RESUMO
BACKGROUND: Psoriasis is an inflammatory long-term condition involving comorbidities, unhealthy lifestyle and significant life impact. Patients' understanding of psoriasis is limited and support lacking. The Common-Sense Model of Self-Regulation of Health and Illness emphasizes the role of illness and treatment beliefs on coping and self-management. New 'Pso Well® ' patient materials informed by the model, addressed psoriasis as a long-term condition, medication management and lifestyle behaviours. OBJECTIVES: To investigate whether Pso Well® materials (i) broaden understanding of psoriasis without increasing anxiety; (ii) are acceptable; and (iii) comprise features that appear to effect change. METHODS: The Revised Illness Perceptions Questionnaire (IPQ-R modified) and the Hospital Anxiety and Depression Scale (HADS) were administered in patients before and after intervention. Numerical rating scales assessed perceptions of change in understanding and anxiety resulting from engagement with the materials. Qualitative interviews explored acceptability and perceived 'active ingredients'. RESULTS: Fifty-five patients completed pre- and postintervention questionnaires (56% female; median age 59 years). Postintervention, a large effect size was indicated in two IPQ-R domains - illness coherence [t(55) = -3·48, P = 0·001 (two-tailed), η2 = 0·19] and personal control [t(55) = -2·98, P = 0·004 (two-tailed), η2 = 0·14] - and a medium effect in one, treatment control [t(55) = -2·08, P = 0·042 (two-tailed), η2 = 0·08]. HADS scores did not change. For numerical rating scales, 80% of participants reported increased understanding of psoriasis and none reported increased anxiety. Interviews with 19 patients indicated the materials were acceptable and usable. Factors reported to broaden understanding and promote engagement with self-management included linking of related disease aspects, personally relevant content and high-quality design. CONCLUSIONS: High-quality, theory-based psoriasis materials are acceptable to patients and can improve understanding and sense of control without increasing anxiety.
Assuntos
Compreensão , Psoríase/psicologia , Adulto , Idoso , Ansiedade/etiologia , Estudos de Viabilidade , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Percepção , Psoríase/terapia , Escalas de Graduação Psiquiátrica , Autocuidado/métodos , Autoimagem , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Psoriasis is a common long-term, immune-mediated skin condition associated with behavioural factors (e.g. smoking, excess alcohol, obesity), which increase the risk of psoriasis onset, flares and comorbidities. Motivational interviewing (MI) is an evidence-based approach to health-related behaviour change that has been used successfully for patients with long-term conditions. This study assessed change in clinicians' MI skills and psoriasis knowledge following Psoriasis and Wellbeing (Pso Well® ) training. OBJECTIVES: To investigate whether the Pso Well training intervention improves clinicians' MI skills and knowledge about psoriasis-related comorbidities and risk factors; and to explore the acceptability and feasibility of the Pso Well training content, delivery and evaluation. METHODS: Clinicians attended the 1-day training programme focused on MI skills development in the context of psoriasis. MI skills were assessed pre- and post-training using the Behaviour Change Counselling Index. Knowledge about psoriasis-related comorbidity and risk factors was assessed with a novel 22-point measure developed for the study. Interviews with clinicians were analysed qualitatively to identify perceptions about the feasibility and acceptability of the training. RESULTS: Sixty-one clinicians completed the training (35 dermatology nurses, 23 dermatologists and three primary-care clinicians). Clinicians' MI skills (P < 0·001) and knowledge (P < 0·001) increased significantly post-training. Clinicians found the training valuable and relevant to psoriasis management. CONCLUSIONS: Attendance at the Pso Well training resulted in improvements in clinicians' knowledge and skills to manage psoriasis holistically. Clinicians deemed the training itself and the assessment procedures used both feasible and acceptable. Future research should investigate how this training may influence patient outcomes.
