RESUMO
Phrenic-sparing analgesic techniques for shoulder surgery are desirable. Intra-articular infiltration analgesia is one promising phrenic-sparing modality, but its role remains unclear because of conflicting evidence of analgesic efficacy and theoretical concerns regarding chondrotoxicity. This systematic review and meta-analysis evaluated the benefits and risks of intra-articular infiltration in arthroscopic shoulder surgery compared with systemic analgesia or interscalene brachial plexus block. We sought randomised controlled trials comparing intra-articular infiltration with interscalene brachial plexus block or systemic analgesia (control). Cumulative 24-h postoperative oral morphine equivalent consumption was designated as the primary outcome. Secondary outcomes included visual analogue scale pain scores during the first 24 h postoperatively; time-to-first analgesic request; patient satisfaction; opioid-related side-effects; block-related adverse events; and any indicators of chondrotoxicity. Fifteen trials (863 patients) were included. Compared with control, intra-articular infiltration reduced 24-h postoperative analgesic consumption by a weighted mean difference (95%CI) of -30.9 ([-38.9 to -22.9]; p < 0.001). Intra-articular infiltration also reduced the weighted mean difference (95%CI) pain scores up to 12 h postoperatively, with the greatest reduction at 4 h (-2.2 cm [(-4.4 to -0.04]); p < 0.05). Compared with interscalene brachial plexus block, there was no difference in opioid consumption, but patients receiving interscalene brachial plexus block had better pain scores at 2, 4 and 24 h postoperatively. There was no difference in opioid- or block-related adverse events, and none of the trials reported chondrotoxic effects. Compared with systemic analgesia, intra-articular infiltration provides superior pain control, reduces opioid consumption and enhances patient satisfaction, but it may be inferior to interscalene brachial plexus block patients having arthroscopic shoulder surgery.
Assuntos
Analgesia/métodos , Ombro/cirurgia , Analgésicos Opioides/uso terapêutico , Artroscopia , Bloqueio do Plexo Braquial , Humanos , Injeções Intra-Articulares , Morfina/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/patologiaRESUMO
Effective analgesic alternatives to interscalene brachial plexus block are sought for shoulder surgery. Peri-articular infiltration analgesia is a novel, less invasive technique, but evidence surrounding its use is unclear. This systematic review and meta-analysis aims to evaluate the utility of peri-articular infiltration analgesia in shoulder surgery. We searched literature for trials comparing peri-articular infiltration analgesia with control or with interscalene brachial plexus block. Control groups received no intervention, placebo or systemic opioids. The primary outcome was cumulative oral morphine equivalent consumption during the first 24 h postoperatively. Secondary outcomes included: rest pain scores up to 48 h; risk of side-effects; and durations of post-anaesthetic care unit and hospital stay. Data were pooled with random-effects modelling. Seven trials (383 patients) were included. Compared with control, peri-articular infiltration analgesia reduced 24-h oral morphine consumption by a mean difference (95%CI) of -38.0 mg (-65.5 to -10.5; p = 0.007). It also improved pain scores up to 6 h, 36 h and 48 h, with the greatest improvement observed at 0 h (-2.4 (-2.7 to -1.6); p < 0.001). Peri-articular infiltration analgesia decreased postoperative nausea and vomiting by an odds ratio (95%CI) of 0.3 (0.1-0.7; p = 0.006). In contrast, peri-articular infiltration analgesia was not different from interscalene brachial plexus block for analgesic consumption, pain scores or side-effects. This review provides moderate evidence supporting peri-articular infiltration for postoperative analgesia following shoulder surgery. The absence of difference between peri-articular infiltration analgesia and interscalene brachial plexus block for analgesic outcomes suggests that these interventions are comparable, but further trials are needed to support this conclusion and identify the optimal peri-articular infiltration technique.
Assuntos
Analgesia/métodos , Manejo da Dor/métodos , Dor Pós-Operatória/tratamento farmacológico , Ombro/cirurgia , HumanosRESUMO
Mammography and fecal occult blood testing (FOBT) improve the detection, management, and prognosis of breast and colorectal cancer, respectively, but are underperformed in the recent immigrant and refugee population. We aimed to identify barriers to screening and potential solutions in this population. A mixed-methods study involving a retrospective chart review and focus group interviews was conducted, with data analyzed using univariate logistic regression and thematic analysis, respectively. Mammography completion was associated with greater time in Canada (p = 0.01) and region of origin (p = 0.04), while FOBT completion was associated with region of origin (p = 0.03). Barriers included time constraints, language and cultural differences, and poor interprofessional communication. This study of recent immigrants and refugees identifies barriers to screening and supports potential solutions including culturally-congruent peer workers, targeted screening workshops, and visual screening aids. Further work is needed to address the unique healthcare needs of this diverse and growing population.
