肠道微生态影响动脉粥样硬化发生发展的机制

动脉粥样硬化(AS)不仅是一种炎症性疾病,而且属于一种代谢性疾病。肠道微生态的改变可对AS的发生发展产生双面影响。一方面,肠道菌群紊乱可以通过影响机体的胆碱代谢、氧化应激、炎症反应等机制直接促进AS产生发展,此外,可通过导致AS危险因素肥胖、高脂血症、糖尿病等的产生这些间接机制促AS的进展。另一方面,益生菌及益生元的增加则可有效地降低肠道微生物内毒素产生、增强肠道屏障、减轻机体质量、缓解炎症反应、改善胰岛素抵抗,进而在AS的进展方面发挥重要作用。因此,合理调控机体肠道微生态环境成为AS防治的新型重要手段。     

PNPLA3 I148M polymorphism and progressive liver disease

The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as a major determinant of liver fat content.Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver:from simple steatosis to steatohepatitis and progressive fibrosis.Furthermore,the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis,and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis,and possibly chronic hepatitis B virus hepatitis,hereditary hemochromatosis and primary sclerosing cholangitis.All in all,studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases.Remarkably,the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation,suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes,directly promoting fibrogenesis.Therefore,PNPLA3 is a key player in liver disease progression.Assessment of the I148M polymorphism will possibly inform clinical practice in the future,whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.     

瓣膜性房颤定义及抗凝治疗研究进展

现阶段对于"瓣膜病变型"房颤(AF)与"非瓣膜病变型"AF的定义尚未达成共识,不仅如此,各指南在表述这些概念时也存在差异。临床试验对于"瓣膜病变型"AF与"非瓣膜病变型"AF定义的阐述不甚理想。两类AF血栓栓塞风险差异较大,抗凝治疗策略也有所不同。本文将对瓣膜性AF定义及抗凝治疗的研究进展予以综述。     

Endoscopic resection techniques for colorectal neoplasia:Current developments

Endoscopic polypectomy and endoscopic mucosal resection(EMR) are the established treatment standards for colorectal polyps. Current research aims at the reduction of both complication and recurrence rates as well as on shortening procedure times. Cold snare resection is the emerging standard for the treatment of smaller(< 5 mm) polyps and is possibly also suitable for the removal of noncancerous polyps up to 9 mm. The method avoids thermal damage, has reduced procedure times and probably also a lower risk for delayed bleeding. On the other end of the treatment spectrum, endoscopic submucosal dissection(ESD)offers en bloc resection of larger flat or sessile lesions. The technique has obvious advantages in the treatment of high-grade dysplasia and early cancer. Due to its minimal recurrence rate, it may also be an alternative to fractionated EMR of larger flat or sessile lesions. However, ESD is technically demanding and burdened by longer procedure times and higher costs. It should therefore be restricted to lesions suspicious for high-grade dysplasia or early invasive cancer.The latest addition to endoscopic resection techniques is endoscopic fullthickness resection with specifically developed devices for flexible endoscopy.This method is very useful for the treatment of smaller difficult-to-resect lesions,e.g., recurrence with scar formation after previous endoscopic resections.     

Lymph node staging in colorectal cancer:Old controversies and recent advances

Outcome prediction based on tumor stage reflected by the American Joint Committee on Cancer(AJCC)/Union for International Cancer Control(UICC)tumor node metastasis(TNM)system is currently regarded as the strongest prognostic parameter for patients with colorectal cancer.For affected patients,the indication for adjuvant therapy is mainly guided by the presence of regional lymph node metastasis.In addition to the extent of surgical lymph node removal and the thoroughness of the pathologist in dissecting the resection specimen,several parameters that are related to the pathological work-up of the dissected nodes may affect the clinical significance of lymph node staging.These include changing definitions of lymph nodes,involved lymph nodes,and tumor deposits in different editions of the AJCC/UICC TNM system as well as the minimum number of nodes to be dissected.Methods to increase the lymph node yield in the fatty tissue include methylene blue injection and acetone compression.Outcome prediction based on the lymph node ratio,defined as the number of positive lymph nodes divided by the total number of retrieved nodes,may be superior to the absolute numbers of involved nodes.Extracapsular invasion has been identified as additional prognostic factor.Adding step sectioning and immunohistochemistry to the pathological work-up may result in higher accuracy of histological diagnosis.The clinical value of more recent technical advances,such as sentinel lymph node biopsy and molecular analysis of lymph nodes tissue still remains to be defined.     

