Review 2014.12 CM DNA Damage Response and Metabolic Disease

DNA Damage Response and Metabolic Disease

Ippei Shimizu,1,2Yohko Yoshida,1,2Masayoshi Suda,1and Tohru Minamino1,3,*

1Department of Cardiovascular Biology and Medicine,Niigata University Graduate School of Medical and Dental Sciences,Niigata951-8510, Japan

2Department of Molecular Aging and Cell Biology,Niigata University Graduate School of Medical and Dental Sciences,Niigata951-8510, Japan

3PRESTO,Japan Science and Technology Agency,4-1-8Honcho Kawaguchi,Saitama332-0012,Japan

*Correspondence:t_minamino@yahoo.co.jp

https://www.doczj.com/doc/542255538.html,/10.1016/j.cmet.2014.10.008

Accumulation of DNA damage has been linked to the process of aging and to the onset of age-related dis-eases including diabetes.Studies on progeroid syndromes have suggested that the DNA damage response is involved in regulation of metabolic homeostasis.DNA damage could impair metabolic organ functions by causing cell death or senescence.DNA damage also could induce tissue in?ammation that disturbs the homeostasis of systemic metabolism.Various roles of molecules related to DNA repair in cellular metabolism are being uncovered,and such molecules could also have an impact on systemic metabolism.This review explores mechanisms by which the DNA damage response could contribute to metabolic dysfunction.

Introduction

Accumulation of DNA damage has been implicated in the phe-notypic manifestations of aging in rodents and humans.DNA damage can be caused by various endogenous or exogenous stresses,including oxidative stress,telomere erosion,onco-genic mutations,genotoxic stress,and metabolic stress(Lo′-pez-Ot?′n et al.,2013)(Figure1).p53is a key player in the intrinsic cellular responses to DNA damage,and activation of p53leads to cell-cycle arrest,apoptosis,and senescence(Stewart and Weinberg,2006).Cellular senescence is de?ned as a state of irreversible growth arrest accompanied by changes of both cell morphology and gene expression(Hay?ick and Moorhead, 1961).Accumulation of senescent cells,particularly senescent stem cells,could impair tissue regeneration and homeostasis, leading to metabolic dysfunction.In addition,accumulation of senescent cells in the tissues leads to chronic in?ammation mediated by various proin?ammatory cytokines and chemo-kines(Rodier et al.,2009).There is accumulating evidence that chronic in?ammation associated with senescence has a pivotal role in the progression of age-related diseases such as diabetes, cardiovascular disease,and cancer(Tchkonia et al.,2013). The number of people with obesity has increased dramatically in the modern world,and this has become a major healthcare problem for many societies.Obesity is known to be involved in the development of diabetes and atherosclerotic disease and has also been reported to increase the mortality rate,particularly deaths from cardiovascular disease(Van Gaal et al.,2006).Sys-temic insulin resistance is one of the crucial underlying molecular mechanisms that accelerates various disease states in individ-uals with obesity.It is widely accepted that an in?ammatory response in visceral fat plays an important role in the develop-ment of systemic insulin resistance associated with obesity (Rajah et al.,2001).Excessive energy intake induces the hy-pertrophy of adipocytes by increasing the in?ux of fatty acids and promotes a proin?ammatory phenotype in adipose tissue. These changes upregulate the production of chemoattractants, including the chemokine(C-C motif)ligand2(CCL2),which is also known as monocyte chemoattractant protein-1(MCP-1).Subsequent recruitment of in?ammatory cells results in a vicious cycle of adipose tissue in?ammation that leads to impairment of glucose and lipid metabolism(Hotamisligil,2006;Hotamisligil et al.,1993;Kanda et al.,2006;Weisberg et al.,2003;Xu et al., 2003).Tumor necrosis factor-alpha(TNF-a)is the best-charac-terized proin?ammatory cytokine secreted by in?ammatory macrophages that contributes to the development of systemic insulin resistance via activation of c-Jun N-terminal kinase (JNK)and I k B kinase(IKK),which inhibit insulin signaling in meta-bolic organs by serine phosphorylation of insulin receptor sub-strates(Hotamisligil,2006)(Figure2).It has been reported that inhibition of TNF-a by administration of a neutralizing antibody improves insulin sensitivity in rodents(Arau′jo et al.,2007;Borst et al.,2004).

The DNA repair system has evolved in eukaryotes to overcome DNA damage,and it includes processes such as homologous recombination(HR),nonhomologous end joining(NHEJ),base excision repair(BER),and nucleotide excision repair(NER) (Lombard et al.,2005).Double-strand DNA breaks are repaired by HR or NHEJ,whereas single-strand breaks are repaired by BER or NER.The ef?ciency of the DNA repair system appears to decrease with advancing age,leading to accumulation of DNA damage in tissues(Lombard et al.,2005).In mice and hu-mans,mutations of genes related to the DNA repair machinery result in phenotypic changes that share features with age-asso-ciated pathological conditions,including metabolic and cardio-vascular abnormalities,as well as being associated with an increased incidence of malignancies and a shortened lifespan (Hasty et al.,2003;Lombard et al.,2005).Recent studies have shown that factors involved in DNA repair also regulate cellular metabolism in response to DNA damage to avoid further genomic instability(Berkers et al.,2013;Imai and Guarente, 2014;Jeong et al.,2013).Evidence has also been obtained that suggests the cellular response to DNA damage is critically involved in the processes leading to impairment of glucose metabolism.This review focuses on the role of the DNA damage response,particularly activation of p53,in obesity and diabetes, and also explores the mechanisms that may be

involved.

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Link between the DNA Damage Response and Chronological Aging

Aging is de?ned as a progressive decline of physiological func-tion,leading to an increase in vulnerability and eventually to death.DNA damage and mutations accumulate with age,and this has been suggested to contribute to aging phenotypes and to the onset of age-associated diseases (Lombard et al.,2005).DNA damage can cause cells to enter an irreversible state of cell-cycle arrest known as cellular senescence.Although cellular senescence was initially discovered through in vitro studies (Hay?ick and Moorhead,1961),it was subsequently observed in vivo,and it was found that the number of senescent cells increases with advancing age (Dimri et al.,1995;Herbig et al.,2006).Cellular senescence has been suggested to have a potent anticancer effect,but evidence has emerged that links cellular senescence to age-related pathology (Campisi,2005;Collado et al.,2007).

The p53/p21and p16/Rb signaling pathways are known to be involved in regulation of cellular senescence,and p53protein is the best-characterized transcriptional factor mediating the DNA damage response that is involved in preserving genomic stability and inhibiting tumorigenesis.However,p53has recently been shown to have undesirable effects on aging and age-associated diseases (Vousden and Lane,2007).p53-mediated trans-criptional activity increases with age,suggesting a role of DNA damage-induced p53activation in the development of aging phe-notypes.Initial studies demonstrated that mice with one trun-cated p53mutant allele and constitutive p53activation develop premature aging,as well as showing resistance to cancer (Tyner et al.,2002)(Table 1).Likewise,mice with overexpression of a naturally occurring truncated p53isoform have a short lifespan and display premature aging (Maier et al.,2004)(Table 1).Activa-tion of p53signaling is also found in aged vessels,failing hearts,and the visceral fat of obese persons,and it reportedly contrib-utes to negative remodeling in atherosclerosis,as well as to pro-gression of heart failure and the onset of diabetes (Minamino and Komuro,2008;Minamino et al.,2009;Sano et al.,2007).Other studies have demonstrated that normal regulation of p53may in-crease longevity in mice (Garc?

′a-Cao et al.,2002;Matheu et al.,2007)(Table 1),suggesting that abnormal chronic activation of p53confers protection against cancer at the expense of reducing the lifespan.Expression of p16is also known to increase with ag-ing in mice and humans and has been found to contribute to aging phenotypes in the regenerative organs of mice (Kim and Sharp-less,2006;Krishnamurthy et al.,2004).

Association of In?ammation with Cellular Senescence Chronic low-grade sterile in?ammation is associated with age-related diseases,such as diabetes,cancer,and cardiovascular disease,and has been postulated to have a central role in accel-erating these disease processes (Hu et al.,2004;Pai et al.,2004;Schetter et al.,2010;Spranger et al.,2003).Interestingly,proin-?ammatory cytokines are elevated in the vascular cells (Donato et al.,2008)and serum (Seidler et al.,2010)of elderly persons with no overt disease,suggesting that in?ammation accompa-nying the natural aging process may contribute to the onset of age-related diseases.Cellular senescence provides a possible link between in?ammation and aging (Freund et al.,2010).An important feature shared by several types of senescent cells is persistent upregulation of in?ammatory molecules,including cy-tokines and adhesion molecules that recruit in?ammatory cells (Tchkonia et al.,2013).Proin?ammatory phenotypic changes of senescent cells may be triggered by the DNA damage response,which leads to activation of NF-k B and increased production of in?ammatory cytokines (Freund et al.,2010;Liu et al.,2011;Rod-ier et al.,2009).A number of reports have demonstrated that senescence-associated in?ammation acts as a two-edged sword.It is involved in maintaining tissue homeostasis as well as inhibiting malignancy,since proin?ammatory signals emitted by senescent cells may help to prevent the development

of

Figure 1.Stresses that Provoke the DNA Damage

Response

Figure 2.Signaling Molecules that Promote Insulin Resistance via DNA Damage

DNA damage activates p53that directly or indirectly inhibits insulin signaling via JNK/IKK-mediated pathways.DNA damage also induces b cell failure that impairs insulin secretion.Expression of glucose transporters and enzymes is directly regulated by p53,and it also in?uences glucose homeostasis by modulating key metabolic regulators such as PGC-1.ATM,PARP,and sirtuins have dual roles in DNA repair and metabolic processes,linking both in a coordinated fashion.

