Medical teachers' experience of emergency remote teaching during the COVID-19 pandemic: a cross-institutional study.

BACKGROUND: The COVID-19 pandemic and the consequent social distancing measures caused unprecedented disruption for medical and healthcare education. This study examined medical teachers' experience with emergency remote teaching during the pandemic and their acceptance of online teaching after the pandemic. METHODS: In this sequential mixed methods study, online surveys were disseminated to teachers (n = 139) at two Asia-Pacific medical schools to evaluate their experience with emergency remote teaching during the pandemic. Subsequently, in-depth interviews were conducted with teachers from both institutions (n = 13). Each interviewee was classified into an adopter category based on Rogers' Diffusion of Innovations Theory. Interview transcripts were analyzed thematically, and the descriptive themes were mapped to broader themes partly based on the Technology Acceptance Model and these included: (i) perceived usefulness of online teaching, (ii) perceived ease of delivering online teaching, (iii) experience with institutional support and (iv) acceptance of online teaching after the pandemic. RESULTS: Our participants described accounts of successes with their emergency remote teaching and difficulties they experienced. In general, most participants found it difficult to deliver clinical skills teaching remotely and manage large groups of students in synchronous online classes. With regards to institutional support, teachers with lower technological literacy required just-in-time technical support, while teachers who were innovative in their online teaching practices found that IT support alone could not fully address their needs. It was also found that teachers' acceptance of online teaching after the pandemic was influenced by their belief about the usefulness of online teaching. CONCLUSIONS: This study demonstrated that our participants managed to adapt to emergency remote teaching during this pandemic, and it also identified a myriad of drivers and blockers to online teaching adoption for medical teachers. It highlights the need for institutes to better support their teaching staff with diverse needs in their online teaching.

Heart-type fatty acid binding protein (H-FABP) as a biomarker for acute myocardial injury and long-term post-ischemic prognosis.

Acute myocardial infarction (AMI) is a life-threatening event. Even with timely treatment, acute ischemic myocardial injury and ensuing ischemia reperfusion injury (IRI) can still be difficult issues to tackle. Apart from radiological and other auxiliary examinations, laboratory tests of applicable cardiac biomarkers are also necessary for early diagnosis and close monitoring of this disorder. Heart-type fatty acid binding protein (H-FABP), which mainly exists inside cardiomyocytes, has recently emerged as a potentially promising biomarker for myocardial injury. In this review we discuss the sensitivity and specificity of H-FABP in the assessment of myocardial injury and IRI, especially in the early stage, and its long-term prognostic value in comparison with other commonly used cardiac biomarkers, including myoglobin (Mb), cardiac troponin I (cTnI), creatine kinase MB (CK-MB), C-reactive protein (CRP), glycogen phosphorylase isoenzyme BB (GPBB), and high-sensitivity cardiac troponin T (hs-cTnT). The potential and value of combined application of H-FABP with other biomarkers are also discussed. Finally, the prospect of H-FABP is summarized; several technical issues are discussed to facilitate wider application of H-FABP in clinical practice.

Remifentanil Preconditioning Reduces Postischemic Myocardial Infarction and Improves Left Ventricular Performance via Activation of the Janus Activated Kinase-2/Signal Transducers and Activators of Transcription-3 Signal Pathway and Subsequent Inhibition of Glycogen Synthase Kinase-3ß in Rats.

OBJECTIVES: Remifentanil preconditioning attenuates myocardial ischemia reperfusion injury, but the underlying mechanism is incompletely understood. The Janus activated kinase-2 (JAK2)/signal transducers and activators of transcription-3 (STAT3) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways are critical in both ischemic and pharmacologic preconditioning cardioprotection, which involve the inactivation of glycogen synthase kinase-3ß. We hypothesized that remifentanil preconditioning confers cardioprotection via the JAK2/STAT3 and/or PI3K/Akt activation-mediated glycogen synthase kinase-3ß inhibition. DESIGN: Pharmacologic intervention. SETTING: Research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: In vivo and in vitro treatments. MEASUREMENTS AND MAIN RESULTS: Male Sprague-Dawley rats (n = 6 per group) were sham operated or subjected to myocardial ischemia reperfusion injury. The JAK2 inhibitor AG490 (3 mg/kg), the PI3K inhibitor wortmannin (15 µg/kg), or the glycogen synthase kinase-3ß inhibitor SB216763 (600 µg/kg) were given before inducing in vivo myocardial ischemia reperfusion injury achieved by occluding coronary artery for 30 minutes followed by 120 minutes of reperfusion in the absence or presence of remifentanil preconditioning (6 µg/kg/min). Also, isolated rat hearts were Langendorff perfused and subjected to 30 minutes of global ischemia and 120 minutes of reperfusion without or with remifentanil preconditioning (100 ng/mL) in the presence or absence of AG490 and/or SB216763. Isolated rat cardiomyocytes and H9C2 cells were subjected to hypoxia/reoxygenation alone or in combination with AG490 (100 µM), wortmannin (100 nM), or SB216763 (3 µM) without or with remifentanil preconditioning (2.5 µM). Remifentanil preconditioning reduced postischemic myocardial infarction and hemodynamic dysfunction induced by myocardial ischemia reperfusion injury concomitant with increased phosphorylation of STAT3 at tyr-705 (p-STAT3) and glycogen synthase kinase-3ß but not Akt. AG490 but not wortmannin cancelled remifentanil preconditioning cardioprotection, and SB216763 restored it despite the presence of AG490. In Langendorff-perfused hearts, AG490-mediated cancellation of remifentanil preconditioning cardioprotection in attenuating postischemic myocardial infarction and creatinine kinase-MB release was reverted by concomitant administration of SB216763. Remifentanil preconditioning also attenuated posthypoxic cardiomyocyte injury and increased p-STAT3 and glycogen synthase kinase-3ß in isolated primary cardiomyocytes and H9C2 cells. STAT3 gene knockdown with specific synthetic RNA cancelled remifentanil preconditioning cardioprotection, whereas glycogen synthase kinase-3ß gene knockdown, which per se did not affect STAT3 under hypoxia/reoxygenation condition, preserved remifentanil preconditioning cardioprotection regardless of STAT3 abrogation. CONCLUSIONS: Remifentanil preconditioning confers cardioprotection primarily via activation of JAK2/STAT3 signaling that can function independent of PI3K/Akt activation. Glycogen synthase kinase-3ß is a critical downstream effector of remifentanil preconditioning cardioprotection.

