Assessment of the cardiovascular and gastrointestinal autonomic complications of diabetes

The global prevalence of diabetes mellitus is increasing; arguably as a consequence of changes in diet, lifestyle and the trend towards urbanization. Unsurprisingly, the incidence of both micro and macrovascular complications of diabetes mirrors this increasing prevalence. Amongst the complications with the highest symptom burden, yet frequently under-diagnosed and sub-optimally treated, is diabetic autonomic neuropathy, itself potentially resulting in cardiovascular autonomic neuropathy and gastrointestinal(GI) tract dysmotility. The aims of this review are fourfold. Firstly to provide an overview of the pathophysiological processes that cause diabetic autonomic neuropathy. Secondly, to discuss both the established and emerging cardiometric methods for evaluating autonomic nervous system function in vivo. Thirdly, to examine the tools for assessing pan-GI and segmental motility and finally, we will provide the reader with a summary of putative non-invasive biomarkers that provide a pathophysiological link between lowgrade neuro inflammation and diabetes, which may allow earlier diagnosis and intervention, which in future may improve patient outcomes.

Hewei Jiangni granule alleviates visceral hypersensitivity in a rat model of non-erosive reflux disease via transient receptor potential channel signaling

Objective:To uncover the underlying mechanism of Hewei Jiangni granule(HWJNG)on non-erosive reflux disease(NERD)treatment by examining histological changes,gastrointestinal neurochemicals release and visceral hypersensitivity-related receptor expression in NERD model rats.Methods:A NERD rat model was established via a combination of basal sensitization and acid perfusion.HWJNG treatments at different doses were then administered.Pathological changes to tissues,mast cell(MC)activation,serum levels of esophageal visceral hypersensitivity-related neurochemicals,and transient receptor potential(TRP)receptor mRNA and protein levels were investigated.Results:Compared with the control group,the expression of tryptase in MCs,the changes of intercellular space,and the serum levels of substance P(SP),calcitonin gene-related peptides(CGRP)and proteinaseactivated receptor 2(PAR2)increased in the model group(all P<.05).The expression of TRP vanilloid 1(Trpv1)mRNA decreased in esophagus and dorsal root ganglia(DRG)of the model group(P=.030&P=.013),and the expression of TRP melastatin channel subfamily member 8(Trpm8)mRNA decreased in the esophagus of model group(P<.01).The level of esophageal TRPV1 protein increased in the model group(P<.01)and the level of TRPM8 protein decreased in esophagus and DRG of the model group(both P<.05).Compared with the model group,the serum levels of SP,CGRP,and PAR2 in the mediumdose HWJNG group showed significant decreases(all P<.05).The expression of Trpv1 mRNA in esophagus and DRG of the HWJNG groups and the Omeprazole group remarkably decreased(all P<.05),as was the expression of Trpm8 mRNA in esophagus of the HWJNG groups(all P<.05).Conclusion:HWJNG alleviated visceral hypersensitivity in NERD model rats by regulating TRP-mediated signaling.Our results indicate that HWJNG has potential as a therapeutic agent for NERD.

Impact of high dose vitamin C on platelet function

AIM To examine the effect of high doses of vitamin C(VitC) on ex vivo human platelets(PLTs).METHODS Platelet concentrates collected for therapeutic or prophylactic transfusions were exposed to:(1) normal saline(control);(2) 0.3 mmol/L VitC(Lo VitC); or(3) 3 mmol/L VitC(Hi VitC, final concentrations) and stored appropriately. The Vit C additive was preservative-free buffered ascorbic acid in water, pH 5.5 to 7.0, adjusted with sodium bicarbonate and sodium hydroxide. The doses of Vit C used here correspond to plasma Vit C levels reported in recently completed clinical trials. Prior to supplementation, a baseline sample was collected for analysis. PLTs were sampled again on days 2, 5 and 8 and assayed for changes in PLT function by: Thromboelastography(TEG), for changes in viscoelastic properties; aggregometry, for PLT aggregation and adenosine triphosphate(ATP) secretion in response to collagen or adenosine diphosphate(ADP); and flow cytometry, for changes in expression of CD-31, CD41 a, CD62 p and CD63. In addition, PLT intracellular Vit C content was measured using a fluorimetric assay for ascorbic acid and PLT poor plasma was used for plasma coagulation tests [prothrombin time(PT), partial thrombplastin time(PTT), functional fibrinogen] and Lipidomics analysis(UPLC ESI-MS/MS).RESULTS VitC supplementation significantly increased PLTs intracellular ascorbic acid levels from 1.2 mmol/L at baseline to 3.2 mmol/L(Lo VitC) and 15.7 mmol/L(Hi VitC, P < 0.05). VitC supplementation did not significantly change PT and PTT values, or functional fibrinogen levels over the 8 d exposure period(P > 0.05). PLT function assayed by TEG, aggregometry and flow cytometry was not significantly altered by Lo or Hi VitC for up to 5 d. However, PLTs exposed to 3 mmol/L VitC for 8 d demonstrated significantly increased R and K times by TEG and a decrease in the α-angle(P < 0.05). There was also a fall of 20 mm in maximum amplitude associated with the Hi VitC compared to both baseline and day 8 saline controls. Platelet aggregation studies, showed uniform declines in collagen and ADP-induced platelet aggregations over the 8-d study period in all three groups(P > 0.05). Collagen and ADP-induced ATP secretion was also not different between the three groups(P > 0.05). Finally, VitC at the higher dose(3 mmol/L) also induced the release of several eicosanoids including thromboxane B2 and prostaglandin E2, as well as products of arachidonic acid metabolism via the lipoxygenases pathway such as 11-/12-/15-hydroxyicosatetraenoic acid(P < 0.05).CONCLUSION Alterations in PLT function by exposure to 3 mmol/L VitC for 8 d suggest that caution should be exerted with prolonged use of intravenous high dose VitC.

