Relationship between the Components of the Metabolic Syndrome and Measures of Bone Mineral Density in Post-Menopausal Women

Aim: To examine the association between individual components of metabolic syndrome (MetS) and bone mineral density (BMD) among postmenopausal women. Methods: A total of 177 postmenopausal women participated in a cross-sectional study. They were interviewed to collect anthropometric and demographic characteristics. BMD was measured and biochemical parameters were estimated in fasting blood samples. Univariate and multivariate analyses were used to examine the association between individual components of MetS and BMD. Results: Among 177 postmenopausal women, 116 (66%) had MetS. Women with MetS had significantly higher mean values of BMD and T scores at the total hip (P < 0.05) compared to women without MetS, which disappeared after adjustment for body weight, but not for age (P < 0.05). Features of the MetS other than waist circumference were not significantly related to BMD values at the three skeletal sites, except for diastolic blood pressure association with BMD at the femoral neck (r = 0.150, P < 0.05). BMD at the total hip was also positively associated with both of triglycerides (r = 0.157, P < 0.05) and fasting blood glucose (r = 0.193, P < 0.01). To identify the independent factors affecting the BMD at the 3 skeletal sites according to metabolic states, stepwise multiple linear regression analysis was performed. Conclusions: Body weight and osteocalcin were more strongly associated with bone mass than any other component of MetS in postmenopausal women. However, further studies seem to be needed to confirm their observation.

Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

Piezo proteins are mechanically activated ion channels,which are required for mechanosensing functions in a variety of cell types.While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for boneanabolic processes,there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage.Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis(OA)development.Mice with chondrocyte-specific inactivation of Piezo1(Piezo1^(Col2a1Cre)),but not of Piezo2,developed a near absence of trabecular bone below the chondrogenic growth plate postnatally.Moreover,all Piezo1^(Col2a1Cre) animals displayed multiple fractures of rib bones at 7 days of age,which were located close to the growth plates.While skeletal growth was only mildly affected in these mice,OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age.Likewise,when OA was induced by anterior cruciate ligament transection,only the chondrocyte inactivation of Piezo1,not of Piezo2,resulted in attenuated articular cartilage degeneration.Importantly,osteophyte formation and maturation were also reduced in Piezo1^(Col2a1Cre) mice.We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes.Finally,we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes.Collectively,our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes,but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

Combining GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular disease prevention in type 2 diabetes:A systematic review with multiple network meta-regressions

BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.AIM To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.METHODS The systematic review was conducted according to PRISMA recommendations.The protocol was registered on PROSPERO(ID:42022385007).A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment.Effect modification of prior myocardial infarction(MI)and heart failure(HF)was also explored to provide clinical insight as to when the INTRODUCTION The macro-and micro-vascular benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are independent of their glucose-lowering effects[1].In patients with type 2 diabetes(T2D),the major cardiovascular outcome trials(CVOT)showed that dipeptidyl peptidase-4 inhibitors(DPP-4I)did not improve cardiovascular outcomes[2],whereas cardiovascular benefit of GLP-1RA or SGLT-2I was significant[3,4].Further subgroup analyses indicated that the background cardiovascular risk should be considered when examining the cardiovascular outcomes of these newer glucose-lowering medications.For instance,prevention of major adverse cardiovascular events(MACE)was only seen in those patients with baseline atherosclerotic cardiovascular disease[3,4].Moreover,a series of CVOT conducted in patients with heart failure(HF)have demonstrated that(compared with placebo)SGLT-2I significantly reduced risk of hospitalization for HF or cardiovascular death,irrespective of their history of T2D[5-8].However,similar cardiovascular benefits were not observed in those with myocardial infarction(MI)[9,10].Cardiovascular co-morbidities are not only approximately twice as common but are also associated with dispropor-tionately worse cardiovascular outcomes in patients with T2D,compared to the general population[11].Therefore,it is of clinical importance to investigate whether the combination treatment of GLP-1RA and SGLT-2I could achieve greater cardiovascular benefit,particularly when considering patients with cardiovascular co-morbidities who may not gain sufficient cardiovascular protection from the monotherapies.This systematic review with multiple network meta-regressions was mainly aimed to explore whether combining GLP-1RA and SGLT-2I can provide additional cardiovascular benefit in T2D.Cardiovascular outcomes of these newer antidiabetic medications were also estimated under effect modification of prior cardiovascular diseases.This was to provide clinical insight as to when the combination treatment might be prioritized.

