《内经》中脏气的概念及相关的几个问题

讨论了《内经》中脏气的概念及相关问题。认为各脏气是一身之气中各具相对特异性结构和功能的一类精微物质 ,是一身之气在各脏腑的分布 ,以其运动不息而推动和调控脏腑功能 ,而本身非指脏腑功能 ;脏气的化生本原是脏腑之精 ,并与自然界的清气相合而成 ;脏气分为脏阴与脏阳 ,脏阴与脏阳都是脏气的一部分 ,而非指脏腑之精与脏腑之气 ;气阴两虚应归属于阴虚的范畴 ;脏腑气化是通过脏气的运动以推动脏腑功能以及精气血津液的代谢和相互转化 ,是生命的特征 ;气化脏腑说是对脏腑的哲学性假设 ,无益于中医学藏象理论的现代化。

基于“元精-元气论”阐释填精养脏法与干细胞移植修复组织损伤的理论同一性

干细胞具有元精属性,是元精在机体微观层面的存在形式。从胚胎发生学上看,干细胞基本符合元精所有功能特征,元精化生元气,元精体现物质结构,元气体现代谢和能量传递功能,干细胞的增殖分化及成熟后能量代谢过程即为五行(即5种能量的形式)生克制化理论下元精化生元气的过程。西医利用干细胞功能特点进行组织损伤修复的技术尝试,与中医“元精-元气论”及填精养脏治法在理论上具备同一性。肾藏五脏六腑之精,干细胞直接补充先天肾精,肾精充盛,则五脏六腑之精充盈,脏腑得以濡润而恢复阴阳和合状态,促使受损组织修复,起到任何药力所不能达的效果,可谓是中医“慢病治其本”的经典范式,为中西医结合干细胞修复组织损伤的技术革新与拓展尝试提供新的思路和方法。

Comparative study of galectin-3 and B-type natriuretic peptide as biomarkers for the diagnosis of heart failure

Background Heart failure （HF） is a common disease with complex pathophysiological causes. The diagnosis of HF commonly relies on comprehensive analyses of medical history and symptoms, and results from echocardiography and biochemical tests. Galectin-3, a rela-tively new biomarker in HF, was approved by the US Food and Drug Administration in 2010 as a marker in the stratification of risk for HF. We assessed galectin-3 as a biomarker for HF diagnosis in patients with preserved ejection fraction （pEF） and compared its performance with that of B-type natriuretic peptide （BNP）. Methods Thirty-five pEF patients with HF （HFpEF group） and 43 pEF patients without HF （control group） were enrolled. Plasma levels of galectin-3 and BNP in HFpEF and control subjects were determined. Sensitivity, specificity, pre dictive values, and accuracy of galectin-3 and BNP as markers for HF diagnosis were calculated and compared. Results Levels of galec- tin-3 and BNP were 23.09 ±6.97 ng/mL and 270.46 ± 330.41 pg/mL in the HFpEF group, and 16.74 ± 2.75 ng/mL and 59.94 ± 29.93 pg/mL in the control group, respectively. Differences in levels of galectin-3 and BNP between the two groups were significant （P 〈 0.01）. As a bio- marker for HF diagnosis in study subjects, galectin-3 showed sensitivity and specificity of 94.3% and 65.1%, respectively, at a cutoff value of 17.8 ug/mL. BNP showed sensitivity and specificity of 77.1% and 90.7%, respectively, at a cutoff value of 100 pg/mL. Galectin-3 was a significantly more sensitive （P 〈 0.05） but less specific （P 〈 0.01） biomarker compared with BNP. Differences in positive predictive value, negative predictive value, and accuracy between galectin-3 and BNP markers were not significant （P 〉 0.05）. Areas under the receiver operating characteristic curve （95% confidence interval） were 0.891 （0.808-0.974） and 0.896 （0.809-0.984） for galectin-3 and BNP, respec- tively, with no significant difference between the two values （P 〉 0.05）. Conclusions The level of galectin-3 is significantly elevated in patients with HF. Galectin-3 and BNP are useful biomarkers for the diagnosis of HF in patients with pEF.