Acute kidney injury spectrum in patients with chronic liver disease:Where do we stand?

Acute kidney injury (AKI) is a common complication of liver cirrhosis and is of the utmost clinical and prognostic relevance. Patients with cirrhosis, especially decompensated cirrhosis, are more prone to develop AKI than those without cirrhosis. The hepatorenal syndrome type of AKI (HRS–AKI), a spectrum of disorders in prerenal chronic liver disease, and acute tubular necrosis (ATN) are the two most common causes of AKI in patients with chronic liver disease and cirrhosis. Differentiating these conditions is essential due to the differences in treatment. Prerenal AKI, a more benign disorder, responds well to plasma volume expansion, while ATN requires more specific renal support and is associated with substantial mortality. HRS–AKI is a facet of these two conditions, which are characterized by a dysregulation of the immune response. Recently, there has been progress in better defining this clinical entity, and studies have begun to address optimal care. The present review synopsizes the current diagnostic criteria, pathophysiology, and treatment modalities of HRS–AKI and as well as AKI in other chronic liver diseases (non-HRS–AKI) so that early recognition of HRS–AKI and the appropriate management can be established.     

Prophecy about post-endoscopic retrograde cholangiopancreatography pancreatitis:From divination to science

One unresolved issue of endoscopic retrograde cholangiopancreatography(ERCP)is post-ERCP pancreatitis (PEP),which occurs in up to 40%of patients.Identification of risk factors for PEP is especially important in the field of ERCP practice because it may assist physicians in taking protective measures in situations with high risk.A decade ago,Freeman et al meticulously evaluated a large number of potentially relevant risk factors for PEP,which can be divided into patient-relat-ed and procedure-related issues.In this commentary, we summarize this classic article and reevaluate the risk factors for PEP from the current point of view.This is followed by assessment of strategies for prevention of PEP that can be divided into mechanical and pharmacologic methods.     

Role of endoscopic ultrasound in the screening and follow-up of high-risk individuals for familial pancreatic cancer

Managing familial pancreatic cancer(FPC)is challenging for gastroenterologists,surgeons and oncologists.High-risk individuals(HRI)for pancreatic cancer(PC)(FPC or with germline mutations)are a heterogeneous group of subjects with a theoretical lifetime cumulative risk of PC over 5%.Screening is mainly based on annual magnetic resonance imaging(MRI)and endoscopic ultrasound(EUS).The goal of screening is to identify early-stage operable cancers or high-risk precancerous lesions(pancreatic intraepithelial neoplasia or intraductal papillary mucinous neoplasms with high-grade dysplasia).In the literature,target lesions are identified in 2%-5%of HRI who undergo screening.EUS appears to provide better identification of small solid lesions(0%-46%of HRI)and chronicpancreatitis-like parenchymal changes(14%-77%of HRI),while MRI is probably the best modality to identify small cystic lesions(13%-49%of HRI).There are no specific studies in HRI on the use of contrast-enhanced harmonic EUS.EUS can also be used to obtain tissue samples.Nevertheless,there is still limited evidence on the accuracy of imaging procedures used for screening or agreement on which patients to treat.The cost-effectiveness of screening is also unclear.Certain new EUS-related techniques,such as searching for DNA abnormalities or protein markers in pancreatic fluid,appear to be promising.     

Issues and controversies in esophageal inlet patch

The proximal esophagus is rarely examined,and its inspection is often inadequate.Optical chromoendoscopy techniques such as narrow band imaging improve the detection rate of inlet patches in the proximal esophagus,a region in which their prevalence is likely underestimated.Various studies have reported correlations between these esophageal marks with different issues such as Barrett’s esophagus,but these findings remain controversial.Conflicting reports complicate the process of interpreting the clinical features of esophageal inlet patches and underestimate their importance.Unfortunately,the limited clinical data and statistical analyses make reaching any conclusions difficult.It is hypothesized that inlet patches are correlated with various esophageal and extraesophageal symptoms,diagnoses and the personalized therapeutic management of patients with inlet patches as well as the differential diagnosis for premalignant lesions or early cancers.Due to its potential underdiagnosis,there are no consensus guidelines for the management and follow up of inlet patches.This review focuses on questions that were raised from published literature on esophageal inlet patches in adults.     