Research Findings Using Mindfulness-Based Interventions for Chronic Pain

Chronic pain is a complex condition that is very detrimental to physical and psychological wellbeing. It carries a significant level of disability and economic burden. Pain patients frequently experience comorbid mental illness (e.g. depression, anxiety, PTSD, insomnia) and often require psychotherapeutic interventions in addition to medication management. Mindfulness-based interventions (MBIs) have emerged as a means to treat several chronic conditions (e.g. chronic pain, depression, anxiety, substance abuse, stress, insomnia). The objective of this review is to evaluate the current research on the use of MBIs in chronic pain managment. Although there are several controlled trials on the use of MBIs in chronic pain management, only a few studies were found that demonstrated significant effects on pain intensity, quality of life, as well as physical and psychological functioning. Therefore, the current evidence is mixed and there are insufficient data to definitively confirm the full impact of the use of MBIs in chronic pain conditions such as fibromyalgia, chronic low back pain, rheumatoid arthritis, and chronic musculoskeletal pain. The lack of compelling evidence at this time signals a demand for higher quality investigations in this area. Research examining MBIs and concomitant CBT may be of great value in order to synergize and strengthen patient outcomes.

Geldanamycin induces CHOP expression through a 4-(2-aminoethyl)-benzenesulfonyl fluoride-responsive serine protease

Dear Editor:Geldanamycin is a benzoquinone ansamycin,which wasoriginally described as a tyrosine kinase inhibitor.How-ever,subsequent studies have revealed that geldanamycinbinds to and inhibits heat-shock protein 90(Hsp90)activity[1].Hsp90 is a molecular chaperone involved in the con-formational maturation of proteins such as mutated p53,Raf-1,Akt,Bcr-Ab1,and ErbB2.It is suggested that agentsinhibiting Hsp90 have anti-cancer properties,although theprecise molecular mechanisms underlying the anti-cancereffects of geldanamycin are not well understood.Increasing evidence has suggested that diabetes andneurodegenerative disorders such as Parkinson's andAlzheimer's diseases are related to the disruption ofendoplasmic reticulum(ER)function.In response to ERstress,unfolded proteins accumulate and aggregate in theER,which will trigger many rescuer responses,includingthe unfolded protein response(UPR)and ER-associateddegradation.Interestingly,geldanamycin has been shownto upregulate ER chaperones and the expression of CHOP[2].Moreover,Hsp90 associates with PERK and IRE1α,ER-resident trans-membrane protein kinases involved inER stress response[3].These observations suggest

LL-37 induced cystitis and the receptor for advanced glycation end-products (RAGE) pathway

To elucidate pathways in bladder inflammation, we employed our physiologically relevant LL-37 induced cystitis model. Based on inflammatory studies involving other organ systems implicating the receptor for advanced glycation end-products (RAGE), we first hypothesized that RAGE is critically involved in LL-37 induced cystitis. We further hypothesized that?a common RAGE ligand high mobility group box 1 (HMGB1) is up-regulated in bladders challenged with LL-37. Finally, we hypothesized that NF-κB dependent inflammatory genes are activated in LL-37 induced cystitis. Testing our first hypothesis, C57Bl/6 mice were challenged with either saline (control) or 320 μM of LL-37 intravesically for 1 hr. After 12 or 24 hours, tissues were examined with immunohistochemistry (IHC) for RAGE, and both mRNA and protein isolation for respective qRT-PCR and Western Blot analysis. Our second hypothesis was tested by employing HMGB1 IHC. Testing our final hypothesis, qRT-PCR was performed investigating five genes: TNFα, IL-6, IL-1β, GM-CSF, COX-2. In control and LL-37 challenged tissues, IHC for RAGE revealed similar qualitative expression. Evaluation with qRT-PCR and Western Blot for RAGE revealed diminished expression at the mRNA and protein level within LL-37 challenged bladders. IHC for HMGB1 revealed a moderate qualitative increase within LL-37 challenged tissues. Finally, with the exception of TNFα, all NF-κB dependent inflammatory genes yielded substantial up-regulation. We have employed our LL-37 induced cystitis model to gain insight to wards a possible mechanistic pathway involved in bladder inflammation. This work provides data for future studies involving the inflammatory ligand HMGB1, RAGE, and receptor pathways that activate NF-κB.

