特应性皮炎动物模型表皮脂合成的研究

目的:探讨特应性皮炎(AD)皮肤生理改变(包括表皮水分丢失量和角质层水分含量)是否与表皮脂的代谢有关。方法:在小鼠的背部和躯干外涂2,4-二硝基氟苯(DNFB),建立小鼠特应性皮炎模型,利用14[C]乙酸对AD模型表皮脂的代谢进行研究,并用电子显微镜对AD皮肤的超微结构进行观察。结果:AD表皮的胆固醇和脂肪酸的合成速度明显低于对照组,正常对照组的角质细胞间均为正常的复层板层膜结构。而皮炎组的深层角质细胞间虽可见正常的复层板层结构,但有许多没有加工完全的膜结构存在。结论:推测AD皮肤生理的异常改变可能是由于表皮脂的合成减少和角质细胞间膜异常所致。

Advanced hepatocellular carcinoma responds to MK615, a compound extract from the Japanese apricot “Prunus mume ”

MK615, a compound extracted from the Japanese apricot "Prunus mume " has been reported to have in vitro anti-tumor activities against several cancer cell lines,including hepatocellular carcinoma(HCC). However, the clinical effects and feasibility of administering MK615for patients with HCC were unknown. We experienced a case with advanced HCC for which MK615 was effective against both lymph node and pulmonary metastases. A 60-year-old female underwent surgical resection of a 9 cm HCC in the right lobe. The pathological diagnosis was moderately differentiated HCC with vascular invasion. The HCC recurred in the liver 8 mo after the surgery. Radiofrequency ablation and transarterial infusion chemotherapy were performed, but the recurrence was not controlled. One year after the intrahepatic recurrence, pulmonary and lymph metastasis appeared.Sorafenib was administered, but was not effective.Then, MK615 was administered as a final alternative therapy after informed consent was obtained from the patient. Three months later, her alpha-fetoprotein level decrease and both the lymph node and pulmonary metastases decreased in size. The patient has survived for more than 17 mo after the MK615 administration, and was in good condition. Although further investigations are necessary to clarify its safety and efficacy in humans, MK615 may be useful for the treatment of HCC,without serious adverse effects.

Demographic determinants of risk,colon distribution and density scores of diverticular disease

AIM:To investigate associations between ethnicity,age and sex and the risk,colon distribution and density scores of diverticular disease(DD).METHODS:Barium enemas were examined in 1000 patients:410 male,590 female;760 whites,62 Asians,44 black africans(BAs),and 134 other blacks(OBs).Risks and diverticula density of left-sided DD(LSDD) and rightsided-component DD(RSCDD = right-sided DD + right and left DD + Pan-DD) were compared using logistic regression.RESULTS:Four hundred and forty-seven patients had DD(322 LSDD and 125 RSCDD).Adjusted risks:(1) LSDD:each year increase in age increased the odds by 6%(95% CI:5-8,SE:0.8%,P < 0.001);Asians:odds ratio(OR):0.23(95% CI:0.10-0.53,SE:0.1,P ≤ 0.001) and OBs:OR:0.25(95% CI:0.14-0.43,SE:0.07,P ≤ 0.001) appeared protected vs Whites;(2) RSCDD:each year increase in age increased the odds by 4%(95% CI:2-6,SE:1%,P < 0.001);females were 0.60 times(95% CI:0.40-0.90,SE:0.12,P = 0.01) less likely than males to have RSCDD;BAs were 3.51 times(95% CI:1.70-7.24,SE:1.30,P < 0.001) more likely than Whites to have RSCDD;and(3) DD density scores:each year increase in age increased the odds of highdensity scores by 4%(95% CI:1-6,SE:1%,P < 0.001);RSCDD was 2.77 times(95% CI:1.39-3.32,SE:0.67,P < 0.001) more likely to be of high density than LSDD.No further signif icant differences were found in the adjusted models.CONCLUSION:Right colonic DD might be more common and has higher diverticula density in the west than previously reported.BAs appear predisposed to DD,whereas other ethnic differences appear conserved following migration.

STAT3 deficiency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury

AIM To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide(TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma(HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9(SOX9) and Yes-associated protein(YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.