Dexmedetomidine Combined with General Anesthesia Provides Similar Intraoperative Stress Response Reduction When Compared with a Combined General and Epidural Anesthetic Technique.

BACKGROUND: Epidural anesthesia may attenuate the sympathetic hyperactivity and stress response from surgery. In this study, we compared the stress response, hemodynamic variables, and recovery profiles of patients undergoing total IV anesthesia (TIVA) and intraoperative dexmedetomidine with those receiving epidural anesthesia and TIVA. METHODS: Ninety patients undergoing elective open gastrectomy under TIVA were recruited. The dexmedetomidine group (group D, n = 30) received IV dexmedetomidine 0.6 µg/kg before the induction of general anesthesia, followed by dexmedetomidine 0.4 µg/kg/h until peritoneal closure. The control group (group C, n = 30) received volume-matched normal saline infusion as placebo. The epidural group (group E, n = 30) received epidural anesthesia with 0.375% ropivacaine combined with TIVA. The hemodynamic variables and recovery characteristics during emergence were evaluated. Blood samples for norepinephrine (NE), epinephrine (E), cortisol (Cor), and cytokines (tumor necrosis factor-α [TNF-α], interleukin [IL]-6, and IL-10) were obtained before the administration of dexmedetomidine or epidural anesthesia (baseline), immediately after tracheal intubation, upon incision, at the time of celiac exploration, and at tracheal extubation. RESULTS: Compared with group E, there were no differences in the plasma concentration levels of NE, E, Cor, and cytokines (TNF-α, IL-6, and IL-10) in group D at all time points. The levels of NE and E in groups D and E were significantly lower than that in group C, at all time points following induction (all P < 0.0001 except at incision which were P = 0.001 and P = 0.004), and the level of Cor in groups D and E was significantly lower than that in group C at celiac exploration (P = 0.017 and P = 0.019) and immediately after tracheal extubation (P < 0.0001). The levels of TNF-α, IL-6, and IL-10 increased after the celiac exploration in the 3 groups. The levels of plasma TNF-α, IL-6, and IL-6/IL-10 ratio were higher in group C than in groups D and E at celiac exploration and tracheal extubation (all P < 0.0001 except at celiac exploration which were P = 0.005 and P =0.038 for TNF-α and P = 0.049 and P = 0.038 for IL-6/IL-10 ratio). In group D, the heart rate was significantly slower after commencing dexmedetomidine and remained significantly slower throughout the operative course (all P < 0.0001 except at tracheal extubation which was P = 0.032). The number of patients who required intervention because of intraoperative hypotension was significantly higher in group E (36.7%) compared with groups D and C (13.3% and 10.0%) (P = 0.037, P = 0.015). The times to eye opening and tracheal extubation were similar in all groups. There were fewer incidences of agitation in group D (6.7 %) than in group C (26.6%) (P = 0.038). CONCLUSIONS: When used in conjunction with TIVA, intraoperative dexmedetomidine blunts surgical stress responses to an extent comparable to combined epidural and general anesthesia without compromising hemodynamic stability and with minimal adverse effects during the intraoperative period.

Methylglyoxal-induced neuroinflammatory response in in vitro astrocytic cultures and hippocampus of experimental animals.

