1-磷酸鞘胺醇受体3参与巨噬细胞迁移及脓毒症诱导的心肌损伤

目的探讨巨噬细胞中1-磷酸鞘胺醇受体(sphingosine 1-phosphate receptor,S1PR)的表达及其作用,观察干预S1PR3(S1P3)对脂多糖诱导的心肌损伤的影响。方法传代培养小鼠Ana-1巨噬细胞,给予脂多糖(lipopolysaccharide,LPS,100 ng/ml)刺激或S1P3特异性抑制剂CAY-10444(10μmol/L)干预,细胞随机分为对照组、LPS组、CAY-10444组、CAY-10444预处理2h+LPS组,Transwell小室观测巨噬细胞迁移,蛋白免疫印迹检测巨噬细胞S1PR的表达,并检测p-Akt/Akt蛋白水平。在体实验,6~8周龄雄性C57/B6小鼠,随机分为对照组、LPS组、CAY-10444组、CAY-10444干预+LPS组,每组12只,LPS(10 mg/kg)腹腔注射,或CAY-10444 1 mg/kg于LPS诱导后30 min腹腔注射干预,24 h后取心脏组织HE染色观察病理改变,免疫组化染色观察巨噬细胞浸润程度以及炎症因子的表达情况,实时荧光定量PCR检测心肌损伤标记分子BNP、巨噬细胞表面分子F4/80、炎症因子TNF-α、IL-1β、IL-6的mRNA水平。结果与对照组比较,LPS诱导巨噬细胞大量迁移S1P3蛋白表达增加(P0.01),p-Akt Ser473/Akt表达上调(P0.01);与LPS组相比,S1P3抑制剂CAY-10444干预后再给予LPS刺激,巨噬细胞迁移被抑制(P0.01),p-Akt Ser473/Akt表达也降低(P0.01);在体实验,LPS诱导小鼠后BNP mRNA水平明显上调(P0.01),同时F4/80以及炎症因子TNF-α、IL-1β、IL-6的mRNA水平上调(P0.01),HE染色可见心肌损伤及炎细胞浸润,免疫组化染色法显示F4/80及炎症因子的大量阳性表达(P0.01);使用S1P3抑制剂后,与LPS组比较,心肌损伤减轻免疫组化中巨噬细胞减少(P0.01),炎症因子表达降低(P0.01),BNP mRNA水平降低(P0.01),F4/80以及TNF-α、IL-1β、IL-6的mRNA水平也明显降低(P0.01)。结论抑制巨噬细胞S1P3表达可抑制巨噬细胞的迁移并提示p-Akt/Akt与了这一过程,此外,S1P3抑制剂的干预可有效减轻LPS诱导的心肌损伤。     

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。     

老年2型糖尿病并发ACS患者血清GGT与慢血流-无复流的相关性及其对预后的影响

目的探讨老年2型糖尿病(T2DM)并发急性冠脉综合征(ACS)患者血清γ谷氨酰胺转肽酶(GGT)水平与经皮冠状动脉介入(PCI)治疗术后冠脉慢血流-无复流的相关性及其对预后的影响。方法选取188例诊断为ACS并行急诊PCI的老年T2DM患者,根据TIMI血流分级和校正的TIMI血流帧计数(c TFC)方法评价冠脉血流分为正常血流组(156例)和慢血流-无复流组(32例),分析GGT及其他危险因素与冠脉慢血流-无复流的相关性和主要不良心血管事件(MACE)的发生率。结果慢血流-无复流组的血清GGT水平高于正常血流组[(49±18)U/L vs.(31±13)U/L,P0.01]。相关分析结果显示,血清GGT与冠脉慢血流-无复流呈正相关(r=0.389,P0.01)。血清GGT与PCI术后冠脉慢血流-无复流、住院期间及术后12个月MACE独立相关(分别OR=1.093,95%CI:1.058~1.129,P0.01;OR=1.047,95%CI:1.012~1.082,P0.05及OR=1.058,95%CI:1.028~1.089,P0.01)。结论老年T2DM并发ACS患者血清GGT水平与冠脉慢血流-无复流相关,血清GGT可能是预测冠脉风险的评价指标。     

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.     