Assuntos
Detecção Precoce de Câncer/estatística & dados numéricos , Emigrantes e Imigrantes/estatística & dados numéricos , Mamografia/estatística & dados numéricos , Sangue Oculto , Refugiados/estatística & dados numéricos , Idoso , Neoplasias da Mama/diagnóstico , Canadá , Neoplasias Colorretais/diagnóstico , Centros Comunitários de Saúde/estatística & dados numéricos , Características Culturais , Feminino , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Humanos , Relações Interprofissionais , Idioma , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/etnologia , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND: Diet is a potential determinant of allergic diseases. OBJECTIVE: To examine in schoolchildren the association between food intake and allergic diseases and determine whether there is effect of environment - rural vs. urban. METHODS: A questionnaire survey was performed in 11 473 children aged 7-12 years in 20 schools from urban Guangzhou and rural Shaoguan, China. A nested case-control group, 402 from Guangzhou and 349 from Shaoguan, was recruited. Food ingestion frequency data were collected. Serum-specific IgE to 34 food and airborne allergens was determined. Associations between food ingestion frequency and clinical outcomes were sought by logistic analyses. RESULTS: The prevalence of self-reported asthma (6.6% vs. 2.5%), rhinitis (23.2% vs. 5.3%) and eczema (34.1% vs. 25.9%) was significantly higher in Guangzhou subjects compared to Shaoguan, whereas prevalence of food hypersensitivity (9.7% vs. 9.2%) and food allergy (4.0% vs. 3.5%) was not significantly different. In this case-control study, seafood and fruits were two major food groups causing food hypersensitivity. Urban children consumed more milk, egg, chocolate, fruits, vegetable and cereals compared to rural children. Significantly higher percentage of Guangzhou children was sensitized to egg and milk, whereas more Shaoguan children were sensitized to seafood, nuts and seeds, fruit, vegetables, legumes and cereals. High consumption of milk (OR 2.604, 95 CI% 1.569-4.322, P < 0.001) and vegetables (OR 0.382, 95% CI 0.180-0.809, P = 0.012) were positively and reversely associated with asthma, respectively. CONCLUSION: Difference in prevalence of asthma but not food allergy was observed. Diets of schoolchildren are affected by disease-related modification and country's urbanization. High vegetable intake and low milk intake might protect against asthma.
Assuntos
Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/imunologia , Alimentos/efeitos adversos , População Rural , Estudantes , População Urbana , Estudos de Casos e Controles , Criança , China/epidemiologia , Dieta , Feminino , Alimentos/classificação , Inquéritos Epidemiológicos , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/epidemiologia , Hipersensibilidade/imunologia , Imunização , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Masculino , Razão de Chances , Prevalência , Risco , Fatores de RiscoRESUMO
Myeloid differentiation is blocked in acute myeloid leukemia (AML), but the molecular mechanisms are not well characterized. Meningioma 1 (MN1) is overexpressed in AML patients and confers resistance to all-trans retinoic acid-induced differentiation. To understand the role of MN1 as a transcriptional regulator in myeloid differentiation, we fused transcriptional activation (VP16) or repression (M33) domains with MN1 and characterized these cells in vivo. Transcriptional activation of MN1 target genes induced myeloproliferative disease with long latency and differentiation potential to mature neutrophils. A large proportion of differentially expressed genes between leukemic MN1 and differentiation-permissive MN1VP16 cells belonged to the immune response pathway like interferon-response factor (Irf) 8 and Ccl9. As MN1 is a cofactor of MEIS1 and retinoic acid receptor alpha (RARA), we compared chromatin occupancy between these genes. Immune response genes that were upregulated in MN1VP16 cells were co-targeted by MN1 and MEIS1, but not RARA, suggesting that myeloid differentiation is blocked through transcriptional repression of shared target genes of MN1 and MEIS1. Constitutive expression of Irf8 or its target gene Ccl9 identified these genes as potent inhibitors of murine and human leukemias in vivo. Our data show that MN1 prevents activation of the immune response pathway, and suggest restoration of IRF8 signaling as therapeutic target in AML.
