Protein kinase D3 promotes neutrophil migration during viral infection.

Protein kinase D (PKD) is a serine/threonine kinase family with three isoforms (PKD1-3) that are expressed in most cells and implicated in a wide array of signaling pathways, including cell growth, differentiation, transcription, secretion, polarization and actin turnover. Despite growing interest in PKD, relatively little is known about the role of PKD in immune responses. We recently published that inhibiting PKD limits proinflammatory cytokine secretion and leukocyte accumulation in mouse models of viral infection, and that PKD3 is highly expressed in the murine lung and immune cell populations. Here we focus on the immune-related phenotypes of PKD3 knockout mice. We report that PKD3 is necessary for maximal neutrophil accumulation in the lung following challenge with inhaled polyinosinic:polycytidylic acid, a double-stranded RNA, as well as following influenza A virus infection. Using reciprocal bone marrow chimeras, we found that PKD3 is required in the hematopoietic compartment for optimal neutrophil migration to the lung. Ex vivo transwell and chemokinesis assays confirmed that PKD3-/- neutrophils possess an intrinsic motility defect, partly because of reduced surface expression of CD18, which is critical for leukocyte migration. Finally, the peak of neutrophilia was significantly reduced in PKD3-/- mice after lethal influenza A virus infection. Together, these results demonstrate that PKD3 has an essential, and nonredundant, role in promoting neutrophil recruitment to the lung. A better understanding of the isoform-specific and cell type-specific activities of PKD has the potential to lead to novel therapeutics for respiratory illnesses.

Downregulation of the glucose transporter GLUT 1 in the cerebral microvasculature contributes to postoperative neurocognitive disorders in aged mice.

INTRODUCTION: Glucose transporter 1 (GLUT1) is essential for glucose transport into the brain and is predominantly expressed in the cerebral microvasculature. Downregulation of GLUT1 precedes the development of cognitive impairment in neurodegenerative conditions. Surgical trauma induces blood-brain barrier (BBB) disruption, neuroinflammation, neuronal mitochondria dysfunction, and acute cognitive impairment. We hypothesized that surgery reduces the expression of GLUT1 in the BBB that in turn disrupts its integrity and contributes to metabolic dysregulation in the brain that culminates in postoperative cognitive impairment. METHODOLOGY: Using an abdominal surgery model in aged WT mice, we assessed the perioperative changes in cognitive performance, tight junction proteins expression, GLUT1 expression, and the associated metabolic effects in the hippocampus. Thereafter, we evaluated the effects of these parameters in aged mice with conditional overexpression of GLUT1, and then again in aged mice with conditional overexpression of GLUT1 with or without prior exposure to the GLUT1 inhibitor ST-31. RESULTS: We showed a significant decline in cognitive performance, along with GLUT1 reduction and diminished glucose metabolism, especially in the ATP level in the postoperative mice compared with controls. Overexpression of GLUT1 expression alleviated postoperative cognitive decline and improved metabolic profiles, especially in adenosine, but did not directly restore ATP generation to control levels. GLUT1 inhibition ameliorated the postoperative beneficial effects of GLUT1 overexpression. CONCLUSIONS: Surgery-induced GLUT1 reduction significantly contributes to postoperative cognitive deficits in aged mice by affecting glucose metabolism in the brain. It indicates the potential of targeting GLUT1 to ameliorate perioperative neurocognitive disorders.

ST36 acupoint injection with anisodamine for postoperative nausea and vomiting in female patients after bariatric surgery: a prospective, randomized controlled trial.

