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Generative molecular design (GMD) is an increasingly popular strategy for drug discovery, using machine learning models to propose, evaluate and optimize chemical structures against a set of target design criteria. We present the ATOM-GMD platform, a scalable multiprocessing framework to optimize many parameters simultaneously over large populations of proposed molecules. ATOM-GMD uses a junction tree variational autoencoder mapping structures to latent vectors, along with a genetic algorithm operating on latent vector elements, to search a diverse molecular space for compounds that meet the design criteria. We used the ATOM-GMD framework in a lead optimization case study to develop potent and selective histamine H1 receptor antagonists. We synthesized 103 of the top scoring compounds and measured their properties experimentally. Six of the tested compounds bind H1 withKi’s between 10 and 100 nM and are at least 100-fold selective relative to muscarinic M2 receptors, validating the effectiveness of our GMD approach.

Sleep is essential for proper cognitive functioning. Ozone can delay both the aging process as well as the associated neurodegeneration. An untested hypothesis is that ozone may play a role in reducing the cognitive impairment associated with sleep deprivation. This study was designed to elucidate the mechanism of ozone’s effect on chronic REM sleep deprivation induced cognitive dysfunction in mice. Ozone ameliorated cognitive dysfunction in chronic REM sleep deprived mice, increased the number of dendritic spines in the hippocampus region and decreased neuronal loss. Administration of ozone may protect against chronic REM sleep deprivation induced cognitive dysfunction by enhancing the expression of Semaphorin 3A (Sema3A) and PlexinA1 concentrations as well as P-CRMP2/CRMP2 in the hippocampus. Moreover, ozone was associated with acetylation of α-tubulin, which, in turn, is associated with microtubule network dynamics and modulates ATP synthase activity. In conclusion, ozone may play a neuroprotective role and improve chronic REM sleep deprivation induced spatial recognition and learning memory dysfunction in mice.

Impairments in muscle microvascular function are associated with the pathogenesis of sarcopenia and cardiovascular disease. High-intensity interval training (HIIT) is an intervention by which a myriad of beneficial skeletal muscle/cardiovascular adaptations have been reported across age, including capillarisation and improved endothelial function. Herein, we hypothesised that HIIT would enhance muscle microvascular blood flow and vascular reactivity to acute contractile activity in older adults, reflecting HIIT-induced vascular remodelling. In a randomised controlled-trial, twenty-five healthy older adults aged 65–85 years (mean BMI 27.0) were randomised to 6-week HIIT or a no-intervention control period of an equal duration. Measures of microvascular responses to a single bout of muscle contractions (i.e. knee extensions) were made in the m. vastus lateralis using contrast-enhanced ultrasound during a continuous intravenous infusion of Sonovue™ contrast agent, before and after the intervention period, with concomitant assessments of cardiorespiratory fitness and resting blood pressure. HIIT led to improvements in anaerobic threshold (13.2 ± 3.4 vs. 15.3 ± 3.8 ml/kg/min, P

Lei Gao,1,2,&ast; Jian-Feng Zhang,3,&ast; John P Williams,4 Yi-Ning Yan,1 Xi-Lai Xiao,1 Wan-Rui Shi,5 Xiao-Yan Qian,1 Jian-Xiong An1– 3,6 1Department of Anesthesiology, Pain and Sleep Medicine, Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine, Chinese Academy of Sciences, Beijing, People’s Republic of China; 2School of Anesthesiology, Weifang Medical University, Weifang, Shangdong, People’s Republic of China; 3Savaid Medical School, University of Chinese Academy of Sciences, Beijing, People’s Republic of China; 4Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 5Department of Anesthesiology, Peking University Third Hospital, Beijing, People’s Republic of China; 6School of Medical Science & Engineering, Beijing Advanced Innovation Center for Biomedical Engineering, Beihang University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian-Xiong AnDepartment of Anesthesiology, Pain and Sleep Medicine, Aviation General Hospital of China Medical University, Beiyuan Road 3#, Beijing, 100012, People’s Republic of ChinaTel +86 13801281750Fax +86 59520233Email anjianxiong@yeah.netPurpose: It is unclear whether neuropathological structural changes in the peripheral nervous system and central nervous system can occur in the spared nerve injury model. In this study, we investigated the pathological changes in the nervous system in a model of neuropathic pain as well as the effects of electroacupuncture (EA) and pregabalin (PGB) administration as regards pain relief and tissue repair.Patients and Methods: Forty adult male SD rats were equally and randomly divided into 4 groups: spared nerve injury group (SNI, n = 10), SNI with electroacupuncture group (EA, n = 10), SNI with pregabalin group (PGB, n =10) and sham-operated group (Sham, n=10). EA and PGB were given from postoperative day (POD) 14 to 36. EA (2 Hz and 100 Hz alternating frequencies, intensities ranging from 1– 1.5– 2 mA) was applied to the left “zusanli” (ST36) and “Yanglingquan” (GB34) acupoints for 30 minutes. The mechanical withdrawal thresholds (MWTs) were tested with von Frey filaments. Moreover, the organizational and structural alterations of the bilateral prefrontal cortex, hippocampus, sciatic nerves and the thoracic, lumbar spinal cords and dorsal root ganglions (DRGs) were examined via light and electron microscopy.Results: MWTs of left hind paw demonstrated a remarkable decrease in the SNI model (P < 0.05). In the SNI model, ultrastructural changes including demyelination and damaged neurons were observed at all levels of the peripheral nervous system (PNS) and central nervous system (CNS). In addition, EA improved MWTs and restored the normal structure of neurons. However, the effect was not found in the PGB treatment group.Conclusion: Chronic pain can induce extensive damage to the central and peripheral nervous systems. Meanwhile, EA and PGB can both alleviate chronic pain syndromes in rats, but EA also restores the normal cellular structures, while PGB is associated with no improvement.Keywords: neuropathic pain, structural changes, electroacupuncture, pregabalin

