脂联素依赖p38-MAPK途径抑制衣霉素诱导的内质网应激致心肌细胞凋亡

目的通过原代培养SD大鼠的乳鼠心肌细胞建立衣霉素心肌细胞内质网应激损伤模型,观察脂联素对心肌细胞内质网应激致细胞凋亡的作用及其机制。方法采用酶消化法原代培养乳鼠心肌细胞,倒置相差显微镜下观察细胞生长,通过α-肌动蛋白免疫荧光法对培养的心肌细胞进行鉴定。选用原代培养3～4天的心肌细胞,随机分为五组:对照组、1 mg/L衣霉素组、1 mg/L衣霉素+100 mg/L脂联素组、1 mg/L衣霉素+3μmol/LSB203580组及1 mg/L衣霉素+3μmol/L SB203580+100 mg/L脂联素组。实验终止后,在倒置相差显微镜下观察心肌细胞形态变化,通过流式细胞术检测心肌细胞凋亡,用qRT-PCR及免疫荧光法检测内质网应激指标GRP78和CHOP的mRNA及蛋白表达。结果与对照组相比,给予衣霉素后,细胞凋亡率显著增加,GRP78和CHOP的mR-NA及蛋白表达增加。脂联素预处理后给予衣霉素,可较大程度地逆转上述指标变化,细胞凋亡率显著下降,GRP78和CHOP的mRNA及蛋白表达减少;而加用p38-MAPK抑制剂SB203580后脂联素的保护作用明显减弱,凋亡率显著增加,GRP78和CHOP的mRNA及蛋白表达增高,但较单纯衣霉素处理组凋亡率低,GRP78和CHOP的mRNA及蛋白表达也减少。结论衣霉素可使GRP78和CHOP表达增强,启动内质网应激,导致心肌细胞凋亡,脂联素可以通过减轻内质网应激逆转衣霉素所致的心肌细胞凋亡作用,对心肌细胞有保护作用,且这种保护作用部分是通过p38-MAPK途径实现的。     

BIOPSY PROVEN ACUTE TUBULAR NECROSIS DUE TO RHABDOMYOLYSIS IN A DENGUE FEVER PATIENT: A CASE REPORT AND REVIEW OF LITERATURE

Renal histology results are very scarce in dengue-associated rhabdomyolysis patients developing acute kidney injury (AKI). We report a case of dengue fever-induced AKI associated to rhabdomyolysis with a renal biopsy showing acute tubular necrosis (ATN) and renal deposition of myoglobin. A 28-year-old patient who presented dengue fever (DF) complicated by severe AKI and rhabdomyolysis is described. The patient required hemodialysis for three weeks. A renal biopsy revealed ATN with positive staining for myoglobin in the renal tubuli. The patient was discharged with recovered renal function. In conclusion, this case report described a biopsy proven ATN associated to DF-induced rhabdomyolysis, in which renal deposition of myoglobin was demonstrated. We suggest that serum creatine phosphokinase should be monitored in DF patients to allow for an early diagnosis of rhabdomyolysis and the institution of renal protective measures.     

从凋亡信号通路探讨热休克蛋白保护过氧化氢所致心肌细胞凋亡的机制

为探讨热休克蛋白保护过氧化氢所致心肌细胞凋亡的分子机制，采用热休克对原代培养的新生大鼠心肌细胞进行预处理，以诱导热休克蛋白的表达，观察热休克蛋白对过氧化氢所致心肌细胞凋亡的保护作用。结果发现，热休克预处理导致心肌细胞热休克蛋白70及αB-晶状体蛋白表达明显增加，同时显著抑制过氧化氢所致细胞色素C从线粒体释放，抑制Caspase-8、Caspase-9和Caspase-3活化及随后的心肌细胞凋亡。以上结果提示，热休克蛋白通过抑制线粒体信号通路与死亡受体通路的活化保护过氧化氢导致的心肌细胞凋亡，为临床防治心血管疾病提供了新的信息。     

Super High‐Flux Continuous Venovenous Hemodialysis Using Regional Citrate Anticoagulation: Long‐Term Stability of Middle Molecule Clearance