Novel interactions of mitochondria and reactive oxygen/nitrogen species in alcohol mediated liver disease

Mitochondrial dysfunction is known to be a contributing factor to a number of diseases including chronic alcohol induced liver injury. While there is a detailed understanding of the metabolic pathways and proteins of the liver mitochondrion, little is known regarding how changes in the mitochondrial proteome may contribute to the development of hepatic pathologies. Emerging evidence indicates that reactive oxygen and nitrogen species disrupt mitochondrial function through post-translational modifications to the mitochondrial proteome. Indeed, various new affinity labeling reagents are available to test the hypothesis that post-translational modification of proteins by reactive species contributes to mitochondrial dysfunction and alcoholic fatty liver disease. Specialized proteomic techniques are also now available, which allow for identification of defects in the assembly of multi-protein complexes in mitochondria and the resolution of the highly hydrophobic proteins of the inner membrane. In this review knowledge gained from the study of changes to the mitochondrial proteome in alcoholic hepatotoxicity will be described and placed into a mechanistic framework to increase understanding of the role of mitochondrial dysfunction in liver disease.

Animal models for studying hepatitis C and alcohol effects on liver

Chronic consumption of ethanol has a dramatic effect on the clinical outcome of patients with hepatitis C virus (HCV) infection, but the mechanism linking these two pathologies is unknown. Presently, in vitro systems are limited in their ability to study the interaction between a productive wild-type HCV infection and chronic ethanol exposure. Mouse models are potentially very useful in dissecting elements of the HCV-ethanol relationship. Experiments in mice that transgenically express HCV proteins are outlined, as are experiments for the generation of mice with chimeric human livers. The latter models appear to have the most promise for accurately modeling the effects of chronic ethanol intake in HCV-infected human livers.

Transjugular intrahepatic portosystemic shunt-placement increases arginine/asymmetric dimethylarginine ratio in cirrhotic patients

AIM:To analyze the change of dimethylarginine plasma levels in cirrhotic patients receiving transjugular intrahepatic portosystemic shunt(TIPS).METHODS:To determine arginine,asymmetric dimethylarginine(ADMA),symmetric dimethylarginine(SDMA),and nitric oxide(NO) plasma levels,blood samples were collected from the superior cava,hepatic,and portal vein just before,directly after,and 3 mo after TIPS-placement.RESULTS:A significant increase in the arginine/ADMA ratio after TIPS placement was shown.Moreover,TIPS placement enhanced renal function and thereby decreased systemic SDMA levels.In patients with renal dysfunction before TIPS placement,both the arginine/ADMA ratio and creatinine clearance rate increased significantly,while this was not the case in patients with normal renal function before TIPS placement.Hepatic function did not change significantly after TIPS placement and no significant decline in ADMA plasma levels was measured.CONCLUSION:The increase of the arginine/ADMA ratio after TIPS placement suggests an increase in intracellular NO bioavailability.In addition,this study suggests that TIPS placement does not alter dimethylarginine dimethylaminohydrolase(DDAH) activity and confirms the major role of the liver as an ADMA clearing organ.

Effects of arginine supplementation on splenocyte cytokine mRNA expression in rats with gut-derived sepsis