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cancer by promoting the elimination of cells with elevated onco-gene expression that have malignant potential(Kang et al.,2011; Lujambio et al.,2013).However,senescence-associated chronic in?ammation could also promote tumor progression by disrupting tissue architecture and inducing cellular damage (Campisi et al.,2011;Yoshimoto et al.,2013).In a similar way, senescence-associated in?ammation may be bene?cial by con-tributing to the clearance of damaged cells and limiting?brosis during tissue repair,but persistent in?ammation may have a detrimental effect on tissue homeostasis that promotes age-related diseases including diabetes(Tchkonia et al.,2013). Association of Oxidative DNA Damage and Telomere Shortening with Diabetes

A high level of oxidative DNA damage associated with an in-crease of reactive oxygen species is found in rodents and humans with diabetes.An increased serum level of8-hydroxy 20-deoxy-guanosine,a sensitive biomarker for oxidative DNA damage,has been found in obesity and diabetes and has also been reported to show a positive correlation with the body mass index of diabetic subjects(Al-Aubaidy and Jelinek, 2011).Telomeres are repeating DNA sequences located at the ends of chromosomes that have a critical role in maintaining genomic integrity(Stewart and Weinberg,2006).As a conse-quence of semiconservative DNA replication,the extreme termi-nals of chromosomes are not completely duplicated,resulting in successive shortening of the telomeres with each cell division. When the telomeres reach a critically short length,they become dysfunctional and the p53-dependent DNA damage response is activated.Telomeres are known to become shorter with ad-vancing age in humans,and telomere shortening is thought to provoke age-associated pathology(Armanios,2013).Progres-sive telomere shortening is associated with obesity and insulin resistance(Gardner et al.,2005).Among subjects with type2 diabetes,those with atherosclerotic plaques have greater short-ening of telomere length compared to those without plaques (Adaikalakoteswari et al.,2007).Since oxidative stress is known to accelerate telomere shortening,it is conceivable that the dia-betic state further exacerbates impaired glucose homeostasis by promoting telomere dysfunction.

Telomerase is an enzyme that adds telomeres to the terminals of chromosomes.Telomerase-de?cient mice have a normal phenotype in the?rst generation,presumably because mice possess very long telomeres(Blasco et al.,1997;Lee et al., 1998).However,their telomeres become shorter with successive generations,and these mice then exhibit a shortened lifespan as well as various types of age-related pathology,including a reduced capacity to respond to stresses such as wound healing and hematopoietic ablation(Rudolph et al.,1999)(Table1). When fed a high-calorie diet,these mice develop glucose intol-erance and insulin resistance without enhancement of obesity (Minamino et al.,2009)(Table1).Telomere dysfunction promotes senescence of adipocytes by activating p53-dependent signaling,thus inducing chronic in?ammation in adipose tissue and systemic insulin resistance(Figure2).Telomere dysfunction is also associated with impaired mitochondrial biogenesis and function,decreased gluconeogenesis,and an increase of reactive oxygen species(Sahin et al.,2011).Mechanistically, telomere dysfunction leads to p53activation,thereby downregu-lating the expression of peroxisome proliferator-activated re-ceptor-g coactivator(PGC)-1a and b,which are transcriptional cofactors that modulate expression of various genes involved in mitochondrial function and glucose metabolism(Sahin et al., 2011)(Figure2).Insulin secretion is impaired in mice with short telomeres,leading to glucose intolerance despite their b cell mass being normal(Guo et al.,2011)(Table1).Impaired insulin secretion seems to be multifactorial and may be mediated by b cell-autonomous defects of mitochondrial function as well as aberrant Ca2+handling.Taken together,these reports suggest that age-associated telomere shortening can lead to impairment of glucose homeostasis by inducing tissue in?ammation and dis-turbing cellular metabolism,as well as by reducing tissue regen-eration.

Role of p53Activation in Metabolic Disorders

White adipose tissue was initially thought to be mainly involved in energy storage,but it is now also recognized to be an endocrine organ that secretes various cytokines and chemokines,which are called adipokines(Hotamisligil,2006;Ouchi et al.,2011). It has been shown that in?ammation of adipose tissue,charac-terized by in?ltration of in?ammatory cells and increased pro-duction of in?ammatory cytokines,induces systemic insulin resistance and accelerates the processes underlying the devel-opment of diabetes(Johnson and Olefsky,2013).DNA damage has been linked to adipose tissue in?ammation and systemic in-sulin resistance(Shimizu et al.,2012).A high-calorie diet pro-motes hypertrophy of adipocytes by increasing the in?ux of fatty acids,leading to overproduction of reactive oxygen species, accumulation of DNA damage,and cellular senescence in adi-pose tissue.Under such conditions,p53in adipose tissue plays a pivotal role in inducing in?ammation and systemic insulin resis-tance(Minamino et al.,2009)(Figure2and Table1).In mice fed a chow diet,overexpression of adipose tissue p53also provokes in?ammation and impairs glucose metabolism.Semaphorins and their receptors(plexins)were originally identi?ed as mole-cules involved in axon guidance(Luo et al.,1993;Tamagnone et al.,1999),but have been shown to also contribute to develop-ment of the cardiovascular system during embryogenesis(Gitler et al.,2004;Torres-Va′zquez et al.,2004).Semaphorin3E (Sema3E)is one of the class3semaphorins,and its receptor is plexinD1(Christensen et al.,1998).It was recently reported that Sema3E is upregulated in obese visceral fat via a p53-dependent mechanism and acts as a chemoattractant for plex-inD1-positive in?ammatory macrophages,thus contributing to adipose tissue in?ammation and systemic metabolic dysfunc-tion through production of in?ammatory cytokines(Shimizu et al.,2013).It has been demonstrated that the p53/p21signaling pathway is critically involved in adipocyte differentiation and hy-pertrophy,which links it to obesity and insulin resistance(Inoue et al.,2008).There is also evidence that pancreatic b cell senes-cence contributes to the pathogenesis of diabetes(Tavana and Zhu,2011).One recent study demonstrated that elevation of glucose metabolism by b cells causes DNA double-strand breaks and activation of p53,leading to b cell failure in mice with type2diabetes(Tornovsky-Babeay et al.,2014)(Figure2). Likewise,mice expressing a truncated isoform of p53show hy-poinsulinemia and glucose intolerance with increased p21 expression in islets(Hinault et al.,2011)(Table1).In contrast to Cell Metabolism20,December2,2014a2014Elsevier Inc.969

these negative metabolic impacts of p53activation,it has been reported that defects in p53Ser18phosphorylation result in glucose intolerance and insulin resistance(Armata et al.,2010; Sluss et al.,2004),whereas an additional copy of normally re-gulated p53improves glucose tolerance(Franck et al.,2012) (Table1),suggesting that physiological p53activity is required to maintain metabolic homeostasis.

Recently,information on the metabolic role of p53at a cellular level has emerged with regard to regulation of tumor develop-ment as well as normal cellular homeostasis(Berkers et al., 2013;Vousden and Ryan,2009).For example,p53downregu-lates the expression of glucose transporters and glycolytic en-zymes(Kondoh et al.,2005;Schwartzenberg-Bar-Yoseph et al.,2004),while it upregulates TP53-induced glycolysis and apoptosis regulator(Bensaad et al.,2006),thereby inhibiting glycolysis(which is the preferred metabolic pathway for tumor cells).p53could negatively regulate the insulin signaling pathway by upregulating PTEN(Stambolic et al.,2001)(Figure2). Under mild stress,p53drives oxidative phosphorylation and helps to maintain mitochondrial integrity(Lebedeva et al., 2009;Matoba et al.,2006).In contrast,severe stress causes p53to repress expression of the transcriptional cofactors PGC-1a and PGC-1b that are critical regulators of mitochondrial biogenesis(Sahin et al.,2011)(Figure2).Moreover,p53func-tions as a negative regulator of lipid synthesis by activating fatty acid oxidation and by inhibiting fatty acid synthesis(

Goldstein Table1.Mutant Mice that Exhibit or Are Protected against Aging Phenotypes with Metabolic Dysfunction

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and Rotter,2012).These metabolic functions of p53may be related to regulation of systemic metabolic homeostasis,but its precise role remains to be determined.

