Faster improvement in outcome scores in posterior stabilised total knee arthroplasty compared to medial congruent system with posterior cruciate ligament retained.

Most studies comparing medial pivot to the posterior stabilised (PS) systems sacrifice the PCL. It is unknown whether retaining the PCL in the Medial Congruent (MC) system may provide further benefit compared to the more commonly used PS system. A retrospective review of a single-surgeon's registry data comparing 44 PS and 26 MC with PCL retained (MC-PCLR) TKAs was performed. Both groups had similar baseline demographics. The PS and MC-PCLR groups had similar pre-operative range of motion (ROM) (PS:104º ± 20º vs. MC-PCLR: 101º ± 19º, p = 0.70), Oxford Knee Score (OKS) (PS: 27 ± 6 vs. MC-PCLR: 26 ± 7, p = 0.62), and Knee Society Scoring System (KS) Function Score (KS-FS) (PS: 52 ± 24 vs. MC-PCLR: 56 ± 23, p = 0.49). The pre-operative KS Knee Score (KS-KS) was significantly lower in the PS group (PS: 44 ± 14 vs. MC-PLR: 53 ± 18, p < 0.05). At 12-months post-operation, there was significant improvement in all parameters (p < 0.01). Both groups had similar ROM (PS: 115º ± 13º vs. MC-PCLR: 114º ± 10º, p = 0.98), OKS (PS: 41 ± 5 vs. MC-PCLR: 40 ± 4, p = 0.50), KS-FS (PS: 74 ± 22 vs. MC-PCLR: 77 ± 16, p = 0.78), and KS-KS (PS: 89 ± 10 vs. MC-PCLR: 89 ± 10, p = 0.89). The PS group had significant improvement in all parameters from preoperation to 3-month postoperation (p < 0.05), but not from 3-month to 1-year postoperation (p ≥ 0.05). The MC-PCLR group continued to have significant improvement from 3-month to 1-year postoperation (p < 0.05). Preserving the PCL when using MC may paradoxically cause an undesired additional restrain that slows the recovery process of the patients after TKA. Compared to MC-PCLR, a PS TKA may expect significantly faster improvement at 3 months post operation, although they will achieve similar outcomes at 1-year post operation.

The impact of preoperative sarcopenia on postoperative ileus following colorectal cancer surgery.

PURPOSE: Sarcopenia is associated with poor short- and long-term patient outcomes following colorectal surgery. Despite postoperative ileus (POI) being a major complication following colorectal surgery, the predictive value of sarcopenia for POI is unclear. We assessed the association between sarcopenia and POI in patients with colorectal cancer. METHODS: Elective colorectal cancer surgery patients were retrospectively included (2018-2022). The cross-sectional psoas area was calculated using preoperative staging imaging at the level of the 3rd lumbar vertebrae. Sarcopenia was determined using gender-specific cut-offs. The primary outcome POI was defined as not achieving GI-2 by day 4. Demographics, operative characteristics, and complications were compared via univariate and multivariate analyses. RESULTS: Of 297 patients, 67 (22.6%) were sarcopenic. Patients with sarcopenia were older (median 74 (IQR 67-82) vs. 69 (58-76) years, p < 0.001) and had lower body mass index (median 24.4 (IQR 22.2-28.6) vs. 28.8 (24.9-31.9) kg/m2, p < 0.001). POI was significantly more prevalent in patients with sarcopenia (41.8% vs. 26.5%, p = 0.016). Overall rate of complications (85.1% vs. 68.3%, p = 0.007), Calvien-Dindo grade > 3 (13.4% vs. 10.0%, p = 0.026) and length of stay were increased in patients with sarcopenia (median 7 (IQR 5-12) vs. 6 (4-8) days, p = 0.013). Anastomotic leak rate was higher in patients with sarcopenia although the difference was not statistically significant (7.5% vs. 2.6%, p = 0.064). Multivariate analysis demonstrated sarcopenia (OR 2.0, 95% CI 1.1-3.8), male sex (OR 1.9, 95% CI 1.0-3.5), postoperative hypokalemia (OR 3.2, 95% CI 1.6-6.5) and increased opioid use (OR 2.4, 95% CI 1.3-4.3) were predictive of POI. CONCLUSION: Sarcopenia demonstrates an association with POI. Future research towards truly identifying the predictive value of sarcopenia for postoperative complications could improve informed consent and operative planning for surgical patients.