AIM： To investigate the effects of arginine （Arg）-enriched diets before sepsis and/or Arg-containing total parenteral nutrition （TPN） after sepsis or both on cytokine mRNA expression levels in splenocytes of rats with gut-derived sepsis. METHODS： Rats were assigned to four experimental groups. Groups 1 and 2 were fed with a semipurified diet, while groups 3 and 4 had part of the casein replaced by Arg which provided 2% of the total calories. After the rats were fed with these diets for 10 d, sepsis was induced by cecal ligation and puncture （CLP）, at the same time an internal jugular vein was cannulated. All rats were maintained on TPN for 3 d. Groups 1 and 3 were infused with conventional TPN, while groups 2 and 4 were supplemented with Arg which provided 2% of the total calories in the TPN solution. All rats were killed 3 d after CLP to examine their splenocyte subpopulation distribution and cytokine expression levels. RESULTS： Plasma interleukin （IL）-2, IL-4, tumor necrosis factor-α （TNF-α） and interferon （IFN-γ） were not detectable 3 d after CL.P. There were no differences in the distributions of CD45Ra＋, CD3＋, CD4＋, and CD8＋ cells in whole blood and splenocytes among the four groups. The splenocyte IL-2 mRNA expression in the Arg-supplemented groups was significantly higher than that in group 1. IL-4 mRNA expression in groups 3 and 4 was significantly higher than that in groups 1 and 2. The mRNA expression of IL-10 and IFN-γ was significantly higher in group 4 than in the other three groups. There was no difference in TNF-α mRNA expression among thefour groups CONCLUSION： The influence of Arg on the whole blood and splenic lymphocyte subpopulation distribution is not obvious. However, Arg administration, especially before and after CLP, significantly enhances the mRNA expression levels of Thl and Th2 cytokines in the spleen of rats with gut-derived sepsis.

Mechanisms of alcohol-mediated hepatotoxicity in human-immunodeficiency-virus-infected patients

Clinical observations have demonstrated that excessive chronic alcohol use negatively affects human immuno- deficiency virus (HIV) infection and contributes to the liver manifestations of the disease, even in HIV mono- infection. HIV/hepatitis C virus (HCV) co-infection is as- sociated with increased progression of HVC liver disease compared to HCV infection alone, and both of these are negatively affected by alcohol use. Recent data suggest that alcohol use and HIV infection have common targets that contribute to progression of liver disease. Both HIV infection and chronic alcohol use are associated with increased gut permeability and elevated plasma levels of lipopolysaccharide; a central activator of inflammatory responses. Both alcoholic liver disease and HIV infec tionresult in non-specific activation of innate immunity, proinflammatory cytokine cascade upregulation, as well as impaired antigen presenting cell and dendritic cell functions. Finally, alcohol, HIV and antiretroviral therapyaffect hepatocyte functions, which contributes to liver damage. The common targets of alcohol and HIV infection in liver disease are discussed in this minireview.

Predicting utility of a model for end stage liver disease in alcoholic liver disease

AIM： To validate the statistic utility of both the Maddrey Discriminant Function score and the Model for End-Stage Liver Disease as predictors of short term （30 d and 90 d） mortality in patients with alcoholic hepatitis and to assess prognostic factors among clinical characteristics and laboratory variables of patients with alcoholic hepatitis. METHODS： Thirty-four patients with the diagnosis of alcoholic hepatitis admitted to Hippokration University Hospital of Athens from 2000 to 2005 were assessed in the current retrospective study and a statistical analysis was conducted. RESULTS： 30- and 90-d mortality rates were reported at 5.9% （2/34） and 14.7% （5/34）, respectively. Significant correlation was demonstrated for the Model for End- Stage Liver Disease （P30 = 0.094, P90 = 0.046） and the Maddrey Discriminant Function score （P30 = 0.033, P90 = 0.038） with 30- and 90-d mortality whereas a significant association was also established for alanine aminotrans- ferase （P = 0.057）, fibrin degradation products （P = 0.048） and C-reactive protein （P = 0.067） with 90-d mortality. For 30-d mortality the Area Under the Curve was 0.969 （95%CI： 0.902-1.036, P = 0.028） for the Model for End-Stage Liver Disease score and 0.984 （95%CI： 0.942-1.027, P = 0.023） for the Maddrey Discriminant Function score with the optimal cut off point of 30.5 （sensitivity 1, specificity 0.937） and 108.68 （sensitivity 1, specificity 0.969）, respectively. Accordingly, for 90-d mortality the Area Under the Curve was 0.762 （95%CI： 0.559-0.965, P = 0.065） for the Model for End-Stage Liver Disease score and 0.752 （95%CI： 0.465-1.038, P = 0.076） for the Maddrey Discriminant Function score with the optimal cut off point of 19 （sensitivity 0.6, specificity 0.6） and 92 （sensitivity 0.6, specificity 0.946）, respectively. The observed Kaplan Meier survival rates for different score-categories were compared with logrank tests and higher score values were correlated with a lower survival. CONCLUSION： Equivalency of the Model for End-Stage Liver Disease and the Maddrey Discriminant Function score is implied by the current study, verified by the plotted Receiver Operative Curves and the estimated survival rates. A statistically significant utility of C-reactive protein, fibrin degradation products and alanine aminotransferase as independent predictors of 90-d mortality has also been verified.