Continuous renal replacement therapy is a standard treatment in critically ill patients with acute kidney injury. All CRRT techniques provide a high low‐molecular weight clearance but even with hemofiltration, clearance of middle molecules is low. We investigated whether a new super high‐flux hemofilter provides effective and sustained middle molecule clearance during citrate‐anticoagulated continuous venovenous hemodialysis for up to 72 h. We included 14 critically ill patients with AKI‐KDIGO‐III in a prospective observational trial. We measured/calculated blood and urine concentrations, clearances and sieving coefficients of eight molecules with molecular weights from 60 to 66 kDa, hemodynamic parameters and SAPS‐II scores. All filters were patent at 72 h. Clearance and sieving coefficients of small solutes were high and sustained over time, those for larger solutes decreased over 72 h but remained high enough to decrease blood concentrations of solutes up to 25 kDa. Albumin serum levels remained unaffected. Catecholamine doses and SAPS‐II scores decreased significantly. This new hemofilter may improve blood purification in critically ill patients with AKI.     

Milk Fat Globule EGF Factor 8 Attenuates Sepsis‐Induced Apoptosis and Organ Injury in Alcohol‐Intoxicated Rats

Background: Despite advances in our understanding of excessive alcohol‐intake‐related tissue injury and modernization of the management of septic patients, high morbidity and mortality caused by infectious diseases in alcohol abusers remain a prominent challenge. Our previous studies have shown that milk fat globule epidermal growth factor‐factor VIII (MFG‐E8), a protein required to opsonize apoptotic cells for phagocytosis, is protective in inflammation. However, it remains unknown whether MFG‐E8 ameliorates sepsis‐induced apoptosis and organ injury in alcohol‐intoxicated rats. The purpose of this study was to determine whether recombinant murine MFG‐E8 (rmMFG‐E8) attenuates organ injury after acute alcohol exposure and subsequent sepsis. Methods: Acute alcohol intoxication was induced in male adult rats by a bolus injection of intravenous alcohol at 1.75 g/kg BW, followed by an intravenous infusion of 300 mg/kg BW/h of alcohol for 10 hours. Sepsis was induced at the end of 10‐hour alcohol infusion by cecal ligation and puncture (CLP). rmMFG‐E8 or vehicle (normal saline) was administered intravenously 3 times (i.e., at the beginning of alcohol injection, the beginning of CLP, and 10 hours post‐CLP) at a dose of 20 μg/kg BW each. Blood and tissue samples were collected 20 hours after CLP in alcoholic animals for various measurements. Results: Acute alcohol exposure per se did not affect the production of MFG‐E8; however, it primed the animal and enhanced sepsis‐induced MFG‐E8 downregulation in the spleen. Administration of rmMFG‐E8 reduces alcohol/sepsis‐induced apoptosis in the spleen, lungs, and liver. In addition, administration of rmMFG‐E8 after alcohol exposure and subsequent sepsis decreases circulating levels of TNF‐α and interleukin‐6 and attenuates organ injury. Conclusions: rmMFG‐E8 attenuates sepsis‐induced apoptosis and organ injury in alcohol‐intoxicated rats.     

Potential Role of Neutrophil Gelatinase‐Associated Lipocalin in Identifying Critically Ill Patients With Acute Kidney Injury Stage 2–3 Who Subsequently Require Renal Replacement Therapy

Delayed initiation of renal replacement therapy (RRT) in critically ill acute kidney injury (AKI) patients results in high mortality while too early RRT causes unnecessary risks of the treatment. Current traditional indications cannot clearly identify the appropriate time for initiating RRT. This prospective cohort study was conducted to determine the accuracy of using plasma neutrophil gelatinase‐associated lipocalin (pNGAL) and urine NGAL (uNGAL) in early identifying of the AKI patients who subsequently required RRT. Forty‐seven critically ill patients with AKI stage 2–3 who did not reach the traditional indications for RRT were enrolled in this study. The pNGAL, uNGAL, and other parameters were determined in each patient. The primary end point was RRT initiation according to the traditional indications within 3 days. The mean age of the patients was 63.0 ± 18.1 years. pNGAL could predict subsequent RRT requirements with area under ROC 0.813 (P < 0.001, 95%CI 0.66–0.90). The cut‐off point of 960 ng/mL provided sensitivity and specificity of 72.2 and 89.6%, respectively, and positive and negative predictive values of 81.25% and 83.8%, respectively. The uNGAL provided slightly lower significance of statistical parameters. The combination of pNGAL level of 960 ng/mL and APACHE II score of 20 improved statistical values. In conclusion, pNGAL is an excellent early biomarker for RRT initiation in critically ill patients with AKI stage 2–3. The pNGAL value of 960 ng/mL, alone or in combination with APACHE II score might be used as the early new indicator for early initiation of RRT in AKI stage 2–3 and this might improve patient survival.     