The water-soluble TF3 component from Eupolyphaga sinensis Walker promotes tibial fracture healing in rats by promoting osteoblast proliferation and angiogenesis

Objective:To determine the active components of Eupolyphaga sinensis Walker(Tu Bie Chong)and explore the mechanisms underlying its fracture-healing ability.Methods: A modified Einhorn method was used to develop a rat tibial fracture model.Progression of bone healing was assessed using radiological methods.Safranin O/fast green and CD31 immunohistochemical staining were performed to evaluate the growth of bone cells and angiogenesis at the fracture site.Methylthiazoletetrazolium blue and wound healing assays were used to analyze cell viability and migration.The Transwell assay was used to explore the invasion capacity of the cells.Tubule formation assays were used to assess the angiogenesis capacity of human vascular endothelial cells(HUVECs).qRT-PCR was used to evaluate the changes in gene transcription levels.Results: Tu Bie Chong fraction 3(TF3)significantly shortened the fracture healing time in model rats.X-ray results showed that on day 14,fracture healing in the TF3 treatment group was significantly better than that in the control group(P=.0086).Tissue staining showed that cartilage growth and the number of H-shaped blood vessels at the fracture site of the TF3 treatment group were better than those of the control group.In vitro,TF3 significantly promoted the proliferation and wound healing of MC3T3-E1s and HUVECs(all P<.01).Transwell assays showed that TF3 promoted the migration of HUVECs,but inhibited the migration of MC3T3-E1 cells.Tubule formation experiments confirmed that TF3 markedly promoted the ability of vascular endothelial cells to form microtubules.Gene expression analysis revealed that TF3 significantly promoted the expression of VEGFA,SPOCD1,NGF,and NGFR in HUVECs.In MC3T3-E1 cells,the transcript levels of RUNX2 and COL2A1 were significantly elevated following TF3 treatment.Conclusion: TF3 promotes fracture healing by promoting bone regeneration associated with the RUNX2 pathway and angiogenesis associated with the VEGFA pathway.

Is there a relationship between vitamin D with insulin resistance and diabetes mellitus?

Available data suggest a possible link between abnormalvitamin D level and abnormal glucose homeostasis,two of the most common chronic medical conditions.Both conditions are associated with inflammation,and the exact mechanism for role of either on the other is not well clear.Literature investigating the link between vitamin D and either pre-diabetic states or diabetes is reviewed.Vitamin D deficiency is detrimental to insulin synthesis and secretion in animal and human studies.In humans,it has been shown by majority of observational studies,that vitamin D is positively correlated with insulin sensitivity and its role is mediated both by direct mechanism through the availability of vitamin D receptors in several tissues and indirectly through the changes in calcium levels.Large number of,but not all,variable samples cross sectional human trials have demonstrated an inverse relation between vitamin D status and impaired glucose tolerance,insulin resistance or diabetes.To compliment this conclusively,evidence from intervention studies is critically warranted before we can frankly state that vitamin D plays a role in diabetes prevention or treatment.Absence of both sizable prospective observational trials utilizing 25(OH)D as the main variable and the non-availability of randomized studies specifically designed to assess the effects of vitamin D on pre-diabetes and diabetes states,are the main obstacles to draw solid and conclusive relationships.