BACKGROUND: The use of multimodal pharmacological prophylactic regimes has decreased postoperative nausea and vomiting (PONV) in general but it still occurs in over 60% of female patients after bariatric surgery. This study aimed to evaluate the efficacy of ST36 acupoint injection with anisodamine in prevention of PONV among female patients after bariatric surgery. METHODS: Ninety patients undergoing laparoscopic sleeve gastrectomy were randomly allocated to anisodamine or control group at the ratio of 2:1. Anisodamine or normal saline was injected into Zusanli (ST36) bilaterally after induction of general anesthesia. The incidence and severity of PONV were assessed during the first 3 postoperative days and at 3 months. The quality of early recovery of anesthesia, gastrointestinal function, sleep quality, anxiety, depression, and complications were also evaluated. RESULTS: Baseline and perioperative characteristics were comparable between two groups. In the anisodamine group, 25 patients (42.4%) experienced vomiting within postoperative 24 h compared with 21 (72.4%) in the control group (relative risk 0.59; 95% confidence interval 0.40-0.85). Time to first rescue antiemetic was 6.5 h in anisodamine group, and 1.7 h in the control group (P = 0.011). Less rescue antiemetic was required during the first 24 h in the anisodamine group (P = 0.024). There were no differences in either postoperative nausea or other recovery characteristics. CONCLUSIONS: The addition of ST36 acupoint injection with anisodamine significantly reduced postoperative vomiting without affecting nausea in female patients with obesity undergoing laparoscopic sleeve gastrectomy.

Prehabilitative resistance exercise reduces neuroinflammation and improves mitochondrial health in aged mice with perioperative neurocognitive disorders.

BACKGROUND: Postoperative neurocognitive dysfunction remains a significant problem in vulnerable groups such as the elderly. While experimental data regarding its possible pathogenic mechanisms accumulate, therapeutic options for this disorder are limited. In this study, we evaluated the neuroprotective effect of a period of preconditioning resistant training on aged mice undergoing abdominal surgery. Further, we examined the underlying mechanisms from the perspective of neuroinflammatory state and synaptic plasticity in the hippocampus. METHODS: 18-month-old C57BL/6N mice were trained for 5 weeks using a ladder-climbing protocol with progressively increasing weight loading. Preoperative baseline body parameters, cognitive performance and neuroinflammatory states were assessed and compared between sedentary and trained groups of 9-month-old and 18-month-old mice. To access the neuroprotective effect of resistance training on postoperative aged mice, both sedentary and trained mice were subjected to a laparotomy under 3% sevoflurane anesthesia. Cognitive performance on postoperative day 14, hippocampal neuroinflammation, mitochondrial dysfunction and synaptic plasticity were examined and compared during groups. RESULTS: 18-month-old mice have increased body weight, higher peripheral and central inflammatory status, reduction in muscle strength and cognitive performance compared with middle-aged 9-month-old mice, which were improved by resistance exercise. In the laparotomy group, prehabilitative resistant exercise improved cognitive performance and synaptic plasticity, reduced inflammatory factors and glial cells activation after surgery. Furthermore, resistance exercise activated hippocampal PGC-1α/BDNF/Akt/GSK-3ß signaling and improved mitochondrial biogenesis, as well as ameliorated mitochondrial dynamics in postoperative-aged mice. CONCLUSIONS: Resistance exercise reduced risk factors for perioperative neurocognitive disorders such as increased body weight, elevated inflammatory markers, and pre-existing cognitive impairment. Accordantly, preoperative resistance exercise improved surgery-induced adverse effects including cognitive impairment, synaptic deficit and neuroinflammation, possibly by facilitate mitochondrial health through the PGC1-a/BDNF pathway.

A comparison of two methods for the detection of circulating tumour cells in patients with oral cavity cancer.

BACKGROUND: Circulating tumour cells (CTCs) detected in patient blood samples are relevant as diagnostic and prognostic markers offering insights into tumour behaviour and guiding treatment of cancer at an individualised level. The aim of this study was to ascertain the feasibility of detecting CTCs in oral squamous cell carcinoma (OSCC) using two different methods so as to determine the optimal method for the study of this cancer. METHODS: Comparison of the numbers of CTCs, circulating tumour micro-emboli (CTMs) and circulating tumour endothelial cells (CTECs), was undertaken in forty clinical samples of oral squamous cell carcinoma (OSCC) determined by filtration (ISET® ) and in situ fluorescent immunostaining (i-FISH, Cytelligen® ) immunostaining and in situ hybridisation. RESULTS: i-FISH detected CTCs in 80% of samples compared with 40% of samples analysed by microfiltration. i-FISH detected CTCs in a further 40% of samples in which microfiltration did not detect CTCs. No CTC clusters were detected by microfiltration while i-FISH detected CTM in 12.5% of samples. i-FISH analysis detected CTECs in 20/40 samples. CONCLUSION: These results highlight significant differences in detection of CTCs, CTM and CTECs between i-FISH and microfiltration when applied to OSCC samples, suggesting that technologies capable of detecting circulating aneuploid cells more accurately detect CTCs. i-FISH also detected CTM and CTEC not detected using ISET® . With proven prognostic relevance in adenocarcinomas, accurate enumeration of CTCs, CTMs and CTECs may be a clinically useful tool in the management of OSCC and may aid in the reduction of false-negative diagnoses.