Pathways to heroin dependence: time to re‐appraise self‐medication

The self‐medication hypothesis emphasizes the role of distressing affect as the primary motivator for the compulsive use that leads to substance dependence. The model also postulates that there will be psychopharmacological specificity between symptom presentation and the primary drug of dependence. In this review, the self‐medication hypothesis is examined in relation to the development and chronicity of heroin dependence. It is argued that if self‐medication has a role in engendering and extending substance dependence, it should be apparent in the use of a drug that carries such overwhelming personal risk. The psychopathology seen among adult users is certainly consistent with the model. More importantly, however, are the extraordinarily high levels of childhood trauma and psychopathology that occur typically well before the initiation of heroin use. In contrast, the postulate of drug specificity appears less supported by the polydrug use patterns typical of heroin users, and does not appear to be a necessary corollary of the model.     

Síndrome cardiorrenal: clasificación,fisiopatología,diagnóstico y tratamiento. Una revisión de las publicaciones médicas

The cardiorenal syndrome is a complex entity in which a primary heart dysfunction causes kidney injury (Types 1 and 2) and vice versa (Types 3 and 4), being either acute or chronic events, or maybe the result of a systemic disease that involves both organs (Type 5). Approximately 49% of heart failure cases present some grade of kidney dysfunction, significantly increasing morbidity and mortality rates. Its pathogenesis involves a variety of hemodynamic, hormonal and immunological factors that in the majority of cases produce fluid overload; the diagnosis and treatment of such constitutes the disease’s management basis. Currently, a clinical based diagnosis is insufficient and the use of biochemical markers, such as natriuretic peptides, or lung and heart ultrasound is required. These tools, along with urinary sodium levels, allow the evaluation of therapy effectiveness. The preferred initial decongestive strategy is based on a continuous infusion of a loop diuretic with a step-up dosing regimen, aiming for a minimal daily urine volume of 3 liters, with the possibility to sequentially add potassium sparing diuretics, thiazide diuretics and carbonic anhydrase inhibitors to reach the diuresis goal, leaving ultrafiltration as a last resource due to its higher rate of complications. Finally, evidence-based therapy should be given to improve quality of life, decrease mortality, and delay the deterioration of kidney and heart function over the long term.     

Protecting kidneys in liver transplant patients:A pathway to preventive interventions

Acute kidney injury(AKI) is a frequent postoperative complication after liver transplantation. The etiology is multifactorial,including perioperative renal status,surgery related events,and postoperative immunosuppression therapy. The role of renal hypoperfusion and hepatic ischemia-reperfusion injury as causes of early AKI are now being increasingly recognized. Further studies should focus on therapies that would attenuate this injury.     

Prevalence and short‐term outcome of acute kidney injury in patients with acute‐on‐chronic liver failure: A meta‐analysis

Acute kidney injury (AKI) in patients with acute‐on‐chronic liver failure (ACLF) is a distinct syndrome to that in patients with cirrhosis, yet is less characterized. The aim of this meta‐analysis was to investigate the impact of AKI on outcome of ACLF. We searched PubMed, Web of Science and Cochrane Library for original articles that evaluated the impact of AKI on outcome of ACLF from 2011 to 2019. Odds ratio (OR) with 95% confidence interval (CI) for 1‐month and 3‐month mortality was calculated. The response rate of vasoconstrictor for hepatorenal syndrome (HRS)‐AKI was assessed. Eight relevant articles with 3610 patients were included. The prevalence of AKI in ACLF patients was 41% (95% CI 32%‐50%). The presence of AKI was significantly associated with 1‐month mortality of ACLF (OR 3.98, 95% CI 3.09‐5.12; P < .001) and 3‐month mortality (OR 4.98, 95% CI 3.59‐6.92; P < .001). Additionally, patients with AKI stage ≥2 showed a higher 3‐month mortality than stage 1 (OR 3.89, 95% CI 2.60‐5.82; P < .001), and those of stage 3 had a higher mortality than stage ≤2 (OR 3.77, 95% CI 2.10‐6.77; P < .001). The pooled response rate of vasoconstrictors was 32% (95% CI 26%‐37%). This meta‐analysis indicated that about 40% of ACLF patients complicated with AKI and the presence of AKI substantially increased the short‐term mortality, together with a poor response rate of vasoconstrictors for HRS‐AKI.