The authors present the clinical case of a 67-year-old man with severe insomnia for 5 years with an exacerbation about 1 year before consultation. He did not have enough concentration and energy for his daily work and developed depression and anxiety because of his excessive daytime sleepiness. During his insomniac state, a drug treatment provided partial relief, but the effects were not long-lasting. Consequently, the drug dosage increased, and major side effects gradually manifested. We decided to use a completely new therapeutic strategy for this patient to improve his sleep quality and mental symptoms. In time, the patient could stop oral medications and that is multimodal sleep. After the end of multimodal sleep, the patient typically experiences improvement in sleep quality and architecture. Additionally, the dosage of hypnotics used before multimodal sleep is discontinued without severe withdrawal symptoms. CITATION: Zhang J-F, Williams JP, Zhao Q-N, et al. Multimodal sleep, an innovation for treating chronic insomnia: case report and literature review. J Clin Sleep Med. 2021;17(8):1737–1742.

Postherpetic neuralgia (PHN) is a devastating disease with extraordinarily poor treatment outcomes. Both pulsed radiofrequency (PRF) and ozone have good effects on the treatment of the disease. However, whether PRF and ozone have a synergistic effect on PHN remains unclear. Therefore, this study aimed to assess the therapeutic effects of ozone alone and in combination with PRF in the treatment of PHN. Ninety-one patients with PHN were assigned into two groups: PRF combined with ozone (PRF + ozone group, n = 44) and ozone therapy alone (ozone group, n = 47). In PRF + ozone group, the high-voltage, long-duration PRF was applied to the target dorsal root ganglions. Then ozonated water (11.5 µg/mL) was injected through the inner cannula. In the ozone group, all other processes were the same as those in the PRF + ozone group apart from the electrical stimulation. The therapeutic efficacy was evaluated by visual analog scale and tactile sensation at pre-treatment and post-treatment 3, 6, and 12 months. Compared with pre-treatment data, the visual analog scale score was significantly decreased in both groups after treatment. Compared with the ozone group, the visual analog scale score was significantly decreased in the PRF + ozone group at 3, 6, and 12 months. Similarly, the tactile sensation was also significantly decreased at post-treatment when compared to pre-treatment. However, there were no statistical differences between the two groups. Regression analysis results showed that the history of diabetes mellitus and age had significant negative and positive effects, respectively, on the treatment results. To conclude, the administration of PRF + ozone and ozone therapy alone could both improve pain symptoms. Moreover, treatment effects and total efficacy rates tended to be higher for the combination of PRF and ozone than ozone alone. This conclusion was especially true for long-term therapeutic effects.

Anesthesia and surgery are associated with perioperative neurocognitive disorders (PND). Dexmedetomidine is known to improve PND in rats; however, little is known about the mechanisms. Male Sprague-Dawley rats were subjected to resection of the hepatic apex under propofol anesthesia to clinically mimic human abdominal surgery. The rats were divided into four groups: control group (C), anesthesia group (A), model group (M), and model + dex group (D). Cognitive function was evaluated with the Morris water maze (MWM). Neuronal morphology was observed with HE staining, Nissl's staining and immunohistochemistry. Transcriptome analysis and quantitative real-time PCR were performed to investigate functional mitochondrial mRNA changes in the hippocampus. Protein levels were measured by Western blotting at 1, 3, and 7 days after surgery. Surgery-induced cognitive decline lasted for three days, but not seven days after surgery in the M group; however, rats in the D group were significantly improved by dexmedetomidine. No significant differences in the number of neurons were observed between the groups after surgery. Rats from the M group showed significantly greater expression levels of Iba-1 and GFAP compared with the C group and the D group. Rats in the M group demonstrated increased Surf1 and Cytochrome c expression on days 1 and 3, but not day 7; similar changes were not induced in rats in the D group. Dexmedetomidine appears to reverse surgery-induced behavior, mitigate the higher density of Iba-1 and GFAP, and downregulate the expression of Surf1 and Cytochrome c protein in the hippocampus of rats in a PND model.