Beta-adrenergic receptor polymorphisms: A basis for pharmacogenetics

Aims: Polymorphisms of the β-adrenergic receptor, the frequency of which may differ in ethnic groups, alters β-receptor function. The aim of this study was to elucidate the frequency of β1 and β2-adrenergic receptor polymorphisms in healthy Greeks and to compare with those of Caucasian European (Euro) and African American (AA) origin. Methods: Ninety-nine individuals with a median age of 63 without clinical evidence of any disease were studied. Blood samples were obtained and common β1 and β2-adrenergic receptor polymorphisms that change the en-coded amino acid were determined by pyrosequencing. Results: The most common β1-adrenergic receptor polymorphism in Greeks is nucleotide substitution cytosine for guanine at position 1165 (1165 C/G) resulting in amino acid substitution arginine for glycine at position 389 (389 Arg/Gly) with a minor allele frequency of 28% (Euro 27%, AA 42%);this polymorphism increases the sensitivity of the β1-receptor. The most common β2-adrenergic receptor polymorphism in Greeks is the nucleotide substitution guanine for adenine at position 46 (46 G/A) resulting in amino acid substitution glycine for arginine at position 16 (16 Gly/Arg) with a minor allele frequency of 38% (Euro 41%, AA 50%);this polymerphism facilitates receptor down-regulation during chronic adrenergic stimulation. Conclusion: The most common β1 and β2-adrenergic receptor polymorphisms in the Greek population are similar to those of other European ancestry, and less common than in those of African origin indicating variability in ethnic groups. This information provides insight into common polymorphisms that may assist in optimizing β-antagonist and agonist therapy.

Effect of vitamin D treatment in children with attention-deficit hyperactivity disorder

Background In this research the symptom improvement of attention-deficit hyperactivity disorder (ADHD) of children was assessed by oral vitamin D administration in Tabriz,Iran.Methods In this double-blind,randomized clinical trials,96 children (2-18 years) were enrolled to placebo and vitamin D groups.Children took vitamin D pearl (50,000 IU/week) or placebo for 6 weeks.Children,who had the change in methylphenidate dosage and received any anticonvulsants and corticosteroids were excluded from the research.ADHD symptoms were diagnosed by Conners parent rating scale (CPRS) test at baseline and after intervention.ADHD Conners divided into inattention (IA),hyperactivity/impulsivity (H/I) and combination type (C) subscales.Vitamin D serum level was assessed at baseline and after 8 weeks in both groups.Results The differences between CPRS and its subscales were not significant at baseline (P > 0.05).The Conners IA score was decreased in vitamin D group (P < 0.05;adjusted with age and baseline values).ADHD Conners and all subscale scores reduced remarkably after intervention in patients with insufficient level of vitamin D compared to placebo (P < 0.05).Conclusions Oral vitamin D improved ADHD symptoms with a particular effect on inattention symptoms.In addition,symptoms related to all subscales were improved remarkably in patients with insufficient level of vitamin D.Vitamin D treatment in children with ADHD could be considered due to the expand benefit of vitamin D in body.

卫生经济学评价报告标准共识2022(CHEERS 2022):卫生经济学评价报告指导意见更新版

卫生经济学评价是对备选行动方案的成本和结果的比较分析。2013年发表的《卫生经济学评价报告标准共识》(CHEERS)提出了卫生经济学评价的特点,确保结果正确阐释,以支持决策制订。2013版CHEERS旨在指导研究报告撰写者准确报告卫生干预和对照措施、背景、过程、结果等评价细节,使审稿人理解文章内容,帮助读者使用研究结果。本版共识将取代2013版共识,其更加适用于各类卫生经济学评价,结合学科发展和方法更新的需要,更注重患者、公众等相关利益方的参与。本共识适用多种个体或人群健康干预措施(简单或复杂)在不同政策场景的应用分析,包括医疗服务、公共卫生、教育、社会服务等。本文概要介绍了CHEERS 2022共识中包含的28个检查项及每一个检查项的相关建议。CHEERS 2022共识主要用于指导研究人员撰写拟投递同行评议学术期刊的卫生经济学评价文章,亦可用于期刊编辑和审稿专家对待发表文章的评价。熟悉了解本共识要求,还有助于研究人员规划评价研究。随着决策透明度要求提高,本共识可支持卫生技术评估机构建立评价报告标准。

2型糖尿病的新型药物治疗 新指南采用医患联合制订,并根据风险来推荐治疗方法

目前全世界有超过4.63亿成年人患有糖尿病,预计到2045年患者人数将上升至7亿1。同时,每年有近150万人死于糖尿病,其中60%以上的患者因心血管疾病死亡2,且非致死性心血管事件的风险也显著增加为减少这些风险,医学界推行了一项长达数十年的严格血糖控制策略。然而我们现在知道,这种以降糖为中心的策略对于减少糖尿病相关心血管疾病和死亡只能起到微弱的作用。幸运的是,这一发现使临床实践和药物开发重新致力于改善对患者最关键的结局。