Clinical course and mortality in older patients with COVID-19: a cluster-based study in Hong Kong.

INTRODUCTION: Compared with previous waves of the coronavirus disease 2019 (COVID-19) pandemic in Hong Kong, the third wave involved a greater number of frail older patients. Because local healthcare policy required hospitalisation for all older adults with COVID-19, we aimed to investigate the clinical course and outcomes in such patients. METHODS: This retrospective observational study included all patients aged ≥65 years who were admitted to Tuen Mun Hospital for management of COVID-19 between 1 July 2020 and 31 August 2020. We reviewed baseline characteristics, clinical presentation, laboratory results, complications, and outcomes. We also investigated the associations of age and Clinical Frailty Scale (CFS) score with in-patient mortality. RESULTS: In total, 101 patients were included (median age, 73 years); 52.5% were men and 85% had at least co-morbid chronic disease. The most common symptoms were fever (80.2%) and cough (63.4%). Fifty-two patients (51.5%) developed hypoxia, generally on day 8 (interquartile range, 5-11) after symptom onset. Of the 16 patients who required intensive care unit support, 13 required mechanical ventilation. The overall mortality rate was 16.8%. Patients aged 65-69, 70-79, 80-89, and ≥90 years had mortality rates of 9.1%, 10%, 30%, and 25%, respectively. Patients with CFS scores of 1-2, 3-4, 5-6, and ≥7 had mortality rates of 5.7%, 14.7%, 23.5%, and 40%, respectively. A linear relationship was confirmed between the two mortality trends. CONCLUSION: Clinical deterioration was common in older patients with COVID-19; their overall mortality rate was 16.8%. Mortality increased linearly with both age and CFS score.

High resolution DOA estimation of acoustic plane waves: An innovative comparison among Cuckoo search heuristics and subspace based algorithms.

SONAR signal processing plays an indispensable role when it comes to parameter estimation of Direction of Arrival (DOA) of acoustic plane waves for closely spaced target exclusively under severe noisy environments. Resolution performance of classical MUSIC and ESPRIT algorithms and other subspace-based algorithms decreases under scenarios like low SNR, smaller number of snapshots and closely spaced targets. In this study, optimization strength of swarm intelligence of Cuckoo Search Algorithm (CSA) is accomplished for viable DOA estimation in different scenarios of underwater environment using a Uniform Linear Array (ULA). Higher resolution for closely spaced targets is achieved using smaller number of snapshots viably with CSA by investigating global minima of the highly nonlinear cost function of ULA. Performance analysis of CSA for different number of targets employing estimation accuracy, higher resolution, variance analysis, frequency distribution of RMSE over the monte Carlo runs and robustness against noise in the presence of additive-white Gaussian measurement noise is achieved. Comparative studies of CSA with Root MUSIC and ESPRIT along with Crammer Rao Bound analysis witnesses better results for estimating DOA parameters which are further endorsed from the results of Monte Carlo simulations.

The ASAS-OMERACT core domain set for axial spondyloarthritis.

BACKGROUND: The current core outcome set for ankylosing spondylitis (AS) has had only minor adaptations since its development 20 years ago. Considering the significant advances in this field during the preceding decades, an update of this core set is necessary. OBJECTIVE: To update the ASAS-OMERACT core outcome set for AS into the ASAS-OMERACT core outcome set for axial spondyloarthritis (axSpA). METHODS: Following OMERACT and COMET guidelines, an international working group representing key stakeholders (patients, rheumatologists, health professionals, pharmaceutical industry and drug regulatory agency representatives) defined the core domain set for axSpA. The development process consisted of: i) Identifying candidate domains using a systematic literature review and qualitative studies; ii) Selection of the most relevant domains for different stakeholders through a 3-round Delphi survey involving axSpA patients and axSpA experts; iii) Consensus and voting by ASAS; iv) Endorsement by OMERACT. Two scenarios are considered based on the type of therapy investigated in the trial: symptom modifying therapies and disease modifying therapies. RESULTS: The updated core outcome set for axSpA includes 7 mandatory domains for all trials (disease activity, pain, morning stiffness, fatigue, physical function, overall functioning and health, and adverse events including death). There are 3 additional domains (extra-musculoskeletal manifestations, peripheral manifestations and structural damage) that are mandatory for disease modifying therapies and important but optional for symptom modifying therapies. Finally, 3 other domains (spinal mobility, sleep, and work and employment) are defined as important but optional domains for all trials. CONCLUSION: The ASAS-OMERACT core domain set for AS has been updated into the ASAS-OMERACT core domain set for axSpA. The next step is the selection of instruments for each domain.