Background: Numerous therapies have been developed for the treatment of chronic pelvic pain (CPP). Oxygen-ozone therapy is a new method for the treatment of CPP. Objectives: This article evaluated the feasibility of ultrasound-guided peritoneal perfusion with ozone in patients with CPP. Study Design: This is a bicenter retrospective study. Setting: The study was conducted at 2 pain centers of a university hospital. Methods: The medical records of patients with CPP (n = 60) from March 2016 until October 2018 were collected and reviewed. Group A contained 19 patients who were treated with a 1500 mcg dose of ozonated water (10 mcg/mL concentration and 150 mL volume), group B contained 23 patients using the same dose of ozonated water but a 15 mcg/mL concentration and 100 mL volume. Group C included 18 patients using a similar ozone dose but delivered in an oxygen-ozone mixture (15 mcg/mL concentration and 100 mL volume oxygen-ozone mixture). Visual Analog Scale (VAS) scores for pain of the 3 groups were compared at pretreatment, posttreatment, 1, 3, and 6 months posttreatment. The injection pain was evaluated using a 4-point verbal rating scale. Quality of life (QoL), anxiety, and depression were assessed at pretreatment and at 6 months posttreatment. Results: The VAS scores of the 3 groups decreased over time following treatment. Group A showed much higher pain scores compared with groups B and C at 1, 3, and 6 months posttreatment. However, the injection pain for groups B and C was higher than group A, but there was no difference seen between group B and C. At 6 months posttreatment, the QoL for all patients improved compared with pretreatment, whereas the anxiety and depression did not demonstrate differences. Limitations: The main limitations of this study are the retrospective study design, limited case number, and short follow-up period. Conclusions: Ultrasound-guided peritoneal perfusion with ozone is a feasible therapy for patients with CPP. Key words: Chronic pelvic pain, ozone, peritoneal perfusion

Summary Systematic reviews and meta-analyses (SRMAs) are increasing in popularity, but should they be used to inform clinical decision-making in anaesthesia? We present evidence that the certainty of evidence from SRMAs in anaesthesia (and in general) may be unacceptably low because of risks of bias exaggerating treatment effects, unexplained heterogeneity reducing certainty in estimates, random errors, and widespread prevalence of publication bias. We also present the latest methodological advances to help improve the certainty of evidence from SRMAs. The target audience includes both review authors and practising clinicians to help with SRMA appraisal. Issues discussed include minimising risks of bias from included trials, trial sequential analysis to reduce random error, updated methods for presenting effect estimates, and novel publication bias tests for commonly used outcome measures. These methods can help to reduce spurious conclusions on clinical significance, explain statistical heterogeneity, and reduce false positives when evaluating small-study effects. By reducing concerns in these domains of Grading of Recommendations, Assessment, Development and Evaluation, it should help improve the certainty of evidence from SRMAs used for decision-making in anaesthesia, pain, and perioperative medicine.

Globalization unleashed trends such as the free movement of capital, people, and goods; trickle-down economics, and diminished stature of nation-states. While largely embraced by most countries in the WTO, a growing tension within the European Union to push back went largely ignored until recently. Britain’s exit represents such a push back, a rejection of a single banking system, a single budget, and a single political entity. This article examines the historic 2016 British referendum that saw 52 percent of voters favor England leaving the EU. This research serves four purposes: one, to identify the origins of this important referendum as well as the positions of both its supporters and detractors; two, to analyze the fallout of the vote and its impact on other European nations; three, to correlate the results of this referendum and the rise of populist parties on the left and right in the EU; and four, to discuss briefly what the future holds for globalism.