Down-regulation of pancreatic transcription factors and incretin receptors in type 2 diabetes

Type 2 diabetes is one of the most prevalent and serious metabolic diseases.Under diabetic conditions,chronic hyperglycemia and subsequent induction of oxidative stress deteriorate pancreaticβ-cell function,which leads to the aggravation of type 2 diabetes.Although such phenomena are well known as glucose toxicity,its molecular mechanism remains unclear.In this review article,we describe the possible molecular mechanism forβ-cell dysfunction found in type 2 diabetes,focusing on(1)oxidative stress,(2)pancreatic transcription factors(PDX-1 and MafA)and(3)incretin receptors(GLP-1 and GIP receptors).Under such conditions,nuclear expression levels of PDX-1 and MafA are decreased,which leads to suppression of insulin biosynthesis and secretion.In addition,expression levels of GLP-1 and GIP receptors are decreased,which likely contributes to the impaired incretin effects found in diabetes.Taken together,it is likely that downregulation of pancreatic transcription factors(PDX-1and MafA)and down-regulation of incretin receptors(GLP-1 and GIP receptors)explain,at least in part,the molecular mechanism forβ-cell dysfunction found in type 2 diabetes.

Assessment of stable coronary artery disease by cardiovascular magnetic resonance imaging: Current and emerging techniques

Coronary artery disease(CAD) is a leading cause of death and disability worldwide. Cardiovascular magnetic resonance(CMR) is established in clinical practice guidelines with a growing evidence base supporting its use to aid the diagnosis and management of patients with suspected or established CAD. CMR is a multi-parametric imaging modality that yields high spatial resolution images that can be acquired in any plane for the assessment of global and regional cardiac function, myocardial perfusion and viability, tissue characterisation and coronary artery anatomy, all within a single study protocol and without exposure to ionising radiation. Advances in technology and acquisition techniques continue to progress the utility of CMR across a wide spectrum of cardiovascular disease, and the publication of large scale clinical trials continues to strengthen the role of CMR in daily cardiology practice. This article aims to review current practice and explore the future directions of multi-parametric CMR imaging in the investigation of stable CAD.

Clinical significance of visceral adiposity assessed by computed tomography: A Japanese perspective

Abdominal obesity,rather than total amount of fat,is linked to obesity-related disorders.Visceral adiposity is an important component of obesity-related disorders in Japanese individuals with a mild degree of adiposity compared with Western subjects.In 1983,our group reported techniques for body fat analysis using computed tomography(CT)and established the concept of visceral fat obesity in which intra-abdominal fat accumulation is an important factor in the development of obesity-related complications,such as diabetes,lipid disorders,hypertension and atherosclerosis.Our group also established ideal imaging conditions for determining abdominal fat area at the umbilical level CT scan.Visceral fat area(VFA)measured in a single slice at L4level correlated significantly with the total abdominal visceral fat volume measured on multislice CT scan.In a large-scale study of a Japanese population,the mean number of obesity-related cardiovascular risk factors(hypertension,low high-density lipoprotein cholesterolemia and/or hypertriglyceridemia,and hyperglycemia)was greater than 1.0 at 100 cm2 of VFA,irrespective of gender,age and body mass index.Our group also demonstrated that reduction of visceral fat accumulation subsequent to voluntary lifestyle modification,"Hokenshido",correlated with a decrease in the number of obesity-related cardiovascular risk factors.It is important to select the most appropriate subjects from the general population(e.g.,non-obese subjects with a cluster of risk factors for the metabolic syndrome)that are most suitable for body weight reduction,with the goal of preventing atherosclerotic cardiovascular diseases.