A systematic review of nudge theories and strategies used to influence adult health behaviour and outcome in diabetes management.

BACKGROUND: Diabetes is a chronic disease associated with a variety of complications, and nudging may be a potential solution to improve diabetes control. Since nudging is a new concept, no review of literature on nudging diabetic patients into improving their health behaviour has been done. Therefore, we aim to collate a list of nudge intervention and determine the context in which nudging is successful. METHODS: We adopted a two-arm search strategy comprising the search of literature databases and snowballing using relevant search terms. We summarized patient characteristics, the nudge intervention, according to nudging strategies, delivery mode and their outcomes. The conditions present in effective nudge interventions were assessed and reported. RESULTS: We retrieved 11,494 studies from our searches and included 33. An additional five studies were added through snowballing. Studies included utilized framing (n=5), reminders (n=10), gamification (n=2), social modelling (n=5) and social influence (n=16). Studies on reminders and gamification were more likely to have a statistically significant outcome. The targeted health behaviours identified were medication adherence, physical activity, diet, blood glucose monitoring, foot care, self-efficacy, HbA1c and quality of life. Of these, studies with adherence to medication, foot care practice and quality of life as targeted health behaviours were more likely to show a statistically significant outcome. CONCLUSION: Nudging has shown potential in changing health behaviour of patients with diabetes in specific context. We identified two possible factors (delivery mode and patient characteristics) that may affect the effectiveness of nudge intervention.

Natural clinical course of progressive supranuclear palsy in Chinese patients in Hong Kong.

INTRODUCTION: Progressive supranuclear palsy (PSP) is a common type of atypical parkinsonism. To the best of our knowledge, there has been no study of its natural clinical course among Chinese patients. METHODS: This retrospective study included 21 patients with PSP who had radiological evidence of midbrain atrophy (confirmed by magnetic resonance imaging) from the geriatrics clinics of Queen Mary Hospital and Tuen Mun Hospital. Clinical information was retrieved from clinical records, including age at onset, age at presentation, age at death, duration of symptoms, level of education, sex, presenting scores on Cantonese version of Mini-Mental State Examination, clinical symptoms, and history of levodopa or dopamine agonist intake and response. Clinical symptoms were clustered into the following categories and the dates of development of these symptoms were determined: motor symptoms, bulbar symptoms, cognitive symptoms, and others. RESULTS: Motor symptoms developed early in the clinical course of disease. Cox proportional hazards modelling showed that the number of episodes of pneumonia, time to vertical gaze palsy, and presence of pneumonia were predictive of mortality. Apathy, dysphagia, pneumonia, caregiver stress, and pressure injuries were predictive of mortality when analysed as time-dependent covariates. There was a significant negative correlation between the age at presentation and time to mortality from presentation (Pearson correlation=-0.54, P=0.04). Approximately 40% of caregivers complained of stress during the clinical course of disease. CONCLUSION: Important clinical milestones, including the development of dysphagia, vertical gaze palsy, significant caregiver stress, pressure injuries, and pneumonia, may guide advanced care planning for patients with PSP.

Impact of Weight Loss During Chemotherapy in Chinese Patients with Unresectable Pancreatic Cancer.