Assuntos
Competência Clínica/normas , Conhecimentos, Atitudes e Prática em Saúde , Entrevista Motivacional/métodos , Psoríase/terapia , Comunicação , Comorbidade , Aconselhamento , Dermatologistas/normas , Dermatologia/educação , Educação Médica/métodos , Feminino , Humanos , Capacitação em Serviço , Masculino , Enfermeiras e Enfermeiros/normas , Satisfação do Paciente , Relações Médico-Paciente , Médicos de Atenção Primária/normas , Fatores de RiscoRESUMO
BACKGROUND: Studies assessing cardiovascular disease (CVD) risk factors in patients with psoriasis have been limited by selection bias, inappropriate controls or a reliance on data collected for clinical reasons. OBJECTIVES: To investigate whether screening for CVD risk factors in patients with psoriasis in primary care augments the known prevalence of CVD risk factors in a cross-sectional study. METHODS: Patients listed as having psoriasis in primary care were recruited, screened and risk assessed by QRISK2. RESULTS: In total, 287 patients attended (mean age 53 years, 57% women, 94% white British, 22% severe disease, 33% self-reported psoriatic arthritis). The proportion with known and screen-detected (previously unknown) risk factors was as follows: hypertension 35% known and 13% screen-detected; hypercholesterolaemia 32% and 37%; diabetes 6·6% and 3·1% and chronic kidney disease 1·1% and 4·5%. At least one screen-detected risk factor was found in 48% and two or more risk factors were found in 21% of patients. One in three patients (37%) not previously known to be at high risk were found to have a high (> 10%) 10-year CVD risk. Among the participants receiving treatment for known CVD risk factors, nearly half had suboptimal levels for blood pressure (46%) and cholesterol (46%). CONCLUSIONS: Cardiovascular risk factor screening of primary care-based adults with psoriasis identified a high proportion of patients (i) at high CVD risk, (ii) with screen-detected risk factors and (iii) with suboptimally managed known risk factors. These findings need to be considered alongside reports that detected limited responses of clinicians to identified risk factors before universal CVD screening can be recommended.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Psoríase/complicações , Artrite Psoriásica/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos Transversais , Complicações do Diabetes/complicações , Inglaterra/epidemiologia , Feminino , Humanos , Hipercolesterolemia/complicações , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Prevalência , Insuficiência Renal Crônica/complicações , Fatores de Risco , AutorrelatoRESUMO
Ly-49 is a recently identified cell surface molecule expressed on a subpopulation of natural killer (NK) cells and certain T lymphomas. It has been suggested, based on gene transfection and antibody blocking studies, that Ly-49 is a negative regulator of NK lytic activity, possibly through an interaction with target cell class I molecules. However, it has not been demonstrated that class I molecules indeed serve as ligands for Ly-49. We have found that T lymphomas expressing Ly-49 bind isolated class I major histocompatibility complex (MHC) molecules but not class II molecules immobilized on plastic. Adhesion to class I molecules was not found with T lymphomas lacking Ly-49 expression. The Ly-49 expressing EL4 lymphoma bound Dd, Dk, and Kb, but not Kd, Kk, or Db, thus demonstrating a restricted pattern of class I adhesion. The observed cell adhesion was class I density dependent, and binding to Dd and Dk was extensively inhibited by the A1 monoclonal antibody directed against Ly-49. These results provide direct evidence for Ly-49 serving as a receptor for a subset of class I MHC molecules.
Assuntos
Adesão Celular/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Linfoma de Células T/imunologia , Proteínas de Membrana/metabolismo , Animais , Linhagem Celular , Antígenos HLA-D/imunologia , Antígenos HLA-D/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/isolamento & purificação , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/isolamento & purificação , Antígenos de Histocompatibilidade Classe II/metabolismo , Hibridomas/imunologia , Células Matadoras Naturais/imunologia , Cinética , Linfoma , Proteínas de Membrana/imunologia , Camundongos , Células Tumorais CultivadasRESUMO
It is not known whether all forms of cell surface peptide-class I complexes, when bound with relevant peptide antigen, are recognized by T cells. We demonstrate herein that two distinct subsets of the murine H-2 Kb molecule can be separately isolated from H-2b-expressing cell lines using Y3 mAb immunoaffinity chromatography. Although both isolated Kb subsets were found to be strongly reactive with Y3 mAb by ELISA, one Kb subset is S19.8 mAb reactive (Ly-m11+Kb subset) and exhibits low reactivity with the M1/42 antibody, while the other subset is negative for the Ly-m11 epitope and highly reactive with the M1/42 antibody (M1/42high Kb subset). More importantly, whereas the M1/42high Kb subset is a very effective ligand for both TCR and CD8, the Ly-m11+ Kb subset could only function as a CD8 ligand, as determined in allo-specific CD8+ CTL clone adhesion and degranulation assays. Peptides acid-eluted from both Kb subsets sensitized Kb-transfected T2 cells expressing "peptide empty" Kb for lysis to a similar extent by allo-CTL clones, indicating that relevant endogenous peptide antigens are not limiting in the Ly-m11+ Kb subset. The major distinction identified between the two Kb subsets is that they differ substantially in their degree of N-linked glycosylation, with the Ly-m11+ subset containing Kb molecules with larger and more complex carbohydrate modifications than the M1/42high subset. The differences in glycosylation may explain the functional differences observed between the two Kb subsets. It is therefore possible that some forms of glycosylation on class I molecules interfere with TCR recognition and may limit CD8+ T cell responses, perhaps under circumstances where peptide antigen is limiting.