Role of tissue microenvironment resident adipocytes in colon cancer

Colorectal cancer(CRC) is a multifactorial disease characterized by several genetic and epigenetic alterations occurring in epithelial cells. It is increasingly recognized that tumour progression is also regulated by tumour microenvironment(TME). The bidirectional cross-talk between tumour resident adipocytes and cancer cells within TME has been proposed as active contributor to carcinogenesis. Tumour resident adipocytes exhibit an activated phenotype characterized by increased secretion of pro-tumorigenic factors(angiogenic/inflammatory/immune) which contribute to cancer cell proliferation, invasion, neoangiogenesis, evasion of immune surveillance and therapy resistance. Furthermore, adipocytes represent a fuel rich source for increasing energy demand of rapidly proliferating tumour cells. Interestingly, a relationship between obesity and molecular variants in CRC has recently been identified. Whether adipose tissue promotes cancer progression in subsets of molecular phenotypes or whether local tissue adipocytes are involved in inactivation of tumour suppressor genes and/or activation of oncogenes still needs to be explored. This editorial highlights the major findings related to crosstalk between adipocytes and colon cancer cells and how local paracrine interactions may promote cancer progression. Furthermore, we provide future strategies in studying colonic TME which could provide insights in bidirectional cross-talk mechanisms between adipocytes and colonic epithelial cells. This could enable to decipher critical signalling pathways of both early colonic carcinogenesis and cancer progression.

Adiponectin deficiency exacerbates lipopolysaccharide/ D-galactosamine-induced liver injury in mice

AIM： To examine the effects of adiponectin on the functions of Kupffer cells, key modulators of lipopolysaccharide （LPS） -induced liver injury.METHODS： D-galactosamine （GAIN） and LPS were injected intraperitoneally into adiponectin-/- mice and wild type mice. Kupffer cells, isolated from Sprague-Dawley rats, were preincubated with or without adiponectin, and then treated with LPS.RESULTS： In knockout mice, GalN/LPS injection significantly lowered the survival rate, significantly raised the plasma levels of alanine transaminase and tumor necrosis factor-α （TNF-α） and significantly reduced IL-10 levels compared with wild type mice. TNF-α gene expression in the liver was which higher and those of IL-10 were lower in knockout mice than in wild type mice. In cultured adiponectin-pre-treated Kupffer cells, LPS significantly lowered TNF-α levels and raised IL-10 levels in the culture media and their respective gene expression levels, compared with Kupffer cells without adiponectinpre-treatment.CONCLUSION： Adiponectin supresses TNF-α production and induces IL-10 production by Kupffer cells in response to LPS stimulation, and a lack of adiponectin enhances LPS-induced liver injury.

Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by azoxymethane in mice

AIM:To investigate the causal relationship between hypoadiponectinemia and colorectal carcinogenesis in in vivo experimental model,and to determine the con-tribution of adiponectin defi ciency to colorectal cancer development and proliferation.METHODS:We examined the influence of adiponectin defi ciency on colorectal carcinogenesis induced by the administration of azoxymethane(AOM)(7.5 mg/kg,in-traperitoneal injection once a week for 8 wk),by using adiponectin-knockout(KO) mice.RESULTS:At 53 wk after the fi rst AOM treatment,KOmice developed larger and histologically more progres-sive colorectal tumors with greater frequency com-pared with wild-type(WT) mice,although the tumor incidence was not different between WT and KO mice.KO mice showed increased cell proliferation of colorec-tal tumor cells,which correlated with the expression levels of cyclooxygenase-2(COX-2) in the colorectal tumors.In addition,KO mice showed higher incidence and frequency of liver tumors after AOM treatment.Thirteen percent of WT mice developed liver tumors,and these WT mice had only a single tumor.In contrast,50% of KO mice developed liver tumors,and 58% of these KO mice had multiple tumors.CONCLUSION:Adiponectin deficiency enhances colorectal carcinogenesis and liver tumor formation induced by AOM in mice.This study strongly suggests that hypoadiponectinemia could be involved in the pathogenesis for colorectal cancer and liver tumor in human subjects.