Diabetes mellitus is characterized by chronic hyperglycemia and its diverse complications. Hyperglycemia is associated with inflammatory responses in different organs and diabetic patients have a higher risk of developing neurodegenerative disorders. Methylglyoxal is a reactive advanced glycation end product precursor that accumulates in diabetic patients. It induces various stress responses in the central nervous system and causes neuronal dysfunction. Astrocytes are actively involved in maintaining neuronal homeostasis and possibly play a role in protecting the brain against neurodegeneration. However it is not clear whether methylglyoxal exerts any adverse effects towards these astrocytes. In the present study we investigated the effects of methylglyoxal in astrocytic cultures and hippocampi of experimental animals. The cells from the astrocytic line DITNC1 were treated with methylglyoxal for 1 to 24 h. For the in vivo model, 3 months old C57BL/6 mice were treated with methylglyoxal solution for 6 weeks by intraperitoneal injection. Following the treatment, both astrocytes and hippocampi were harvested for MTT assay, Western blot and real time PCR analyses. We found that methylglyoxal induced astrogliosis in DITNC1 astrocytic cultures and C57BL/6 mice. Further, activation of the pro-inflammatory JNK signaling pathway and its downstream effectors c-Jun were observed. Furthermore, increased gene expression of pro-inflammatory cytokines and astrocytic markers were observed from real time PCR analyses. In addition, inhibition of JNK activities resulted in down-regulation of TNF-α gene expression in methylglyoxal treated astrocytes. Our results suggest that methylglyoxal may contribute to the progression of diabetes related neurodegeneration through JNK pathway activation in astrocytes and the subsequent neuroinflammatory responses in the central nervous system.

Propofol ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction via heme oxygenase-1/signal transducer and activator of transcription 3 signaling pathway in rats.

OBJECTIVES: Heme oxygenase-1 is inducible in cardiomyocytes in response to stimuli such as oxidative stress and plays critical roles in combating cardiac hypertrophy and injury. Signal transducer and activator of transcription 3 plays a pivotal role in heme oxygenase-1-mediated protection against liver and lung injuries under oxidative stress. We hypothesized that propofol, an anesthetic with antioxidant capacity, may attenuate hyperglycemia-induced oxidative stress in cardiomyocytes via enhancing heme oxygenase-1 activation and ameliorate hyperglycemia-induced cardiac hypertrophy and apoptosis via heme oxygenase-1/signal transducer and activator of transcription 3 signaling and improve cardiac function in diabetes. DESIGN: Treatment study. SETTING: Research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: In vivo and in vitro treatments. MEASUREMENTS AND MAIN RESULTS: At 8 weeks of streptozotocin-induced type 1 diabetes in rats, myocardial 15-F2t-isoprostane was significantly increased, accompanied by cardiomyocyte hypertrophy and apoptosis and impaired left ventricular function that was coincident with reduced heme oxygenase-1 activity and signal transducer and activator of transcription 3 activation despite an increase in heme oxygenase-1 protein expression as compared to control. Propofol infusion (900 µg/kg/min) for 45 minutes significantly improved cardiac function with concomitantly enhanced heme oxygenase-1 activity and signal transducer and activator of transcription activation. Similar to the changes seen in diabetic rat hearts, high glucose (25 mmol/L) exposure for 48 hours led to cardiomyocyte hypertrophy and apoptosis, both in primary cultured neonatal rat cardiomyocytes and in H9c2 cells compared to normal glucose (5.5 mmol/L). Hypertrophy was accompanied by increased reactive oxygen species and malondialdehyde production and caspase-3 activity. Propofol, similar to the heme oxygenase-1 inducer cobalt protoporphyrin, significantly increased cardiomyocyte heme oxygenase-1 and p-signal transducer and activator of transcription protein expression and heme oxygenase-1 activity and attenuated high-glucose-mediated cardiomyocyte hypertrophy and apoptosis and reduced reactive oxygen species and malondialdehyde production (p < 0.05). These protective effects of propofol were abolished by heme oxygenase-1 inhibition with zinc protoporphyrin and by heme oxygenase-1 or signal transducer and activator of transcription 3 gene knockdown. CONCLUSIONS: Heme oxygenase-1/signal transducer and activator of transcription 3 signaling plays a critical role in propofol-mediated amelioration of hyperglycemia-induced cardiomyocyte hypertrophy and apoptosis, whereby propofol improves cardiac function in diabetic rats.

Time to adequate oxygenation following ventilation using the Enk oxygen flow modulator versus a jet ventilator via needle cricothyrotomy in rabbits.