Assuntos
Antígenos H-2/fisiologia , Isoantígenos/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/fisiologia , Animais , Antígenos CD8/metabolismo , Células Clonais , Ensaio de Imunoadsorção Enzimática , Glicosilação , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Células Tumorais CultivadasRESUMO
Cytotoxic T lymphocyte (CTL) activation requires specific T cell receptor (TCR)-class I major histocompatibility complex (MHC) antigen complex interactions as well as the participation of coreceptor or accessory molecules on the surface of CTL. CD8 can serve as a coreceptor in that it binds to the same MHC class I molecules as the TCR to facilitate efficient TCR signaling. In addition, CD8 can be "activated" by TCR stimulation to bind to class I molecules with high avidity, including class I not recognized by the TCR as antigenic complexes (non-antigen [Ag] class I), to augment CTL responses and thus serve an accessory molecule function. A Glu/Asp227-->Lys substitution in the class I alpha 3 domain acidic loop abrogates lysis of target cells expressing these mutant molecules by alloreactive CD8-dependent CTL. Lack of response is attributed to the destruction of the CD8 binding site in the alpha 3 domain which is likely to disrupt CD8 coreceptor function. The relative importance of the class I alpha 3 domain acidic loop Glu227 in coreceptor as opposed to accessory functions of CD8 is unclear. To address this issue, we examined CTL adhesion and degranulation in response to immobilized class I-peptide complexes formed in vitro from antigenic peptides and purified class I molecules containing wild-type or Glu227-->Lys substituted alpha 3 domains. The alpha 3 domain mutant class I-peptide complexes were bound by CTL and triggered degranulation, however to much lower levels than wild-type class I-peptide complexes. In further experiments, it is directly demonstrated that the alpha 3 domain mutant class I molecules, which lack the Glu227 CD8 binding site, still serve as TCR-activated, avidity-enhanced CD8 accessory ligands. However, mutant class I peptide Ag complexes failed to effectively serve as CD8 coreceptor ligands to initiate TCR-dependent signals required to induce avidity-enhanced CD8 binding to coimmobilized non-Ag class I molecules. Thus the Glu227-->Lys mutation effectively distinguishes CD8 coreceptor and avidity-enhanced CD8 accessory functions.
Assuntos
Antígenos CD8/imunologia , Ácido Glutâmico/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Mutação , Linfócitos T Citotóxicos/imunologia , Sítios de Ligação/genética , Adesão Celular , Degranulação Celular , Células Clonais , Citotoxicidade Imunológica , Ácido Glutâmico/genética , Antígenos H-2/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Ligantes , Ativação Linfocitária , Lisina/genética , Fragmentos de Peptídeos/imunologia , Conformação Proteica , Receptores de Antígenos de Linfócitos T , Proteínas Recombinantes de Fusão/imunologia , Transdução de Sinais , Proteínas do Core Viral/imunologiaRESUMO
Classical class I major histocompatibility complex (MHC) molecules, as well as the nonclassical class I histocompatibility leukocyte antigen (HLA)-E molecule, can negatively regulate natural killer (NK) cell cytotoxicity through engagement of NK inhibitory receptors. We show that expression of murine (m)CD1.1, a nonpolymorphic nonclassical MHC class I-like molecule encoded outside the MHC, protects NK-sensitive RMA/S target cells from adherent lymphokine-activated killer cell (A-LAK) cytotoxicity. Passage of effector cells in recombinant interleukin (rIL)-2 enhanced protection by mCD1.1, suggesting an expansion of relevant A-LAK population(s) or modulation of A-LAK receptor expression. Murine CD1. 1 conferred protection from lysis by rIL-2-activated spleen cells of recombination activating gene (Rag)-1(-/-) mice, which lack B and T cells, demonstrating that mCD1.1 can protect RMA/S cells from lysis by NK cells. An antibody specific for mCD1.1 partially restored A-LAK lysis of RMA/S.CD1.1 transfectants, indicating that cell surface mCD1.1 can confer protection from lysis; therefore, mCD1.1 possibly acts through interaction with an NK inhibitory receptor. CD1.1 is by far the most divergent class I molecule capable of regulating NK cell activity. Finally, mCD1.1 expression rendered RMA/S cells resistant to lysis by A-LAK of multiple mouse strains. The conserved structure of mCD1.1 and pattern of mCD1.1 resistance from A-LAK lysis suggest that mCD1.1 may be a ligand for a conserved NK inhibitory receptor.