Resistance exercise training (RET) can counteract negative features of muscle ageing but older age associates with reduced adaptive capacity to RET. Altered muscle protein networks likely contribute to ageing RET adaptation; therefore, associated proteome-wide responses warrant exploration. We employed quantitative sarcoplasmic proteomics to compare age-related proteome and phosphoproteome responses to RET. Thigh muscle biopsies were collected from eight young (25 ± 1.1 years) and eight older (67.5 ± 2.6 years) adults before and after 20 weeks supervised RET. Muscle sarcoplasmic fractions were pooled for each condition and analysed using Isobaric Tags for Relative and Absolute Quantification (iTRAQ) labelling, tandem mass spectrometry and network-based hub protein identification. Older adults displayed impaired RET-induced adaptations in whole-body lean mass, body fat percentage and thigh lean mass (P 0.05). iTRAQ identified 73 differentially expressed proteins with age and/or RET. Despite possible proteomic stochasticity, RET improved ageing profiles for mitochondrial function and glucose metabolism (top hub; PYK (pyruvate kinase)) but failed to correct altered ageing expression of cytoskeletal proteins (top hub; YWHAZ (14-3-3 protein zeta/delta)). These ageing RET proteomic profiles were generally unchanged or oppositely regulated post-RET in younger muscle. Similarly, RET corrected expression of 10 phosphoproteins altered in ageing, but these responses were again different vs. younger adults. Older muscle is characterised by RET-induced metabolic protein profiles that, whilst not present in younger muscle, improve untrained age-related proteomic deficits. Combined with impaired cytoskeletal adhesion responses, these results provide a proteomic framework for understanding and optimising ageing muscle RET adaptation.

Thalamic pain (TP), also known as central post-stroke pain, is a chronic neuropathic pain syndrome that follows a stroke and is a severe pain that is usually intractable. No universally applicable and effective therapies have been proposed. Emerging studies have reported that electroacupuncture (EA) can potentially be used as an effective therapy for the treatment of neuropathic pain. However, whether EA influences TP and if so, by what potential mechanism, remains poorly understood.The aim of this study was to detect the efficacy of EA and explore possible mechanisms for treating TP.Controlled animal study.The laboratory at the Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine.Male Sprague Dawley rats were randomly divided into 3 groups (n = 15 / group): sham-operated (SH) group, thalamic pain model (TP) group, EA treatment (EA) group. After the TP rat model was successfully established, EA was used for intervention. During the experiment, the mechanical pain thresholds of rats were detected among the groups. The right thalamus of the rats was extracted on postoperative day 28 for RNA-sequencing (RNA-Seq) analysis to find the changes in gene expression in different groups of rats. The key genes were screened using reverse transcription-polymerase chain reaction (RT-PCR) detection and subsequently identified with western blotting and immunofluorescence.The mechanical withdrawal threshold (MWT) value of the right facial skin in the TP group and the EA group decreased significantly on the 3rd day after surgery, compared to the SH group (P0.01). From 7 to 28 days, the MWT value increased continually in the EA group; however, there was no significant change in the TP group. The results of RNA-seq showed that compared to the TP group, 377 genes changed in the EA group. Moreover, ADCY1 expression increased significantly in the TP group as compared to the SH group, while EA treatment reversed the expression of ADCY1.In addition to ADCY1, the mechanism(s) of other signaling pathways in TP need to be explored in future research.EA treatment may promote the recovery of TP model rat by regulating ADCY1 expression.

PURPOSE OF REVIEW Many forms of acute and chronic disease are linked to changes in renal blood flow, perfusion, vascular density and hypoxia, but there are no readily available methods to assess these parameters in clinical practice. Dynamic contrast enhanced ultrasound (DCE-US) is a method that provides quantitative assessments of organ perfusion without ionising radiation or risk of nephrotoxicity. It can be performed at the bedside and is suitable for repeated measurements. The purpose of this review is to provide updates from recent publications on the utility of DCE-US in the diagnosis or assessment of renal disease, excluding the evaluation of benign or malignant renal masses. RECENT FINDINGS DCE-US has been applied in clinical studies of acute kidney injury (AKI), renal transplantation, chronic kidney disease (CKD), diabetic kidney disease and to determine acute effects of pharmacological agents on renal haemodynamics. DCE-US can detect changes in renal perfusion across these clinical scenarios and can differentiate healthy controls from those with CKD. In sepsis, reduced DCE-US measures of perfusion may indicate those at increased risk of developing AKI, but this requires confirmation in larger studies as there can be wide individual variation in perfusion measures in acutely unwell patients. Recent studies in transplantation have not provided robust evidence to show that DCE-US can differentiate between different causes of graft dysfunction, although it may show more promise as a prognostic indicator of graft function 1 year after transplant. DCE-US can detect acute haemodynamic changes in response to medication that correlate with changes in renal plasma flow as measured by para-aminohippurate clearance. SUMMARY DCE-US shows promise and has a number of advantages that make it suitable for the assessment of patients with various forms of kidney disease. However, further research is required to evidence its reproducibility and utility before clinical use can be advocated.