INTRODUCTION: Limited information is available on the management of the 'cannot intubate, cannot ventilate' (CICV) situation in infants. We compared the time to achieve adequate oxygenation following rescue ventilation using the Enk oxygen flow modulator (OFM) with a jet ventilator in a simulated CICV situation using the rabbit as an infant respiratory model. METHODS: Following institutional ethics committee approval, needle cricothyrotomy was performed under direct vision in nine anesthetized rabbits following surgical exposure of the larynx. After ensuring adequate level of anesthesia and analgesia, and confirming proper positioning of the 18G cannula, apnea was induced by the administration of myorelaxant and the SpO2 was allowed to drop to 75% before initiating rescue ventilation via either the OFM or jet ventilator. RESULTS: Five rabbits were ventilated with the OFM and four with the jet ventilator. Ventilation was maintained with either device for 15 min. All rabbits were successfully rescued using either device. There was no statistical difference in the time required for SpO2 to return to 80%, 85%, 90%, and 95%. CONCLUSIONS: Both devices facilitated successful rescue ventilation through a needle cricothyrotomy.

Susceptibility to myocardial ischemia reperfusion injury at early stage of type 1 diabetes in rats.

BACKGROUND: Large body of evidences accumulated in clinical and epidemiological studies indicate that hearts of diabetic subjects are more sensitive to ischemia reperfusion injury (IRI), which results in a higher rate of mortality at post-operation than that of non-diabetes. However, experimental results are equivocal and point to either increased or decreased susceptibility of the diabetic hearts to IRI, especially at the early stage of the disease. The present study was designed to test the hypothesis that the duration/severity of the indexed ischemia is a major determinant of the vulnerability to myocardial IRI at early stage of diabetes. METHODS: Four weeks streptozotocin (STZ)-induced diabetic (D) and non-diabetic (C) Sprague-Dawley rats were randomly assigned to receive 30 or 45 min of left anterior descending artery ligation followed by 2 or 3 hours of reperfusion, respectively. Cardiac function was recorded by using Pressure-Volume (PV) conduction system. Myocardial infarct size was determined with triphenyltetrazolium chloride staining. Plasma Creatine kinase-MB (CK-MB), Lactate dehydrogenase (LDH) release, myocardial nitric oxide(NO) content and nitrotyrosine formation, 15-F(2t)-Isoprostane and plasma superoxide dismutase (SOD) were measured with colorimetric assays. Cardiomyocyte apoptosis was assessed by TUNEL staining. Myocardial TNFα, Caspase-3, STAT3, Akt, and GSK-3ß were determined by Western blotting. RESULTS: Prolongation of ischemia but not reperfusion from 30 min to 45 min significantly increased infarct size in D compared to C rats (P < 0.05), accompanied with significantly increased plasma CK-MB (P < 0.05). Prolongation of the duration of either ischemia or reperfusion significantly increased plasma LDH release and myocardial 15-F(2t)-Isoprostane and reduced plasma SOD activity, with concomitant reduction of myocardial NO and increase of nitrotyrosine formation in D relative to C (P < 0.05). Prolongation of ischemia and reperfusion significantly reduced left ventricular ejection fraction and increased the peak rate of pressure, accompanied with increased end systolic pressure in D relative to C rats (P < 0.05) but reduced phosphorylations of myocardial STAT3 at site Ser727 and Akt at site Ser473 as well as GSK-3ß at Ser 9 (P < 0.05). CONCLUSIONS: Diabetic hearts, even at early stage of the disease are more sensitive to IRI, and this increased severity of post-ischemic myocardial injury depends more on the duration of ischemia than that of reperfusion.

PKCß inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfunction in rats with streptozotocin-induced diabetes.

Oxidative stress plays critical roles in the development of diabetic cardiovascular complications, including myocardial hypertrophy. The ß isoform of PKC (protein kinase C) is preferentially overexpressed in the myocardium of diabetic subjects accompanied with increased activation of the pro-oxidant enzyme NADPH oxidase, which may exacerbate oxidative stress. We hypothesized that myocardial PKCß is a major upstream mediator of oxidative stress in diabetes and that PKCß inhibition can attenuate myocardial hypertrophy and dysfunction. Control or streptozotocin-induced diabetic rats were treated with the selective PKCß inhibitor RBX (ruboxistaurin; 1 mg/kg of body weight per day) or the antioxidant NAC (N-acetylcysteine) for 4 weeks. LV (left ventricular) dimensions and functions were detected by echocardiography. 15-F2t-isoprostane (a specific index of oxidative stress) and myocardial activities of superoxide dismutase as well as protein levels of NADPH oxidase were assessed by immunoassay or Western blotting. Echocardiography revealed that the LV mass/body weight ratio was significantly increased in diabetic rats (P<0.01 compared with the control group) in parallel with the impaired LV relaxation. A significant increase in cardiomyocyte cross-sectional area was observed in diabetic rats accompanied by an increased production of O2- (superoxide anion) and 15-F2t-isoprostane (all P<0.05 compared with the control group). RBX normalized these changes with concomitant inhibition of PKCß2 activation and prevention of NADPH oxidase subunit p67phox membrane translocation and p22phox overexpression. The effects of RBX were comparable with that of NAC, except that NAC was inferior to RBX in attenuating cardiac dysfunction. It is concluded that RBX can ameliorate myocardial hypertrophy and dysfunction in diabetes, which may represent a novel therapy in the prevention of diabetic cardiovascular complications.