Background: Weight loss is frequently observed in pancreatic cancer patients. We aimed to study the prognostic impacts of weight loss early during chemotherapy. Methods: A total of 72 patients of Chinese ethnicity with unresectable pancreatic cancer who underwent chemotherapy were reviewed. Critical weight loss (CWL) was defined as weight loss ≥ 5% within one month after treatment. The prognostic impact of weight loss and CWL were analyzed. Results: 47 patients (65.3%) had weight loss after one month of treatment, with 14 (19.4%) suffering from CWL. Baseline characteristics were similar between patients with and without CWL. The median OS and Time-to-treatment-failure (TTF) of patients with CWL were shorter than those without CWL (OS: 4.8 months [CWL] versus [vs.] OS 7.1 months [No CWL]; TTF 1.6 months [CWL] vs. 3.2 months [No CWL]; both P < 0.01). CWL was an independent adverse prognosticator for OS (Hazard Ratio [HR] = 2.50; P = 0.01) and TTF (HR = 2.71; P < 0.01). Other independent prognosticators for OS were serum albumin <35 mg/dl and CA19-9 ≥ 1000 IU/ml, while CWL was the only independent prognosticator for TTF (HR 2.71 [95% CI 1.33-5.52]; P < 0.01). Conclusions: Development of CWL in early course of chemotherapy was associated with worse prognosis in Chinese patients with unresectable pancreatic cancers.

Increased nicotinamide adenine dinucleotide pool promotes colon cancer progression by suppressing reactive oxygen species level.

Nicotinamide adenine dinucleotide (NAD) exists in an oxidized form (NAD+ ) and a reduced form (NADH). NAD+ plays crucial roles in cancer metabolism, including in cellular signaling, energy production and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD+ and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD+ /NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD+ salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two-photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive reactive oxygen species (ROS) levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT-mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.

A systematic review of factors affecting medication adherence among patients with osteoporosis.

The aim of this review was to identify factors that influence patients' adherence to anti-osteoporotic therapy. Factors identified that were associated with poorer medication adherence included polypharmacy, older age, and misconceptions about osteoporosis. Physicians need to be aware of these factors so as to optimize therapeutic outcomes for patients. INTRODUCTION: To identify factors that influence patients' adherence to anti-osteoporotic therapy. METHODS: A systematic review of literature was performed for articles published up till January 2018 using PubMed®, PsychINFO®, Embase®, and CINAHL®. Peer-reviewed articles which examined factors associated with anti-osteoporotic medication adherence were included. Classes of anti-osteoporotic therapy included bisphosphonates, parathyroid hormone-related analogue, denosumab, selective estrogen receptor modulators, estrogen/progestin therapy, calcitonin, and strontium ranelate. Meta-analyses, case reports/series, and other systematic reviews were excluded. Identified factors were classified using the World Health Organization's five dimensions of medication adherence (condition, patient, therapy, health-system, and socio-economic domains). RESULTS: Of 2404 articles reviewed, 124 relevant articles were identified. The prevalence of medication adherence ranged from 12.9 to 95.4%. Twenty-four factors with 139 sub-factors were identified. Bisphosphonates were the most well-studied class of medication (n = 59, 48%). Condition-related factors that were associated with poorer medication adherence included polypharmacy, and history of falls was associated with higher medication adherence. Patient-related factors which were associated with poorer medication adherence included older age and misconceptions about osteoporosis while therapy-related factors included higher dosing frequency and medication side effects. Health system-based factors associated with poorer medication adherence included care under different medical specialties and lack of patient education. Socio-economic-related factors associated with poorer medication adherence included current smoker and lack of medical insurance coverage. CONCLUSION: This review identified factors associated with poor medication adherence among osteoporotic patients. To optimize therapeutic outcomes for patients, clinicians need to be aware of the complexity of factors affecting medication adherence.

Automated real-time detection of drug-resistant Mycobacterium tuberculosis on a lab-on-a-disc by Recombinase Polymerase Amplification.