Background Patient-controlled analgesia (PCA) is an "on-demand" system which allows patients to self-administer intravenous medications in small bolus doses. Based on the principles of PCA, we developed Patient-Controlled Sleep (PCSL) for chronic intractable insomnia where the traditional analgesics in PCA were replaced with dexmedetomidine (Dex), an alpha-2 agonist widely used for premedication, sedation, anxiolysis and analgesia. The purpose of this study was to assess the feasibility of the new method for the treatment of chronic intractable insomnia. Patients and methods Patients with chronic intractable insomnia undergoing PCSL (n=20) were evaluated with the Pittsburgh Sleep Quality Index (PSQI), Symptom Checklist 90 (SCL-90), Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) before and after the treatment. The patient characteristics, overall outcomes and related side effects were also assessed. Results Fifteen patients completed the treatment protocol. The duration of PCSL varied from a few days to four months, and the dosage of Dex gradually decreased without eliciting signs or symptoms of tolerance or physical dependence. The sleep quality improvement occurred immediately after the therapy in 12/15 patients, and of which, 7/12 patients achieved continuously improved sleep quality in follow-up. Conclusion PCSL with Dex might be a potential treatment for patients with chronic intractable insomnia. However, it is an off-label use, and the potential side effects of dexmedetomidine with long-term use needs further evaluation.

Objective High‐intensity interval training (HIIT) has been shown to be more effective than moderate continuous aerobic exercise for improving cardiorespiratory fitness (CRF) in a limited time frame. However, the length of time required for HIIT to elicit clinically significant improvements in the CRF of older adults is currently unknown. The aim of this study was to compare changes in the CRF of older adults completing identical HIIT protocols of varying durations. Methods Forty healthy, community‐dwelling older adults completed a cardiopulmonary exercise test (CPET) before and after 2, 4, or 6 weeks of fully supervised HIIT on a cycle ergometer, or a no‐intervention control period. Results Anaerobic threshold (AT) was increased only after 4 (+1.9 [SD 1.1] mL/kg/min) and 6 weeks (+1.9 [SD 1.8] mL/kg/min) of HIIT (both P, High intensity interval training (HIIT) is a time‐efficient exercise strategy to improve cardiorespiratory fitness. In older adults, 4‐weeks of our specific HIIT regime can improve anaerobic threshold while 6‐weeks is needed to improve VO2 peak.

Ageing compromises skeletal muscle mass and function through poorly defined molecular aetiology. Here we have used untargeted metabolomics using UHPLC-MS to profile muscle tissue from young (n=10, 25±4y), middle aged (n=18, 50±4y) and older (n=18, 70±3y) men and women (50:50). Random Forest was used to prioritise metabolite features most informative in stratifying older age, with potential biological context examined using the prize-collecting Steiner forest algorithm embedded in the PIUMet software, to identify metabolic pathways likely perturbed in ageing. This approach was able to filter a large dataset of several thousand metabolites down to subnetworks of age important metabolites. Identified networks included the common age-associated metabolites such as androgens, (poly)amines/amino acids and lipid metabolites, in addition to some potentially novel ageing related markers such as dihydrothymine and imidazolone-5-proprionic acid. The present study reveals that this approach is a potentially useful tool to identify processes underlying human tissue ageing, and could therefore be utilised in future studies to investigate the links between age predictive metabolites and common biomarkers linked to health and disease across age.

Objectives To assess the efficacy of high-intensity interval training (HIIT) for improving cardiorespiratory fitness (CRF) in patients awaiting resection for urological malignancy within four weeks. Subjects/patients and methods A randomised control trial of consecutive patients aged (>65 years) scheduled for major urological surgery in a large secondary referral centre in a UK hospital. The primary outcome is change in anaerobic threshold (VO2AT) following HIIT vs. standard care. Results Forty patients were recruited (mean age 72 years, male (39): female (1)) with 34 completing the protocol. Intention to treat analysis showed significant improvements in anaerobic threshold (VO2AT; mean difference (MD) 2.26 ml/kg/min (95% CI 1.25–3.26)) following HIIT. Blood pressure (BP) also significantly reduced in following: HIIT (SBP: −8.2 mmHg (95% CI −16.09 to −0.29) and DBP: −6.47 mmHg (95% CI −12.56 to −0.38)). No reportable adverse safety events occurred during HIIT and all participants achieved >85% predicted maximum heart rate during sessions, with protocol adherence of 84%. Conclusions HIIT can improve CRF and cardiovascular health, representing clinically meaningful and achievable pre-operative improvements. Larger randomised trials are required to investigate the efficacy of prehabilitation HIIT upon different cancer types, post-operative complications, socio-economic impact and long-term survival.