Liver biopsy in a district general hospital:Changes over two decades

AIM： To study liver biopsy practice over two decades in a district general hospital in the United Kingdom.METHODS： We identified all patients who had at least one liver biopsy between 1986 and 2006 from the databases of the radiology and gastroenterology departments. Subjects with incomplete clinical data were excluded from the study.RESULTS： A total of 103 liver biopsies were performed. Clinical data was available for 88 patients, with 95 biopsies. Between 1986 and 1996, 18 （95%） out of the 19 liver biopsies performed were blind and 6 （33%） were for primary biliary cirrhosis. Between 1996 and 2006, 14 （18%） out of 76 biopsies were blind; and the indications were abnormal liver tests （33%）, hepatitis C （12%） and targeted-biopsies （11%）. Liver biopsies were unhelpful in 5 （50） subjects. Pain was the most common complication of liver biopsy （5%）. No biopsy-related mortality was reported. There was a trend towards more technical failures and complications with the blind biopsy technique.CONCLUSION： Liver biopsies performed in small district hospitals are safe and useful for diagnostic and staging purposes. Abnormal liver tests, non-alcoholic fatty liver disease and targeted biopsies are increasingly common indications. Ultrasound-guided liver biopsies are now the preferred method and are associated with fewer complications.

Is the iron regulatory hormone hepcidin a risk factor for alcoholic liver disease?

Despite heavy consumption over a long period of time, only a small number of alcoholics develop alcoholic liver disease. This alludes to the possibility that other factors, besides alcohol, may be involved in the progression of the disease. Over the years, many such factors have indeed been identified, including iron. Despite being crucial for various important biological processes, iron can also be harmful due to its ability to catalyze Fenton chemistry. Alcohol and iron have been shown to interact synergistically to cause liver injury. Iron-mediated cell signaling has been reported to be involved in the pathogenesis of experimental alcoholic liver disease. Hepcidin is an iron-regulatory hormone synthesized by the liver, which plays a pivotal role in iron homeostasis. Both acute and chronic alcohol exposure suppress hepcidin expression in the liver. The sera of patients with alcoholic liver disease, particularly those exhibiting higher serum iron indices, have also been reported to display reduced prohepcidin levels. Alcohol-mediated oxidative stress is involved in the inhibition of hepcidin promoter activity and transcription in the liver. This in turn leads to an increase in intestinal iron transport and liver iron storage. Hepcidin is expressed primarily in hepatocytes. It is noteworthy that both hepatocytes and Kupffer cells are involved in the progression of alcoholic liver disease. However, the activation of Kupffer cells and TNF-α signaling has been reported not to be involved in the down-regulation of hepcidin expression by alcohol in the liver. Alcohol acts within the parenchymal cells of the liver to suppress the synthesis of hepcidin. Due to its crucial role in the regulation of body iron stores, hepcidin may act as a secondary risk factor in the progression of alcoholic liver disease. The clarification of the mechanisms by which alcohol disrupts iron homeostasis will allow for further understanding of the pathogenesis of alcoholic liver disease.

Aging effects on QT interval： Implications for cardiac safety of antipsychotic drugs