Assuntos
Fatores Reguladores de Interferon/metabolismo , Leucemia Mieloide Aguda/prevenção & controle , Transdução de Sinais , Diferenciação Celular , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores , Ativação Transcricional , Proteínas Supressoras de Tumor/metabolismoRESUMO
The productivity decline in drug discovery and development is mainly caused by two factors; higher regulatory hurdles and low-hanging fruits being all picked. In addition, the recent target-based approach is thought to be increasing the price of innovation. Although target-based approach had many successes, a postreductionism method, which is systems biology, is on the rise. In this review, we discuss the foundations of two distinct approaches in finding a new drug.
RESUMO
Hypoxia-induced pulmonary vasoconstriction (HPV) is critical for matching of ventilation/perfusion in lungs. Although hypoxic inhibition of K(+) channels has been a leading hypothesis for depolarization of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia, pharmacological inhibition of K(+) channels does not induce significant contraction in rat pulmonary arteries. Because a partial contraction by thromboxane A(2) (TXA(2)) is required for induction of HPV, we hypothesize that TXA(2) receptor (TP) stimulation might activate depolarizing nonselective cation channels (NSCs). Consistently, we found that 5-10 nM U46619, a stable agonist for TP, was indispensible for contraction of rat pulmonary arteries by 4-aminopyridine, a blocker of voltage-gated K(+) channel (K(v)). Whole cell voltage clamp with rat PASMC revealed that U46619 induced a NSC current (I(NSC,TXA2)) with weakly outward rectifying current-voltage relation. I(NSC,TXA2) was blocked by ruthenium red (RR), an antagonist of the transient receptor potential vanilloid-related channel (TRPV) subfamily. 2-Aminoethoxydiphenyl borate, an agonist for TRPV1-3, consistently activated NSC channels in PASMCs. In contrast, agonists for TRPV1 (capsaicin), TRPV3 (camphor), or TRPV4 (α-PDD) rarely induced an increase in the membrane conductance of PASMCs. RT-PCR analysis showed the expression of transcripts for TRPV2 and -4 in rat PASMCs. Finally, it was confirmed that pretreatment with RR largely inhibited HPV in the presence of U46619. The pretreatment with agonists for TRPV1 (capsaicin) and TRPV4 (α-PDD) was ineffective as pretone agents for HPV. Taken together, it is suggested that the concerted effects of I(NSC,TXA2) activation and K(v) inhibition under hypoxia induce membrane depolarization sufficient for HPV. TRPV2 is carefully suggested as the TXA(2)-activated NSC in rat PASMC.
Assuntos
Hipóxia/metabolismo , Hipóxia/patologia , Canais Iônicos/fisiologia , Artéria Pulmonar/fisiologia , Receptores de Tromboxano A2 e Prostaglandina H2/fisiologia , Vasoconstrição/fisiologia , Animais , Capsaicina/farmacologia , Canais Iônicos/agonistas , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores de Tromboxano A2 e Prostaglandina H2/agonistasRESUMO
Sasang constitutional medicine (SCM) is a traditional form of medicine that is widely used in Korea to clinically diagnose and treat disease. The main characteristic of SCM is its classification of people according to physical constitution. The theory asserts that four different types of physical constitution exist: Taeyang, Soyang, Taeeum, and Soeum. One noticeable clinical observation in SCM is that Taeeum-type people are prone to obesity. Although extensive clinical investigations have shown this tendency in SCM, no scientific hypothesis has been proposed to delineate its mechanism. According to SCM theory, Taeeum-type people have a hypoactive lung system and a hyperactive liver system. In this paper, we propose a new hypothesis explaining this finding from a physiological viewpoint. A functional weakness in the lung system indicates intrinsic hypoactivity in the consumption of metabolic energy, therefore we deduced that the tendency can easily induce body weight gain via an increase in anabolism.