Hemoglobin-based oxygen carriers (HBOCs) may cause coagulopathy, changes in total hemoglobin (THb), and affect mortality. Low total hemoglobin concentrations [THb] during hemorrhage may worsen outcomes.The database of the Hemopure HEM-0115 phase III trial was queried to determine the use of platelets, plasma, or cryoprecipitate and compare transfusion requirements and coagulation studies between patients randomized to erythrocyte transfusion or HBOC-201 infusion. Modeling of hemoglobin (Hb) changes produced by HBOC-201, erythrocyte, and blood product administration were related to [THb], coagulopathy, and mortality.Hemopure HEM-0115 phase III trial database.Retrospective and Novel Hemoglobin Deficit Formulas Tested Against Existing Database.The HBOC-201 database (n = 688) demonstrated less than 6% of subjects in both groups were administered non-Hb containing blood products (fresh frozen plasma, platelets, or cryoprecipitate) and low rates of coagulopathies in both erythrocyte and HBOC-201 arms. There were no differences in mortality in elective orthopedic patients administered up to 10 bags HBOC-201 (equivalent to 3 units erythrocytes). Low total [Hb] and lack of adequate oxygen carrying capacity was found to be an independent predictor of morbidity/mortality.The elective use of HBOC-201 for orthopedics versus erythrocytes demonstrated low incidence of blood product requirements in both cohorts and no differences in mortality up to the HBOC-201 equivalent of 3 units erythrocytes. High total Hb may be important to maintain in acute hemorrhage and [Hb] deficit, whereas later in recovery might not be as crucial. Future trauma trials may benefit from the use of HBOC-201 containing 13 g/dL in prehospital management, when erythrocytes are commonly not available.

Therapeutic interventions aimed at enhancing blood flow may combat the postprandial vascular and metabolic dysfunction that manifests with chronological ageing. We compared the effects of acute curcumin (1000 mg) coupled with an oral nutritional supplement (ONS, 7.5 g protein, 24 g carbohydrate and 6 g fat) versus a placebo and ONS (control) on cerebral and leg macrovascular blood flow, leg muscle microvascular blood flow, brachial artery endothelial function, and leg insulin and glucose responses in healthy older adults (n = 12, 50% male, 73 ± 1 year). Curcumin enhanced m. tibialis anterior microvascular blood volume (MBV) at 180 and 240 min following the ONS (baseline: 1.0 vs. 180 min: 1.08 ± 0.02, p = 0.01 vs. 240 min: 1.08 ± 0.03, p = 0.01), and MBV was significantly higher compared with the control at both time points (p < 0.05). MBV increased from baseline in the m. vastus lateralis at 240 min after the ONS in both groups (p < 0.05), and there were no significant differences between groups. Following the ONS, leg blood flow and leg vascular conductance increased, and leg vascular resistance decreased similarly in both conditions (p < 0.05). Brachial artery flow-mediated dilation and middle cerebral artery blood flow were unchanged in both conditions (p > 0.05). Similarly, the curcumin and control groups demonstrated comparable increases in glucose uptake and insulin in response to the ONS. Thus, acute curcumin supplementation enhanced ONS-induced increases in m. tibialis anterior MBV without potentiating m. vastus lateralis MBV, muscle glucose uptake, or systemic endothelial or macrovascular function in healthy older adults.

Sleep deprivation is a common health problem in modern society and is negatively associated with deleterious effects on cognitive functions such as learning and memory ability. This study was undertaken to provide a detailed account of the effect of chronic ozone intraperitoneal injection on the deleterious effects of sleep deprivation on brain function in rats.Sleep deprivation was induced using the modified multiple platform model. The rats received REM sleep deprivation with an intraperitoneal injection of ozone or midazolam for 28 days. The effects of ozone on REM sleep deprivation-induced hippocampus-dependent learning and memory deficits were studied by the following approaches: Morris water maze (MWM) tests were used to evaluate spatial learning and memory of rats. Morphological changes in the brain were evaluated using hematoxylin and eosin (HE) staining. RNA-sequence was performed to seek a common mechanism. The expression of the targeted gene was examined by qPCR and Western blotting.Ozone intraperitoneal injection reversed spatial learning and memory deficits associated with REM sleep deprivation, ameliorating pathological brain damage and down-regulating the hippocampal expression ofOzone intraperitoneal injection alleviated sleep deprivation-induced spatial learning and memory deficits by protecting hippocampal neurons via down-regulation of the expression of