Assuntos
Antígenos CD1/imunologia , Citotoxicidade Imunológica , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Ativadas por Linfocina/imunologia , Animais , Antígenos H-2 , Antígenos HLA-B , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Receptores ImunológicosRESUMO
Cloned allospecific cytolytic T lymphocytes (CTL) adhere to purified class I alloantigen immobilized on plastic and degranulate in response to it. Binding and degranulation are inhibited by drugs that impair cytoskeletal function. Cytochalasins D and E, which interfere with microfilament function, and colchicine, which disrupts microtubules, were used and gave qualitatively similar results. Concentrations of these drugs that inhibited degranulation in response to alloantigen did not inhibit response to immobilized anti-T cell receptor (TCR) antibody. Neither did they inhibit response when alloantigen was co-immobilized with an antibody against class I on the CTL to promote adhesion between the CTL and antigen-bearing surface. Thus, neither transmembrane signal generation via the TCR nor degranulation per se were prevented. Instead, the drugs act to prevent the initial adhesion to alloantigen. CTL binding to alloantigen depends in part on CD8-class I interaction, and adhesion via CD8 is "activated" by crosslinking the TCR with soluble anti-TCR antibody. This adhesion, too, is shown to be cytoskeleton dependent.
Assuntos
Antígenos de Diferenciação de Linfócitos T/fisiologia , Citoesqueleto/fisiologia , Antígenos de Histocompatibilidade Classe I/imunologia , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos CD8 , Adesão Celular/efeitos dos fármacos , Adesão Celular/imunologia , Citocalasinas/farmacologia , Grânulos Citoplasmáticos/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Isoantígenos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacosRESUMO
To assess the sensitivity of B cell tolerance with respect to receptor/autoantigen affinity, we identified low affinity ligands to the 3-83 (anti-major histocompatibility complex class I) antibody and tested the ability of these ligands to induce central and peripheral tolerance in 3-83 transgenic mice. Several class I protein alloforms, including Kbm3 and Dk, showed remarkably low, but detectable, affinity to 3-83. The 3-83 antibody bound Kb with K lambda approximately 2 x 10(5) M-1 and bound 10-fold more weakly to the Kbm3 (K lambda approximately 2 x 10(4) M-1) and Dk antigens. Breeding 3-83 immunoglobulin transgenic mice with mice expressing these ultralow affinity Kbm3 and Dk ligands resulted in virtually complete deletion of the autoreactive B cells from the peripheral lymphoid tissues. These low affinity antigens also induced receptor editing, as measured by elevated RAG mRNA levels in the bone marrow and excess levels of id- variant B cells bearing lambda light chains in the spleen. Reactive class I antigens were also able to mediate deletion of mature B cells when injected into the peritoneal cavity of 3-83 transgenic mice. Although the highest affinity ligand, Kk, was consistently able to induce elimination of the 3-83 peritoneal B cells, the lower affinity ligands were only partially effective. These results demonstrate the remarkable sensitivity of the deletion and receptor-editing mechanisms in immature B cells, and may suggest a higher affinity threshold for deletion of peripheral, mature B cells.
Assuntos
Linfócitos B/imunologia , Tolerância Imunológica/genética , Modelos Imunológicos , Receptores de Antígenos de Linfócitos B/genética , Animais , Autoantígenos/imunologia , Medula Óssea/imunologia , Deleção Clonal , Reações Cruzadas , Antígenos H-2/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Idiótipos de Imunoglobulinas , Ligantes , Tecido Linfoide/imunologia , Camundongos , Camundongos Transgênicos , Peritônio/citologia , Peritônio/imunologia , Ligação ProteicaRESUMO
We isolated major histocompatibility complex (MHC)-specific viral peptides from cells infected with influenza virus in the continuous presence of the drug brefeldin A, which blocks exocytosis of newly synthesized MHC class I molecules. MHC-specific peptides were also isolated from cells expressing mouse Kd class I MHC molecules whose cytoplasmic domain was substituted by that of the adenovirus E3/19K glycoprotein. This molecule was retained in an intracellular pre-Golgi complex compartment as demonstrated by immunocytochemical and biochemical means. Since we show that intracellular association of antigenic peptides with such retained class I molecules is necessary for their isolation from cellular extracts, this provides direct evidence that naturally processed peptides associate with class I MHC molecules in an early intracellular exocytic compartment.
Assuntos
Antígenos Virais/metabolismo , Retículo Endoplasmático/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Peptídeos/metabolismo , Proteínas de Ligação a RNA , Animais , Brefeldina A , Linhagem Celular , Ciclopentanos/farmacologia , Exocitose , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Hemaglutininas Virais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas do Nucleocapsídeo , Nucleoproteínas/metabolismo , Peptídeos/imunologia , Proteínas do Core Viral/metabolismoRESUMO
BACKGROUND: The concept of endoscopic diagnosis and procedures on the nasal cavity had been investigated for several decades in Europe in the early part of the twentieth century. It was Prof Walter Messerklinger and his assistant, Heinz Stammberger, with US colleague, David Kennedy, who brought the science and technique of functional endoscopic sinus surgery to the wider world. METHODS: The author, an English-speaking surgeon, was present at this movement from the commencement of its propagation, and has recorded the remarkable ascendency of this technique throughout the world. CONCLUSION: The technique revolutionised the diagnosis and management of intranasal, sinus and intracranial conditions.