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.

Identifying and articulating the student experience in the Intercalated Enrichment Year.

BACKGROUND: Benefits of intercalation during an undergraduate medical degree are well-recognized. The University of Hong Kong implemented a compulsory Enrichment Year (EY) in its Bachelor of Medicine and Bachelor of Surgery degree programme (MBBS) in 2016. In their third year of study, students could work on an area of interest in any of three programme categories (i) intercalation/ university exchange (IC); (ii) research (RA); (iii) service/ humanitarian work (SH). This study aimed to explore the barriers, enablers, and overall student learning experiences from the first cohort of EY students in order to inform future development of the EY. METHODS: An exploratory sequential mixed-method study in 2019-20. Twenty students were purposively selected to attend three semi-structured focus group interviews. Conventional thematic analysis was employed and results assisted the design of a cross-sectional questionnaire. Sixty-three students completed the questionnaire. ANOVA or chi-square test was used to compare the difference in student's characteristics, barriers, enablers and perspectives on EY between programme categories. Adjusting student's characteristics, logistic regressions were conducted to identify the effect of programme categories on the EY experience. RESULTS: Most students (95% in the questionnaire) agreed that EY was worthwhile and more rewarding than expected. EY was positively regarded for enhancing personal growth and interpersonal relationships. The main barriers were financial difficulties, scholarship issues and insufficient information beforehand. A few students had practical (i.e. accommodation, cultural adaptation) problems. Potential enablers included better financial support, more efficient information exchange and fewer assignments and preparation tasks. Similar barriers were encountered by students across all three categories of EY activities. CONCLUSIONS: Personal growth was the most important benefit of the EY. Barriers were consistent with those identified in the literature except for cultural adaptation, which could be related to Hong Kong's unique historical context. Financial limitation was the most concerning barrier, as it could result in unequal access to educational opportunities. Better and timely access to scholarships and other funding sources need to be considered. TRIAL REGISTRATION: Ethics approval was obtained from the local Institutional Review Board of The University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 19-585 ).

Sevoflurane Induces Neurotoxicity in the Animal Model with Alzheimer's Disease Neuropathology via Modulating Glutamate Transporter and Neuronal Apoptosis.

Perioperative neurocognitive disorders are frequently observed in postoperative patients and previous reports have shown that pre-existing mild cognitive impairment with accumulated neuropathology may be a risk factor. Sevoflurane is a general anesthetic agent which is commonly used in clinical practice. However, the effects of sevoflurane in postoperative subjects are still controversial, as both neurotoxic or neuroprotective effects were reported. The purpose of this study is to investigate the effects of sevoflurane in 3 × Tg mice, a specific animal model with pre-existing Alzheimer's disease neuropathology. 3 × Tg mice and wild-type mice were exposed to 2 h of sevoflurane respectively. Cognitive function, glutamate transporter expression, MAPK kinase pathways, and neuronal apoptosis were accessed on day 7 post-exposure. Our findings indicate that sevoflurane-induced cognitive deterioration in 3 × Tg mice, which was accompanied with the modulation of glutamate transporter, MAPK signaling, and neuronal apoptosis in the cortical and hippocampal regions. Meanwhile, no significant impact was observed in wild-type mice. Our results demonstrated that prolonged inhaled sevoflurane results in the exacerbation of neuronal and cognitive dysfunction which depends on the neuropathology background.

Cross-phase modulational instability of circularly polarized helical Bloch modes carrying optical vortices in a chiral three-core photonic crystal fiber.