Sleep,immunity and inflammation in gastrointestinal disorders

Sleep disorders have become a global issue,and discovering their causes and consequences are the focus of many research endeavors.An estimated 70 million Americans suffer from some form of sleep disorder.Certain sleep disorders have been shown to cause neurocognitive impairment such as decreased cognitive ability,slower response times and performance detriments.Recent research suggests that individuals with sleep abnormalities are also at greater risk of serious adverse health,economic consequences,and most importantly increased all-cause mortality.Several research studies support the associations among sleep,immune function and inflammation.Here,we review the current research linking sleep,immune function,and gastrointestinal diseases and discuss the interdependent relationship between sleep and these gastrointestinal disorders.Different physiologic processes including immune system and inflammatory cytokines help regulate the sleep.The inflammatory cytokines such as tumor necrosis factor,interleukin-1(IL-1),and IL-6 have been shown to be a significant contributor of sleep disturbances.On the other hand,sleep disturbances such as sleep deprivation have been shown to up regulate these inflammatory cytokines.Alterations in these cytokine levels have been demonstrated in certain gastrointestinal diseases such as inflammatory bowel disease,gastro-esophageal reflux,liver disorders and colorectal cancer.In turn,abnormal sleep brought on by these diseases is shown to contribute to the severity of these same gastrointestinal diseases.Knowledge of these relationships will allow gastroenterologists a great opportunity to enhance the care of their patients.     

The Eurodiab study: What has this taught us about diabetic peripheral neuropathy?

Apart from tight blood glucose control, no other treatments have been shown to retard the progression of diabetic peripheral neuropathy (DPN). Therefore, identifying potential risk factors for DPN is important, particularly if they are modifiable. The Eurodiab baseline DPN study found a prevalence of 28% for DPN, with glycemic control and duration of diabetes being major determinants. It was also observed that a substantial proportion of those with good glucose control (hemoglobin A1c < 7%) were found to have DPN, which raised the possibility that other risk factors may be involved. Having excluded those with DPN at baseline, researchers followed 1172 type 1 diabetic subjects for 7.3 years (SD, 0.6) looking for risk factors for the development of DPN. DPN developed in 23.5% over the follow-up period; and apart from glycemic control and duration of diabetes, known to be important risk factors for DPN, traditional markers of macrovascular disease (eg, hypertension, smoking, obesity, and triglycerides) were found to be independent risk factors. The study was published in the New England Journal of Medicine and suggested that a need exists for clinical trials to confirm if modifying cardiovascular risk factors is an effective treatment for DPN.     

Glycemic profile variability: An independent risk factor for diabetic neuropathy in patients with type 2 diabetes

BackgroundImpaired glycemic control is a potential predictor for macro- and microvascular complications of diabetes, which could be recognized by glycemic variability. The aim of this 10-year prospective cohort study presented here is to gain a better understanding of the correlation between GV and diabetic peripheral neuropathy (DPN) as one of the most common complications of T2DM.MethodsSince February 2010, 1152 adult patients with T2DM have been followed-up. Baseline features, anthropometric measurements, and laboratory findings were collected and documented during ten years. The association between DPN incidence and glycemic profile variability was evaluated using cox regression analysis. The coefficient of variation of glycemic indices within subjects was calculated and compared using an independent sample t-test.ResultsIndividuals who developed neuropathy had significantly higher mean levels of glycemic indices (HbA1c, FBS, and 2hpp), urinary albumin excretion, mean creatinine levels, and a longer duration of diabetes. A significant positive correlation between incidence of DPN and glycemic profile variability (cv-FBS10 %, cv-FBS20 %, cv-2hpp20 %, cv-HbA1c5 % and cv-HbA1c10 %) was revealed. Results also showed that higher variability of FBS was associated with the higher risk of neuropathy incidence (HR: 12.29, p-value: 0.045), which indicates that glycemic profile variability is an independent risk factor for DPN in patients with T2DM.ConclusionVariability of glycemic profiles from a visit to visit, regardless of sustained hyperglycemia, was indeed a significant risk factor for DPN in diabetic type 2 patients. CV-FBS was the most critical glycemic variability indices for DPN development.     