Risk stratification for ST segment elevation myocardial infarction in the era of primary percutaneous coronary intervention

Acute coronary syndromes presenting with ST elevation are usually treated with emergency reperfusion/revascularisation therapy. In contrast current evidence and national guidelines recommend risk stratification for non ST segment elevation myocardial infarction(NSTEMI) with the decision on revascularisation dependent on perceived clinical risk. Risk stratification for STEMI has no recommendation. Statistical risk scoring techniques in NSTEMI have been demonstrated to improve outcomes however their uptake has been poor perhaps due to questions over their discrimination and concern for application to individuals who may not have been adequately represented in clinical trials. STEMI is perceived to carry sufficient risk to warrant emergency coronary intervention [by primary percutaneous coronary intervention(PPCI)] even if this results in a delay to reperfusion with immediate thrombolysis. Immediate thrombolysis may be as effective in patients presenting early, or at low risk, but physicians are poor at assessing clinical and procedural risks and currently are not required to consider this. Inadequate data on risk stratification in STEMI inhibits the option of immediate fibrinolysis, which may be cost-effective. Currently the mode of reperfusion for STEMI defaults to emergency angiography and percutaneous coronary intervention ignoring alternative strategies. This review article examines the current risk scores and evidence base for risk stratification for STEMI patients. The requirements for an ideal STEMI risk score are discussed.

Diabetic cardiomyopathy: Pathophysiology, theories and evidence to date

The prevalence of type 2 diabetes(T2D)has increased worldwide and doubled over the last two decades.It features among the top 10 causes of mortality and morbidity in the world.Cardiovascular disease is the leading cause of complications in diabetes and within this,heart failure has been shown to be the leading cause of emergency admissions in the United Kingdom.There are many hypotheses and well-evidenced mechanisms by which diabetic cardiomyopathy as an entity develops.This review aims to give an overview of these mechanisms,with particular emphasis on metabolic inflexibility.T2D is associated with inefficient substrate utilisation,an inability to increase glucose metabolism and dependence on fatty acid oxidation within the diabetic heart resulting in mitochondrial uncoupling,glucotoxicity,lipotoxicity and initially subclinical cardiac dysfunction and finally in overt heart failure.The review also gives a concise update on developments within clinical imaging,specifically cardiac magnetic resonance studies to characterise and phenotype early cardiac dysfunction in T2D.A better understanding of the pathophysiology involved provides a platform for targeted therapy in diabetes to prevent the development of early heart failure with preserved ejection fraction.

ApoE isoforms,treatment of diabetes and the risk of coronary heart disease

AIM:To analyze the risk of coronary heart disease in patients with type 2 diabetes mellitus(T2DM)receiving standard medical treatment.METHODS:We performed a retrospective chart analysis of 269 middle-aged patients(age 45-64 years,mean age,53.9±5.5 years)with T2DM and without atherosclerotic cardiovascular events who underwent typing to determine their apolipoprotein E(apoE)isoforms.The apoE isoforms were determined using isoelectric focusing,followed by immunoblotting.We retrospectively evaluated the charts of the 269 patients,recorded between their first visit to the hospital(the study's start point,between 1987 and 1992)and the occurrence of an atherosclerotic cardiovascular event(the study's endpoint)or January 2004,whichever came first.The age-adjusted mean values and the prevalences of covariates were calculated to compare the laboratory data among the apoE phenotypes.To investigate the association of risk factors with the incidence of coronary heart disease during the follow-up period,monovariate and multivariate Cox regression models were used.RESULTS:At enrollment,the mean serum low density lipoprotein(LDL)cholesterol levels were lowest(2.92± 0.89 mmol/L)among the subjects with apoE2(apoE2/2 or apoE2/3)and highest(3.52±0.77 mmol/L)among the subjects with apoE4(apoE3/4 or apoE4/4).No significant differences in mean age or the percentage of smokers were observed among the three groups.Furthermore,no significant differences were observed in the systolic and diastolic blood pressures,body mass index,HbA1c level or serum triglyceride levels among the three groups.There were 47 cases of coronary heart disease over 3285 person-years of follow-up.An age-adjusted multivariate Cox proportional model identified diabetic retinopathy(hazard ratio,2.38,95% CI:1.28-4.43,P=0.006),a high systolic blood pressure(hazard ratio,1.04,95%CI:1.02-1.06,P<0.001) and high HbA1c values(hazard ratio,1.19,95%CI:1.02-1.38,P=0.0029),but not the LDL cholesterol value at enrollment(hazard ratio,1.01,95%CI:0.97-1.05,P=0.77)nor the specific apoE isoform,as significant predictors of coronary heart disease.CONCLUSION:Under standard medical treatment of diabetes,including the control of LDL cholesterol levels,the apoE4 isoform was not associated with coronary heart disease among T2DM patients.