Acute cytomegalovirus infection in liver transplant recipients:An independent risk for venous thromboembolism

Acute cytomegalovirus(CMV) infection is a commonly encountered complication in the post liver transplant setting. We present a case of a 71-year-old male with acute CMV infection, initially presenting with a gastro- intestinal bleed due to acute CMV gastritis and later on complicated by acute venous thromboembolism occur- ring as an unprovoked event in the post liver transplant period. Traditional risk factors for venous thromboem- bolism have been well described in the medical litera- ture. Sporadic cases of thromboembolism due to CMV infection in the immune compromised patients have been described, especially in the post kidney transplant patients. Liver transplant recipients are equally prone to CMV infection particularly in the first year after suc- cessful transplantation. Venous thromboembolism in this special population is particularly challenging due to the fact that these patients may have persistent throm- bocytopenia and anticoagulation may be a challenge for the treating physician. Since liver transplantation is severely and universally limited by the availability of donor organs, we feel that this case report will provide valuable knowledge in the day to day management of these patients, whose clinical needs are complex and require a multidisciplinary approach in their care and management. Evidence and pathophysiology link- ing both the conditions is presented along with a brief discussion on the management, common scenarios en- countered and potential impact in this special group of patients.

AMACR is associated with advanced pathologic risk factors in sporadic colorectal adenomas

AIM: To analyze α-methylacyl CoA racemase (AMACR) expression in relation to various dysplasia phenotypes and clinicopathological parameters of sporadic colorectal adenomas.METHODS: Fifty-f ive cases of sporadic colorectal adenomas were categorized according to the Vienna classif ication for Gastrointestinal Neoplasia.These corresponded to a total of 98 different intra-lesion microscopic f ields that were further independently assigned a histological grade based on the old nomenclature (mild,moderate,severe dyplasia and carcinoma in situ).AMACR expression was evaluated by immunohistochemistry and statistical analysis was performed to investigate possible associations with various clinicopathologic parameters of adenomas i.e.gender,age,localization,grade of dysplasia,size and conf iguration.RESULTS: Patient age ranged from 41 to 84 years (mean 65 ± 13.2 years);37 patients were males and 18 were females.Adenomas ranged in size between 0.5 and 30 cm (mean 2 ± 1.3 cm),including 18 tubular,16 villous,20 mixed or tubulovillous,and 1 giant sessile villous adenoma.AMACR expression was observed in 3 out of 16 (18.8%) of low-grade vs 23 out of 35 (62.8%) of high-grade lesions (P = 0.002).Most adenomas exhibiting high grade dysplasia with in situ carcinoma-like areas stained positive for AMACR (15/17 or 88.2%) as compared to adenomas with high grade dysplasia which contained severe dysplasia-like foci (6/15 or 40%),(P = 0.005).In AMACR positive adenomas featuring severe dysplasia-like or in situ carcinoma-like areas,AMACR staining was not necessarily observed in the in situ component.Positivity in intra-lesion of mild,moderate or severe dysplasia-like foci was more often encountered in adenomas harboring in situ,intramucosal or inf iltrative carcinoma [21/33 (63.6%) vs 9/40 (22.5%),P < 0.001].Strong AMACR expression was found in 11 out of 17 villous adenomas,but in only 1 out of 18 tubular lesions (P = 0.005).Larger lesions,i.e.> 1 cm stained more frequently for AMACR than smaller ones [27/45 (60%) vs 2/10 (20%),P = 0.02].Overall,AMACR expression was associated with the grade of dysplasia,as well as with the size and conf iguration of adenomas,i.e.the consensus risk factors applied to colorectal adenoma patient surveillance.CONCLUSION: It may be worthy to further evaluate the possible use of AMACR as an additional risk factor for the assessment of colorectal adenoma patients.

Independent effects of diet and exercise training on fat oxidation in non-alcoholic fatty liver disease