Assuntos
Endoscopia/história , Sinusite/diagnóstico , Sinusite/cirurgia , Congressos como Assunto , História do Século XX , HumanosRESUMO
Post-operative outcomes after simultaneous bilateral total knee arthroplasty in 115 patients randomly assigned to two rehabilitation protocols were compared. The traditional-protocol group performed a series of exercises on one leg and then repeated the same sequence on the other leg. The alternate-protocol group performed the same exercises, but alternated between legs with each individual repetition. Symptoms and function were assessed pre-operatively and at 1, 3, 6 and 12 months post-operatively. The alternate-protocol group had lower visual analogue pain scale scores in the early post-operative period, as well as higher Knee Society Scores and SF-12 physical and mental health summary scores after 1 and 3 months compared with the traditional-protocol group, but there were no differences between the two groups from 6 months post-operatively. There were no significant differences between the groups in terms of range of knee motion or incidence of deep vein thrombosis. The alternate-protocol for rehabilitation resulted in an early return to function and decreased pain levels following simultaneous bilateral total knee arthroplasty and was associated with the potential to produce more positive emotional states and earlier functional independence.
Assuntos
Artroplastia do Joelho/reabilitação , Idoso , China/epidemiologia , Demografia , Feminino , Nível de Saúde , Humanos , Masculino , Medição da Dor , Amplitude de Movimento Articular/fisiologia , Recuperação de Função Fisiológica , Inquéritos e Questionários , Trombose Venosa/epidemiologia , Trombose Venosa/fisiopatologiaRESUMO
BACKGROUND AND PURPOSE: Torsade de pointes (TdP) can be induced in several species by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether combined I(Kr) and I(Ks) blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP. EXPERIMENTAL APPROACH: Experiments were performed in open-chest, pentobarbital-anaesthetized, adrenaline-stimulated male Dunkin Hartley guinea pigs, which received three consecutive i.v. infusions of either vehicle, the I(Kr) blocker E-4031 (3, 10 and 30 nmol kg(-1) min(-1)), the I(Ks) blocker HMR1556 (75, 250, 750 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. Phenylephrine-stimulated guinea pigs were also treated with the K(+) channel blockers in combination. Arterial blood pressure, ECGs and epicardial monophasic action potential (MAP) were recorded. KEY RESULTS: TdP was observed in 75% of adrenaline-stimulated guinea pigs given the K(+) channel blockers in combination, but was not observed in guinea pigs treated with either I(K) blocker alone, or in phenylephrine-stimulated guinea pigs. Salvos and ventricular tachycardia occurred with adrenaline but not with phenylephrine. No changes in STV or triangulation of the MAP signals were observed before TdP. CONCLUSIONS AND IMPLICATIONS: Combined blockade of both I(Kr) and I(Ks) plus the addition of adrenaline were required to induce TdP in anaesthetized guinea pigs. This suggests that there must be sufficient depletion of repolarization reserve and an appropriate trigger for TdP to occur.
Assuntos
Canais de Potássio de Retificação Tardia/antagonistas & inibidores , Epinefrina/farmacologia , Bloqueadores dos Canais de Potássio/toxicidade , Torsades de Pointes/induzido quimicamente , Potenciais de Ação/efeitos dos fármacos , Animais , Cromanos/administração & dosagem , Cromanos/toxicidade , Relação Dose-Resposta a Droga , Eletrocardiografia , Epinefrina/administração & dosagem , Cobaias , Masculino , Modelos Biológicos , Fenilefrina/farmacologia , Piperidinas/administração & dosagem , Piperidinas/toxicidade , Bloqueadores dos Canais de Potássio/administração & dosagem , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Piridinas/administração & dosagem , Piridinas/toxicidade , Sulfonamidas/administração & dosagem , Sulfonamidas/toxicidadeRESUMO
BACKGROUND AND PURPOSE: Torsade de pointes (TdP) can be induced by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether IKs blockade or enhancement of INa could potentiate TdP induced by IKr blockade and to investigate whether short-term variability (STV) or triangulation of action potentials preceded TdP. EXPERIMENTAL APPROACH: Experiments were performed in open-chest, pentobarbital-anaesthetized, alpha 1-adrenoceptor-stimulated, male New Zealand White rabbits, which received three consecutive i.v. infusions of either the IKr blocker E-4031 (1, 3 and 10 nmol kg(-1) min(-1)), the IKs blocker HMR1556 (25, 75 and 250 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. In a second study rabbits received either the same doses of E-4031, the INa enhancer, ATX-II (0.4, 1.2 and 4.0 nmol kg(-1)) or both of these drugs. ECGs and epicardial monophasic action potentials were recorded. KEY RESULTS: HMR1556 alone did not cause TdP but increased E-4031-induced TdP from 25 to 80%. ATX-II alone caused TdP in 38% of rabbits, as did E-4031; 75% of rabbits receiving both drugs had TdP. QT intervals were prolonged by all drugs but the extent of QT prolongation was not related to the occurrence of TdP. No changes in STV were detected and triangulation was only increased after TdP occurred. CONCLUSIONS AND IMPLICATIONS: Giving modulators of ion channels in combination substantially increased TdP but, in this model, neither STV nor triangulation of action potentials could predict TdP.