Restrictive Cardiomyopathy Resulting from a Troponin Ⅰ Type 3 Mutation in a Chinese Family

Objective To identify the pathogenic variant responsible for restrictive cardiomyopathy （RCM） in aChinese family.Methods Next generation sequencing was used for detecting the mutation and results verified bysequencing. We used restriction enzyme digestion to test the mutation in the family members and 200 unrelatednormal subjects without any cardiac inherited diseases when the mutation was identified.Results Five individuals died from cardiac diseases, two of whom suffered from sudden cardiacdeath. Two individuals have suffered from chronic cardiac disorders. Mutation analysis revealed a novelmissense mutation in exon 7 of troponin I type 3 （TNNI3）, resulting in substitution of serine （S） withproline （P） at amino acid position 150, which cosegregated with the disease in the family, which is predictedto be probably damaging using PolyPhen-2. The mutation was not detected in the 200 unrelated subjectswe tested.Conclusion Using next generation sequencing, which has very recently been shown to be successfulin identifying novel causative mutations of rare Mendelian disorders, we found a novel mutation of TNNI3 in aChinese family with RCM.

国际糖尿病足工作组:糖尿病足溃疡分类指南——《国际糖尿病足工作组:糖尿病足防治国际指南(2019)》的一部分

国际糖尿病足工作组(IWGDF)自1999年以来一直以循证为基础发布糖尿病足病的预防和管理指南。本文中针对日常临床工作中糖尿病足溃疡的分类提出了新指南,并对既有的分类进行了综述。新指南只对现患糖尿病足溃疡进行分类,不包括用于定义未来溃疡风险的分类系统。本指南的制定是基于对现有文献的综述以及专家对最大程度影响临床结局的8个关键因素的鉴定。分类级别是根据关键因素的数量、内部和外部有效性验证以及使用意向而制定的。判定分类评分的关键因素有3种:患者相关的因素(终末期肾衰竭)、肢体相关的因素(周围动脉病变和保护性感觉丧失)和溃疡相关的因素(面积、深度、部位、单发或多发以及感染)。特殊分类系统要考虑以下5种临床情况:①卫生专业人员之间交流;②预测单个溃疡预后;③对个案临床决策的辅助;④伤口评估,有感染或无感染及周围动脉病变(评估灌注及血管重建的潜在益处);⑤用于地方、区域或国家人群结局的稽查。指南推荐:①医务人员之间交流使用SINBAD系统。②无适用于预测个体溃疡预后的分类。③感染的评估采用美国传染病学会/国际糖尿病足工作组(IDSA/IWGDF)分类系统。④评估灌注及血管重建的潜在获益使用创面、缺血、足感染(WIfI)系统。⑤人群结局的稽查使用SINBAD系统。

What is artificial endocrine pancreas? Mechanism and history

The artificial endocrine pancreas is a feedback control instrument that regulates insulin delivery on a minute-by-minute basis according to measured blood glucose levels. Only one type of bedsidetype artificial endocrine pancreas is now available in Japan: STG-22 (Nikkiso Co. Ltd., Japan). In the insulin infusion algorithm, insulin is infused on the basis ofits proportional and derivative actions, to blood glucose concentrations with a constant time delay. The bedside-type artificial endocrine pancreas has been proven to be useful not only as a therapeutic tool for diabetes mellitus, but also as an elegant research tool for investigating the pathophysiology of the disease, by using the euglycemic hyperinsulinemic glucose clamp technique. The wearable type of closed-loop system has been developed recently. The breakthrough is the establishment of a needle-type glucose sensor. The development of closed-loop glycemic control systems that enable long-term physiological regulation has focused on implantable devices. Much effort has been expended to realize these devices.