We report the first, to the best of our knowledge, observation of cross-phase modulational instability (XPMI) of circularly polarized helical Bloch modes carrying optical vortices in a twisted photonic crystal fiber with a three-fold symmetric core, formed by spinning the fiber preform during the draw. When the fiber is pumped by a superposition of left-circular polarization (LCP) and right-circular polarization (RCP) modes, a pair of orthogonal circularly polarized sidebands of opposite topological charge is generated. When, on the other hand, a pure LCP (or RCP) mode is launched, the XPMI gain is zero, and no sidebands are seen. This observation has not been seen before in any system and is unique to chiral structures with N-fold rotational symmetry. The polarization state and topological charge of the generated sidebands are measured. By decomposing the helical Bloch modes into their azimuthal harmonics, we are able to deduce the selection rules for the appearance of modulational instability sidebands. We showed that the four waves in the nonlinear mixing process must exhibit the same set of azimuthal harmonic orders.

RGS4 promotes allergen- and aspirin-associated airway hyperresponsiveness by inhibiting PGE2 biosynthesis.

BACKGROUND: Allergens elicit host production of mediators acting on G-protein-coupled receptors to regulate airway tone. Among these is prostaglandin E2 (PGE2), which, in addition to its role as a bronchodilator, has anti-inflammatory actions. Some patients with asthma develop bronchospasm after the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs, a disorder termed aspirin-exacerbated respiratory disease. This condition may result in part from abnormal dependence on the bronchoprotective actions of PGE2. OBJECTIVE: We sought to understand the functions of regulator of G protein signaling 4 (RGS4), a cytoplasmic protein expressed in airway smooth muscle and bronchial epithelium that regulates the activity of G-protein-coupled receptors, in asthma. METHODS: We examined RGS4 expression in human lung biopsies by immunohistochemistry. We assessed airways hyperresponsiveness (AHR) and lung inflammation in germline and airway smooth muscle-specific Rgs4-/- mice and in mice treated with an RGS4 antagonist after challenge with Aspergillus fumigatus. We examined the role of RGS4 in nonsteroidal anti-inflammatory drug-associated bronchoconstriction by challenging aspirin-exacerbated respiratory disease-like (ptges1-/-) mice with aspirin. RESULTS: RGS4 expression in respiratory epithelium is increased in subjects with severe asthma. Allergen-induced AHR was unexpectedly diminished in Rgs4-/- mice, a finding associated with increased airway PGE2 levels. RGS4 modulated allergen-induced PGE2 secretion in human bronchial epithelial cells and prostanoid-dependent bronchodilation. The RGS4 antagonist CCG203769 attenuated AHR induced by allergen or aspirin challenge of wild-type or ptges1-/- mice, respectively, in association with increased airway PGE2 levels. CONCLUSIONS: RGS4 may contribute to the development of AHR by reducing airway PGE2 biosynthesis in allergen- and aspirin-induced asthma.

The timing of propofol administration affects the effectiveness of remote ischemic preconditioning induced cardioprotection in rats.

The cardioprotection of remote ischemic preconditioning (RIPC) is abolished under propofol maintained anesthesia. Transient receptor potential vanilloid 1 (TRPV1) channel is present in the heart, and its activation could induce cardioprotection. Therefore, we tested whether the anesthetic propofol administration phase interfered with the RIPC-induced cardioprotection, and RIPC-induced cardioprotection via the cardiac TRPV1 channel. Male Sprague-Dawley rats were subjected to myocardial 30 minutes of ischemia followed by 2 hours of reperfusion. RIPC consisted of three cycles of 5-minute ischemia/reperfusion applied to a hindlimb. Propofol infusion at 12 mg/kg/h was commenced either at 10 minutes before the start of RIPC in the P-pre + RIPC group, or immediately after myocardial ischemia at the onset of reperfusion (P-post + RIPC) while performing RIPC. These two propofol infusion regimes were applied to another two grou bs without RIPC (P-pre and P-post groups). Infarct size (IS) was assessed by triphenyltetrazolium staining. Heart TRPV1 expression was detected by Western blot and immunofluorescence. RIPC significantly reduced myocardial IS compared with the control group (36.7 ± 3% versus 57.2 ± 4%; P < .01). When propofol was started before RIPC, the IS sparing effect of RIPC was completely abolished. However, propofol infusion starting immediately after myocardial ischemia did not affect RIPC-induced cardioprotection. TRPV1 expression significant increase after RIPC, then propofol inhibited the TRPV1 activation of RIPC if given before RIPC but not after. Our results suggest that the timing of propofol administration is critical to preserve the cardioprotection of RIPC. Propofol might cancel RIPC-induced cardioprotection via the cardiac TRPV1 receptor.

Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer's disease mice.

BACKGROUND: Both human and animal studies have shown beneficial effects of physical exercise on brain health but most tend to be based on aerobic rather than resistance type regimes. Resistance exercise has the advantage of improving both muscular and cardiovascular function, both of which can benefit the frail and the elderly. However, the neuroprotective effects of resistance training in cognitive impairment are not well characterized. METHODS: We evaluated whether short-term resistant training could improve cognitive function and pathological changes in mice with pre-existing cognitive impairment. Nine-month-old 3xTg mouse underwent a resistance training protocol of climbing up a 1-m ladder with a progressively heavier weight loading. RESULTS: Compared with sedentary counterparts, resistance training improved cognitive performance and reduced neuropathological and neuroinflammatory changes in the frontal cortex and hippocampus of mice. In line with these results, inhibition of pro-inflammatory intracellular pathways was also demonstrated. CONCLUSIONS: Short-term resistance training improved cognitive function in 3xTg mice, and conferred beneficial effects on neuroinflammation, amyloid and tau pathology, as well as synaptic plasticity. Resistance training may represent an alternative exercise strategy for delaying disease progression in Alzheimer's disease.

Comparison of gastric insufflation using LMA-supreme and I-gel versus tracheal intubation in laparoscopic gynecological surgery by ultrasound: a randomized observational trial.

BACKGROUND: The application of bedside ultrasound to evaluate gastric content and volume can assist in determining aspiration risk. Applying positive pressure ventilation via supraglottic airway devices (SAD) can result in a degree of gastric insufflation. This study assessed and compared the antral cross-sectional area (CSA) in patients undergoing laparoscopic gynecological surgery when managed with different SAD. METHODS: One hundred American Society of Anesthesiologists I or II female patients were assessed for inclusion in this study and divided into three groups of different ventilation devices. Patients were randomly allocated into three groups to receive LMA-Supreme (Group S), I-gel (Group I) or tracheal tube (Group T). The primary outcome was the antral cross-sectional area and secondary outcomes included haemodynamic parameters and postoperative morbidity such as sore throat, hoarseness, dry throat, nausea and vomiting. RESULTS: The antral CSA was not significantly different among three groups before induction (P = 0.451), after induction (P = 0.456) and at the end of surgery (P = 0.195). The haemodynamic variables were significantly higher in the tracheal tube group than in the LMA-Supreme and I-gel groups after insertion (P < 0.0001) and after removal (P < 0.01). Sore throat was detected in none in the I-gel group compare to two patients (6.7%) in the LMA-Supreme group and fifteen patients (50%) in the tracheal tube group. Hoareness was detected in one (3.3%) in the I-gel group compare to two patients (6.7%) in the LMA-Supreme group and eleven patients (36.7%) in the tracheal tube group. CONCLUSIONS: The SADs do not cause obvious gastric insufflation. Thus, LMA-Supreme and I-gel can be widely used as alternative to endotracheal intubation for the short laparoscopic gynecological surgery. TRIAL REGISTRATION: This trial was registered at the Chinese Clinical Trial Registry (ChiCTR1800018212, data of registration, September 2018).

The beneficial effects of physical exercise in the brain and related pathophysiological mechanisms in neurodegenerative diseases.

Growing evidence has shown the beneficial influence of exercise on humans. Apart from classic cardioprotection, numerous studies have demonstrated that different exercise regimes provide a substantial improvement in various brain functions. Although the underlying mechanism is yet to be determined, emerging evidence for neuroprotection has been established in both humans and experimental animals, with most of the valuable findings in the field of mental health, neurodegenerative diseases, and acquired brain injuries. This review will discuss the recent findings of how exercise could ameliorate brain function in neuropathological states, demonstrated by either clinical or laboratory animal studies. Simultaneously, state-of-the-art molecular mechanisms underlying the exercise-induced neuroprotective effects and comparison between different types of exercise will be discussed in detail. A majority of reports show that physical exercise is associated with enhanced cognition throughout different populations and remains as a fascinating area in scientific research because of its universal protective effects in different brain domain functions. This article is to review what we know about how physical exercise modulates the pathophysiological mechanisms of neurodegeneration.