With the emergence of multi- and extensive-drug (MDR/XDR) resistant Mycobacterium tuberculosis (M. tb), tuberculosis (TB) persists as one of the world's leading causes of death. Recently, isothermal DNA amplification methods received much attention due to their ease of translation onto portable point-of-care (POC) devices for TB diagnosis. In this study, we aimed to devise a simple yet robust detection method for M. tb. Amongst the numerous up-and-coming isothermal techniques, Recombinase Polymerase Amplification (RPA) was chosen for a real-time detection of TB with or without MDR. In our platform, real-time RPA (RT-RPA) was integrated on a lab-on-a-disc (LOAD) with on-board power to maintain temperature for DNA amplification. Sputa collected from healthy volunteers were spiked with respective target M. tb samples for testing. A limit of detection of 102 colony-forming unit per millilitre in 15 min was achieved, making early detection and differentiation of M. tb strains highly feasible in extreme POC settings. Our RT-RPA LOAD platform has also been successfully applied in the differentiation of MDR-TB from H37Ra, an attenuated TB strain. In summary, a quantitative RT-RPA on LOAD assay with a high level of sensitivity was developed as a foundation for further developments in medical bedside and POC diagnostics.

The association between distance to public amenities and cardiovascular risk factors among lower income Singaporeans.

Existing evidence on the association between built environment and cardiovascular disease (CVD) risk factors focused on the general population, which may not generalize to higher risk subgroups such as those with lower socio-economic status (SES). We examined the associations between distance to 5 public amenities from residential housing (public polyclinic, subsidized private clinic, healthier eatery, public park and train station) and 12 CVD risk factors (physical inactivity, medical histories and unhealthy dietary habits) among a study sample of low income Singaporeans aged ≥ 40 years (N = 1972). Using data from the Singapore Heart Foundation Health Mapping Exercise 2013-2015, we performed a series of logistic mixed effect regressions, accounting for clustering of respondents in residential blocks and multiple comparisons. Each regression analysis used the minimum distance (in km) between residential housing and each public amenity as an independent continuous variable and a single risk factor as the dependent variable, controlling for demographic characteristics. Increased distance (geographical inaccessibility) to a train station was significantly associated with lower odds of participation in sports whereas greater distance to a subsidized private clinic was associated with lower odds of having high cholesterol diagnosed. Increasing distance to park was positively associated with higher odds of less vegetable and fruits consumption, deep fried food and fast food consumption in the preceding week/month, high BMI at screening and history of diabetes, albeit not achieving statistical significance. Our findings highlighted potential effects of health-promoting amenities on CVD risk factors in urban low-income setting, suggesting gaps for further investigations.

From SARS to Avian Influenza Preparedness in Hong Kong.

The first human H5N1 case was diagnosed in Hong Kong in 1997. Since then, experience in effective preparedness strategies that target novel influenza viruses has expanded. Here, we report on avian influenza preparedness in public hospitals in Hong Kong to illustrate policies and practices associated with control of emerging infectious diseases. The Hong Kong government's risk-based preparedness plan for influenza pandemics includes 3 response levels for command, control, and coordination frameworks for territory-wide responses. The tiered levels of alert, serious, and emergency response enable early detection based on epidemiological exposure followed by initiation of a care bundle. Information technology, laboratory preparedness, clinical and public health management, and infection control preparedness provide a comprehensive and generalizable preparedness plan for emerging infectious diseases.

A systematic review of factors that influence treatment adherence in paediatric oncology patients.

WHAT IS KNOWN AND OBJECTIVE: Treatment adherence is an essential component in ensuring best outcomes in the management of paediatric cancers. Compared to the adult population, treatment adherence in the paediatric population is a more complex subject which involves unique dimensions. In this study, we aimed to systematically review the literature to identify factors associated with treatment adherence in the paediatric oncology population. METHODS: A literature search was carried out using related keywords on electronic databases. RESULTS AND DISCUSSION: A total of 1036 articles were reviewed, and 39 articles were found to be relevant. A comprehensive review of these articles identified 17 factors that influence adherence. These factors were classified into five major categories: patient-/caregiver-related factors; therapy-related factors; condition-related factors; health system-related factors; and social/economic factors. A baby bear model was proposed to better visualize these five categories that affect treatment adherence, and a framework of questions was designed to help clinicians identify those at risk of non-adherence for early intervention. WHAT IS NEW AND CONCLUSION: Seventeen factors reviewed were categorized into five main categories, namely patient-/caregiver-related factors, therapy-related factors, condition-related factors, health system factors and social/economic factors, as causes for poor medication adherence in the paediatric oncology population. Clinicians need to be aware that these factors can interact to influence treatment adherence and that some factors may be more relevant in specific contexts (e.g. third world countries, minority groups). The baby bear model is presented to help understand the issues affecting adherence in the paediatric oncology population, and a framework of questions is proposed to help clinicians identify patients at risk of non-adherence.