RESUMO
Glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP, glucose-dependent insulinotropic polypeptide) are produced in enteroendocrine L-cells and K-cells, respectively. They are known as incretins because they potentiate postprandial insulin secretion. Although unresponsiveness of type 2 diabetes (T2D) patients to GIP has now been reconsidered, GLP-1 mimetics and inhibitors of the GLP-1 degradation enzyme dipeptidyl peptidase (DPP)-4 have now been launched as drugs against T2D. The major roles of GLP-1 in T2D are reduction of appetite, gastric motility, glucagon secretion, enhancement of insulin secretion and ß-cell survival. For insulin secretion and peripheral insulin function, GLP-1 and its mimetics sensitise ß-cells to glucose; accelerate blood glucose withdrawal, in-cell glucose utilisation and glycogen synthesis in insulin-sensitive tissues; and assist in the function and survival of neurons mainly using glucose as an energy source. Taken together, GLP-1 acts to potentiate glucose availability of various cells or tissues to assist with their essential functions and/or survival. Herein, we review the signalling pathways and clinical relevance of GLP-1 in enhancing cellular glucose availability. On the basis of our recent research results, we also describe a mechanism that regulates GLP-1 for glucokinase activity. Because diabetic tissues including ß-cells resist glucose, GLP-1 may be useful for treating T2D.
Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Animais , Cálcio/metabolismo , Exocitose , Humanos , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/enzimologiaRESUMO
To clarify the mechanisms underlying the pancreatic ß-cell response to varying glucose concentrations ([G]), electrophysiological findings were integrated into a mathematical cell model. The Ca(2+) dynamics of the endoplasmic reticulum (ER) were also improved. The model was validated by demonstrating quiescent potential, burst-interburst electrical events accompanied by Ca(2+) transients, and continuous firing of action potentials over [G] ranges of 0-6, 7-18, and >19 mM, respectively. These responses to glucose were completely reversible. The action potential, input impedance, and Ca(2+) transients were in good agreement with experimental measurements. The ionic mechanisms underlying the burst-interburst rhythm were investigated by lead potential analysis, which quantified the contributions of individual current components. This analysis demonstrated that slow potential changes during the interburst period were attributable to modifications of ion channels or transporters by intracellular ions and/or metabolites to different degrees depending on [G]. The predominant role of adenosine triphosphate-sensitive K(+) current in switching on and off the repetitive firing of action potentials at 8 mM [G] was taken over at a higher [G] by Ca(2+)- or Na(+)-dependent currents, which were generated by the plasma membrane Ca(2+) pump, Na(+)/K(+) pump, Na(+)/Ca(2+) exchanger, and TRPM channel. Accumulation and release of Ca(2+) by the ER also had a strong influence on the slow electrical rhythm. We conclude that the present mathematical model is useful for quantifying the role of individual functional components in the whole cell responses based on experimental findings.
Assuntos
Cálcio/metabolismo , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Potenciais de Ação , Trifosfato de Adenosina/metabolismo , Animais , Membrana Celular/metabolismo , Simulação por Computador , Eletrofisiologia , Canais Iônicos/metabolismo , Camundongos , Canais de Cátion TRPM/metabolismoRESUMO
This study examined the mechanisms of hypertension in diabetes. We investigated the effects of serotonin (5-HT) on voltage-dependent K(+) (Kv) channel activity, vasoconstriction, 5-HT receptor expression levels, and the involvement of protein kinase C (PKC) in mesenteric arteries of Otsuka Long-Evans Tokushima fatty (OLETF) rats compared with Long-Evans Tokushima Otsuka (LETO) rats. Blood pressure, body weight, blood glucose level, and mesenteric arterial wall thickness were greater in OLETF rats. The 5-HT-induced vasoconstriction of mesenteric arteries was greater in OLETF rats than in LETO rats and inhibited by the 5-HT(2A) inhibitor inhibitor, ketanserin. The Kv currents in mesenteric arterial smooth muscle cells (MASMCs), determined using a perforated patch clamp technique, was inhibited by 1 mM 4-AP (42.5 +/- 4.1% vs. 63.5 +/- 2.3% in LETO vs. OLETF rats at +40 mV), but was insensitive to 1 mM TEA and 100 nM iberiotoxin. The inhibition of Kv current by 1 microM 5-HT in MASMCs was greater in OLETF rats than in LETO rats (17.1 +/- 2.2% vs. 33.2 +/- 2.7% in LETO vs. OLETF rats at +40 mV), and the inhibition was prevented by treatment with the PKCalpha- and beta- selective inhibitor, Gö6976. The expression level of 5-HT(2A), but not 5-HT(2B), receptor and the expression levels of total PKC, PKCbeta, and PKCepsilon, but not PKCalpha, were higher in the mesenteric arteries of OLETF rats compared with LETO rats. The enhanced expression of 5-HT(2A) receptor together with PKCbeta may promote mesenteric vasoconstriction and increase vascular resistance in OLETF rats.