Objectives To explore the effect of aging on cardiac toxicity specifically the interaction of age and antipsychotic drugs to alter the QT interval. Methods The Medline databases were searched using the OvidSP platforms with the search strategy： ＂QT interval＂ or ＂QT＂ and ＂age＂ or ＂aging＂. The entry criteria were： over 10,000 apparently healthy individuals with data on both sexes; QT interval corrected for heart rate （QTc） and an expression of its variance for multiple age decades extending into the older ages. Results QTc increased in duration with increasing age. Considering a modest one SD increment in QTc in the normal population, the addition of Chlorpromazine produced a QTc on average greater than 450 ms for ages 70 years and older. Risperidone, that did not on average alter QTc, would be expected to produce a QTc of 450 ms in persons in their mid 70 years under some circumstances. QTc prolongation 〉 500 ms with antipsychotic drugs is more likely for persons with QTc initially at the 99th percentile. It may occur with Haloperidol which does not on average alter QTc. Conclusions The range of values for the QT interval in apparently normal older men or women, when combined with the range of expected QT interval changes induced by antipsychotic drugs, can readily be associated with prolonged QTc. Individuals with QTc at the 99th percentile may have serious QTc prolongation with antipsychotic drugs even those that are not usually associated with QTc prolongation.

Alcohol and liver

Liver is a primary site of ethanol metabolism, which makes this organ susceptible to alcohol-induced damage. Alcoholic liver disease （ALD） has many manifestations and complicated pathogenesis. In this Topic Highlight, we included the key reviews that characterize new findings about the mechanisms of ALD development and might be of strong interest for clinicians and researchers involved in liver alcohol studies.

Role of cytokines and chemokines in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) includes a variety of histological conditions (ranging from liver steatosis and steatohepatitis, to fibrosis and hepatocarcinoma) that are characterized by an increased fat content within the liver. The accumulation/deposition of fat within the liver is essential for diagnosis of NAFLD and might be associated with alterations in the hepatic and systemic inflammatory state. Although it is still unclear if each histological entity represents a different disease or rather steps of the same disease, inflammatory processes in NAFLD might influence its pathophysiology and prognosis. In particular, non-alcoholic steatohepatitis (the most inflamed condition in NAFLDs, which more frequently evolves towards chronic and serious liver diseases) is characterized by a marked activation of inflammatory cells and the upregulation of several soluble inflammatory mediators. Among several mediators, cytokines and chemokines might play a pivotal active role in NAFLD and are considered as potential therapeutic targets. In this review, we will update evidence from both basic research and clinical studies on the potential role of cytokines and chemokines in the pathophysiology of NAFLD.

Heart failure in the elderly

The aging of the population is, currently, a major phenomenon, drawing the attention of a number of investigators. The significant increase of life expectancies over the past few decades, in addition to social and economic consequences, has lead to a major change in the morbidity and mortality profile of elders. Heart failure （HF） is a condition in which the heart can not pump enough blood to meet the body＇s needs. HF is predominantly a disorder of the elderly with rates increasing exponentially. The prevalence of HF approximately doubles with each decade of life. As people live longer, the occurrence of HF rises, as well as other conditions that complicate its treatment. Impaired heart function implies a reduced duration of survival. Fortunately, many factors that can prevent HF and improve outcome are known and can be applied at any stage. This review emphasizes the importance of factors inherent in aging itself, focusing on heart disease, particularly as a disease of aging, can help critically refine management of this acute and chronic disease, as well as foster preventive strategies to reduce the incidence of this common malady.

An annual topic highlight: Alcohol and liver, 2011

An annual topic highlight: Alcohol and Liver, 2011, covers the important and new aspects of pathogenesis of alcoholic liver diseases (ALD). It includes broad topics ranging from the exacerbation of ALD by infectious (viral) agents (hepatitis C virus and human immunodeficiency virus) to the influence of alcohol on liver fibrogenesis, lipid rafts, autophagy and other aspects. This issue is recommended for both basic scientists and clinicians who are involved in alcoholic liver research.

Is iron overload in alcohol-related cirrhosis mediated by hepcidin?

In this case report we describe the relationship between ferritin levels and hepcidin in a patient with alcohol-related spur cell anemia who underwent liver transplantation.We demonstrate a reciprocal relation-ship between serum or urinary hepcidin and serum ferritin,which indicates that inadequate hepcidin production by the diseased liver is associated with elevated serum ferritin.The ferritin level falls with increasing hepcidin production after transplantation.Neither inflammatory indices(IL6)nor erythropoietin appear to be related to hepcidin expression in this case.We suggest that inappropriately low hepcidin production by the cirrhotic liver may contribute substantially to elevated tissue iron stores in cirrhosis and speculate that hepcidin replacement in these patients may be of therapeutic benefi t in the future.