AIM To investigate the independent effects of 6-mo of dietary energy restriction or exercise training on wholebody and hepatic fat oxidation of patients with nonalcoholic fatty liver disease(NAFLD).METHODS Participants were randomised into either circuit exercise training(EX;n = 13;3 h/wk without changes in dietary habits),or dietary energy restriction(ER) without changes in structured physical activity(ER;n = 8).Respiratory quotient(RQ) and whole-body fat oxidation rates(Fatox) were determined by indirect calorimetry under basal,insulin-stimulated and exercise conditions.Severity of disease and steatosis was determined by liver histology;hepatic Fatox was estimated from plasma β-hydroxybutyrate co.ncentrations;cardiorespiratory fitness was expressed as VO2 peak.Complete-case analysis was performed(EX:n = 10;ER:n = 6).RESULTS Hepatic steatosis and NAFLD activity score decreased with ER but not with EX.β-hydroxybutyrate concentrations increased significantly in response to ER(0.08 ± 0.02 mmol/L vs 0.12 ± 0.04 mmol/L,P = 0.03) but remained unchanged in response to EX(0.10 ± 0.03 mmol/L vs 0.11 ± 0.07 mmol/L,P = 0.39).Basal RQ decreased(P = 0.05) in response.to EX,while this change was not significant after ER(P = 0.38).VO_(2peak)(P < 0.001) and maximal Fa_(tox) during aerobic exercise(P = 0.03) improved with EX but not with ER(P > 0.05).The increase in β-hydroxybutyrate concentrations was correlated with the reduction in hepatic steatosis(r =-0.56,P = 0.04).CONCLUSION ER and EX lead to specific benefits on fat metabolism of patients with NAFLD.Increased hepatic Fat_(ox) in response to ER could be one mechanism through which the ER group achieved reduction in steatosis.

KH型剪切调控蛋白:星形胶质细胞炎性细胞因子生成检测点

中枢神经系统(CNS)慢性炎性反应是许多神经退行性疾病和自身免疫性疾病的主要病理特点之一。作为免疫活性细胞,星形胶质细胞(Ast)在CNS炎性反应过程中发挥了重要作用。它可表达许多细胞因子,如肿瘤坏死因子-α(TNF-α)和白介素-1β(IL-1β)等,这些细胞因子可直接或通过募集免疫细胞等途径间接促进炎性反应。检测点的存在可保证这些细胞因子的生成受到严密控制。细胞因子mRNA3’-非翻译区的腺苷酸/尿苷酸富含元件(ARE)由于可调节mRNA稳定性和翻译效率而扮演着主要检测点的角色。KH型剪切调控蛋白(KSRP)是一种RNA结合蛋白,可通过与ARE结合降低mRNA的稳定性。本研究检测了KSRP对Ast细胞因子表达和旁分泌表型的影响。笔者发现了一个包括TNF-α和L-1β在内的炎性介质网络。与同窝出生的对照小鼠相比,KSRP-/-小鼠Ast上述炎性介质的表达在RNA水平增高了2～4倍。而这种KSRP-/-小鼠Ast激活后产生的TNF-α和IL-1β甚至能达到对照组的15倍以上。离体情况下,KSRP-/-Ast条件性培养液有趋化作用且能诱导神经元死亡。令人惊讶的是,笔者发现仅通过特定途径激活Ast后才能观察到部分mRNA半衰期延长。荧光素酶报告系统研究显示KSRP可在转录水平和转录后水平调节细胞因子基因的表达。本研究提示KSRP在促炎介质的调控方面发挥重要作用,因此在CNS炎性和自身免疫性疾病中有广泛意义。

novel treatment approaches in hypertensive type 2 diabetic patients

Type 2 diabetes mellitus(T2DM)and hypertension represent two common conditions worldwide.Their frequent association with cardiovascular diseases makes management of hypertensive patients with T2DM an important clinical priority.Carvedilol and renal denervation are two promising choices to reduce plasma glucose levels and blood pressure in hypertensive patients with T2DM to reduce future complications and improve clinical outcomes and prognosis.Pathophysiological mechanisms of both options are under investigation,but one of the most accepted is an attenuation in sympathetic nervous system activity which lowers blood pressure and improves insulin sensitivity.Choice of these therapeutic approaches should be individualized based on specific characteristics of each patient.Further investigations are needed to determine when to consider their use in clinical practice.