The TP53gene has a common polymorphism at codon72,re-sulting in two variants(Arg and Pro)that differ with respect to their ef?ciency for inducing apoptosis and inhibiting tumorigen-esis.Genetic analysis has demonstrated that p53polymorphism (Arg72Pro)in?uences insulin resistance in patients with type2 diabetes(Burgdorf et al.,2011).Interestingly,single-nucleotide polymorphism of a noncoding region near CDKN2A and CDKN2B shows a strong association with diabetes(Saxena et al.,2007).Variations of genes involved in DNA damage and repair such as CHEK2have been implicated in the onset of type2diabetes(North et al.,2010),further emphasizing the crucial role of the DNA damage response in human glucose metabolism.

Metabolic and Cardiovascular Effects of the DNA Damage Response

Heart failure develops when myocardial injury reduces cardiac pump function.There is evidence of a close link between heart failure and diabetes,and clinical studies have shown that sys-temic metabolic dysfunction is prevalent among patients with cardiac dysfunction(Witteles and Fowler,2008).In addition,sys-temic insulin resistance has been shown to be a risk factor for the development of heart failure(Ingelsson et al.,2005).Heart failure has been reported to promote the accumulation of DNA damage in visceral fat and cardiac tissue that provokes adipose tissue in?ammation and systemic insulin resistance(Shimizu et al., 2012).Excessive lipolysis related to activation of the sympa-thetic nervous system leads to an increase of oxidative stress that promotes DNA damage and adipose tissue in?ammation via p53-dependent signaling.Interestingly,inhibition of adipose tissue in?ammation by deletion of p53can suppress metabolic abnormalities and improve cardiac dysfunction,indicating that a vicious feedback loop may exist between the heart and fat tis-sue.Another line of evidence has suggested a close relationship between vascular function and diabetes(Yokoyama et al.,2014). Endothelial expression of p53is markedly upregulated when mice are fed a high-calorie diet,presumably due to an increase of DNA damage related to metabolic stress.Inhibition of endo-thelial p53activation leads to improvement of insulin resistance and obesity,while upregulation of endothelial p53precipitates metabolic abnormalities by inhibiting glucose homeostasis in skeletal muscle(Table1).These?ndings raise the possibility that inhibiting the DNA damage response in certain tissues could be a therapeutic target for blocking the vicious cycle between metabolic abnormalities and cardiovascular dysfunction.

Role of Sirtuins in Metabolic Regulation and DNA Repair Silencing information regulator2(Sir2)was originally identi?ed as a transcriptional silencer of mating foci and then was found to mediate calorie restriction-induced longevity in the budding yeast Saccharomyces cerevisiae(Lin et al.,2000).A number of Sir2-related proteins(collectively known as sirtuins)have been identi?ed in many species ranging from yeasts to mammals (Longo and Kennedy,2006).Sirtuins are NAD+-dependent en-zymes that display a conserved role in age-related pathology and longevity(Finkel et al.,2009;Longo and Kennedy,2006).Mammalian sirtuins have seven isoforms,and each isoform shows distinctive localization(Haigis and Guarente,2006). SIRT1and SIRT2are found in both the nucleus and the cyto-plasm,while SIRT3,SIRT4,and SIRT5are localized to the mito-chondria.SIRT6and SIRT7show nuclear localization.Because of being NAD+dependent,it has been suggested that sirtuins play a critical role in regulating energy metabolism(Haigis and Guarente,2006).It is now widely accepted that sirtuins are important regulators of various metabolic pathways,including those involved in gluconeogenesis,glycolysis,oxidative phos-phorylation,and fatty acid oxidation(Schwer and Verdin,2008). SIRT1has been studied most extensively and is known to have a role in both gluconeogenesis and glycolysis by regulating various key modulators,such as PGC-1a and forkhead tran-scription factors(FOXO)(Brooks and Gu,2009)(Figure2). SIRT1also regulates lipid metabolism by modulating various transcriptional factors,including peroxisome proliferator-acti-vated receptor(PPAR)-a and sterol-response element-binding protein(SREBP)1c(Rodgers and Puigserver,2007;Walker et al.,2010).With regard to DNA metabolism,sirtuins have been reported to be involved in the DNA repair system,regula-tion of chromatin structure,and maintenance of telomere integ-rity(Lombard et al.,2005;Palacios et al.,2010).A critical role of SIRT1in DNA repair is strongly suggested by the observation that most Sirt1-de?cient mice undergo embryonic death due to impairment of the DNA damage response and chromosomal ab-normalities(Wang et al.,2008)(Table1).SIRT6is another nuclear sirtuin like SIRT1,and it has also been shown to have a role both in DNA repair and cellular metabolism.Sirt6-de?cient mice develop fatal hypoglycemia due to enhanced glucose uptake by muscle and brown adipose tissue with loss of subcutaneous fat,indicating a crucial role of SIRT6in glucose and lipid homeo-stasis(Mostoslavsky et al.,2006)(Table1).Sirt6de?ciency also results in hypersensitivity to genotoxic stress and genomic insta-bility,thereby leading to various abnormalities that overlap with age-associated pathology in mice(Mostoslavsky et al.,2006). In contrast,mice that overexpress Sirt6are protected against both dietary and age-associated metabolic abnormalities,and also have a longer lifespan(Kan?et al.,2010,2012)(Table1).It has been reported that SIRT6is involved in repair of double-strand DNA breaks by stabilizing DNA-dependent protein kinase at sites of NHEJ repair(McCord et al.,2009).SIRT6is also known to contribute to maintenance of telomere integrity(Michishita et al.,2008)and activates poly-ADP ribose polymerase(PARP) 1,thereby enhancing the repair of double-strand breaks by NHEJ and HR(Mao et al.,2011).

Although PARPs have long been considered to be DNA dam-age repair enzymes,recent evidence has suggested that these enzymes have an important role in metabolic regulation by in?u-encing mitochondrial function and oxidative metabolism(Krish-nakumar and Kraus,2010).PARP1and PARP2interact with a large number of nuclear receptor transcriptional factors(such as PPAR g and FOXO)to regulate mitochondrial and lipid oxida-tion genes(Bai et al.,2007;Sakamaki et al.,2009).PARP1is responsible for the majority of cellular PARP activity(Krishnaku-mar and Kraus,2010).Given that SIRT1and PARP1are both NAD+dependent,these enzymes compete for the NAD+pool, and PARP1probably in?uences Sirt1activity by reducing the bioavailability of NAD+(Imai and Guarente,2014)(Figure2).In Cell Metabolism20,December2,2014a2014Elsevier Inc.971

fact,Parp1-de?cient mice display increased energy expenditure along with a reduced fat mass and increased glucose clearance due to increased activity of SIRT1in skeletal muscle and brown adipose tissue and are therefore protected against metabolic disease(Bai et al.,2011)(Table1).Consistent with these?nd-ings,a gain-of-function mouse model with overexpression of human PARP1shows premature onset of age-associated pa-thology,enhanced adiposity(Mangerich et al.,2010),and glucose intolerance(Table1),indicating an essential role of this enzyme in metabolic regulation and age-related diseases. Since sirtuins and PARP are involved in both DNA repair and cellular metabolism,they could function as a convergence point in the regulation of both processes.It has been shown that DNA damage directly activates metabolic responses in a coordinated fashion.SIRT4is best known for its role in glutamine metabolism (Haigis and Guarente,2006).Recently,it was reported that SIRT4inhibits entry of glutamine into the TCA cycle under geno-toxic stress,thus preventing dysregulated cell proliferation and genomic instability(Jeong et al.,2013).PARP shows chronic activation with aging,and this is thought to contribute to an age-associated decline of NAD+(Imai and Guarente,2014). NAD+supplementation has a protective effect against age-induced impairment of glucose metabolism(Yoshino et al., 2011),which further suggests a pathological in?uence of DNA damage on metabolic regulation.

