Intra-articular infiltration analgesia for arthroscopic shoulder surgery: a systematic review and meta-analysis.

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.

Peri-articular infiltration analgesia for shoulder surgery: a systematic review and meta-analysis.

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.

Frequency of food group consumption and risk of allergic disease and sensitization in schoolchildren in urban and rural China.

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.

c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function.

Chromatin organization plays a key role in the regulation of gene expression. The evolutionarily conserved SWI/SNF complex is one of several multiprotein complexes that activate transcription by remodelling chromatin in an ATP-dependent manner. SWI2/SNF2 is an ATPase whose homologues, BRG1 and hBRM, mediate cell-cycle arrest; the SNF5 homologue, INI1/hSNF5, appears to be a tumour suppressor. A search for INI1-interacting proteins using the two-hybrid system led to the isolation of c-MYC, a transactivator. The c-MYC-INI1 interaction was observed both in vitro and in vivo. The c-MYC basic helix-loop-helix (bHLH) and leucine zipper (Zip) domains and the INI1 repeat 1 (Rpt1) region were required for this interaction. c-MYC-mediated transactivation was inhibited by a deletion fragment of INI1 and the ATPase mutant of BRG1/hSNF2 in a dominant-negative manner contingent upon the presence of the c-MYC bHLH-Zip domain. Our results suggest that the SWI/SNF complex is necessary for c-MYC-mediated transactivation and that the c-MYC-INI1 interaction helps recruit the complex.

Role of thromboxane A2-activated nonselective cation channels in hypoxic pulmonary vasoconstriction of rat.

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.

Inhibition of HIV-1 virion production by a transdominant mutant of integrase interactor 1.

Integase interactor 1 (INI1), also known as hSNF5, is a protein that interacts with HIV-1 integrase. We report here that a cytoplasmically localized fragment of INI1 (S6; aa183-294) containing the minimal integrase-interaction domain potently inhibits HIV-1 particle production and replication. Mutations in S6 or integrase that disrupt integrase-INI1 interaction abrogated the inhibitory effect. An integrase-deficient HIV-1 transcomplemented with integrase fused to Vpr was not affected by S6. INI1 was specifically incorporated into virions and was required for efficient HIV-1 particle production. These results indicate that INI1 is required for late events in the viral life cycle, and that ectopic expression of S6 inhibits HIV-1 replication in a transdominant manner via its specific interaction with integrase within the context of Gag-Pol, providing a novel strategy to control HIV-1 replication.

Differential recruitment of mechanisms for myogenic responses according to luminal pressure and arterial types.

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).

A model of Na+/H+ exchanger and its central role in regulation of pH and Na+ in cardiac myocytes.

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.

Identification of the large-conductance background K+ channel in mouse B cells as TREK-2.

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).

Stretch-activated non-selective cation channel: a causal link between mechanical stretch and atrial natriuretic peptide secretion.

The polypeptide hormone atrial natriuretic peptide (ANP) plays vital roles in maintaining blood volume and arterial blood pressure. The recognition of clinical benefits of ANP both in healthy and diseased heart identifies ANP as a potential candidate for therapeutic strategy in the treatment of heart disease. ANP is synthesized and stored in cardiac myocytes and it is released through the exocytosis of ANP granules both constitutively and in response to stimuli. It is well known that mechanical stretch is the predominant stimulus for ANP secretion. However, the mechanistic link between mechanical stimuli and exocytosis of ANP vesicles in single atrial myocyte has not yet been demonstrated. Over the last decade, compelling evidence suggested that stretch-activated ion channels might function as mechanosensors. We showed previously that direct stretch of single atrial myocyte using two micro-electrodes activated a non-selective cation channel (SAC). So far it is not known whether activation of SAC is involved in stretch-induced ANP secretion. The present article aims to give an overview of the mechanism of mechanical stretch-stimulated ANP secretion and describes an innovative technique to detect ANP secretion from isolated rat atrial myocytes with high time-resolution. Combined with capacitance measurement and patch-clamp technique in conjunction with in situ ANP bioassay, we were able to demonstrate that SAC in rat atrial myocytes acts as a mechanosensor to transduce stretch signals into the ANP secretion pathway.

Electrophysiological modelling of pulmonary artery smooth muscle cells in the rabbits--special consideration to the generation of hypoxic pulmonary vasoconstriction.