Can Na+/K+ATPase be a novel target to treat anxiety?A hint from its regulatory effect on neuroinflammation

OBJECTIVE Na+/K+-ATPase(NKA)is large membrane protein expressed uni⁃versally which is indispensable for the mainte⁃nance of ionic gradient as well as neuronal excit⁃ability.The role of NKA in inflammatory regula⁃tion is still unclear.Inflammatory responses are initiated upon the activation of inflammasomes.In order to investigate the crosslink between NKA and inflammasome,NKAα1 knockout(KO)N2a cells were generated using CRISPR/Cas9 system.METHODS AND RESULTS qPCR results showed that NLRP1 and NLRP3 were upregulated in response to NKAα1 loss while both NLRC4 and AIM2 remained unaffected.Meanwhile,consistent with the change in NLRP1 and NLRP3,both the mRNA level of ASC and IL-1βwere significantly increased in NKAα1 KO cells.These data indicated that NKAα1 interfer⁃ence might influence the level of NLRP1 and NLRP3 inflammasomes in neuronal cells.Further evidence indicating the potential link between NKA and inflammasome pathway were provided using cytokine array assay where all the differen⁃tiated protein detected were closely linked to NLRP1 and NLRP3.To confirm this effect,we also observed the transcriptional levels of inflam⁃masome proteins in the brain cortex from both NKAα1+/+and NKAα1+/-mice.In line with the observation gained in NKAα1 KO cells,the mRNA level of NLRP1,NLRP3 and IL-1βwere significantly upregulated in NKAα1+/-mice brain.Interestingly,in the primary cultured astrocytes,treatment with LPS/ATP significantly reduced the mRNA and protein levels of NKAα1 expression.These data imply that a negative regulation loop between NKAα1 and inflammation may exist in the central nervous system.Since neuroinflam⁃matory mechanism is currently considered the most potential of interventions to target anxiety,we therefore perform behavioural experiments to investigate the role of NKAα1 in anxiety.Chronic restraint stress(CRS)for 10 d significantly reduced the time and frequency of entering the open arm and prolonged the retention time in the closed arm in the elevated plus-maze test.In the open field test,CRS also reduced both duration and frequency of entering into the central region.Although NKAα1 loss itself did not alter the behaviour performance in the normal condition,it exacerbated CRS-induced above behaviour abnormalities.CONCLUSION NKAα1 is regulat⁃ed upon inflammatory challenger and may be a novel target to treat anxiety.

Methemoglobinemia—A biomarker and a link to ferric iron accumulation in Alzheimer’s disease

Understanding the mechanism of oxidative stress is likely to yield new insights regarding the pathogenesis of Alzheimer’s disease (AD). Our earlier work focused on the difference between hemoglobin and methemoglobin degradation, respectively leading to ferrous (Fe2+) iron, or ferric (Fe3+) iron. Methemoglobin has the role of carrier, the donor of cytotoxic and redox-active ferric (Fe3+) iron, which can directly accumulate and increase the rate of capillary endothelial cell apoptosis, and may cross into the brain parenchyma, to the astrocytes, glia, neurons, and other neuronal cells (neurovascular unit). This supposition helps us to understand the transport and neuronal accumulation process of ferric iron, and determine how iron is transported and accumulated intracellularly, identifiable as “Brain rust”. Earlier research found that the incidences of neonatal jaundice (p = 0.034), heart murmur (p = 0.011) and disorders such as dyslalia and learning/memory impairments (p = 0.002) were significantly higher in those children born from mothers with methemoglobinemia. Our hypothesis suggests that prenatal iron abnormalities could lead to greater neuronal death, the disease ageing process, and neurodegenerative disorders such as AD and other neurodegenerative diseases.

Safety and Performance of Harmonic®HD 1000i Shears in Thoracoscopic Procedures: A Retrospective Study

Background: Ultrasonic energy devices are utilized for transection, incision, and hemostasis in traditional open and laparoscopic procedures. The Harmonic HD 1000i Shears, designed to deliver a precise amount of thermal energy during tissue transection and vessel sealing, has been utilized in many specialties. This study aimed to confirm real-world safety and performance of the Harmonic device in two thoracoscopic procedures: lobectomy and segmentectomy. Methods: The primary endpoint of this retrospective, observational, single-arm study was rate of post-operative blood transfusions related to study device or procedure. Secondary endpoints included occurrence of intra- and post-operative adverse events (AEs) or complications device- or procedure-related, and rate of required additional hemostatic measures. Adults included those who underwent thoracoscopic lobectomy or segmentectomy where HD 1000i shears were used while excluding those where additional advanced energy devices were used. The study was conducted at Severance Hospital, Yonsei University Health System, South Korea from May 1, 2018, to November 30, 2020. Results: Subjects included n = 766 lobectomies (mean age 63.79, 52% male) and n = 215 segmentectomies (mean age 63.19, 54% male). Estimated blood loss was 50 mL (0 min, 3200 max) and 20 mL (0 min, 800 max), intraoperative transfusion rate 0.001% and 0%, intraoperative complication/AE rate 1% and 2%, and post-operative complication/AE rate 9% and 4% in the lobectomy and segmentectomy groups, respectively. Median operative times were 108 min. (35 min, 395 max) for lobectomies and 105 min. (32 min, 574 max) for segmentectomies. Conclusion: Given the low rate of blood loss and intra- and post-operative complication/AE rates, HD 1000i can be used confidently for thoracoscopic pulmonary resection in adults.