Relationship between DNA Damage and Metabolic Dysfunction in Progeroid Syndromes

Progeroid syndromes are heritable human disorders that cause premature aging.All of the known progeroid syndromes involve defects of the DNA repair and DNA damage responses,suggest-ing that maintenance of genomic stability has a central role in the aging process,although these syndromes only partially mimic normal human aging(Martin,2005).Among the various human progeroid syndromes,Werner syndrome(WRN)and Hutchin-son-Gilford progeria syndrome(HGPS)are two of the best-char-acterized disorders that most closely reproduce the features of normal aging.The mutation causing WRN has been identi?ed as affecting a member of the RecQ family of helicases(Yu et al.,1996).WRN protein has helicase,exonuclease,and sin-gle-stranded DNA annealing activities and is involved in DNA recombination,replication,repair,and transcription,as well as in maintaining the integrity of telomeres(Opresko et al.,2004). WRN is characterized by short stature,early graying and hair loss,increased susceptibility to relatively uncommon cancers (such as sarcomas,lymphomas,thyroid neoplasms,malignant melanoma,and meningioma),scleroderma-like skin changes, type2diabetes,and atherosclerosis.Death usually occurs in middle life due to myocardial infarction or stroke.HGPS is referred to as‘‘childhood progeria’’to differentiate it from WRN,which is referred to as‘‘adult progeria.’’Patients with HGPS appear normal at birth,but soon show premature aging that is characterized by alopecia,atherosclerosis,osteolysis, scleroderma,hyperpigmentation,and systemic insulin resis-tance(Hennekam,2006).Their mean lifespan is around13years, and the main causes of death are coronary artery disease and stroke.The genetic basis of HGPS was discovered in2003, when it was found that most persons with this disease have a sin-gle nucleotide substitution that leads to aberrant splicing of the LMNA gene encoding A-type nuclear lamins(Eriksson et al., 2003).Lamin A protein is synthesized as a precursor protein (prelamin A),and the mutation creates an abnormal prelamin A protein termed progerin.Enhancement of the DNA damage response and resulting p53-dependent senescence have been postulated to contribute to the pathogenesis of these progeroid syndromes(Gordon et al.,2014;Lombard et al.,2005).

Since patients with WRN and HGPS share common age-related features,including type2diabetes,it has been assumed that DNA damage per se can lead to impaired glucose homeo-stasis in the general population.WRN protein null mice develop normally and do not exhibit premature aging(Lombard et al., 2000)(Table1).In contrast,WRN protein-de?cient mice with shorter telomeres like humans show a variety of changes similar to those seen in WRN patients,including diabetes,graying and loss of hair,osteoporosis,and cataracts(Chang et al.,2004) (Table1),suggesting that telomere shortening is a key element in the pathology of WRN.When fed a high-calorie diet,Wrn null mice also develop weight gain,insulin resistance,and im-paired glucose tolerance(Moore et al.,2008)(Table1).It seems likely that enhancement of genomic instability by additional stresses leads to exacerbation of metabolic dysfunction in pro-geroid syndromes,although the precise mechanisms leading to development of type2diabetes in patients with WRN and HGPS have not been fully elucidated.

The BUB1B(also known as BUBR1)gene encodes a mitotic regulator that ensures accurate segregation of chromosomes. BUB1B mutations are known to cause mosaic variegated aneu-ploidy syndrome,which is a rare condition characterized by a short lifespan,increased incidence of cancer,and develop-mental delay(Hanks et al.,2004).It has been reported that Bub1b expression decreases with age in various murine tissues, while sustained Bub1b overexpression protects against aneu-ploidy and cancer,delays the onset of age-related dysfunction, and extends the lifespan of mice(Baker et al.,2013a)(Table1), suggesting a potential role of Bub1b in chronological aging. Mutant mice carrying Bub1b hypomorphic alleles develop various phenotypic features of premature aging that include a short lifespan,fat loss,sarcopenia,and cataracts(Table1). These mice show selective accumulation of p16-positive cells in tissues that develop age-associated pathological changes, including adipose tissue,skeletal muscle,and the eye(Baker et al.,2004).The contribution of cellular senescence to aging in this mouse model has been demonstrated through an elegant transgenic system that involved elimination of p16-positive cells by a drug-inducible caspase.The inducible deletion of p16-pos-itive senescent cells delays age-related tissue changes in mice with a Bub1b progeroid background(Baker et al.,2011),indi-cating that removal of senescent cells can inhibit tissue dysfunc-tion associated with aging.In contrast to other mouse models of premature aging,loss of p53or p21has been shown to accel-erate cellular senescence in the adipose tissue and skeletal mus-cles of Bub1b progeroid mice(Baker et al.,2013b),suggesting that the p53/p21pathways regulate cellular senescence in a context-dependent manner.

ERCC1-ERCC4(also known as XPF)is a structure-speci?c heterodimeric endonuclease required for NER as well as for repair of DNA interstrand crosslinks.Mutations in both of its sub-units have been found to cause segmental progeroid syndromes

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in humans (Grillari et al.,2007),while mouse models of Ercc1or Ercc4de?ciency show a severe progeroid phenotype (McWhir et al.,1993;Tian et al.,2004)(Table 1).It was recently reported that DNA damage triggers adipose tissue in?ammation in a pro-geroid mouse model of Ercc1de?ciency,resulting in fat loss and insulin resistance (Table 1).Deletion of Ercc1leads to persistent DNA damage and increases the expression of proin?ammatory cytokines in adipocytes via histone modi?cations associated with transcriptional activation and dissociation of nuclear recep-tor corepressor complexes from the promoters of proin?amma-tory cytokines (Karakasilioti et al.,2013).These ?ndings clearly indicate that DNA damage itself is suf?cient to trigger in?am-mation that leads to impaired glucose metabolism.Investigation of Ercc1-de?cient mice has also revealed a shift toward anabo-lism and reduced signaling via the growth hormone/insulin-like growth factor (IGF)-1pathway (Niedernhofer et al.,2006).Since similar changes occur in response to chronic genotoxic stress and calorie restriction or with aging,it is assumed that DNA dam-age induces a metabolic shift from growth to preservation of the organism in order to minimize further damage.Consistent with this hypothesis,genetic disruption of Sirt6in mice increases genomic instability and shortens the lifespan along with suppres-sion of the IGF axis (Mostoslavsky et al.,2006;Schwer et al.,2010).There is evidence that p53may be one of the regulators

linking the DNA damage response to the IGF axis (Maier et al.,2004),but it remains unclear how the metabolic shift induced by DNA damage contributes to age-related pathology such as effects on glucose homeostasis and the lifespan in progeroid syndromes and during the normal aging process.

Ataxia telangiectasia (A-T)is an autosomal recessive disease caused by mutations of the ataxia telangiectasia mutated (ATM)gene (Martin,2005).ATM is a protein kinase that has a critical role in the DNA damage response to double-stranded DNA breaks (Lombard et al.,2005).When ATM is activated,it phos-phorylates p53at a site that regulates transcriptional activity.Patients with A-T are characterized by growth retardation,an increased incidence of cancer,and neuronal degeneration.They also have an elevated risk of insulin resistance and type 2diabetes (Bar et al.,1978;Schalch et al.,1970).Against an Apoe null back-ground,Atm de?ciency in mice causes exacerbation of various features of metabolic syndrome,including increased adiposity,in-sulin resistance,hypertension,and atherosclerosis (Schneider et al.,2006)(Table 1).ATM seems to play a protective role by inhibiting JNK,a kinase involved in in?ammation and insulin resis-tance (Aguirre et al.,2000;Hirosumi et al.,2002)(Figure 2).In addi-tion,it was reported that Atm de?ciency does not affect fasting glucose levels and insulin sensitivity,but signi?cantly impairs glucose tolerance related to delayed insulin secretion by pancre-atic b cells (Miles et al.,2007)(Figure 2and Table 1).Furthermore,Atm activation is required for insulin-induced phosphorylation of Akt and for glucose transport in mouse skeletal muscle (Ching et al.,2013)(Figure 2).Interestingly,the effects of Atm de?ciency are also observed in the absence of DNA damage,suggesting that it can mediate the response to metabolic stress via a mechanism independent of the DNA damage response.Mammalian cells that lack ATM are known to have high ROS levels and show hypersen-sitivity to oxidative stress (Barzilai et al.,2002).ATM is the sensor for reactive oxygen species in human ?broblasts (Guo et al.,2010),and it has also been reported to mediate mitochondrial ROS signaling and to extend the lifespan of yeast (Schroeder et al.,2013).A more recent study demonstrated that ATM pro-motes antioxidant defenses and the repair of double-strand DNA breaks by activating the pentose phosphate pathway,which represents a link between DNA repair processes and cellular metabolism (Cosentino et al.,2011).

Conclusions

Accumulation of DNA damage can promote metabolic dysfunc-tion in two ways,which are cell-autonomous and non-cell-auton-omous mechanisms (Figure 3).Tissue regeneration is impaired by DNA damage-induced senescence and/or apoptosis of stem cells and somatic cells,leading to metabolic dysfunction such as pancreatic b cell loss.DNA damage induces non-cell-auto-nomous tissue in?ammation through upregulation of cytokines and chemokines,resulting in interference with systemic insulin signaling.DNA damage can also affect systemic metabolic ho-meostasis through in?uences on cellular metabolism and the endocrine system.In particular,activation of the DNA damage response in certain tissues could in?uence the function of vital metabolic organs,thereby provoking systemic insulin resistance.Thus,better understanding of the systemic DNA damage res-ponse may help us to develop novel therapeutic strategies for metabolic

disorders.