Diabetes Mellitus, Cognitive Impairment, and Traditional Chinese Medicine.

Diabetes mellitus (DM) is a metabolic disorder affecting a large number of people worldwide. Numerous studies have demonstrated that DM can cause damage to multiple systems, leading to complications such as heart disease, cancer, and cerebrovascular disorders. Numerous epidemiological studies have shown that DM is closely associated with dementia and cognition dysfunction, with recent research focusing on the role of DM-mediated cerebrovascular damage in dementia. Despite the therapeutic benefits of antidiabetic agents for the treatment of DM-mediated cognitive dysfunction, most of these pharmaceutical agents are associated with various undesirable side-effects and their long-term benefits are therefore in doubt. Early evidence exists to support the use of traditional Chinese medicine (TCM) interventions, which tend to have minimal toxicity and side-effects. More importantly, these TCM interventions appear to offer significant effects in reducing DM-related complications beyond blood glucose control. However, more research is needed to further validate these claims and to explore their relevant mechanisms of action. The aims of this paper are (1) to provide an updated overview on the association between DM and cognitive dysfunction and (2) to review the scientific evidence underpinning the use of TCM interventions for the treatment and prevention of DM-induced cognitive dysfunction and dementia.

Relaxation effect of a novel Danshensu/tetramethylpyrazine derivative on rat mesenteric arteries.

Danshen (Radix Salviae miltiorrhizae) and ChuanXiong (Ligusticum wallichii) are two traditional herbal medicines commonly used in China for the treatment of cardiovascular diseases. The active components in Danshen and ChuanXiong are Danshensu (DSS, (R)-3, 4-dihydroxyphenyllactic acid) and tetramethylpyrazine (TMP), respectively. In the present study, a new compound named ADTM, which is a conjugation of DSS and TMP, was synthesized and its effect on the contractility of rat mesenteric arteries was examined. The relaxation effect of ADTM on rat mesenteric arteries was studied using myography. The effects of ADTM on Ca(2+) channels were measured by Ca(2+) imaging and patch-clamp techniques. The results showed that ADTM caused a concentration-dependent relaxation of rat mesenteric arteries. This relaxation effect was not affected by the removal of endothelium or inhibitors of nitric oxide synthase, cyclooxygenase, guanylyl cyclase and adenylyl cyclase. Potassium channel blockers including tetraethylammonium, iberiotoxin, apamin, 4-aminopyridine, BaCl2 and glibenclamide also failed to inhibit the relaxation response to ADTM. ADTM inhibited CaCl2-induced contractions and reduced the Ca(2+) influx in isolated mesenteric arterial muscle cells. Our results suggest that ADTM may be a novel relaxing agent. Its mechanism of action involves the direct blockade of voltage-gated Ca(2+) channels in vascular smooth muscle cells, resulting in a decrease in Ca(2+) influx into the cells.

Uptake and protective effects of ergothioneine in human endothelial cells.

Ergothioneine is a thiourea derivative of histidine found in food, especially mushrooms. Experiments in cell-free systems and chemical assays identified this compound as a powerful antioxidant. Experiments were designed to test the ability of endothelial cells to take up ergothioneine and hence benefit from protection against oxidative stress. Reverse-transcription polymerase chain reaction and Western blotting demonstrated transcription and translation of an ergothioneine transporter in human brain microvascular endothelial cells (HBMECs). Uptake of [(3)H]ergothioneine occurred by the organic cation transporter novel type-1 (OCTN-1), was sodium-dependent, and was reduced when expression of OCTN-1 was silenced by small interfering RNA (siRNA). The effect of ergothioneine on the production of reactive oxygen species (ROS) in HBMECs was measured using dichlorodihydrofluorescein and lucigenin, and the effect on cell viability was studied using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. ROS production and cell death induced by pyrogallol, xanthine oxidase plus xanthine, and high glucose were suppressed by ergothioneine. The antioxidant and cytoprotective effects of ergothioneine were abolished when OCTN-1 was silenced using siRNA. The expression of NADPH oxidase 1 was decreased, and those of glutathione reductase, catalase, and superoxide dismutase enhanced by the compound. In isolated rat basilar arteries, ergothioneine attenuated the reduction in acetylcholine-induced relaxation caused by pyrogallol, xanthine oxidase plus xanthine, or incubation in high glucose. Chronic treatment with the compound improved the response to acetylcholine in arteries of rats with streptozotocin-induced diabetes. In summary, ergothioneine is taken up by endothelial cells via OCTN-1, where the compound then protects against oxidative stress, curtailing endothelial dysfunction.