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.     

HBV endemicity in Mexico is associated with HBV genotypes H and G

Hepatitis B virus(HBV)genotypes have distinct genetic and geographic diversity and may be associated with specific clinical characteristics,progression,severity of disease and antiviral response.Herein,we provide an updated overview of the endemicity of HBV genotypes H and G in Mexico.HBV genotype H is predominant among the Mexican population,but not in Central America.Its geographic distribution is related to a typical endemicity among the Mexicans which is characterized by a low hepatitis B surface antigen seroprevalence,apparently due to a rapid resolution of the infection,low viral loads and a high prevalence of occult B infection.During chronic infections,genotype H is detected in mixtures with other HBV genotypes and associated with other co-morbidities,such as obesity,alcoholism and co-infection with hepatitis C virus or human immunodeficiency virus.Hepatocellular carcinoma prevalence is low.Thus,antiviral therapy may differ significantly from the standard guidelines established worldwide.The high prevalence of HBV genotype G in the Americas,especially among the Mexican population,raises new questions regarding its geographic origin that will require further investigation.     

Harnessing the potential of gene editing technology using CRISPR in inflammatory bowel disease

The molecular scalpel of clustered regularly interspersed short palindromic repeats/CRISPR associated protein 9(CRISPR/Cas9) technology may be sharp enough to begin cutting the genes implicated in inflammatory bowel disease(IBD) and consequently decrease the 6.3 billion dollar annual financial healthcare burden in the treatment of IBD. For the past few years CRISPR technology has drastically revolutionized DNA engineering and biomedical research field. We are beginning to see its application in gene manipulation of sickle cell disease,human immunodeficiency virus resistant embryologic twin gene modification and IBD genes such as Gatm(Glycine amidinotransferase, mitochondrial),nucleotide-binding oligomerization domain-containing protein 2, KRT12 and other genes implicated in adaptive immune convergence pathways have been subjected to gene editing, however there are very few publications. Furthermore,since Crohn's disease and ulcerative colitis have shared disease susceptibility and share genetic gene profile, it is paramount and is more advantageous to use CRISPR technology to maximize impact. Although, currently CRISPR does have its limitations due to limited number of specific Cas enzymes, off-target activity,protospacer adjacent motifs and crossfire between different target sites. However,these limitations have given researchers further insight on how to augment and manipulate enzymes to enable precise gene excision and limit crossfire between target sites.     

Abdominal compartment syndrome:Often overlooked conditions in medical intensive care units

Intra-abdominal hypertension(IAH)and abdominal compartment syndrome are well recognized entities among surgical patients.Nevertheless,a number of prospective and retrospective observational studies have shown that IAH is prevalent in about half of the critically ill patients in the medical intensive care units(ICU)and has been widely recognized as an independent risk factor for mortality.It is alarming to note that many members of the critical care team in medical ICU are not aware of the consequences of untreated IAH and the delay in making the diagnosis leads to increased morbidity and mortality.Frequently it is underdiagnosed and undertreated in this patient population.Elevated intraabdominal pressure decreases the blood flow to the kidneys and other abdominal viscera and also results in reduced cardiac output and difficulties in ventilating the patient because of increased intrathoracic pressure.When intraabdominal hypertension is not promptly recognized and treated,it leads to abdominal compartment syndrome,multiorgan dysfunction syndrome and death.Large volume fluid resuscitation is very common in medical ICU patients presenting with sepsis,shock and other inflammatory conditions like pancreatitis and it is one of the major risk factors for the development of intra-abdominal hypertension.This article presents an overview of the epidemiology,definitions,risk factors,pathophysiology and management of IAH and abdominal compartment syndrome in critically ill medical ICU patients.     