Figure 3.Potential Mechanisms by which the DNA Damage Response Contributes to Metabolic Dysfunction

Various stresses provoke the DNA damage response,leading to an increase of in?ammation,a decrease of regeneration,impairment of cellular metabolism,and suppression of endocrine function.These changes can disturb systemic metabolic homeostasis and contribute to the onset of diabetes.

Cell Metabolism 20,December 2,2014a2014Elsevier Inc.973

Cells have evolved various systems to actively regulate nutrient availability in order to maintain homeostasis,and have also developed active DNA repair machinery to avoid detri-mental genomic instability.Evidence has been obtained that suggests that these two distinct cellular activities are highly co-ordinated.In this review,we have described some of the key reg-ulatory molecules with dual roles in regulating DNA repair and cellular metabolism,including p53,sirtuins,PARP,and ATM. Future studies are expected to identify additional factors that modulate both processes and shed further light on the role of DNA damage in metabolic homeostasis.

Another intriguing aspect of DNA damage is that cellular re-sponses are determined by the extent of the damage.For example,mild DNA damage induces reversible cell-cycle arrest to allow repair,whereas moderate to severe DNA damage leads to senescence or death that prevents the accumulation of potentially tumorigenic damaged cells.However,an exces-sively prolonged DNA damage response has a detrimental impact on metabolic homeostasis as well as on tumorigenesis via cell-autonomous and/or non-cell-autonomous mechanisms. Likewise,normal p53activity is required for the physiological regulation of glucose metabolism,but inhibiting dysregulated p53activation is bene?cial for attenuating insulin resistance associated with dietary obesity,suggesting that?ne-tuning of the DNA damage response is critical for the prevention and treatment of metabolic diseases.

ACKNOWLEDGMENTS

This work was supported by a Grant-in-Aid for Scienti?c Research,a Grant-in-Aid for Scienti?c Research on Innovative Areas(Stem Cell Aging and Disease), and a Grant-in-Aid for Exploratory Research from the Ministry of Education, Culture,Sports,Science and Technology(MEXT)of Japan and grants from the Ono Medical Research Foundation,the Japan Diabetes Foundation,the Takeda Science Foundation,and the Takeda Medical Research Foundation (to T.M.),and by a grant from Bourbon(to T.M.,I.S.,and Y.Y.). REFERENCES

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二级乙等医院评审标准

二级综合医院评审标准（2012年版） 发表者：徐江 为全面推进深化医药卫生体制改革和公立医院改革，逐步建立我国医院评审评价体系，促进医疗机构加强自身建设和管理，持续改进医疗质量，保证医疗安全，改善医疗服务，更好地履行社会职责和义务，提高医疗行业整体服务水平与服务能力，满足人民群众多层次的医疗服务需求，在总结我国第一周期医院评审和医院管理年活动等工作经验基础上制定本标准。用于二级综合性医院，其他各类二级医院参照使用。 设置7章69节356条标准与监测指标。 第一章至第六章共63节321条标准，用于医院自我评价与改进，并作为对二级综合医院实地评审。 第七章共6节35条监测指标，用于对二级综合医院的日常运行、医疗质量与安全指标的监测与评审后的追踪评价。 说明： 1.二级医院是向含有多个社区的地区(人口一般在数十万左右)提供医疗为主，兼顾预防、保健和康复医疗服务并承担一定教学和科研任务的综合或专科的地区性医疗机构；本标准中，“县医院”为政府举办的县域内医疗卫生中心，应结合当地疾病谱特点，重点加强严重危及当地人民群众健康的疑难病救治及危急重症患者抢救能力。同时，承担对乡镇卫生院、村卫生室的业务技术指导和卫生人员的进修培训。 2.本标准中引用的疾病名称与ICD-10编码采用《疾病和有关健康问题的国际统计分类》，人民卫生出版社，第十次修订本第二版（北京协和医院、世界卫

生组织、国际分类家族合作中心编译）。 3.本标准中引用的手术名称与ICD-9-CM-3编码采用《国际疾病分类手术与操作》，人民军医出版社，第九版临床修订本2008版（刘爱民主编译）。 第一章医院功能任务 一、医院设置、功能和任务符合区域卫生规划和医疗机构设置规划的定 位和要求 （一）医院的功能、任务和定位明确，保持适度规模。 （二）主要承担常见病、多发病、部分疑难病的诊疗工作，兼顾预防、 保健、康复功能，可提供24小时急危重症诊疗服务。 （三）临床科室诊疗科目设置、人员梯队与诊疗技术能力达到省级卫生 行政部门规定的二级医院标准。 （四）医技科室服务能满足临床科室需要，项目设置、人员梯队与技术 能力达到省级卫生行政部门规定的二级医院标准。 二、科学规范的内部管理机制 （一）坚持公立医院公益性，把维护人民群众健康权益放在第一位。 （二）按照省级卫生行政部门规定，实施住院医师规范化培训工作。 （三）将推进规范诊疗、临床路径管理和单病种质量控制，作为推动医 疗质量持续改进的重点项目。 （四）提高工作绩效，优化医疗服务系统与流程，缩短平均住院日、缩 短患者就医等候时间。 （五）按照《国家基本药物临床应用指南》、《国家基本药物处方集》及 医疗机构药品使用管理有关规定，规范医师处方行为，确保基本药物得到优 先合理使用。

《三级综合医院评审标准》

《三级综合医院评审标准》 一、医院功能与任务 (50分) (一)医疗服务 (20分) 能提供全面连续的医疗护理、预防保健和康复医疗服务。 1、在高质量综合性医疗服务的基础上，提供高水平的专科服务。承担危急重症和疑难病诊治任务，开展双向转诊。 2、有足够的医疗服务辐射能力,年出院病人中应有一定比例来自医院所在地以外的地区或省。 3、按国家有关规定，参加当地急诊医疗网，在卫生行政部门领导下，能配合急救中心迅速做出应急反应，承担灾害事故的紧急救援任务，并能接受成批伤病员进行院内急救。 4、开展心理卫生、遗传找寻门诊服务和支持、指导社区医疗、护理、康复医疗服务。 (二)教学科研 (15分) 1、承担高等医学院的临床教学和实习，能培养高级临床医学人才。并承担二级医院技术骨干的临床专业进修任务。 2、承担国家、省 (自治区,直辖市)科研课题。 (三)业务技术指导 (10分) 履行对下级医疗机构技术指导是医院的职责和义务，建立经常性技术指导与合作关系，帮助开展新技术、新项目，解决疑难问题，培养卫生技术和管理人才。完成当地卫生行政部门的卫生或支农工作。 (四)预防保健 (5分) 1、开展健康教育 2、承担当地卫生行政部门交办的预防保健，主要慢性非传染性疾病(心、脑血管疾病、恶性肿瘤)的临床流行病学调查和防治工作。 3、参与城市初级卫生保健工作。 二、科室设置(30分) 医院科室设置应与其功能、任务和规模相适应。职能科室的设置应符合精简、高效的原则，适应管理工作的需要。业务科室应在《医疗机构设置规划》的指导下和整体发展的基础上，加强专科建设，部分一级科室实行二级分科，突出专科优势。 （一）临床科室(20分) 1、一级专业科室 应符合《医疗机构基本标准》及当地<医疗设置规划>的规定。

三级综合医院评审标准(2011年版)

三级综合医院评审标准（2011年版）为全面推进深化医药卫生体制改革，积极稳妥推进公立医院改革，逐步建立我国医院评审评价体系，促进医疗机构加强自身建设和管理，不断提高医疗质量，保证医疗安全，改善医疗服务，更好地履行社会职责和义务，提高医疗行业整体服务水平与服务能力，满足人民群众多层次的医疗服务需求，在总结我国第一周期医院评审和医院管理年活动等工作经验的基础上，制定本标准。 本标准在关注医疗质量和医疗安全的同时，紧紧围绕医改中心任务，结合公立医院改革总体设计，将评价的重点放在改进服务管理、加强护理管理、城乡对口支援、住院医师规范化培训、推进规范诊疗和单病种费用控制等工作落实情况。同时，针对群众关心的热点、焦点问题，重点考核反映医院管理理念、服务理念的制度、措施及落实情况，以及医院的学科建设和人才培养情况、辐射带动作用等。促使医疗机构改进思维模式和管理习惯，坚持“以人为本”、“以病人为中心”，走以内涵建设为主、内涵与外延相结合的发展道路。 本标准共7章72节，设置391条标准与监测指标。 第一章至第六章共66节354条标准，用于对三级综合医院实地评审，并作为医院自我评价与改进之用。 第七章共6节37条监测指标，用于对三级综合医院的运行、医疗质量与安全指标的监测与追踪评价。 本标准适用于三级综合性公立医院，其余各级各类医院可参照使

用。 特别说明：在本标准中引用的疾病名称与ICD-10编码采用人民卫生出版社出版的《疾病和有关健康问题的国际统计分类》第十次修订本第二版（北京协和医院、世界卫生组织、国际分类家族合作中心编译）。 在本标准中引用的手术名称与ICD-9-CM-3编码采用人民军医出版社出版的《国际疾病分类手术与操作》第九版临床修订本2008版（刘爱民主编译）。 2