Assuntos
Artérias Mesentéricas/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Ratos Endogâmicos OLETF , Serotonina/farmacologia , Animais , Diabetes Mellitus/metabolismo , Modelos Animais de Doenças , Hipertensão/metabolismo , Artérias Mesentéricas/citologia , Artérias Mesentéricas/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Ratos , Receptores de Serotonina/metabolismoRESUMO
Mechanosensitive nonselective cation channels (NSC(ms)), protein kinase C (PKC), and Rho kinase (ROCK) are suggested as underlying mechanisms for the myogenic contractile response (MR) to luminal pressure (P(lum)). Here we compared relative contributions from these mechanisms using pharmacological inhibitors in rabbit middle cerebral (RbCA), rat middle cerebral (RtCA), rat femoral (RtFA), and rat mesenteric (RtMA) small arteries. Inner diameters of pressurized arteries under various P(lum) were video-analyzed. 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS, 10 microM) was used as a blocker of NSC(ms). In general, RbCA and RtCA showed higher P(lum) sensitivity of MR than RtFA and RtMA. Ten micromolars of DIDS commonly decreased MRs more effectively at low P(lum) (40-60 mmHg) in all tested arteries except RtCA. In RbCA, PKC inhibitors (100 nM of Go6976 or Go6983) decreased the MR at relatively high P(lum) (80-100 mmHg) whereas ROCK inhibitor (Y-27632, 1 microM) showed a P(lum)-independent inhibition. In RtMA and RtCA, PKC inhibitors (Go6976 and Go6983) had no significant effect whereas Y-27632 generally inhibited the MR. In RtFA, neither PKC inhibitor nor Y-27632 alone affected MRs. Interestingly, in the presence of 10 microM DIDS, Go6983 and Y-27632 decreased the MR of RtFA. In RtMA, it was notable that the MR decreased spontaneously on repeated protocol of P(lum) increase, and the 'run-down' could be effective reversed by maxi-K(+) channel blocker (tetraethylammonium or iberiotoxin). In summary, our study shows the variability of MRs according to the arterial types in terms of their pressure sensitivity and underlying mechanisms that are recruited according to P(lum).
Assuntos
Artérias/metabolismo , Canais Iônicos/metabolismo , Mecanotransdução Celular , Proteína Quinase C/metabolismo , Vasoconstrição , Quinases Associadas a rho/metabolismo , Animais , Artérias/efeitos dos fármacos , Artérias/enzimologia , Cátions , Relação Dose-Resposta a Droga , Artéria Femoral/metabolismo , Técnicas In Vitro , Canais Iônicos/antagonistas & inibidores , Masculino , Mecanotransdução Celular/efeitos dos fármacos , Moduladores de Transporte de Membrana/farmacologia , Artérias Mesentéricas/metabolismo , Artéria Cerebral Média/metabolismo , Pressão , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Coelhos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Vasoconstrição/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
A new kinetic model of the Na(+)/H(+) exchanger (NHE) was developed by fitting a variety of major experimental findings, such as ion-dependencies, forward/reverse mode, and the turnover rate. The role of NHE in ion homeostasis was examined by implementing the NHE model in a minimum cell model including intracellular pH buffer, Na(+)/K(+) pump, background H(+), and Na(+) fluxes. This minimum cell model was validated by reconstructing recovery of pH(i) from acidification, accompanying transient increase in [Na(+)](i) due to NHE activity. Based on this cell model, steady-state relationships among pH(i), [Na(+)](I), and [Ca(2+)](i) were quantitatively determined, and thereby the critical level of acidosis for cell survival was predicted. The acidification reported during partial blockade of the Na(+)/K(+) pump was not attributed to a dissipation of the Na(+) gradient across the membrane, but to an increase in indirect H(+) production. This NHE model, though not adapted to the dimeric behavioral aspects of NHE, can provide a strong clue to quantitative prediction of degree of acidification and accompanying disturbance of ion homeostasis under various pathophysiological conditions.