Peripheral neuropathy in prediabetes and the metabolic syndrome

Peripheral neuropathy is a major cause of disability worldwide. Diabetes is the most common cause of neuropathy, accounting for 50% of cases. Over half of people with diabetes develop neuropathy, and diabetic peripheral neuropathy (DPN) is a major cause of reduced quality of life due to pain, sensory loss, gait instability, fall‐related injury, and foot ulceration and amputation. Most patients with non‐diabetic neuropathy have cryptogenic sensory peripheral neuropathy (CSPN). A growing body of literature links prediabetes, obesity and metabolic syndrome to the risk of both DPN and CSPN. This association might be particularly strong in type 2 diabetes patients. There are no effective medical treatments for CSPN or DPN, and aggressive glycemic control is an effective approach to neuropathy risk reduction only in type 1 diabetes. Several studies suggest lifestyle‐based treatments that integrate dietary counseling with exercise might be a promising therapeutic approach to early DPN in type 2 diabetes and CSPN associated with prediabetes, obesity and metabolic syndrome.     

Diabetic neuropathy--a continuing enigma

In this article we will review the clinical signs and symptoms of diabetic somatic polyneuropathy (DPN), its prevalence and clinical management. Staging and classification of DPN will be exemplified by various staging paradigms of varied sophistication. The results of therapeutic clinical trials will be summarized. The pathogenesis of diabetic neuropathy reviews an extremely complex issue that is still not fully understood. Various recent advances in the understanding of the disease will be discussed, particularly with respect to the differences between neuropathy in the two major types of diabetes. The neuropathology and natural history of diabetic neuropathy will be discussed pointing out the heterogeneities of the disease. Finally, the various prospective therapeutic avenues will be dealt with and discussed.     

Diabetic neuropathy: new strategies for treatment

Current therapeutic possibilities can be divided into two groups: the pathogenetically oriented and the symptomatic therapy. One of the most important component of etiology-based treatment is the stabilization of glycemic control. Based on efficacy and safety data benfotiamine and alpha-lipoic acid should be considered as first choices among pathogenetically oriented treatments of diabetic neuropathy. Promising data were published about the aldose reductase inhibitor ranirestat. The symptomatic effect of antiepileptic drugs in diabetic painful neuropathy (DPN) is originated from several possible pharmacological properties. Pregabalin and gabapentin have the highest efficacy and the lowest frequency of adverse events among these drugs. Antidepressants also extensively used for symptomatic treatment in DPN. In the last years several studies were published about the benefial effect of duloxetine. Most likely combination therapy will be frequently applied in the future for the treatment of DPN, the optimal choice could be to combine pathogenetically oriented and symptomatic treatment.     

Diabetic neuropathies in the elderly: management update

Diabetic neuropathy is a common, varied, and disabling disease that is potentially responsive to therapy. While its pathogenesis is as yet unclear, its clinical presentations and natural history are well known. Present information suggests glycemic control can prevent neuropathy and in some cases cause established neuropathy to regress. Drug therapy is useful only for painful neuropathy. Avoidance of alcohol and behavioral and surgical relief of nerve entrapment are helpful in certain cases.     

Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with diabetes and is a major cause of morbidity and increased mortality. Its clinical manifestations include painful neuropathic symptoms and insensitivity, which increases the risk for burns, injuries and foot ulceration. Several recent studies have implicated poor glycaemic control, duration of diabetes, hyperlipidaemia (particularly hypertryglyceridaemia), elevated albumin excretion rates and obesity as risk factors for the development of DPN. Although there is now strong evidence for the importance of nerve microvascular disease in the pathogenesis of DPN, the risk factors for painful DPN are not known. However, emerging evidence regarding the central correlates of painful DPN is now afforded by brain imaging. The diagnosis of DPN begins with a careful history of sensory and motor symptoms. The quality and severity of neuropathic pain if present should be assessed using a suitable scale. Clinical examination should include inspection of the feet and evaluation of reflexes and sensory responses to vibration, light touch, pinprick and the 10-g monofilament. Glycaemic control and addressing cardiovascular risk is now considered important in the overall management of the neuropathic patient. Pharmacological treatment of painful DPN includes tricyclic compounds, serotonin-norepinephrine reuptake inhibitors (e.g. duloxetine), anticonvulsants (e.g. pregabalin), opiates, membrane stabilizers, the antioxidant alpha lipoic acid and others. Over the past 7 years, new agents with perhaps less side effect profiles have immerged. Management of patients with painful neuropathy must be tailored to individual requirements and will depend on the presence of other co-morbidities. There is limited literature with regard to combination treatment.     

Pathophysiology and treatment of diabetic peripheral neuropathy: the case for diabetic neurovascular function as an essential component

Worldwide, diabetes and its complications are major causes of morbidity, decreased quality of life, mortality and increasing health care costs. Patients with diabetes attempt to control blood pressure, lipids and blood glucose levels to decrease their risk of macrovascular and microvascular complications, such as diabetic peripheral neuropathy (DPN). Even with control of these risk factors for vascular disease, many patients still develop complications. Targeted therapies to the underlying mechanisms of diabetic neuropathy are essential to slow the progression of the disease. This review describes the signs, symptoms and diagnosis of DPN. Additionally, new therapies and the complex etiology that contributes to the development of diabetic neuropathy are described (oxidative stress, hyperglycemia, advanced glycated end products, autoimmunity, neurotrophic factors and protein kinase C beta).     

糖尿病周围神经病相关发病机制研究进展

糖尿病周围神经病（DPN）作为糖尿病最常见的并发症,一定程度上表现为周围神经功能障碍,影响患者的生活质量。基于近年来国内外对DPN相关发病机制的研究,本文主要围绕DPN在代谢、免疫、基因、降糖药等方面的相关发病机制展开综述,为今后DPN的机制研究与治疗提供思路。     

Recent advances in the management of diabetic distal symmetrical polyneuropathy

There is now little doubt that poor blood glucose control is an important risk factor for the development of diabetic peripheral neuropathy (DPN). Furthermore, traditional cardiovascular risk factors for macrovascular disease appear to be associated with an increased risk of DPN. The recently established International Expert Group on Diabetic Neuropathy has recommended new criteria for the diagnosis of DPN in the context of clinical and research settings. Studies in experimental diabetes examining the pathogenesis of DPN have identified a number of metabolic abnormalities including polyol pathway hyperactivity, increased advanced glycation end‐point formation, alterations in the protein kinase C beta pathway through diacylglycerol and oxidative stress. There is now strong evidence implicating nerve ischemia as the cause of DPN. Studies in human and animal models have shown reduced nerve perfusion and endoneurial hypoxia. These endoneurial microvascular changes strongly correlate with clinical severity and the degree of nerve‐fiber pathology. Unfortunately, many compounds that have been effective in animal models of neuropathy have not been successful in human diabetic neuropathy. The only compounds found to be efficacious in human diabetic neuropathy, and are in clinical use, are the anti‐oxidant, α‐lipoic acid and the aldose reductase inhibitor, epalrestat. Overall, the evidence emphasizes the importance of vascular dysfunction, driven by metabolic change, in the etiology of DPN, and highlights potential therapeutic approaches. Epidemiological data on diabetic painful neuropathic pain (DPNP) are limited. In one population‐based study, the prevalence of DPNP, as assessed by a structured questionnaire and examination, was estimated at 16%. It was notable that, of these patients, 12.5% had never reported symptoms to their doctor and 39% had never received treatment for their pain. Thus, despite being common, DPNP continues to be underdiagnosed and undertreated. Pharmacological treatment of DPNP include tricyclic compounds, serotonin noradrenalin reuptake inhibitors, the anti‐oxidant α‐lipoic acid, anticonvulsants, opiates, membrane stabilizers, topical capsaicin and so on. Management of the patient with DPNP must be tailored to individual requirements and will depend on the presence of other comorbidities. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00083.x)