Pulse-repetition-rate tuning of a harmonically mode-locked fiber laser using a tapered photonic crystal fiber.

Strong enhancement of optoacoustic interactions in the micrometer-sized core of a photonic crystal fiber (PCF) enables stable, harmonic mode locking of a soliton fiber laser at GHz frequencies. Here we report that by tapering the PCF during the draw, the optoacoustic gain bandwidth can be broadened to ∼47 MHz, more than 3 times wider than in the untapered fiber. This made possible broad pulse-repetition-rate tuning over 66 MHz (from 2.042 to 2.108 GHz) of an optoacoustically mode-locked soliton fiber laser. Within this tuning range, the harmonically mode-locked pulse trains at the laser output were observed to be quite robust, with better than 40 dB supermode suppression ratio, sub-ps pulse timing jitter, and <0.2%relative intensity noise. This gigahertz-rate, near-infrared soliton fiber laser has remarkable pulse-rate tunability and low noise level, and has important potential applications in frequency metrology, high-speed optical sampling, and fiber telecommunications.

Generation of broadband circularly polarized supercontinuum light in twisted photonic crystal fibers.

We compare the properties of the broadband supercontinuum (SC) generated in twisted and untwisted solid-core photonic crystal fibers when pumped by circularly polarized 40 picosecond laser pulses at 1064 nm. In the helically twisted fiber, fabricated by spinning the preform during the draw, the SC is robustly circularly polarized across its entire spectrum whereas, in the straight fiber, axial fluctuations in linear birefringence and polarization-dependent nonlinear effects cause the polarization state to vary randomly with the wavelength. Theoretical modelling confirms the experimental results. Helically twisted photonic crystal fibers permit the generation of pure circularly polarized SC light with excellent polarization stability against fluctuations in input power and environmental perturbations.

Management of common femoral artery occlusive disease: A review of endovascular treatment strategies and outcomes.

Isolated atherosclerotic lesions of the common femoral artery (CFA) are rare but can produce significant claudication and critical limb ischemia. To date, the "gold standard" treatment for this entity has been common femoral endarterectomy (CFE) with or without patch angioplasty. However, surgery does have significant early postoperative complications, with a 15% combined mortality/morbidity. This manuscript sought to perform a comprehensive review of all studies and available data on endovascular treatment of isolated CFA disease and compare its utility to the traditional gold standard treatment. Twenty-one studies from 1987 to 2018 were included exploring the various CFA endovascular therapies (percutaneous transluminal angioplasty, intravascular stenting, drug-coated balloons, and directional atherectomy employed to treat CFA disease, in terms of efficacy, safety, and complications). As a conclusion, endovascular interventions provide acceptable short-term technical outcomes for CFA disease while limiting procedural complications. While only two randomized controlled trials compare short and long-term outcomes of surgical versus endovascular treatment, further studies are required to clarify the role of endovascular therapy.

Mechanisms of U46619-induced contraction in mouse intrarenal artery.

Thromboxane A2 (TXA2 ) has been implicated in the pathogenesis of vascular complications, but the underlying mechanism remains unclear. The contraction of renal arterial rings in mice was measured by a Multi Myograph System. The intracellular calcium concentration ([Ca2+ ]i ) in vascular smooth muscle cells (VSMCs) was obtained by using a fluo-4/AM dye and a confocal laser scanning microscopy. The results show that the U46619-induced vasoconstriction of renal artery was completely blocked by a TXA2 receptor antagonist GR32191, significantly inhibited by a selective phospholipase C (PI-PLC) inhibitor U73122 at 10 µmol/L and partially inhibited by a Phosphatidylcholine - specific phospholipase C (PC-PLC) inhibitor D609 at 50 µmol/L. Moreover, the U46619-induced vasoconstriction was inhibited by a general protein kinase C (PKC) inhibitor chelerythrine at 10 µmol/L, and a selective PKCδ inhibitor rottlerin at 10 µmol/L. In addition, the PKC-induced vasoconstriction was partially inhibited by a Rho-kinase inhibitor Y-27632 at 10 µmol/L and was further completely inhibited together with a putative IP3 receptor antagonist and store-operated Ca2+ (SOC) entry inhibitor 2-APB at 100 µmol/L. On the other hand, U46619-induced vasoconstriction was partially inhibited by L-type calcium channel (Cav1.2) inhibitor nifedipine at 1 µmol/L and 2-APB at 50 and 100 µmol/L. Last, U46619-induced vasoconstriction was partially inhibited by a cell membrane Ca2+ activated C1- channel blocker 5-Nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) at 50 and 100 µmol/L. Our results suggest that the U46619-induced contraction of mouse intrarenal arteries is mediated by Cav1.2 and SOC channel, through the activation of thromboxane-prostanoid receptors and its downstream signaling pathway.