Assuntos
Modelos Cardiovasculares , Miócitos Cardíacos/fisiologia , Trocadores de Sódio-Hidrogênio/metabolismo , Sódio/metabolismo , Acidose/metabolismo , Algoritmos , Animais , Membrana Celular/metabolismo , Sobrevivência Celular/fisiologia , Simulação por Computador , Homeostase/fisiologia , Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Espaço Intracelular/metabolismo , Íons/metabolismo , Cinética , Ramos Subendocárdicos/fisiologiaRESUMO
KIOM-79, a mixture of ethanol extracts from four herbs (parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix), has been developed for the potential therapeutic application to diabetic symptoms. Because screening of unexpected cardiac arrhythmia is compulsory for the new drug development, we investigated the effects of KIOM-79 on the action potential (AP) and various ion channel currents in cardiac myocytes. KIOM-79 decreased the upstroke velocity (V(max)) and plateau potential while slightly increased the duration of action potential (APD). Consistent with the decreased V(max) and plateau potential, the peak amplitude of Na+ current (I(Na)) and Ca2+ current (I(Ca,L)) were decreased by KIOM-79. KIOM-79 showed dual effects on hERG K+ current; increase of depolarization phase current (I(depol)) and decreased tail current at repolarization phase (I(tail)). The increase of APD was suspected due to the decreased I(tail). In computer simulation, the change of cardiac action potential could be well simulated based on the effects of KIOM-79 on various membrane currents. As a whole, the influence of KIOM-79 on cardiac ion channels are minor at concentrations effective for the diabetic models (0.1-10 microg/mL). The results suggest safety in terms of the risk of cardiac arrhythmia. Also, our study demonstrates the usefulness of the cardiac computer simulation in screening drug-induced long-QT syndrome.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Canais Iônicos/fisiologia , Miócitos Cardíacos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Linhagem Celular , Simulação por Computador , Feminino , Zingiber officinale/química , Humanos , Síndrome do QT Longo/diagnóstico , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Miócitos Cardíacos/fisiologia , Técnicas de Patch-Clamp , Pueraria/química , Ramos Subendocárdicos/efeitos dos fármacos , Ramos Subendocárdicos/fisiologia , Coelhos , Ratos , Ratos Sprague-DawleyRESUMO
Mouse B cells and their cell line (WEHI-231) express large-conductance background K(+) channels (LK(bg)) that are activated by arachidonic acids, characteristics similar to TREK-2. However, there is no evidence to identify the molecular nature of LK(bg); some properties of LK(bg) were partly different from the reported results of TREK type channels. In this study, we compared the properties of cloned TREK-2 and LK(bg) in terms of their sensitivities to ATP, phosphatidylinositol 4,5-bisphosphate (PIP(2)), intracellular pH (pH(i)), and membrane stretch. Similar to the previous findings of LK(bg), TREK-2 showed spontaneous activation after membrane excision (i-o patch) and were inhibited by MgATP or by PIP(2). The inhibition by MgATP was prevented by wortmannin, suggesting membrane-delimited regulation of TREKs by phosphoinositide (PI) kinase. The same was observed with the property of LK(bg); the activation of TREK-2 by membrane stretch was suppressed by U73122 (PLC inhibitor). As with the known properties of TREK-2, LK(bg) were activated by acidic pH(i) and inhibited by PKC activator. Finally, we confirmed the expression of TREK-2 in WEHI-231 by using RT-PCR and immunoblot analyses. The amplitude of background K(+) current and the TREK-2 expression in WEHI-231 were commonly decreased by genetic knockdown of TREK-2 using small interfering RNA. The downregulation of TREK-2 attenuated Ca(2+)-influx induced by arachidonic acid in WEHI-231. As a whole, these results strongly indicate that TREK-2 encodes LK(bg) in mouse B cells. We also newly suggest that the low activity of TREK-2 in intact cells is due to the inhibition by intrinsic PIP(2).