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Cromanos/toxicidade , Venenos de Cnidários/toxicidade , Piperidinas/toxicidade , Piridinas/toxicidade , Sulfonamidas/toxicidade , Torsades de Pointes/induzido quimicamente , Animais , Cromanos/administração & dosagem , Venenos de Cnidários/administração & dosagem , Canais de Potássio de Retificação Tardia/antagonistas & inibidores , Canais de Potássio de Retificação Tardia/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Eletrocardiografia , Eletrofisiologia , Previsões , Síndrome do QT Longo/induzido quimicamente , Masculino , Piperidinas/administração & dosagem , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Piridinas/administração & dosagem , Coelhos , Canais de Sódio/efeitos dos fármacos , Sulfonamidas/administração & dosagemRESUMO
Short-term fasting of mature ewes during diestrus results in increased serum concentrations of progesterone and a delayed pre-ovulatory surge release of LH. To determine if these changes in reproductive hormones influence subsequent follicular development, mature ewes observed in estrus were assigned randomly to control (n=10) or fasted (n=15) groups. Control ewes had ad libitum access to feed, whereas fasted ewes were not fed from day 7 through 11 of their estrous cycle. Daily blood samples were collected from control and fasted ewes throughout the fasting period. Fasting increased (P<0.001) serum concentrations of progesterone (4.4 ng/mL versus 2.7 ng/mL [+/-0.3]). On day 12, all ewes were treated with 10mg of PGF(2alpha) and fasted ewes were returned to ad libitum feed. Ovaries were collected from ewes (n=5 each group) at 0 and 72 h following PGF(2alpha) in control and 0, 72 and 96 h in fasted ewes. Ovaries were weighed and small (< or =2mm), medium (3-4mm), and large (> or =5mm) follicles were enumerated. Total numbers of follicles were less (P<0.001) in fasted than fed ewes (14.6 versus 30.2 [+/-2.2]) at 0 h, but did not differ (P=0.9) when numbers of follicles were compared at similar times before the anticipated LH surge (i.e., at 72 h versus 96 h in control and fasted ewes, respectively). Within follicular size class, numbers of small and medium follicles were decreased (P=0.04) at 0 h in fasted ewes. Numbers of large follicles did not differ (P=1.0) between groups. Although numbers of small and medium ovarian follicles in fasted ewes recovered by 96 h to values comparable to fed ewes at 72 h following PGF(2alpha), serum concentrations of estradiol 17beta (P=0.08) and FSH (P=0.06) tended to be decreased in fasted ewes before the anticipated surge release of LH. Pituitary content of LH and FSH also tended to be lower (P< or =0.09) at 96 h in fasted ewes than at 72 h in control ewes, but did not differ (P> or =0.4) at hour 0 following PGF(2alpha). Hypothalamic and stalk median eminence contents of GnRH were not influenced (P> or =0.2) by fasting at any time period. Fasting during the luteal phase perturbs gonadotropin secretion and may influence fertility by causing a delay in ovarian follicle development.
Assuntos
Dinoprosta/farmacologia , Ciclo Estral/fisiologia , Privação de Alimentos , Folículo Ovariano/crescimento & desenvolvimento , Ovinos/fisiologia , Animais , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Privação de Alimentos/fisiologia , Fase Luteal/fisiologia , Hormônio Luteinizante/sangue , Ovariectomia/veterinária , Progesterona/sangue , Distribuição Aleatória , Ovinos/sangue , Fatores de TempoRESUMO
Chemokine (C-X-C motif) ligand 12 (CXCL12) and its receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), are involved in significant biological processes associated with early pregnancy including increasing trophoblast invasion and stimulating placental vascularization. To further elucidate functions of CXCL12-CXCR4 signaling during early gestation, our objective was to inhibit CXCR4 in vivo using a CXCR4 antagonist, AMD3100. We hypothesized that inhibition of CXCR4 would negatively affect chemokine and angiogenic factor regulation imperative for placental development in sheep. Osmotic pumps containing PBS (control) or AMD3100 (CXCR4 antagonist) were surgically installed ipsilateral to the corpus luteum on d 12 of gestation and administered treatments directly into the uterine lumen. Maternal (caruncle and intercaruncle) and fetal membrane tissues were collected on d 23 of gestation and mRNA and protein expression were analyzed for vascular endothelial growth factor (VEGF), kinase insert domain receptor (KDR), fms related tyrosine kinase 1 (FLT1), fibroblast growth factor 2 (FGF2), angiopoietin 1 (ANGPT1), hypoxia inducible factor 1 É subunit (HIF1A), CXCL12, and its corresponding receptors (CXCR4 and CXCR7). Immunohistochemical procedures were performed for analysis of CXCL12 and cell proliferation. In caruncle tissue ipsilateral to the pump, mRNA for KDR, ANGPT1, HIF1A, and CXCL12 increased (P < 0.05) in treated ewes compared to control, whereas caruncle tissue contralateral to the pump had increased expression (P < 0.05) of KDR, and CXCL12 in treated ewes. In fetal membrane, CXCR4 mRNA and protein decreased (P < 0.05), while VEGF protein decreased (P < 0.05) in caruncle and fetal membrane tissue from treated ewes. Results from this study highlight the importance of CXCL12-CXCR4 signaling at the fetal-maternal interface. Inhibiting this axis may disrupt typical regulation of angiogenic factors needed for placental development and embryo growth.