Current status of endoscopic retrograde cholangiopancreatography in patients with surgically altered anatomy

Endoscopic retrograde cholangiopancreatography(ERCP)in patients with surgically altered anatomy must be performed by a highly experienced endoscopist.The challenges are accessing the afferent limb in different types of reconstruction,cannulating a papilla with a reverse orientation,and performing therapeutic interventions with uncommon endoscopic accessories.The development of endoscopic techniques has led to higher success rates in this group of patients.Device-assisted ERCP is the endoscopic procedure of choice for high success rates in short-limb reconstruction;however,these success rate is lower in long-limb reconstruction.ERCP assisted by endoscopic ultrasonography is now popular because it can be performed independent of the limb length;however,it must be performed by a highly experienced and skilled endoscopist.Stent deployment and small stone removal can be performed immediately after ERCP assisted by endoscopic ultrasonography,but the second session is needed for other difficult procedures such as cholangioscopy-guided electrohydraulic lithotripsy.Laparoscopic-assisted ERCP has an almost 100%success rate in longlimb reconstruction because of the use of a conventional side-view duodenoscope,which is compatible with standard accessories.This requires cooperation between the surgeon and endoscopist and is suitable in urgent situations requiring concomitant cholecystectomy.This review focuses on the advantages,disadvantages,and outcomes of various procedures that are suitable in different situations and reconstruction types.Emerging new techniques and their outcomes are also discussed.     

Metabolic remission with octreotide in patients with insulinoma

Abstract. Objectives . The efficacy of octreotide was studied in a group of patients with biochemical evidence of insulinoma. Design . A phase-II study Setting . A university department of internal medicine. Subjects . Seven patients with biochemical evidence of insulinoma and without metastatic lesions. Intervention . Daily treatment with octreotide, a somatostatin analogue, mainly within the dosage of 100–300 μg day^-1. The treatment was continued in patients with biochemical evidence of response or until surgery was undertaken. Main outcome . Five patients avoided hypoglycaemic symptoms and had normalization of blood glucose values for a median of 15+ months (range 0.2–54 months). Two did not improve metabolically. The treatment was well tolerated and had no deleterious effects on blood glucose regulation. Conclusion . Octreotide seems to be a promising treatment for many of the patients with insulinoma who are not suitable for surgery.     

Changes in coagulation parameters with exercise in patients with classic hemophilia

Vigorous exercise is known to increase VIII:C and VIIIR:Ag levels transiently in normal individuals. Although exercise programs are frequently advocated in the management of hemophilia, the effects of exercise on coagulation parameters in these patients have not been well studied. Eleven hemophiliacs were exercised on a bicycle ergometer to maximum voluntary effort as evidenced by an increase in pulse, blood pressure, and plasma catecholamine (norepinephrine and epinephrine) levels. The effects of this exercise on coagulation parameters, including functional and antigenic components of the factor VIII molecule, were determined. The entire group demonstrated a decrease in mean prothrombin time (11.7 to 11.2 sec). Four mild hemophiliacs demonstrated an increase in mean VIII:C (14.5% to 17.3%), and VIII:CAg (12% to 17.8%). Changes in VIII:C and VIII:CAg were not noted in the seven severe hemophiliacs. Both severe and mild patients demonstrated significant changes in fibrinogen, factor II, and factor VII after exercise. This study indicates that submaximal exercise modifies coagulation parameters in patients with hemophilia.     

Experience with ponatinib in paediatric patients with leukaemia

Ponatinib has proven to be effective in adults with Philadelphia chromosome-positive leukaemias, but data in paediatrics are scarce. Among paediatric patients with chronic myeloid leukaemia (n = 9) or acute lymphoblastic leukaemia (n = 12) treated with varying doses of ponatinib in 13 centres, 71% showed a decrease in disease burden after a median of three months. Ponatinib was well tolerated, with grade 3 toxicities occurring in 29% of patients. Toxicities were similar to those reported in adults, with the exception of arterial thrombotic events, which were not observed. Ponatinib has a favourable safety profile in this paediatric cohort, but dose-finding studies are needed.     