In vascular smooth muscle cells, it has been suggested that membrane potential is an important component that initiates contraction. We developed a mathematical model to elucidate the quantitative contributions of major ion currents [a voltage-gated L-type Ca2+ current (ICaL), a voltage-sensitive K+ current (IKV), a Ca2+-activated K+ current (IKCa) and a nonselective cation current (INSC)] to membrane potential. In order to typify the diverse nature of pulmonary artery smooth muscle cells (PASMCs), we introduced parameters that are not fixed (variable parameters). The population of cells with different parameters was constructed and the cells that have the electrophysiological properties of PASMCs were selected. The contributions of each membrane current were investigated by sensitivity analysis and modification of the current parameters. Consequently, IKV and INSC were found to be the most important currents that affect the membrane potential. The occurrence of depolarisation in hypoxic pulmonary vasoconstriction (HPV) was also examined. In hypoxia, IKV and IKCa were reduced, but the consequent depolarisation in simulation was not enough to initiate contractions. If we add an increase of INSC (2.5-fold), the calculated membrane potential was enough to induce contraction. From the results, we conclude that the balance of various ion channel activities determines the resting membrane potential of PASMCs and our model was successful in explaining the depolarisation in HPV. Therefore, this model can be a powerful tool to investigate the various electrical properties of PASMCs in both normal and pathological conditions.

Simulation of spontaneous action potentials of cardiomyocytes in pulmonary veins of rabbits.

Atrial fibrillation is the most prevalent arrhythmia, but the mechanisms by which it develops are not clear. Recently, over 90% of paroxysmal atrial fibrillation was found to be located inside the main pulmonary veins (PVs). We found that single cardiac myocytes isolated from the main PVs of rabbits generate spontaneous action potentials (SAP). We therefore assayed the electrical characteristics of these cardiomyocytes. Among the diverse ionic currents identified were INa, ICa,L, IK1, IKr, IKs, Ito, IKsus, Incx, Ipump, IKH and ICl,Ca. In contrast, IK1 was minimal, IKs could be detected only in the presence of 10 microM forskolin, and we were unable to detect If and ICa,T, the most important currents for pacemaking activity in sinoatrial node cells. To identify the main cause of SAP, we developed a model that can explain the electrical properties of these cardiomyocytes. After reconstructing the ionic currents based on experimental observations, we were able to use our model to successfully reconstruct the characteristics of the SAP of PV cardiomyocytes. The simulation showed that the major currents contributing to pacemaking depolarization were ICaL, IKr, a background current and Na+-K+ pump current. Deactivation kinetics of IKr was one of the major determinants of the rate of pacemaking depolarization. The steady state inactivation of Ito was shifted to the negative voltage and the activity of Ito was minimal in the range of the SAP. The major currents for the repolarization were IKr and Ipump. The amplitude of most currents in these cardiac myocytes was small and no currents did not exceed 30 pA during the SAP, indicating that slight activation of other inward or outward currents will have profound effects on the SAP. To our knowledge, this report is the first to show the simulation of SAP of PV cardiomyocytes. This model may help to study on the electrophysiological basis of paroxysmal atrial fibrillation originating from PVs.

Stretch-activated currents in cardiomyocytes isolated from rabbit pulmonary veins.

Evidence is growing of a relationship between atrial dilation and atrial fibrillation (AF), the most prevalent type of arrhythmia. Pulmonary veins, which are important ectopic foci for provoking AF, are of increasing interest in relation to the early development of AF. Here, using single cardiomyocytes isolated from rabbit pulmonary veins, we characterised the stretch-activated currents induced by swelling and axial mechanical stretching. Swelling induced both a stretch-activated nonselective cationic current (NSC) and a Cl(-) current. The swelling-induced Cl(-) current (I Cl,swell) was inhibited by DIDS, whereas the swelling-induced NSC (I NSC,swell) was inhibited by Gd3+. The cationic selectivity of the I NSC,swell was K+ >Cs+ >Na+ >Li+, whilst the PK/PNa, PCs/PNa, and PLi/PNa permeability ratios were 2.84, 1.86, and 0.85, respectively. Activation of the I NSC,swell was faster than that of the I Cl,swell. Given a high K+ concentration in the bath solution, the I NSC,swell showed limited amplitude (<-70 mV). Mechanical stretching induced an immediate Gd3+- and streptomycin-sensitive NSC (I NSC,stretch) that was permeable to Na+, K+, Cs+ and NMDG. Persistent stretching activated a DIDS-sensitive current (I Cl,stretch). The I NSC,stretch, but not the I NSC,swell, was completely blocked by 400 microM streptomycin; therefore, the two currents may not be associated with the same channel. In addition, the type of current induced may depend on the type of stretching. Thus, stretch-induced anionic and cationic currents are functionally present in the cardiomyocytes of the main pulmonary veins of rabbits, and they may have pathophysiological roles in the development of AF under stretched conditions.