Assuntos
Moduladores da Angiogênese/metabolismo , Quimiocina CXCL12/metabolismo , Quimiocinas/metabolismo , Troca Materno-Fetal/fisiologia , Receptores CXCR/metabolismo , Ovinos/fisiologia , Animais , Proliferação de Células , Quimiocina CXCL12/genética , Quimiocinas/genética , Corpo Lúteo , Feminino , Placenta/irrigação sanguínea , Placentação/fisiologia , Gravidez , RNA Mensageiro/metabolismo , Receptores CXCR/genética , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVES: To examine the agreement in nutrient intake and alternate healthy eating indices (AHEI) between a self-administered Food Frequency Questionnaire (FFQ) and 24-hour recall (24HR) measurements of diet by race, among urban older women. DESIGN: Cross-sectional observational study. SETTING: Urban neighborhoods in Washington, DC, USA. PARTICIPANTS: Community-dwelling White and Black women aged 65 and older. MEASUREMENTS: In 2014 and 2015, 49 White and 44 Black older women were queried on diet using both FFQ and 24-hour recalls. The correlation coefficients of 55 nutrient intake measures and agreements on healthy eating classification between the two instruments were compared overall and by race. RESULTS: The mean correlation coefficient (rho) was 0.46 for Whites and 0.23 for Blacks. For 47 measures, rho was lower for Blacks. Whites had a strong correlation of ≥0.5 for 28 items, while Blacks had strong correlations for only 3 items. Based on FFQ, the mean (SD) of AHEI were 54.0 (10.3) for Whites and 45.9 (8.8) for Blacks (p<0.001). Based on 24HR, the mean (SD) were 43.9 (10.8) for Whites and 33.2 (9.6) for Blacks (p<0.001). Using 32 as the cutoff (40% of maximum AHEI score), 50% of Blacks and 14% of Whites were classified as eating unhealthy based on the 24HR, versus 2.6% and 0% based on the FFQ. CONCLUSION: The FFQ has limited ability to accurately assess nutrient intake among older Black women, and tends to underestimate racial differences in healthy eating. The FFQ should be further improved for use in racial disparities research of healthy eating in older age, using a larger sample of older women with racial and geographic diversities.
Assuntos
Dieta Saudável/etnologia , Rememoração Mental , Inquéritos e Questionários , Negro ou Afro-Americano , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , District of Columbia , Exercício Físico , Feminino , Humanos , Vida Independente , Avaliação Nutricional , Fatores Socioeconômicos , População BrancaRESUMO
BACKGROUND: A thorough understanding of gender differences in physical activity is critical to effective promotion of active living in older adults. OBJECTIVES: To examine gender and age differences in levels, types and locations of physical activity. DESIGN: Cross-sectional observation. SETTING: Car-dependent urban and rural neighborhoods in Worcester County, Massachusetts, USA. PARTICIPANTS: 111 men and 103 women aged 65 years and older. MEASUREMENTS: From 2012 to 2014, participants were queried on type, frequency and location of physical activity. Participants wore an accelerometer for 7 consecutive days. RESULTS: Compared to women, men had a higher mean daily step count (mean (SD) 4385 (2122) men vs. 3671(1723) women, p=0.008). Men reported higher frequencies of any physical activity and moderate-to-vigorous physical activity, and a lower frequency of physical activity inside the home. Mean daily step counts and frequency of physical activity outside the home decreased progressively with age for both men and women. Women had a sharper decline in frequencies of self-reported physical activity. Men had a significant decrease in utilitarian walking, which women did not (p=0.07). Among participants who reported participation in any physical activity (n=190), more women indicated exercising indoors more often (59% vs. 44%, p=0.04). The three most commonly cited locations for physical activity away from home for both genders were streets or sidewalks, shopping malls, and membership-only facilities (e.g., YMCA or YWCA). The most common types of physical activity, performed at least once in a typical month, with over 40% of both genders reporting, included light housework, brisk walking, leisurely walking, and stretching. CONCLUSION: Levels, types and location preferences of physical activity differed substantially by gender. Levels of physical activity decreased progressively with age, with greater decline among women. Consideration of these gender differences is necessary to improve the effectiveness of active living promotion programs among older adults.
