagonistas & inhibidores , Sustitución de Aminoácidos , Animales , Antivirales/química , Antivirales/metabolismo , Dominio Catalítico/efectos de los fármacos , Chlorocebus aethiops , Proteasas 3C de Coronavirus , Cristalografía por Rayos X , Cisteína Endopeptidasas/química , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/clasificación , Dipéptidos/química , Dipéptidos/aislamiento & purificación , Dipéptidos/metabolismo , Compuestos Epoxi/química , Compuestos Epoxi/aislamiento & purificación , Compuestos Epoxi/metabolismo , Modelos Moleculares , Oligopéptidos/química , Oligopéptidos/aislamiento & purificación , Oligopéptidos/metabolismo , Biblioteca de Péptidos , Estructura Terciaria de Proteína , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Relación Estructura-Actividad , Especificidad por Sustrato , Células Vero , Proteínas Virales/química , Replicación Viral/efectos de los fármacosRESUMEN
The purpose of this study was to develop practical prediction equations for estimating adult mid-arm circumference (AC) using self-reported height and weight data from NHANES III 1988-1994 and NHANES 1999-2000. Both surveys used a complex sample design to obtain nationally representative data for the US civilian noninstitutionalized population. The analytic sample consisted of 4801 men and 4854 women in NHANES III and 1960 men and 2180 women from NHANES 1999-2000. Self-reported weight, height, and age data from NHANES III were used for model building, and similar data from NHANES 1999-2000 were used for validation. An all-possible regressions procedure by gender was used to derive the mid-AC prediction equations. The final prediction equations for adult mid-AC are (for self-reported weight in pounds and height in inches) for men: AC (cm) = 32.52145 + 0.10975 x (wt)-0.26057 x (ht)-0.03028 x (age), R2 = 0.76; and for women: AC (cm) = 30.22126 + 0.13534 x (wt)-0.34121 x (ht) + 0.09014 x (age)-0.00082565 x (age2), R2 = 0.81. Based on these equations, tables were created to predict mid-AC using self-reported height and weight. Clinicians can refer to our prediction equations and reference tables to determine mid-AC and proper BP cuff sizes.
Asunto(s)
Brazo/anatomía & histología , Determinación de la Presión Sanguínea/instrumentación , Estatura , Peso Corporal , Encuestas Nutricionales , Adulto , Factores de Edad , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores Sexuales , Estados UnidosRESUMEN
Mid-arm circumference (AC) measurement is a prerequisite for the selection of properly sized blood pressure (BP) cuffs and accurate BP readings. This study examined trends in the frequency distribution of mid-AC and corresponding recommended BP cuff sizes using National Health and Nutrition Examination Survey (NHANES) III (1988-1994) and NHANES 1999-2002 data. Both surveys used a complex sample design to obtain nationally representative samples of the civilian noninstitutionalized US population. The sample consisted of 7453 men and 8372 women from NHANES III and 4295 men and 4838 women from NHANES 1999-2002. Mean mid-AC (cm) and associated American Heart Association-defined cuff sizes were assessed. Variables were analysed by gender, age, race/ethnicity, and by hypertension or diabetic co-morbidity. Mid-AC increased significantly between surveys for all age groups; the greatest increase in mid-AC occurred in the 20-39 year age group. Data from NHANES 1992-2002 show that among nonHispanic white and nonHispanic black men aged 20-59 years, the mean mid-AC was >34 cm. Among NHB women aged 40 years and above, the mean mid-AC was greater than or equal to 34 cm. In all, 42% of all men and 26% of all women aged 40-59 years required large BP cuffs. In all, 39% of individuals classified as hypertensive and 47% of self-reported diabetics required a BP cuff greater than the standard adult size. In conclusion, mean mid-AC has increased across many demographic subgroups in the US with implications for the accuracy of BP measurement in clinical practice.
Asunto(s)
Antropometría , Determinación de la Presión Sanguínea/instrumentación , Adulto , Brazo , Tamaño Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas Nutricionales , Estados UnidosRESUMEN
BACKGROUND: Mercury amalgam dental restorations have been used by dentists since the mid 19th century and issues on safety continue to be periodically debated within the scientific and public health communities. Previous studies have reported a positive association between urine mercury levels and the number of dental amalgams, but this relation has never been described in a nationally representative sample in the United States. AIMS AND METHODS: Using household interview, dietary interview, dental examination, and laboratory data from the 1999-2000 National Health and Nutrition Examination Survey (NHANES), the association between mercury concentrations and dental restorations was examined in US women of reproductive age. RESULTS: In women of childbearing age, approximately 13% of all posterior dental surfaces were restored with amalgams and the average urinary mercury level in women was low (1.34 microg/l). It is estimated that an increase of 1.8 microg/l in the log transformed values for mercury in urine would occur for each 10 dental surfaces restored with amalgam. CONCLUSIONS: Although the findings do not address the important issues of adverse health effects at low thresholds of mercury exposure, they do provide important reference data that should contribute significantly to the ongoing scientific and public health policy debate on the use of dental amalgams in the USA.