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————————————————————————————————作者: ————————————————————————————————日期：

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(2011-11-09 19:16:46) ——组织和策划湛江中心人民医院创建三甲医院实践 第一部分医院服务 预约管理 1、实行多种形式的预约诊疗服务：包括诊室、现场、电话、网络四种形式。 2、预约实行时间段形式。 3、提前预约时间不受限制，门诊和出院病人复诊可采取中长期预约。 4、预约挂号采取实名制，抵制“号贩”。 5、有预约诊疗工作流程，有医院领导层分工负责，医疗事务部负责实施。 6、特殊情况需变动出诊时间，至少提前一周公告。对已预约病人短信告知。 7、有对医务人员，重点是专家门诊、专病门诊等的管理制度。 8、专家门诊、专病门诊全部实行预约，并有限号措施，以保证质量。普通门诊预约不超过20%。 9、在门诊便民服务中心、预约处以及门诊候诊区域有主动提示初诊患者可通过预约挂号复诊的指示或其他告知形式。 10、普通门诊应有一月内医师排班的告知信息。 11、建立有与社区卫生服务机构和基层医院的预约转诊服务。 门诊流程管理 1、门诊布局遵循以疾病群相对集中、疾病群检查相对集中的原则设置。 2、有门诊病人就诊流程。门诊大厅显著位置有病人就诊、检查、住院的流程图。 3、每个候诊区域有检查预约中心、医技检查区域、住院预约中心的图示。 4、各个部门有本部门服务的流程图、时间段。 5、医技部门有预约、检查、取报告的流程及时间表；有检查注意事项告示。 6、有医技检查预约中心，中心有预约流程图。

7、有住院预约中心，有住院服务告知。 8、门办负责门诊就诊流程优化，每季召开专题会议，研究流程优化。 9、开展自助挂号等多种形式，对象为复诊病人及医保、农保病人，缩短挂号时间，缩短就诊流程。 10、医技部门有有效措施为危重病人优化检查、取报告流程。 便民措施 1、门诊挂号区域公开医生出诊信息。 2、缩短候诊时间：挂号排队不超过20分钟，取药不超过15分钟。 3、候诊、侯检有提示，重点科室有二次信息叫号措施。 4、开展夜间门诊、节假日门诊和节假日专家门诊。 5、提供简易的便民物品：如轮椅、雨伞、开水等。 6、开展重点专科简易门诊，包括心内科、神经内科、内分泌科。 7、开展导医服务，提供咨询服务。 8、开展形式多样的志愿者活动。至少节假日有志愿者在门急诊、病区开展活动。 9、对70岁以上老人及外地病员住院，优先安排。 10、每周有医护人员下社区卫生服务中心指导业务工作。每月有医护人员下社区开展健康宣教活动，并有记录。 11、病区：提供费用、价格查询服务；提供出院叫车服务；提供出院预约服务、提供家属生活指南等。查房期间家属等候区提供座椅设施。 12、候诊、侯检区域有通过排队叫号的队列提示。 13、门诊候诊区域提供座椅设施。 14、出院结算全年无休。 医保政策及价格公示 1、相关医疗保险政策、法规及时公示，有明确的渠道，在一周内告知医务人员，并有医务人员接获信息的记录。 2、告知医保病人及家属相关医保（含农保等）信息与自负费用的诊疗项目：

二级综合医院评审标准

二级综合医院评审标准（2012年版） 第五章护理管理与质量持续改进 一、护理管理组织体系 （一）院领导履行对护理工作领导责任，对护理工作实施目标管理，协调与落实全院各部门对护理工作的支持，具体措施落实到位。 （二）执行二级（医院-科室）护理管理组织体系，逐步建立护理垂直管理体系，按照《护士条例》的规定，实施护理管理工作。 （三）建立护士岗位责任制，推行责任制整体护理工作模式，明确临床护理内涵及工作规范，对患者提供全面、全程、专业、人性化的护理服务。 （四）实行护理目标管理责任制、岗位职责明确，落实护理常规、操作规程等，有相应的监督与协调机制。 二、护理人力资源管理 （一）有护士管理规定、岗位职责、岗位技术能力要求和工作标准，同工同酬。 （二）护士人力资源配备与医院的功能和任务一致，有护理单元护士的配置原则，有紧急状态下调配护理人力资源的预案。 （三）以临床护理工作量为基础，根据收住患者特点、

护理等级比例、床位使用率对护理人力资源实行弹性调配。 （四）建立基于护理工作量、质量、患者满意度并结合护理难度、技术要求等要素的绩效考核制度，并将考核结果与护士的评优、晋升、薪酬分配相结合，实现优劳优得，多劳多得，调动护士积极性。 （五）有护士在职培训计划、保障措施到位，并有实施记录。 三、临床护理质量管理与改进 （一）根据分级护理的原则和要求，有护理质量评价标准，有质量可追溯机制。 （二）依据《护士条例》、《综合医院分级护理指导原则》、《临床护理实践指南（2011版）》等文件要求，规范护理行为，措施落实到位。 （三）开展优质护理服务试点工作，（可选，县医院为必选）。 （四）实施责任制整体护理，责任护士全面履行专业照顾、病情观察、治疗处置、康复指导、健康教育等护理职责，为患者提供连续、全程、优质的护理服务。 （五）有危重患者护理常规，密切观察患者的生命体征和病情变化，护理措施到位，患者安全措施有效，记录规范。 （六）遵照医嘱为围手术期患者提供符合规范的术前和术后护理。 （七）遵照医嘱为患者提供符合规范的治疗、用药等护

医院等级评审标准解读(1)

医技部门有预约、检查、取报告的流程及时间表；有检查注意事项告示。 门办负责门诊就诊流程优化，每季召开专题会议，研究流程优化。 (2011-11-09 19:16:46) ――组织和策划湛江中心人民医院创建三甲医院实践 第一部分医院服务 预约管理 1、实行多种形式的预约诊疗服务：包括诊室、现场、电话、网络四种形式。 2、预约实行时间段形式。 3、提前预约时间不受限制，门诊和出院病人复诊可采取中长期预约。 4、预约挂号采取实名制，抵制“号贩”。 5、有预约诊疗工作流程，有医院领导层分工负责，医疗事务部负责实施。 6特殊情况需变动出诊时间，至少提前一周公告。对已预约病人短信告知。 7、有对医务人员，重点是专家门诊、专病门诊等的管理制度。 8、专家门诊、专病门诊全部实行预约，并有限号措施，以保证质量。普通 门诊预约不超过20%。 9、在门诊便民服务中心、预约处以及门诊候诊区域有主动提示初诊患者可 通过预约挂号复诊的指示或其他告知形式。 10、普通门诊应有一月内医师排班的告知信息。 11、建立有与社区卫生服务机构和基层医院的预约转诊服务。 门诊流程管理 1、 门诊布局遵循以疾病群相对集中、疾病群检查相对集中的原则设置。 2、 有门诊病人就诊流程。门诊大厅显著位置有病人就诊、检查、住院的流 程图。 3、 每个候诊区域有检查预约中心、医技检查区域、住院预约中心的图示。 4、 各个部门有本部门服务的流程图、时间段。 5、 6、 有医技检查预约中心，中心有预约流程图。 7、 有住院预约中心，有住院服务告知。 8、

9、开展自助挂号等多种形式，对象为复诊病人及医保、农保病人，缩短挂 号时间，缩短就诊流程。 10、医技部门有有效措施为危重病人优化检查、取报告流程。 便民措施 缩短候诊时间：挂号排队不超过 20分钟，取药不超过15分钟。 开展重点专科简易门诊，包括心内科、神经内科、内分泌科。 开展形式多样的志愿者活动。至少节假日有志愿者在门急诊、病区开展 活动。 10、每周有医护人员下社区卫生服务中心指导业务工作。每月有医护人员下 社区开展健康宣教活动，并有记录。 11、病区：提供费用、价格查询服务；提供出院叫车服务；提供出院预约服 务、提供家属生活指南等。查房期间家属等候区提供座椅设施。 12、候诊、侯检区域有通过排队叫号的队列提示。 13、门诊候诊区域提供座椅设施。 14、出院结算全年无休。 医保政策及价格公示 1、相关医疗保险政策、法规及时公示，有明确的渠道，在一周内告知医务 人员，并有医务人员接获信息的记录。 2、告知医保病人及家属相关医保（含农保等）信息与自负费用的诊疗项目: 门诊途径：医生、便民服务中心、显示屏幕、书面告知； 住院：书面告知，含各类检查、治疗（各种药品、各类耗材、植入性器材） 3、有专（兼）职人员负责实施医保管理。 4、公示服务价格，向社会公开收费项目编码、收费项目和标准，地点：门 诊（查询电脑，1、 门诊挂号区域公开医生出诊信息。 2、 3、 候诊、侯检有提示，重点科室有二次信息叫号措施。 4、 开展夜间门诊、节假日门诊和节假日专家门诊。 5、 提供简易的便民物品：如轮椅、雨伞、开水等。 6、 7、 开展导医服务，提供咨询服务。 8、 9、 对70岁以上老人及外地病员住院，优先安排。