Assuntos
Atividades Cotidianas , Envelhecimento , Exercício Físico , Atividade Motora/fisiologia , Características de Residência , Acelerometria/métodos , Fatores Etários , Idoso , Envelhecimento/fisiologia , Envelhecimento/psicologia , Acessibilidade Arquitetônica , Estudos Transversais , Exercício Físico/fisiologia , Exercício Físico/psicologia , Feminino , Humanos , Masculino , Massachusetts , População Rural/estatística & dados numéricos , Fatores Sexuais , População Urbana/estatística & dados numéricosRESUMO
OBJECTIVE: To examine differences in diet and food purchasing behaviors between Black and White older women living in urban neighborhoods. DESIGN: Cross-sectional observational study. SETTING: Urban neighborhoods in Washington, DC, USA. PARTICIPANTS: Community-dwelling White and Black women of age 65 and older. MEASUREMENTS: Participants were queried on diet via 24-hour recalls, food purchasing habits, their use of neighborhood resources and local travel patterns. Frequency and location of self-reported food purchasing and consumption were compared by race. RESULTS: In 2014 and 2015, 49 White and 44 Black older women were enrolled in the study. Compared to Whites, Blacks reported lower daily caloric intake (mean (SD) 1314 (404) vs. 1529 (448), p=0.02), with a higher percent of calories from protein and fat 1.8 (7.0), p=0.03), and a slightly higher polyunsaturated to saturated fat ratio (p=0.05). Blacks had substantially lower alternate healthy eating index (AHEI) (33.5 (10.2) vs. 43.9 (10.8) of 80 possible points, p<0.001), daily intake (grams) of total fiber (15.3 (8.1) vs. 22.9 (8.5), p<0.001), insoluble fiber (10.8 (6.9) vs. 15.9 (6.5), p<0.001), and soluble fiber (4.5 (2.0) vs. 6.9 (2.8), p<0.001). Blacks had lower intake of micronutrients, alcohol and caffeine. Blacks shopped for groceries less often (4.4 (3.0) vs. 6.2 (3.0) monthly; p=0.006) and spent a longer time traveling to stores (15.8 (9.1) vs. 11.5 (7.2) minutes per trip, p=0.02). A lower percent of Blacks walked to stores (14% vs. 40%, p=0.003) and a higher percent of Blacks rode in a car with someone else (33% vs. 6%, p<0.001). CONCLUSIONS: In an urban setting, food consumption and purchasing behaviors differed substantially between older Black and White women, which should be further investigated and considered to promote healthy eating in older populations.
Assuntos
Dieta/métodos , Comportamento Alimentar/fisiologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Grupos Raciais , População UrbanaRESUMO
The complexity and heterogeneity of neuroimaging findings in individuals with autism spectrum disorder has suggested that many of the underlying alterations are subtle and involve many brain regions and networks. The ability to account for multivariate brain features and identify neuroimaging measures that can be used to characterize individual variation have thus become increasingly important for interpreting and understanding the neurobiological mechanisms of autism. In the present study, we utilize the Mahalanobis distance, a multidimensional counterpart of the Euclidean distance, as an informative index to characterize individual brain variation and deviation in autism. Longitudinal diffusion tensor imaging data from 149 participants (92 diagnosed with autism spectrum disorder and 57 typically developing controls) between 3.1 and 36.83 years of age were acquired over a roughly 10-year period and used to construct the Mahalanobis distance from regional measures of white matter microstructure. Mahalanobis distances were significantly greater and more variable in the autistic individuals as compared to control participants, demonstrating increased atypicalities and variation in the group of individuals diagnosed with autism spectrum disorder. Distributions of multivariate measures were also found to provide greater discrimination and more sensitive delineation between autistic and typically developing individuals than conventional univariate measures, while also being significantly associated with observed traits of the autism group. These results help substantiate autism as a truly heterogeneous neurodevelopmental disorder, while also suggesting that collectively considering neuroimaging measures from multiple brain regions provides improved insight into the diversity of brain measures in autism that is not observed when considering the same regions separately. Distinguishing multidimensional brain relationships may thus be informative for identifying neuroimaging-based phenotypes, as well as help elucidate underlying neural mechanisms of brain variation in autism spectrum disorders.