Virtual ER, a Serious Game for Interprofessional Education to Enhance Teamwork in Medical and Nursing Undergraduates: Development and Evaluation Study.

BACKGROUND: Engaging students in interprofessional education for higher order thinking and collaborative problem-solving skills is challenging. This study reports the development of Virtual ER, a serious game played on a virtual platform, and how it can be an innovative way for delivering interprofessional education to medical and nursing undergraduates. OBJECTIVE: We report the development of a serious online game, Virtual ER, and evaluate its effect on teamwork enhancement and clinical competence. We also explore if Virtual ER can be an effective pedagogical tool to engage medical and nursing students with different learning styles. METHODS: Virtual ER is a custom-made, learning outcome-driven, case-based web app. We developed a game performance scoring system with specific mechanisms to enhance serious gaming elements. Sixty-two students were recruited from our medical and nursing programs. They played the games in teams of 4 or 5, followed by an instructor-led debriefing for concept consolidation. Teamwork attitudes, as measured by the Human Factors Attitude Survey, were compared before and after the game. Learning style was measured with a modified Honey and Mumford learning style questionnaire. RESULTS: Students were satisfied with Virtual ER (mean satisfaction score 5.44, SD 0.95, of a possible 7). Overall, Virtual ER enhanced teamwork attitude by 3.02 points (95% CI 1.15-4.88, P=.002). Students with higher scores as activists (estimate 9.09, 95% CI 5.17-13.02, P<.001) and pragmatists (estimate 5.69, 95% CI 1.18-10.20, P=.01) had a significantly higher degree of teamwork attitude enhancement, while students with higher scores as theorists and reflectors did not demonstrate significant changes. However, there was no difference in game performance scores between students with different learning styles. CONCLUSIONS: There was considerable teamwork enhancement after playing Virtual ER for interprofessional education, in particular for students who had activist or pragmatist learning styles. Serious online games have potential in interprofessional education for the development of 21st century life skills. Our findings also suggest that Virtual ER for interprofessional education delivery could be expanded locally and globally.

Synergy of isoflurane preconditioning and propofol postconditioning reduces myocardial reperfusion injury in patients.

Either isoflurane preconditioning or high-dose propofol treatment has been shown to attenuate myocardial IRI (ischaemia/reperfusion injury) in patients undergoing CABG (coronary artery bypass graft) surgery. It is unknown whether isoflurane and propofol may synergistically attenuate myocardial injury in patients. The present study investigated the efficacy of IsoPC (isoflurane preconditioning), propofol treatment (postconditioning) and their synergy in attenuating postischaemic myocardial injury in patients undergoing CABG surgery using CPB (cardiopulmonary bypass). Patients (n = 120) selected for CABG surgery were randomly assigned to one of four groups (n = 30 each). After induction, anaesthesia was maintained either with fentanyl and midazolam (control; group C); with propofol at 100 µg x kg(-1) of body weight x min(-1) before and during CPB followed by propofol at 60 µg x kg(-1) of body weight x min(-1) for 15 min after aortic declamping (group P); with isoflurane 1-1.5% end tidal throughout the surgery (group I) or with isoflurane 1-1.5% end tidal before CPB and switching to propofol at 100 µg x kg(-1) of body weight x min(-1) during CPB followed by propofol at 60 µg x kg(-1) of body weight x min(-1) for 15 min after aortic declamping (group IP, i.e. IsoPC plus propofol postconditioning). A joint isoflurane and propofol anaesthesia regimen synergistically reduced plasma levels of cTnI (cardiac troponin I) and CK-MB (creatine kinase MB) and f-FABP (heart-type fatty acid-binding protein) (all P < 0.05 compared with control, group P or group I) and facilitated postoperative myocardial functional recovery. During reperfusion, myocardial tissue eNOS (endothelial NO synthase) protein expression in group IP was significantly higher, whereas nitrotyrosine protein expression was lower than those in the control group. In conclusion, a joint isoflurane preconditioning and propofol anaesthesia regimen synergistically attenuated myocardial reperfusion injury in patients.

Remifentanil preconditioning reduces hepatic ischemia-reperfusion injury in rats via inducible nitric oxide synthase expression.