二级医院评审标准

医疗机构基本标准（试行） 本标准为医疗机构执业必须达到的最低标准，是卫生行政部门核发《医疗机构执业许可证》的依据。 少数地区执行本标准确有困难的，可由省、自治区、直辖市卫生行政部门根据实际情况调整某些指标，作为地方标准，报卫生部核准备案后施行。 尚未列入本标准的医疗机构，可比照同类医疗机构基本标准执行。 民族医医院基本标准由各省、自治区、直辖市卫生行政部门制定。 第一部分医院基本标准 综合医院 中医医院 中西医结合医院 民族医医院 专科医院 口腔医院 肿瘤医院 儿童医院 精神病医院 传染病医院 心血管病医院 血液病医院 皮肤病医院

整形外科医院 美容医院 康复医院 疗养院 第二部分妇幼保健院基本标准 一级妇幼保健院 二级妇幼保健院 三级妇幼保健院 第三部分乡（镇）、街道卫生院基本标准 床位总数在１９张以下的乡（镇）、街道卫生院 床位总数２０至９９张的乡（镇）、街道卫生院 第四部分门诊部基本标准 综合门诊部 中医门诊部 中西医结合门诊部 民族医门诊部 专科门诊部 普通专科门诊部 口腔门诊部 整形外科门诊部 医疗美容门诊部 第五部分诊所、卫生所（室）、医务室、中小学卫生保健所、

卫生站基本标准 诊所、卫生所（室）、医务室 中医诊所 中西医结合诊所 民族医诊所 口腔诊所 美容整形外科诊所 医疗美容诊所 精神卫生诊所 中小学卫生保健所 卫生站 第六部分村卫生室（所）基本标准 第七部分专科疾病防治院、所、站基本标准口腔病防治所 职业病防治所 职业病防治院 第八部分急救中心、站基本标准 急救站 急救中心 第九部分临床检验中心基本标准 市（地级）临床检验中心 省临床检验中心

《三级医院评审标准(2020年版)》解读

《三级医院评审标准（2020年版）》解读 一、为什么要修订医院评审标准？ 医院评审是政府实施行业监管，推动医院不断加强内涵建设，完善和落实医院管理制度，促进医院高质量发展的重要抓手，也是国际上医院管理的通行做法。1994年发布的《医疗机构管理条例》明确规定“国家实行医疗机构评审制度”，在法规层面将医院评审工作制度固定下来。1995年，原卫生部发布《医疗机构评审办法》，确定了医疗机构评审的基本原则、方法和程序，开展医疗机构评审工作。为提高医院评审工作的科学性、时代性、精准性，按照《医疗机构管理条例》和《医疗机构评审办法》规定，我委于2011年制定发布《医院评审暂行办法》和《三级综合医院评审标准（2011年版）》。该标准颁布实施9年以来，在指导各地加强评审标准管理、规范评审行为、强化医院主体责任和保障医疗质量安全等方面发挥了重要作用。随着医药卫生体制改革的深入，该标准已不能满足医疗服务管理需要，迫切需要进行修订，主要体现在以下几个方面：一是2011年以后颁布了一系列新的法律、法规、规章以及医院管理的制度、规范，分级诊疗体系建设、现代医院管理制度对医院也提出了明确要求，原评审标准未能体现。二是我委于2017年按照国务院“放管服”改革要求取消了“三级医院评审结果复核与评价”行政审批事项，需要制定新的标准以发挥医院评审工作在推动医

院落实深化医药卫生体制改革，提高管理水平中的作用。三是利用信息化手段开展医疗质量管理工作取得明显成效，能够推动医院评审更加科学、客观、精细、量化，应当纳入医院评审工作中。四是各地在评审工作中积累了很多先进的经验和做法，需要在评审标准中予以吸纳。为此，我们组织修订了《三级医院评审标准（2020年版）》（以下简称《标准》）。 二、修订的原则和思路是什么？ 新标准的修订围绕“医疗质量安全”这条主线，秉承“继承、发展、创新，兼顾普遍适用与专科特点”的原则，精简合并条款，推动医院评审由以现场检查、主观定性、集中检查为主的评审形式转向以日常监测、客观指标、现场检查、定量与定性评价相结合的工作思路和工作方向，符合当前医院管理工作需要，对于进一步促进医院践行“三个转变、三个提高”，努力实现公立医院高质量发展具有重要意义。 三、修订的主要内容是什么？ 《标准》共3个部分101节，设置448条标准和监测指标。修订内容主要体现以下几个方面：一是充分融入新颁政策和医改要求，体现时代性。《标准》在保持2011年版标准延续性的基础上，融入《基本医疗卫生与健康促进法》《医疗纠纷预防与处理条例》《医疗质量管理办法》《医疗技术临床应用管理办法》《医疗质量安全核心制度要点》等近年来颁布实施的法律、条例、规章相关内容，以及分级诊疗体

二级医院评审基本标准

二级医院评审基本标准 本标准是审定二级医院资格的必备条件，达到本标准合格线者才能参加等级评审。 一、医院规模 应具有与二级医院任务、功能、技术水平及管理要求相适应的医院规模。 1.病床不少于100张。 2.每床单元必备设施达到规定的要求（见附件六）。 3.每床建筑面积不少于45平方米。 4.每床病室净使用面积不少于5平方米。 5.日平均每门诊人次占门诊建筑面积不少于3平方米。 6.病床与医院正式职工人数之比为1∶1.3-1.5。 7.必须配备具有国家认定资格的卫生技术人员。卫生技术人员占全院职工总数不少于75%。 二、医院功能与任务 （一）医疗卫生服务 对社区能提供全面、连续的医疗护理、预防保健和康复服务。1.承担地区（地、市、县）内的常见病、多发病和较疑难病症诊治任务；抢救急危重症；接受一级医疗卫生机构的转诊。 2.开展日常院前急救；承担灾害事故的现场急救，迅速组织配套的急救队伍接收成批病员进行院内急救。

3.开展健康教育，掌握社区的疾病动态。参与社区内预防保健和康复服务工作。 （二）与医疗相结合开展教学、科研工作 1.能承担基层医疗单位中各类卫生技术人员的进修、培训和本院职工的在职教育。 2.能承担中等卫生学校临床教学及中等以上医学卫生学校学生的临床实习任务。 3.能承担省或市级科研项目。 （三）指导基层 与有关部门协作指导地区内基层医疗卫生单位做好社区治疗、预防保健、康复和精神卫生等工作。与一级医院建立经常性的业务关系，开展双向转诊，帮助开展新技术，解决疑难问题和培训卫生技术及管理人员。 三、医院管理 医院应有健全的管理体系，有相应的组织机构、人员、制度、措施、实施方案及其考核与评价办法。 （一）组织管理 必备的有： 1.行政管理组织 2.医疗、预防、教学、科研管理组织 3.护理管理组织 4.财务管理组织

二级医院评审标准

二级综合医院评审标准（2012年版） 为全面推进深化医药卫生体制改革和公立医院改革，逐步建立我国医院评审评价体系，促进医疗机构加强自身建设和管理，持续改进医疗质量，保证医疗安全，改善医疗服务，更好地履行社会职责和义务，提高医疗行业整体服务水平与服务能力，满足人民群众多层次的医疗服务需求，在总结我国第一周期医院评审和医院管理年活动等工作经验基础上制定本标准。 本标准适用于二级综合性医院，其他各类二级医院参照使用。 本标准共设置7章69节356条标准与监测指标。 第一章至第六章共63节321条标准，用于医院自我评价与改进，并作为对二级综合医院实地评审。 第七章共6节35条监测指标，用于对二级综合医院的日常运行、医疗质量与安全指标的监测与评审后的追踪评价。 说明： 1.二级医院是向含有多个社区的地区（人口一般在数十万左右）提供医疗为主，兼顾预防、保健和康复医疗服务并承担一定教学和科研任务的综合或专科的地区性医疗机构；本标准中，“县医院”为政府举办的县域内医疗卫生中心，应结合当地疾病谱特点，重点加强严重危及当地人民群众健康的疑难病救治及危急重症患者抢救能力。同时，承担对乡镇卫生院、村卫生室的业务技术指导和卫生人员的进修培训。 2.本标准中引用的疾病名称与ICD 10编码采用《疾病和有关健康问题的国际统计分类》，人民卫生出版社，第十次修订本第二版（北京