Quality-of-life assessment in Chinese families with food-allergic children.

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.

Identifying uncontrolled asthma in young children: clinical scores or objective variables?

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.

Effects of mixed herbal extracts from parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix (KIOM-79) on cardiac ion channels and action potentials.

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.

Breast and Colorectal Cancer Screening Barriers Among Immigrants and Refugees: A Mixed-Methods Study at Three Community Health Centres in Toronto, Canada.

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.

Mechanosensitive nonselective cation channel facilitation by endothelin-1 is regulated by protein kinase C in arterial myocytes.

OBJECTIVE: The mechanosensitive nonselective cation channel (NSC(MS)) and endothelin-1 (ET-1) play critical roles in the regulation of vascular tone. This study was undertaken to investigate the effect of ET-1 on NSC(MS) and on the myogenic response of arteries. METHODS: Cell-attached patch-clamp techniques were applied to rabbit pulmonary and cerebral arterial smooth muscle cells using a 140 mM CsCl pipette and bath solutions (Ca(2+)-free, 1 mM EGTA). Myogenic responses were determined by video analysis of pressurized arteries. RESULTS: The application of negative pressures through the pipette activated NSC(MS), and this was augmented by bath application of ET-1 (1 pM-30 nM). ET-1 lowered the lowest pressure required for NSC(MS) activation. NSC(MS) facilitation by ET-1 was prevented by BQ-123 (1 microM, an ET(A) antagonist) but not by BQ-788 (1 microM, an ET(B) antagonist). Phorbol 12-myristate 13-acetate (PMA, 100 nM), a protein kinase C activator, also increased the activity of NSC(MS). ET-1- or PMA-induced facilitation of NSC(MS) was abolished by GF109203X (10 microM), a protein kinase C inhibitor. Video analysis of pressurized cerebral artery showed inhibition of the myogenic response by the NSC(MS) channel blockers GsMTx-4 (5 microM) and DIDS (3-100 microM). Treatment with ET-1 (10 pM) augmented the myogenic response and this was inhibited by DIDS (30 microM). CONCLUSION: Stimulation of ET-1 receptor (ET(A)) facilitates NSC(MS) via a protein kinase C-dependent signaling pathway in rabbit arterial myocytes. Our findings suggest that NSC(MS) play a role in the myogenic response and its augmentation by ET-1.

Role of stretch-activated channels on the stretch-induced changes of rat atrial myocytes.

The role of stretch-activated channels (SACs) on the stretch-induced changes of rat atrial myocytes was studied using a computer model that incorporated various ion channels and transporters including SACs. A relationship between the extent of the stretch and the activation of SACs was formulated in the model based on experimental findings to reproduce changes in electrical activity and Ca(2+) transients by stretch. Action potentials (APs) were significantly changed by the activation of SACs in the model simulation. The duration of the APs decreased at the initial fast phase and increased at the late slow phase of repolarisation. The resting membrane potential was depolarised from -82 to -70 mV. The Ca(2+) transients were also affected. A prolonged activation of SACs in the model gradually increased the amplitude of the Ca(2+) transients. The removal of Ca((2+)) permeability through SACs, however, had little effect on the stretch-induced changes in electrical activity and Ca(2+) transients in the control condition. In contrast, the removal of the Na(+) permeability nearly abolished these stretch-induced changes. Plotting the peaks of the Ca((2+)) transients during the activation of the SACs along a time axis revealed that they follow the time course of the Na(i)(+) concentration. The Ca((2+)) transients were not changed when the Na(i)(+) concentration was fixed to a control value (5.4mM). These results predicted by the model suggest that the influx of Na(+) rather than Ca(2+) through SACs is more crucial to the generation of stretch-induced changes in the electrical activity and associated Ca(2+) transients of rat atrial myocytes.