BACKGROUND: Opioid preconditioning against ischemia reperfusion injury has been well studied in myocardial and neuronal tissues. The objective of this study was to determine whether remifentanil could attenuate hepatic injury and to investigate the mechanisms. METHODS: A rat model of hepatic ischemia reperfusion injury and a hepatocyte hypoxia reoxygenation (HR) injury model were used, respectively, in two series of experiments. Remifentanil was administered before ischemia or hypoxia and the experiments were repeated with previous administration of naloxone, L-arginine and N-ω-nitro-L-arginine methyl ester, a nonselective opioid receptor antagonist, a nitric oxide donor, and nitric oxide synthase (NOS) inhibitor, respectively. Serum aminotransferase, cytokines, and hepatic lipid peroxidation were measured. Histopathology examination and apoptotic cell detection were assessed. For the in vitro study, cell viability, intracellular nitric oxide, apoptosis, and NOS expression were evaluated. RESULTS: Remifentanil and L-arginine pretreatment reduced concentrations of serum aminotransferases and cytokines, decreased the concentrations of hepatic malondialdehyde and myeloperoxidase activity, and increased superoxide dismutase, nitric oxide, and inducible NOS expression in vivo. Decreased histologic damage and apoptosis were also seen in these two groups. These changes were prevented by previous administration of N-ω-nitro-L-arginine methyl ester but not naloxone. There was an increase in inducible NOS protein expression but not endogenous NOS in remifentanil and L-arginine pretreated groups compared with control, naloxone, and N-ω-nitro-L-arginine methyl ester groups. CONCLUSION: Pretreatment with remifentanil can attenuate liver injury both in vivo and in vitro. Inducible NOS but not opioid receptors partly mediate this effect by exhausting reactive oxygen species and attenuating the inflammatory response.

Brij-functionalized chitosan nanocarrier system enhances the intestinal permeability of P-glycoprotein substrate-like drugs.

The highly expressed P-glycoprotein (Pgp) in the intestine plays a key role in preventing drugs across the intestinal epithelium, which linked by tight junctions (TJs). Thus increasing the oral bioavailability of Pgp substrate-like drugs (PSLDs) remains a great challenge. Herein, we construct a nanocarrier system derived from Brij-grafted-chitosan (BC) to enhance the oral bioavailability and therapeutic effect of berberine (BBR, a typical PLSD) against diabetic kidney disease. The developed BC nanoparticles (BC-NPs) are demonstrated to improve the intestinal permeability of BBR via transiently and reversibly modulating the intercellular TJs (paracellular pathway) and Pgp-mediated drug efflux (transcellular pathway). As compared to free BBR and chitosan nanoparticles, the BC-NPs enhanced the relative oral bioavailability of BBR in rats (4.4- and 2.7-fold, respectively), and the therapeutic potency of BBR in renal function and histopathology. In summary, such strategy may provide an effective nanocarrier system for oral delivery of BBR and PSLDs.

Activation of central opioid receptors induces cardioprotection against ischemia-reperfusion injury.

BACKGROUND: Small doses of intrathecal morphine provide cardioprotection similar to that conferred by IV morphine and ischemic preconditioning (IPC). We investigated the relative role of central versus peripheral opioid receptors in intrathecal morphine preconditioning (ITMPC). METHODS: Forty-eight anesthetized, open-chest, male Sprague-Dawley rats were assigned to 1 of 7 treatment groups (n = 6-7) after successful intrathecal catheter placement. ITMPC was achieved by 3 consecutive 5-min intrathecal infusions of morphine (1.0 microg/kg each). This was repeated in the presence of either IV (IV naloxone methiodide + ITMPC) or intrathecally (intrathecal naloxone methiodide [ITNM] + ITMPC) administered naloxone methiodide. This compound was also given via these same routes in the absence of ITMPC (IV naloxone methiodide + ITNM). Intrathecal normal saline and IPC were used as negative and positive controls, respectively. Myocardial ischemia and reperfusion injury were induced by 30 min of left main coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size, as a percentage of the area-at-risk, was determined by 2,3,5-triphenyltetrazolium staining. RESULTS: The infarct size/area-at-risk were significantly reduced in the IPC (22% +/- 3%) and ITMPC (26% +/- 5%) groups compared with the control group (48% +/- 9%) (P < 0.01). The addition of ITNM reversed the cardioprotective effects of ITMPC (45% +/- 4%), whereas IV administration of the drug did not have any effect on ITMPC (28% +/- 9%, P < 0.01). CONCLUSIONS: Intrathecally administered morphine can produce cardioprotective effects via the activation of central opioid receptors, without the apparent involvement of peripheral opioid receptors.

Remifentanil reduces the release of biochemical markers of myocardial damage after coronary artery bypass surgery: a randomized trial.

OBJECTIVE: Opioids, including remifentanil, have been demonstrated to confer cardiac protection against ischemia reperfusion injury in animals. This study evaluated whether remifentanil preconditioning is protective in first-time elective on-pump coronary artery bypass surgery patients receiving a standardized fentanyl (25 µg/kg in total) and propofol anesthetic. DESIGN: A prospective, double blind, randomized, controlled study. SETTING: University hospital; single institution. PARTICIPANTS: Forty patients scheduled for first-time elective, on-pump coronary artery bypass surgery for at least 3 diseased vessels. INTERVENTIONS: Patients randomized to the remifentanil group (n = 20) received a 1 µg/kg bolus followed by a 0.5 µg/kg/min infusion for 30 minutes after induction but before sternotomy, while the control group (n = 20) received normal saline. Serial samples for measurement of creatine kinase (CK-MB), cardiac troponin I (cTnI), ischemia-modified albumin (IMA) and heart-type fatty-acid-binding protein (hFABP) were taken at baseline, prebypass, T = 10 minutes, 2, 6, 12, and 24 hours after cross-clamp release, to assess the degree of myocardial damage. MEASUREMENTS AND MAIN RESULTS: Patients in the remifentanil group had lower levels of CK-MB from T = 2 hours to 24 hours, cTnI from T = 10 minutes to T = 12 hours, IMA from T = 10 minutes to T = 2 hours and h-FABP from T = 10 minutes to T = 12 hours (p < 0.05). The time to tracheal extubation was shorter in patients in the remifentanil group. The overall lengths of ICU and hospital stays were not different. CONCLUSIONS: The addition of remifentanil to the anesthesia regimen reduced the degree of myocardial damage. This incremental benefit may be attributable either to remifentanil itself or to an overall increased opioid dose, the latter may be necessary to trigger cardiac protection.