协和医院、世界卫生组织、国际分类家族合作中心编译）。 3.本标准中引用的手术名称与ICD9 CM 3编码采用《国际疾病分类手术与操作》，人民军医出版社，第九版临床修订本2008版（刘爱民主编译）。

第一章医院功能任务 一、医院设置、功能和任务符合区域卫生规划和医疗机构设置规划的定位和要求 （一）医院的功能、任务和定位明确，保持适度规模。 （二）主要承担常见病、多发病、部分疑难病的诊疗工作，兼顾预防、保健、康复功能，可提供24小时急危重症诊疗服务。 （三）临床科室诊疗科目设置、人员梯队与诊疗技术能力达到省级卫生行政部门规定的二级医院标准。 （四）医技科室服务能满足临床科室需要，项目设置、人员梯队与技术能力达到省级卫生行政部门规定的二级医院标准。 二、科学规范的内部管理机制 （一）坚持公立医院公益性，把维护人民群众健康权益放在第一位。 （二）按照省级卫生行政部门规定，实施住院医师规范化培训工作。 （三）将推进规范诊疗、临床路径管理和单病种质量控制，作为推动医疗质量持续改进的重点项目。 （四）提高工作绩效，优化医疗服务系统与流程，缩短平均住院日、缩短患者就医等候时间。 （五）按照《国家基本药物临床应用指南》、《国家基本药物处方集》及医疗机构药品使用管理有关规定，规范医师处方行为，确保基本药物得到优先合理使用。 （六）严格控制公立医院开展特需服务。

医院等级评审标准解读

医院等级评审标准解读（4） ——组织和策划湛江中心人民医院创建三甲医院实践 血液净化 1、专业设置和人员、设备配备： （1）血透室，至少有1名主治医师负责日常工作。 （2）血透室护士配备合理，每名护士负责操作及观察的患者数量不得超过5个。 （3）医师、护士接受6 月上岗前培训。 （4）血透室分区与布局合理，“三区”划分清楚。设备设施完善，具备双路电力供应。（5）急救设备和急救药品配置合理，药品无过期。 2、质量管理制度： （1）有质量管理制度与岗位职责，工作人员知晓。 （2）有规范的透析诊疗流程，医师每日查房，护士正确执行透析治疗医嘱，实施透析治疗护理常规，严格查对程序。 （3）建立血液透析患者登记及病历管理。 （4）建立与完善运行数据库，实时记录，定期评价诊疗质量，有持续改进措施。 （5）发生紧急意外情况的应急预案与处理流程，每个工作人员均知晓能遵循。 （6）血液透析常用质量指标达到市质控中心标准。 3、医院感染管理和监测： （1）严格执行医院感染管理制度与程序，有监测记录。消毒、无菌物品标明有效期限并定期更换。 （2）对乙肝、丙肝病人应隔离透析，病人进入血液净化室前作乙肝、丙肝检查，并定期复查。 （3）有医院感染紧急情况的处理预案。 （4）医疗废弃物管理按规定进行分类处理。 （5）定期对反渗机和供水管路进行消毒和冲洗，检测消毒剂残留量。 4、血液透析机与水处理设备： （1）每台透析机建档，内容包括透析机出厂信息、操作运转和维修记录等。 （2）建立水处理设备档案，内容包括水处理设备出厂信息、消毒和冲洗记录和定期维修记录。 （3）各种透析器材应在符合条件的库房内存放，无包装破损并在使用期限。 5、透析液配制： （1）建立透析液和透析用水质量监测程序，有记录。 （2）透析用水参照美国医疗器械协会（AAMI）对血液透析用水的要求管理。定期进行残余氯、硬度及电导率监测，内毒素和反渗水化学污染物检测合格。 （3）透析液和透析粉，符合国家药品监督管理局、卫生部公布的III 类医疗器械（透析液和透析粉，编号6845-07）的标准。 （4）透析液配制有操作常规,透析液配制符合要求 6、透析器复用管理: 不复用。 第四部分护理质量管理与持续改进

二甲综合医院评审标准核心条款

★二甲综合医院评审标准核心条款 一、1.1.2.1主要承担常见病、多发病、部分疑难病的诊疗工作。可提供24小时急诊诊疗服（★） 【C】 1.有承担本辖区常见病、多发病、部分疑难疾病诊疗的设施设备、技术梯队与处臵能力。 2.急诊部门独立设臵，承担本区域急危重症的诊疗。 3.预防、保健、康复独立设臵。 4.根据病源，与三级综合医院距离较远或危重病人转诊困难的二级医院的重症医学床位数可占医院总床位的2%。 5.医学影像可提供24小时急诊诊疗服务。 【B】符合“C”，并 1.重症医学床位占医院总床位的＞3%。 2.且符合重症评估标准的患者≥30%。 3.医学影像（含CT、超声）可提供24小时急诊诊疗服务。 【A】符合“B”，并 1.重症医学科床位占医院总床位的≥5%。 2.且符合重症评估标准的患者≥40%。 二、1.4.3.2编制各类应急预案。（★） 【C】 1.根据灾害易损性分析的结果制订各种专项预案，明确应对不同突发公共事件的标准操作程序。 2.制订医院应对各类突发事件的总体预案和部门预案，明确在应急状态下各个部门的责任和各级各类人员的职责以及应急反应行动的程序。 3.有节假日及夜间应急相关工作预案，配备充分的应急处理资

源，包括人员、 应急物资、应急通讯工具等。 【B】符合“C”，并编制医院应急预案手册，方便员工随时查阅，各部门各级各类人员知晓本部门和本岗位相关职责与流程。 【A】符合“B”，并定期并及时修订总体预案和专项预案，持续完善。 三、1.6.4.1政府指令的受援的二级医院，应将“达标工作”任务作为院长目标责任制与医院年度工作计划，有实施方案，专人负责。（★） 【C】 1、受援的二级医院，应将“达标工作”任务作为院长目标责任制与医院年度工作计划，有实施具体的方案。 2、有专人负责，对口支援工作，保证达标工作进行。 3、相关人员熟悉实施方案的相关内容。 【B】符合“C”，并用当年案例证实在以下二方面能有提升： （1）承担县域内居民的常见病、多发病、危急和部分疑难重症的诊治任务，解决影响群众生产生活的重大疾病能力有一定提升。 （2）开展24小时连续性急诊科院内急救服务，组织建立本县域内医疗急救服务网络，承担日常院前急救救治任务的能力有一定提升。 【A】符合“B”，并 1.有数据及相关案例证实受援方案取得预定目标。 2.数据指标显示在严重外伤（颅腔、胸腔、腹腔内大出血，与其它威胁生命需要紧急手术抢救）、急性心肌梗死（仅STEMI）、急性脑卒中等急危重症病人诊治效率及处理结果取得显著进步，其能力在本区域具有明显优势。 四、2.3.4.2对急性创伤、农药中毒、急诊分娩、急性心肌梗死、急性脑卒中、急性颅脑损伤、高危妊娠孕产妇等重点病种的急诊服务流程与服务时限有明文规定，能落实到位。（★） 【C】

三级综合医院评审标准实施细则(XXXX年版)

三级综合医院评审标准实施细则 （2011年版） 为全面推进深化医药卫生体制改革，积极稳妥推进公立医院改革，逐步建立我国医院评审评价体系，促进医疗机构加强自身建设和管理，不断提高医疗质量，保证医疗安全，改善医疗服务，更好地履行社会职责和义务，提高医疗行业整体服务水平与服务能力，满足人民群众多层次的医疗服务需求，在总结我国第一周期医院评审和医院管理年活动等工作经验的基础上，我部印发了《三级综合医院评审标准（2011年版）》（卫医管发〔2011〕33号）。为增强评审标准的操作性，指导医院加强日常管理与持续质量改进，为各级卫生行政部门加强行业监管与评审工作提供依据，制定本细则。 一、本细则适用围 《三级综合医院评审标准实施细则（2011年版）》适用于三级综合性公立医院，其余各级各类医院可参照使用。 本细则共设置7章73节378条标准与监测指标。 第一章至第六章共67节342条636款标准，用于对三级综合医院实地评审，并作为医院自我评价与改进之用；在本说明的各章节中带“★”为“核心条款”，共48项。 第七章共6节36条监测指标，用于对三级综合医院的医院运行、医疗质量与安全指标的监测与追踪评价。

二、细则的项目分类 （一）基本标准适用于所有三级综合医院。 （二）核心条款为保持医院的医疗质量与患者安全，对那些最基本、最常用、最易做到、必须做好的标准条款，且若未达到合格以上要求，势必影响医疗安全与患者权益的标准，列为“核心条款”，带有★标志。 （三）可选项目主要是指可能由于区域卫生规划与医院功能任务的限制，或是由政府特别控制，需要审批，而不能由医院自行决定即可开展的项目。 表1 第一章至第六章各章节的条款分布 三、评审表述方式 （一）评审采用A、B、C、D、E五档表述方式。 Ａ-优秀 Ｂ-良好 Ｃ-合格