Assuntos
Linfócitos B/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Potássio/metabolismo , 1-Fosfatidilinositol 4-Quinase/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Ácido Araquidônico/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/enzimologia , Cálcio/metabolismo , Linhagem Celular , Forma Celular , Clonagem Molecular , Humanos , Concentração de Íons de Hidrogênio , Mecanotransdução Celular , Potenciais da Membrana , Camundongos , Fosfatidilinositol 4,5-Difosfato/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Canais de Potássio de Domínios Poros em Tandem/efeitos dos fármacos , Canais de Potássio de Domínios Poros em Tandem/genética , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Ratos , Transfecção , Fosfolipases Tipo C/metabolismoRESUMO
OBJECTIVE: Several international asthma guidelines emphasize the importance of assessing asthma control. However, there is limited data on the usefulness of available assessment tools in indicating disease control in young asthmatics. This study investigated the ability of Chinese version of Childhood Asthma Control Test (C-ACT) and other disease-related factors in identifying uncontrolled asthma (UA) in young children. METHODS: During the same clinic visit, asthma patients 4 to 11 years of age completed C-ACT and underwent exhaled nitric oxide and spirometric measurements. Blinded to these results, the same investigator assigned Disease Severity Score (DSS) and rated asthma control according to Global Initiative for Asthma. RESULTS: The mean (SD) age of 113 recruited patients was 9.1 (2.0) years, and 35% of them had UA. C-ACT, DSS and forced expiratory volume in 1 second (FEV(1)) differed among patients with different control status (p < 0.001 for C-ACT and DSS; p = 0.014 for FEV(1)). Logistic regression confirmed that UA was associated with DSS (p < 0.001), PEF (p = 0.002), C-ACT (p = 0.011), and FEV(1) (p = 0.012). By ROC analysis, C-ACT and DSS were the best predictors for UA (p < 0.001), followed by PEF (p = 0.006) and FEV(1) (p = 0.007). When analyzed by the Classification and Regression Tree (CART) approach, the sequential use of DSS and C-ACT had 77% sensitivity and 84% specificity in identifying UA. CONCLUSIONS: C-ACT is better than objective parameters in identifying young Chinese children with UA.
Assuntos
Asma/diagnóstico , Asma/tratamento farmacológico , Asma/fisiopatologia , Testes Respiratórios , Criança , Pré-Escolar , China , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Fluxo Máximo Médio Expiratório/fisiologia , Óxido Nítrico/análise , Pico do Fluxo Expiratório/fisiologia , Curva ROC , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Inquéritos e Questionários , Capacidade Vital/fisiologiaRESUMO
BACKGROUND: Caucasian families with food-allergic children have a compromised quality of life (QoL) for fear of life-threatening food reactions. Such data are limited in Asian children. Based on our recent questionnaire-based survey, 8.1% of young children recruited from local nurseries and kindergartens had parent-reported adverse food reactions (AFRs). OBJECTIVE: This study tested the robustness of the Chinese Food Allergy Quality of Life-Parental Burden questionnaire (FAQL-PB) and assessed QoL in families with childhood AFR. The correlations among FAQL-PB items were evaluated by factor analysis. METHODS: Two hundred and ninety-eight of 3677 children aged 2-7 years had parent-reported AFR, and 197 (66.1%) of them completed the 17 items of our self-administered FAQL-PB. Six hundred and thirty-nine (18.9%) children without AFR returned this questionnaire. Factor analysis was used to delineate the inter-relationship among the FAQL-PB items. RESULTS: Cronbach alpha for our Chinese FAQL-PB was 0.976, and the median (interquartile range) FAQL-PB scores of children with and without parent-reported AFR were 0.10 (0.02-0.32) and 0 (0-0.18), respectively (P < 0.001). Factor analysis confirmed excellent correlations between FAQL-PB items. The 17 items were clustered into two factors, which explained 79.7% of the total variance. Among children with AFR, FAQL-PB scores increased with increasing numbers of foods that caused AFRs (P < 0.001 for trend). Thirty (15.2%) children had impaired QoL, defined as average item FAQL-PB score > or = 0.5. Impaired QoL was associated with AFR that was caused by >3 foods (P = 0.001), current food avoidance (P = 0.005) and AFR caused by peanut (P = 0.003), egg (P = 0.011) and cow's milk (P = 0.028), and current flexural dermatitis (P = 0.011). CONCLUSIONS: FAQL-PB is a robust measure of AFR-specific parental QoL, which is impaired in Chinese children with parent-reported AFR. Flexural dermatitis, current food avoidance and AFR caused by multiple foods are independent risk factors for lower parental QoL.