Intrathecal morphine preconditioning induces cardioprotection via activation of delta, kappa, and mu opioid receptors in rats.

BACKGROUND: Small doses of intrathecal morphine provide cardioprotection similar to that conferred by IV morphine. However, the extent of intrathecal morphine preconditioning (IT-MPC) relative to that resulting from ischemic preconditioning (IPC) is unknown. Further, it is uncertain whether IT-MPC is mediated by opioid receptor dependent pathways. In this study, we compared the extent of cardioprotection conferred by IT-MPC with IPC and investigated the role of opioid receptors in this effect. METHODS: Eighty anesthetized, open-chest, male Sprague-Dawley rats were assigned to 1 of 13 groups (n = 6-7) after successful intrathecal catheter placement. Rats in the IPC group were subjected to three 5-min cycles of myocardial ischemia (induced by occlusion of the left main coronary artery) interspersed with 5 min of reperfusion. After IPC, myocardial ischemia and reperfusion injury was induced by 30 min of left main coronary artery occlusion followed by 2 h of reperfusion. In the IT-MPC groups, the rats were given 3 consecutive 5 min intrathecal morphine infusions (0.03, 0.3, 3.0, or 30.0 microg/kg, respectively) interspersed with 5 min infusion-free periods, before myocardial ischemia reperfusion injury. In 2 other groups either 300microg/kg of IV morphine or 10 microL of intrathecal normal saline were given. The selective delta, kappa, and mu opioid receptor antagonists naltrindole, nor-binaltorphimine, and D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), respectively, were given to groups of animals receiving IT-MPC to evaluate the relative role of the specific opioid receptor subtypes in IT-MPC preconditioning. Myocardial infarct size (IS), as a percentage of the area at risk (AAR), was determined by 2,3,5-triphenyltetrazolium staining. RESULTS: Intrathecal morphine 0.3 to 30 microg/kg reduced myocardial IS compared with intrathecal normal saline control animals. The IS/AAR were 33% +/- 10% (0.3 microg/kg), 29% +/- 10% (3 microg/kg) and 29% +/- 16% (30 mug/kg), versus 53% +/- 8% for the control group (P < 0.01). The reduction in IS/AAR with IT-MPC was similar to that produced by IV morphine (33% +/- 6%, P = 0.84) and IPC (22% +/- 4%, P = 0.41). Myocardial preconditioning due to IT-MPC was attenuated by co-administration of any one of the opioid receptor antagonists (IT-MPC + naltrindole 50% +/- 9%, IT-MPC + nor binaltorphimine 43% +/- 6%, IT-MPC + CTOP 53% +/- 9%, P = 0.14). CONCLUSIONS: IT-MPC produced comparable cardioprotection to myocardial IPC and IV morphine. Myocardial preconditioning from intrathecal morphine seems to involve delta, kappa, and mu opioid receptors.

Impact of postoperative haemoglobin on length of stay post fractured hip repair in patients with standardised perioperative management.

INTRODUCTION:: Perioperative blood transfusion is not without risk and effort should be made to limit patients' exposure to allogeneic blood. However, there is conflicting data regarding the impact of anaemia on postoperative recovery in patients with repaired hip fractures. It is hypothesised that for a given baseline functional status and fracture type, lower postoperative haemoglobin will increase rehabilitation time and prolong total length of hospital stay. METHODS:: This is a retrospective study on data collected prospectively on patients entered into the Clinical Pathway aged >65 years admitted to Queen Mary Hospital (QMH) with a fractured neck of femur during 2011-2013. Potential predictor variables were analysed with linear regression with respect to total length of stay and those that reached a significance level of 0.05 were included in further analysis. RESULTS:: 1092 patients were admitted to QMH with a suspected fractured neck of femur; data from 747 patients were analysed. The fracture sites were neck of femur (50%), intertrochanteric (48%) and subtrochanteric fracture (2%). Approximately 30% of patients received blood transfusions. Of these only the development of postoperative medical complications statistically prolonged hospital stay. No relationship was seen with haemoglobin levels cut-off above and below 10 g/dl with the result remaining non-significant down to a cut-off of above and below 8 g/dl. DISCUSSION:: This study revealed that post-surgical haemoglobin level of between 8 g/dl and 10 g/dL did not have an impact on the total length of hospital stay. The development of postoperative medical complications was the only factor that prolonged the total length of stay.