Therapy with budesonide in patients with refractory sprue

INTRODUCTION: Refractory sprue (RS) is a rare malabsorption syndrome, which often requires long-term corticosteroid treatment. Locally acting budesonide could replace systemic corticosteroid therapy and reduce toxicity in patients with RS. Aims: To evaluate the efficacy and toxicity of budesonide in patients with RS. PATIENTS AND METHODS: Clinical and histological data from patients with RS who received budesonide were analyzed. RS was defined as villous atrophy and malabsorption in spite of a strict gluten-free diet persisting for >6 months or requiring earlier therapeutic intervention. RESULTS: We identified 9 patients (1 with autoimmune enteropathy, 4 with RS type I without and 3 with RS type II with signs of early T cell lymphoma and 1 with CD4-positive sprue-like intestinal T cell lymphoma), who received 9 mg/day of budesonide (range 6-12) for 24 months (1-60), and 7 of whom had an initial treatment with 40 mg/day of prednisolone (30-60) for 4 months (1-144). The initial body mass index was 18 (13.1-22.8) and increased similarly under prednisolone [21.5 (14.9-26.7), p < 0.05] and budesonide therapy [21 (18-27.2), p < 0.05]. The stool frequency per day also decreased similarly from 6 (2-8) to 2 (1-3) and 2 (1-5), each p < 0.05, under prednisolone and budesonide therapy, respectively. Two patients with RS type II did not respond and 7, including all 4 with RS type I, were clinically stable with budesonide therapy. Skin fragility in 1 patient was the only adverse effect of budesonide therapy. CONCLUSIONS: Budesonide may be an effective treatment option in patients with RS type I, which can stabilize the clinical condition similar to prednisolone.     

Gammagraphy with sucralfate labelled with technetium in esophagitis

In previous studies it has been reported that, after being labeled with technetium, sucralfate, an useful drug in peptic diseases, can be used to detect peptic lesions of the digestive tract. In this work we report our experience with this technique in the diagnosis of esophagitis. 25 studies (11 controls and 14 patients) were undertaken. Sucralfate scintigraphy was normal in the 11 control studies, and abnormal in 10 out of 14 patients. Scintigraphy was abnormal in peptic as well as caustic lesions.     

Mental disorders in patients with obesity in comparison with healthy probands

OBJECTIVE: Findings concerning the association of obesity and mental disorders are inconsistent. The present epidemiological study investigates adjusted 4-week, 12-month, and lifetime prevalence rates of mental disorders in obese individuals compared with physically healthy probands and overweight individuals. Correlates of the associations are examined. METHODS: Prevalence rates were calculated from two large epidemiological surveys from both the general population of Germany and inpatient centers. The surveys investigated subjects with obesity (n=910) and overweight (n=1550), as well as physically healthy probands (n=495). The prevalence rates were based on the Munich-composite international diagnostic interview, a standardized interview for the assessment of mental disorders. Correlates of mental disorders in obese individuals were assessed using self-report questionnaires and medical examinations. RESULTS: The adjusted odds ratios (OR) of obese inpatients and obese patients from the general population were significantly elevated in comparison with healthy probands for the 4-week (OR: 2.2; 2.3), 12-month (OR: 1.8; 2.7) and lifetime (OR: 1.4; 2.0) periods. Prevalence rates of overweight individuals were below those of obese individuals. Mood, anxiety and somatoform disorders were most frequent. In particular, sex, marital status and comorbid musculoskeletal diseases proved to be correlates of an increased risk for mental disorders in obese individuals. The presence of comorbid mental disorders was associated with significantly increased health care use and lower quality of life. CONCLUSIONS: There is a strong relationship between obesity and mental disorders. A future task is to improve care of mental disorders in patients with obesity.     

Polymyositis-like syndrome with rhabdomyolysis in association with brucellosis

Diffuse myositis with progression to rhabdomyolysis has been reported in association with wide range of viral infections. We report a case of polymyositis-like syndrome complicated by rhabdomyolysis secondary to brucellosis. This case report thus contributes yet another atypical presentation to a disease already infamous for its protean manifestations.