Osteonecrosis of the femoral head (ONFH) is a progressive and painful disorder due to impaired blood supply to the femoral head, yet little is known about the effect of ozone therapy in femoral head necrosis.We aimed to evaluate the clinical and radiographic outcomes of ozone therapy in the treatment of ONFH.Nonrandomized clinical trial.The study was conducted in a single-center, academic institution.A total of 71 patients (107 hip joints) with Association Research Circulation Osseous (ARCO) stage-I, II, III, and IV ONFH were included and assigned to undergo either intraarticular O2-O3 mixture hip injections with ozonated autohemotherapy (ozone therapy group, n = 39, 58 hip joints) or protected weight bearing (control group, n = 32, 49 hip joints). The primary outcomes included the Visual Analog Scale (VAS) for pain intensity and Harris Hip Score (HHS) for hip function. The secondary outcomes included bone marrow edema examination, and conversion to total hip arthroplasty (THA).Ozone therapy effectively improves VAS for pain intensity and HHS during the follow-up period compared to the control group. Ozone therapy showed a significant resolution of bone marrow edema of the femoral head compared to the control group (P0.001). Thirteen of the 49 hips (26.53%) in the control group underwent THA, whereas only 6 hips (10.34%) in the ozone therapy group required THA during a 30-month follow-up (P = 0.041). The cumulative analysis revealed a low rate of conversion to THA in the ozone therapy group (logrank test; P = 0.022).The study is limited by a single treatment protocol in addition to the lack of a randomized design.Ozone therapy was associated with significant pain relief, improvement in hip function, and bone marrow edema resolution that may delay the need for THA in patients affected by ONFH.Institutional Review Board (IRB) approval number: HK2018-10-28.Clinical trials registration number: ChiCTR1900023449.

Postprandial macro- and microvascular blood flow and metabolic dysfunction manifest with advancing age, so vascular transmuting interventions are desirable. In this randomised, single-blind, placebo-controlled, crossover trial, we investigated the impact of the acute administration of green tea extract (GTE, containing ~500 mg epigallocatechin-3-gallate) versus placebo (CON), alongside an oral nutritional supplement (ONS), on muscle macro- and microvascular, cerebral macrovascular (via ultrasound) and leg glucose/insulin metabolic responses (via arterialised/venous blood samples) in twelve healthy older adults (42% male, 74 ± 1 y). GTE increased m. vastus lateralis microvascular blood volume (MBV) at 180 and 240 min after ONS (baseline: 1.0 vs. 180 min: 1.11 ± 0.02 vs. 240 min: 1.08 ± 0.04, both p &lt, 0.005), with MBV significantly higher than CON at 180 min (p &lt, 0.05). Neither the ONS nor the GTE impacted m. tibialis anterior perfusion (p &gt, 0.05). Leg blood flow and vascular conductance increased, and vascular resistance decreased similarly in both conditions (p &lt, 0.05). Small non-significant increases in brachial artery flow-mediated dilation were observed in the GTE only and middle cerebral artery blood flow did not change in response to GTE or CON (p &gt, 0.05). Glucose uptake increased with the GTE only (0 min: 0.03 ± 0.01 vs. 35 min: 0.11 ± 0.02 mmol/min/leg, p = 0.007), however, glucose area under the curve and insulin kinetics were similar between conditions (p &gt, 0.05). Acute GTE supplementation enhances MBV beyond the effects of an oral mixed meal, but this improved perfusion does not translate to increased leg muscle glucose uptake in healthy older adults.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of antimicrobial treatment for uncomplicated/simple acute appendicitis for resolution of symptoms and complications. Antimicrobial treatment will only be compared with appendectomy.

In drug discovery, it is essential to accurately measure drug-target binding affinity. Here, we revisit the fact that target binding kinetics impact the measurement of affinity, using a case study: development of corticotropin-releasing factor antagonists. Slow dissociation of the drug-target complex results in affinity assays being far from equilibrium, which results in erroneous estimates of affinity. This scenario can impair prediction of human dosing, assessment of target selectivity, identification of high-affinity ligands and determination of SAR. We describe strategies to detect lack of equilibration in affinity assays and methods to correctly measure affinity of slowly dissociating compounds. These considerations will facilitate drug discovery by ensuring reliable measurement of drug-target binding affinity.