Brij-grafted-chitosan copolymers with function of P-glycoprotein modulation: Synthesis, characterization and in vitro investigations.

Chitosan (CS), a nature-derived polysaccharide, is a promising nano-carrier material with good biocompatibility and biodegradability. However, the biomedical applications of CS are hindered because of its poor aqueous solubility. To circumvent this drawback, a series of Brij-grafted-chitosan copolymers (BCs) with various grafting degree of Brij-S20 were first developed and reported. The results indicated that the water solubility of BCs (from 9.13 to 9.54 mg/mL) were much higher than that of CS (0.32 mg/mL), due to the broken intra- and/or inter-molecular hydrogen bonds and the decreased initial crystallinity in BCs. The amphiphilic structure of BCs presented lower critical micelle concentration (0.116-0.376 mg/mL) thus facilitating its self-aggregation into micelles for drug encapsulation. Moreover, BCs markedly enhanced the intracellular uptake of rhodamine-123 in MDCK-MDR1 cells. This inhibition on Pgp-mediated efflux was also confirmed by confocal microscopy. In conclusion, BCs could be further developed as polymeric nano-carriers for those drugs with Pgp-mediated efflux.

Effects of differential-phase remote ischemic preconditioning intervention in laparoscopic partial nephrectomy: A single blinded, randomized controlled trial in a parallel group design.

STUDY OBJECTIVE: There are two windows of protection for remote ischemic preconditioning (RIPC), an early (ERIPC) and a late-phase (LRIPC). While ERIPC has been well studied, works on LRIPC are relatively scarce, especially for the kidneys. We aimed to compare the effects of early-phase versus late-phase RIPC in patients with laparoscopic partial nephrectomy (LPN). DESIGN: A randomized controlled study SETTING: The Second Affiliated Hospital of Anhui Medical University, 1 May 2012 to 30 October 2013 PATIENTS: Sixty-five ASA 1 to 2 patients scheduled for LPN were located randomly to ERIPC group, LRIPC group and CON group (control). INTERVENTIONS: Three five-minute cycles of right upper limb ischaemia and reperfusion were performed after induction of anesthesia in ERIPC group. Patients in LRIPC group received similar treatment 24h before surgery, while control patients were not subjected to preconditioning. MEASUREMENTS: Serum neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C (CysC) were evaluated before the induction of anesthesia (0h), 2h (2h) and 6h (6h) after surgery. Unilateral glomerular filtration rates (GFR) were assessed before and after surgery to evaluate overall renal function. MAIN RESULTS: Serum NGAL and CysC were significantly lower in ERIPC and LRIPC groups at 2h post-operation (P<0.001), 6h post-operation (P<0.001). Additionally, The GFR were significantly lower in ERIPC and LRIPC groups than in CON group at the 3rd month after surgery (P=0.019; P<0.001). Moreover, compared to the ERIPC group, concentration of NGAL and CysC in LRIPC group decreased to a greater extent, while GFR and the percentage of decrement was significantly less in the LRIPC group (P=0.016; P<0.001). CONCLUSIONS: Regardless of early-phase or late-phase intervention, limb remote ischemic preconditioning confers protection on renal ischemia-reperfusion injury in patients with laparoscopic partial nephrectomy, and the late-phase protection is more prominent.

The effect of sevoflurane on cerebral autoregulation in young children as assessed by the transient hyperemic response.

The transient hyperemic response (THR) test is a simple, noninvasive technique to evaluate cerebral autoregulation using transcranial Doppler. It has not yet been used in studies involving children. In this study we evaluated this response in children undergoing general anesthesia using sevoflurane. Twenty ASA physical status I children undergoing elective urological surgery sequentially received sevoflurane at 0.5, 1.0, and 1.5 MAC in a randomized order. Analgesia was solely provided by caudal anesthesia. The right middle cerebral artery flow velocities before (F1), during (F2), and after (F3) a 10-s ipsilateral carotid artery compression were recorded. The THR ratios (THRR) (+/- sd) for 0.5 MAC, 1.0 MAC, and 1.5 MAC were 1.24 +/- 0.11, 1.16 +/- 0.09, and 1.13 +/- 0.07, respectively. The THRR was significantly different between 0.5 MAC versus 1.0 and 1.5 MAC, respectively (P < 0.05). However, no difference was detected between 1.0 and 1.5 MAC. A THRR of more than 1.09 has previously been accepted as the lower limit of a positive response. The results in this study suggest that THR is affected by sevoflurane in a dose-dependent fashion but is maintained at up to 1.5 MAC. This suggests cerebral autoregulation is preserved in children anesthetized with up to 1.5 MAC sevoflurane.