Cerebral vasodilator properties of Danshen and Gegen: a study of their combined efficacy and mechanisms of actions.

Danshen and Gegen are two commonly used Chinese herbal medicines for treatment of cardiovascular diseases. The aim of the present study was to elucidate the combination effects of these two herbs on cerebral vascular tone and their underlying mechanisms of actions. Basilar artery rings were obtained from rats and precontracted with U46619. Cumulative administrations of aqueous extracts of Danshen, Gegen, or the two herbs combined (DG; ratio 7:3) produced concentration-dependent relaxation of the artery rings. Statistical analysis on these findings produced a combination index (CI) of 1.041 at ED50, which indicates the two herbs produced additive vasodilator effects when used as a combined decoction. Removal of the endothelium had no effect on the vasodilator properties of Danshen, Gegen, and DG. However, their maximum effects (Imax) were significantly blunted by a KATP channel inhibitor glibenclamide, a non-selective K(+) channel inhibitor tetraethylammonium (TEA), and by a combination of K(+) channel inhibitors (glibenclamide+TEA+iberiotoxin+4-aminopyridine+barium chloride). In addition, Danshen, Gegen, and DG produced augmentation of KATP currents and inhibited Ca(2+) influx in vascular smooth muscle cells isolated from rat basilar arteries. Furthermore, these agents inhibited CaCl2-induced contraction in the artery rings. In conclusion, the present study showed that Danshen and Gegen produced additive vasodilator effects on rat cerebral basilar arteries. These effects were independent of endothelium-derived relaxant factors (EDRF), but required the opening of KATP channels and inhibition of Ca(2+) influx in the vascular smooth muscle cells. It is suspected that the cerebral vasodilator effects of Danshen and Gegen produced either on their own or in combination, can help patients with obstructive cerebrovascular diseases.

Altered expression of Raet1e, a major histocompatibility complex class 1-like molecule, underlies the atherosclerosis modifier locus Ath11 10b.

RATIONALE: Quantitative trait locus mapping of an intercross between C57.Apoe⁻/⁻ and FVB.Apoe⁻/⁻ mice revealed an atherosclerosis locus controlling aortic root lesion area on proximal chromosome 10, Ath11. In a previous work, subcongenic analysis showed Ath11 to be complex with proximal (10a) and distal (10b) regions. OBJECTIVE: To identify the causative genetic variation underlying the atherosclerosis modifier locus Ath11 10b. METHODS AND RESULTS: We now report subcongenic J, which narrows the 10b region to 5 genes, Myb, Hbs1L, Aldh8a1, Sgk1, and Raet1e. Sequence analysis of these genes revealed no amino acid coding differences between the parental strains. However, comparing aortic expression of these genes between F1.Apoe⁻/⁻ Chr10SubJ((B/F)) and F1.Apoe⁻/⁻ Chr10SubJ((F/F)) uncovered a consistent difference only for Raet1e, with decreased, virtually background, expression associated with increased atherosclerosis in the latter. The key role of Raet1e was confirmed by showing that transgene-induced aortic overexpression of Raet1e in F1.Apoe⁻/⁻ Chr10SubJ((F/F)) mice decreased atherosclerosis. Promoter reporter constructs comparing C57 and FVB sequences identified an FVB mutation in the core of the major aortic transcription start site abrogating activity. CONCLUSIONS: This nonbiased approach has revealed Raet1e, a major histocompatibility complex class 1-like molecule expressed in lesional aortic endothelial cells and macrophage-rich regions, as a novel atherosclerosis gene and represents one of the few successes of the quantitative trait locus strategy in complex diseases.