Update on autoimmune hepatitis

Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features,hyperglobulinemia (IgG),and the presence of circulating autoantibodies,as well as a response to immunosuppressant drugs. Current treatment consists of prednisone and azathioprine and in most patients this disease has become very treatable. Over the past 2 years,a couple of new insights into the genetic aspects,clinical course and treatment of AIH have been reported,which will be the focus of this review. In particular,we concentrate on genome-wide microsatellite analysis,a novel mouse model of AIH,the evaluation of a large AIH cohort for overlap syndromes,suggested novel criteria for the diagnosis of AIH,and the latest studies on treatment of AIH with budenoside and mycophenolate mofetil.

Fibronectin: Functional character and role in alcoholic liver disease

Fibronectins are adhesive glycoproteins that can be found in tissue matrices and circulating in various fluids of the body. The variable composition of fibronectin molecules facilitates a diversity of interactions with cell surface receptors that suggest a role for these proteins beyond the structural considerations of the extracellular matrix. These interactions implicate fibronectin in the regulation of mechanisms that also determine cell behavior and activity. The two major forms, plasma fibronectin (pFn) and cellular fibronectin (cFn), exist as balanced amounts under normal physiological conditions. However, during injury and/or disease, tissue and circulating levels of cFn become disproportionately elevated. The accumulating cFn, in addition to being a consequence of prolonged tissue damage, may in factstimulate cellular events that promote further damage. In this review, we summarize what is known regarding such interactions between fibronectin and cells that may influence the biological response to injury. We elaborate on the effects of cFn in the liver, specifically under a condition of chronic alcohol-induced injury. Studies have revealed that chronic alcohol consumption stimulates excess production of cFn by sinusoidal endothelial cells and hepatic stellate cells while impairing its clearance by other cell types resulting in the build up of this glycoprotein throughout the liver and its consequent increased availability to influence cellular activity that could promote the development of alcoholic liver disease. We describe recent findings by our laboratory that support a plausible role for cFn in the promotion of liver injury under a condition of chronic alcohol abuse and the implications of cFn stimulation on the pathogenesis of alcoholic liver disease. These findings suggest an effect of cFn in regulating cell behavior in the alcohol-injured liver that is worth further characterizing not only to gain a more comprehensive understanding of the role this reactive glycoprotein plays in the progression of injury but also for the insight further studies could provide towards the development of novel therapies for alcoholic liver disease.

Non-alcoholic fatty liver disease and metabolic syndrome in obese children

I read with great interest the article of Fu et al who investigated whether non-alcoholic fatty liver disease(NAFLD)is an early mediator for prediction of metabolic syndrome,and whether liver B-ultrasound could be used for its diagnosis,in a study involving 861 obese children(6-16 years old).In this study,it was reported that NAFLD is not only a liver disease,but also an early mediator that reflects metabolic disorder,and that liver B-ultrasound can be a useful tool for metabolic syndrome(MS)screening.The authors reported that NAFLD and MS were present in 68.18%and 25.67%of obese children,respectively.Moreover,they observed that the prevalence of MS in NAFLD children was 37.64%,which was much higher than that in the non-NAFLD group.Criteria analogous to those of the Adult Treatment PanelⅢdefinition for MS were used for children in this study.The reported prevalence data on MS in the young has varied markedly,in large part because of disagreement among the variously proposed definitions of MS.Therefore,in my opinion,a study aiming to assess the association between MS components and NAFLD in obese children has to take into account a simple,easy-to-apply clinical definition proposed by the international diabetes federation for MS.Interpretation of the results of the Fu et al study are limited byanother major caveat:that the diagnosis or exclusion of NAFLD was based on liver enzymes and ultrasound imaging,but was not confirmed by liver biopsy.Indeed,it is known that liver enzymes may be within the reference interval in up to 70%of patients with diagnosed NAFLD and that the full histopathological spectrum of NAFLD may be present in patients with normal liver enzymes,which therefore cannot be reliably used to exclude the presence of NAFLD.