Vitamin B_(12) Deficiency in Newborns and their Mothers_Novel Approaches to Early Detection,Treatment and Prevention of a Global Health Issue

Vitamin B 12 deficiency,mostly of maternal origin in newborns,is a well treatable condition but can cause severe neurologic sequelae.In women of childbearing age and pregnant women worldwide vitamin B12 deficiency has been reported with frequencies of 10%-50%.Children with vitam in B I2 deficiency are asym ptom atic at birth but may develop severe multisystemic symptoms,including irreversible developmental impairment in the second halfyear of life.Early detection of vitamin B12 deficiency allows for presymptomatic treatment.This article provides an overview over the function of vitamin B12 and discusses causes and frequency of vitamin B12 deficiency in newborns,infants,and women of childbearing age.It describes novel successful approaches to newborn screening(NBS)for vitamin B,2 deficiency and results of a pilot study which performed systematic NBS for vitamin B12 deficiency using so-called second-tier strategies by measuring homocysteine and methylmalonic acid in dried blood spots.Recommendations for diagnostics in mothers of children with vitamin B12 deficiency are described as well as results of systematic work-up in mothers and treatment and follow-up of children with vitamin B12 deficiency detected by NBS.Treatment options of vitamin B12 deficiency are presented including a newly developed standardized supplementation scheme with exclusively oral vitamin BI2 supplementation.Recommendations for preventive approaches to vitamin Bl2 deficiency for children and mothers are stated.Many children worldwide could benefit from systematic inclusion of vitamin B12 deficiency into NBS panels.In addition,preventive approaches to maternal vitamin B12 deficiency should be implemented systematically during maternal care.

GENERATION OF TRANSGENIC MICE FOR IN VIVO DETECTION OF INSULIN-CONTAINING GRANULE EXOCYTOSIS AND QUANTIFICATION OF INSULIN SECRETION

Insulin secretion is a complex and highly regulated process.Although much progress has been made in understanding the cellular mechanisms of insulin secretion and regulation,it remains unclear how conclusions from these studies apply to living animals.That few studies have been done to address these issues is largely due to the lack of suitable tools in detecting secretory events at high spatial and temporal resolution in vivo.When combined with genetically encoded biosensor,optical imaging is a powerful tool for visualization of molecular events in vivo.In this study,we generated a DNA construct encoding a secretory granule resident protein that is linked with two spectrally separate fluorescent proteins,a highly pH-sensitive green pHluorin on the intra-granular side and a red mCherry in the cytosol.Upon exocytosis of secretory granules,the dim pHluorin inside the acidic secretory granules became highly fluorescent outside the cells at neutral pH,while mCherry fluorescence remained constant in the process,thus allowing ratiometric quantification of insulin secretory events.Furthermore,mCherry fluorescence enabled tracking the movement of secretory granules in living cells.We validated this approach in insulin-secreting cells,and generated a transgenic mouse line expressing the optical sensor specifically in pancreaticβ-cells.The transgenic mice will be a useful tool for future investigations of molecular mechanism of insulin secretion in vitro and in vivo.

Management of non-ST-segment elevation myocardial in-farction in patients aged≥80 years:a meta-analysis of ran-domized controlled trials

Coronary artery disease(CAD)is the major cause of morbidity and mortality in elderly patients.^([1])Despite this,elderly patients are under-represented in most trials of CAD.Non-ST-segment elevation myocardial infarction(NSTEMI)is a common cause of hospitalization among patients≥80 years of age,^([2])and with an aging global population,there is a pressing need to establish the optimal management strategy for these patients.Therefore,we conducted a meta-analysis of all randomized control trials(RCTs)performed to date in patients≥80 years of age,comparing an initial invasive versus conservative strategy to provide insights into their optimal initial management strategy.