RGS4 Overexpression in Lung Attenuates Airway Hyperresponsiveness in Mice.

A cardinal feature of asthma is airway hyperresponsiveness (AHR) to spasmogens, many of which activate G protein-coupled receptors (GPCRs) on airway smooth muscle (ASM) cells. Asthma subtypes associated with allergy are characterized by eosinophilic inflammation in the lung due to the type 2 immune response to allergens and proinflammatory mediators that promote AHR. The degree to which intrinsic abnormalities of ASM contribute to this phenotype remains unknown. The regulators of G protein signaling (RGS) proteins are a large group of intracellular proteins that inhibit GPCR signaling pathways. RGS2- and RGS5-deficient mice develop AHR spontaneously. Although RGS4 is upregulated in ASM from patients with severe asthma, the effects of increased RGS4 expression on AHR in vivo are unknown. Here, we examined the impact of forced RGS4 overexpression in lung on AHR using transgenic (Tg) mice. Tg RGS4 was expressed in bronchial epithelium and ASM in vivo, and protein expression in lung was increased at least 4-fold in Tg mice compared with wild-type (WT) mice. Lung slices from Tg mice contracted less in response to the m3 muscarinic receptor agonist methacholine compared with the WT, although airway resistance in live, unchallenged mice of both strains was similar. Tg mice were partially protected against AHR induced by fungal allergen challenge due to weakened contraction signaling in ASM and reduced type 2 cytokine (IL-5 and IL-13) levels in Tg mice compared with the WT. These results provide support for the hypothesis that increasing RGS4 expression and/or function could be a viable therapeutic strategy for asthma.

Evidence of the impact of systemic inflammation on neuroinflammation from a non-bacterial endotoxin animal model.

BACKGROUND: Systemic inflammation induces neuroinflammation and cellular changes such as tau phosphorylation to impair cognitive function, including learning and memory. This study uses a single model, laparotomy without any pathogen, to characterize these changes and their responses to anti-inflammatory treatment in the intermediate term. METHODS: In a two-part experiment, wild-type C57BL/6N mice (male, 3 month old, 25 ± 2 g) were subjected to sevoflurane anesthesia alone or to a laparotomy. Cognitive performance, systemic and neuroinflammatory responses, and tau phosphorylation were evaluated on postoperative days (POD) 1, 3, and 14. The effect of perioperative ibuprofen intervention (60 mg/kg) on these changes was then assessed. RESULTS: Mice in the laparotomy group displayed memory impairment up to POD 14 with initial high levels of inflammatory cytokines in the liver, frontal cortex (IL-1ß, IL-6, and TNF-α), and hippocampus (IL-1ß and IL-8). On POD 14, although most circulating and resident cytokine levels returned to normal, a significant number of microglia and astrocytes remained activated in the frontal cortex and microglia in the hippocampus, as well as abnormal tau phosphorylation in these two brain regions. Perioperative ibuprofen improved cognitive performance, attenuated systemic inflammation and glial activation, and suppressed the abnormal tau phosphorylation both in the frontal cortex and hippocampus. CONCLUSIONS: Our results suggest that (1) cognitive dysfunction is associated with an unbalanced pro-inflammatory and anti-inflammatory response, tauopathy, and gliosis; (2) cognitive dysfunction, gliosis, and tauopathy following laparotomy can persist well beyond the immediate postoperative period; and (3) anti-inflammatory drugs can act rapidly to attenuate inflammatory responses in the brain and negatively modulate neuropathological changes to improve cognition. These findings may have implications for the duration of therapeutic strategies aimed at curtaining cognitive dysfunction following surgery.