Background Thalamic pain is a neuropathic pain syndrome that occurs as a result of thalamic damage. It is difficult to develop therapeutic interventions for thalamic pain because its mechanism is unclear. To better understand the pathophysiological basis of thalamic pain, we developed and characterized a new rat model of thalamic pain using a technique of microinjecting cobra venom into the ventral posterolateral nucleus (VPL) of the thalamus. Objectives This study will establish a new thalamic pain rat model produced by administration of cobra venom to the unilateral ventral posterolateral nucleus. Study design This study used an experimental design in rats. Setting The research took place in the laboratory at the Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine. Methods Male Sprague-Dawley rats were subjected to the administration of cobra venom or saline into the left VPL. The development of mechanical hyperalgesia and changes in pain-related behaviors and motor function were measured after intrathalamic cobra venom microinjection using the von Frey test, video recording, and cylinder test, respectively. On postoperative days 7 to 35, both electroacupuncture and pregabalin (PGB) were administered to verify that the model reproduced the findings in humans. Moreover, the organizational and structural alterations of the thalamus were examined via transmission electron microscopy (TEM). Results The threshold for mechanical stimuli in the left facial skin was significantly decreased on day 3 after thalamic pain modeling as compared with pre-venom treatment. Furthermore, the ultrastructural alterations of neurons such as indented neuronal nuclei, damaged mitochondria and endoplasmic reticulum, and dissolved surrounding tissues were observed under TEM. Moreover, electroacupuncture treatment ameliorated mechanical hyperalgesia, pain-like behaviors, and motor dysfunction, as well as restore normal structures of neurons in the thalamic pain rat model. However, no such beneficial effects were noted when PGB was administered. Limitations The pathophysiological features were different from the present model and the patients in clinical practice (in most cases strokes, either ischemic or hemorrhagic). Conclusion The cobra venom model may provide a reasonable model for investigating the mechanism of thalamic pain and for testing therapies targeting recovery and pain after thalamic lesions. Key words Thalamic pain, cobra venom, electroacupuncture, pregabalin, indented neuronal nuclei, damaged mitochondria, dissolved endoplasmic reticulum, golgi body.

It was media, especially television, coverage of the FIFA World Cup from 1958 which first drew South American football into a more mainstream position in English popular culture. Argentina came to ...

We analyse key circumstances and events in the early life and development of the Argentine soccer player Lionel Messi. We critically considers the influences and choices which helped shape his stel...

How has football hooliganism in England, largely, been successfully managed or displaced over the past 30 years, while violence and disorder caused by sections of the ultras movement in Italy conti...

Background Current evidence suggests that pelvic floor reconstruction following extralevator abdominoperineal excision of rectum (ELAPER) may reduce the risk of perineal herniation of intra-abdominal contents. Options for reconstruction include mesh and myocutaneous flaps, for which long-term follow-up data is lacking. The aim of this study was to evaluate the long-term outcomes of biological mesh (Surgisis®, Biodesign™) reconstruction following ELAPER. Methods A retrospective review of all patients having ELAPER in a single institution between 2008 and 2018 was perfomed. Clinic letters were scrutinised for wound complications and all available cross sectional imaging was reviewed to identify evidence of perineal herniation (defined as presence of intra-abdominal content below a line between the coccyx and the lower margin of the pubic symphysis on sagittal view). Results One hundred patients were identified (median age 66, IQR 59–72 years, 70% male). Median length of follow-up was 4.9 years (IQR 2.3–6.7 years). One, 2- and 5-year mortality rates were 3, 8 and 12%, respectively. Thirty three perineal wounds had not healed by 1 month, but no mesh was infected and no mesh needed to be removed. Only one patient developed a symptomatic perineal hernia requiring repair. On review of imaging a further 7 asymptomatic perineal hernias were detected. At 4 years the cumulative radiologically detected perineal hernia rate was 8%. Conclusions This study demonstrates that pelvic floor reconstruction using biological mesh following ELAPER is both safe and effective as a long-term solution, with low major complication rates. Symptomatic perineal herniation is rare following mesh reconstruction, but may develop sub clinically and be detectable on cross-sectional imaging.

Purpose Patients rank postoperative nausea and vomiting (PONV) as the most undesirable outcome of anesthesia. Mirtazapine is hypothesized to be effective in PONV prophylaxis via 5HT3 receptor antagonism. Design Systematic review and meta-analysis. Methods We identified seven randomized controlled trials by systematically searching electronic databases that compare the efficacy of mirtazapine versus placebo or ondansetron in reducing PONV. Findings Mirtazapine reduced PONV overall versus placebo in three studies (risk ratio [RR] = 0.44; 95% confidence interval [CI] 0.32 to 0.62) both on conventional meta-analysis and trial sequential analysis. One study comparing mirtazapine with ondansetron found similar rates of PONV (RR = 0.96; 95% CI 0.48 to 1.94). Mirtazapine reduced preoperative anxiety versus placebo or ondansetron (standardized mean difference −1.4; 95% CI −2.56 to −0.23) but increased sedation (RR = 22.47; 95% CI 5.61 to 89.93). The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) quality of evidence was moderate to low. Conclusions This meta-analysis suggests that mirtazapine reduces PONV overall versus placebo. We found evidence of reduction in preoperative anxiety, although mirtazapine increased the risk of sedation.