Intestine-derived α-synuclein initiates and aggravates pathogenesis of Parkinson’s disease in Drosophila

Background:Aberrant aggregation ofα-synuclein(α-syn)is a key pathological feature of Parkinson’s disease(PD),but the precise role of intestinalα-syn in the progression of PD is unclear.In a number of genetic Drosophila models of PD,α-syn was frequently ectopically expressed in the neural system to investigate the pathobiology.Method:We investigated the potential role of intestinalα-syn in PD pathogenesis using a Drosophila model.Humanα-syn was overexpressed in Drosophila guts,and life span,survival,immunofluorescence and climbing were evalu-ated.Immunofluorescence,Western blotting and reactive oxygen species(ROS)staining were performed to assess the effects of intestinalα-syn on intestinal dysplasia.High‐throughput RNA and 16S rRNA gene sequencing,quantitative RT‐PCR,immunofluorescence,and ROS staining were performed to determine the underlying molecular mechanism.Results:We found that the intestinalα-syn alone recapitulated many phenotypic and pathological features of PD,including impaired life span,loss of dopaminergic neurons,and progressive motor defects.The intestine-derivedα-syn disrupted intestinal homeostasis and accelerated the onset of intestinal ageing.Moreover,intestinal expression ofα-syn induced dysbiosis,while microbiome depletion was efficient to restore intestinal homeostasis and ameliorate the progression of PD.Intestinalα-syn triggered ROS,and eventually led to the activation of the dual oxidase(DUOX)-ROS-Jun N-terminal Kinase(JNK)pathway.In addition,α-syn from both the gut and the brain synergized to accelerate the progression of PD.Conclusions:The intestinal expression ofα-syn recapitulates many phenotypic and pathologic features of PD,and induces dysbiosis that aggravates the pathology through the DUOX-ROS-JNK pathway in Drosophila.Our findings provide new insights into the role of intestinalα-syn in PD pathophysiology.

Identification of Expression Pattern and Clinical Significance of the Small Cajal Body-specific RNA SCARNA16 in Hepatocellular Carcinoma

Background and Aims:For high morbidity and mortality,hepatocellular carcinoma(HCC)becomes a major health issue worldwide.Nowadays,numerous non-coding RNAs(ncRNAs)are known to regulate the occurrence and patho-genesis of tumors.Some ncRNAs have also been developed as tumor biomarkers and therapeutic targets.However,the potential function of the small Cajal body-specific RNA(scaRNA)SCARNA16,a newly identified ncRNA,remains to be explored in HCC.Methods:In both HCC cell lines and specimens from 120 enrolled patients,the expression val-ues of SCARNA16 were detected.We divided patients into SCARNA16 high and low expression subgroups,and then analyzed the difference of various clinical characteristics and prognosis data between subgroups.Results:Compared to paired controls,SCARNA16 was significantly down-regulated in HCC cell lines and clinical specimens(p<0.01).Besides,HCC patients with lower SCARNA16 expression commonly presented with larger and more tumor lesions,more ves-sel carcinoma emboli,more capsular invasion and higher TNM stages(p<0.05).Moreover,SCARNA16 expression was negatively correlated with postoperative prognosis of HCC patients in 5-year follow-up,including tumor-free survival(TFS)(median time of low vs.high subgroups:14 vs.48 months,p=0.006)and overall survival(OS)(median time of low vs.high subgroups:39 vs.52 months,p=0.001).Besides,SCARNA16 acted as an independent prognostic bio-marker in TFS(hazard ratio[HR]:0.578,95%CI:0.345-0.969,p=0.038)and OS(HR:0.366,95%CI:0.178-0.752,p=0.006).Conclusions:Low expression patterns of SCAR-NA16 remarkably associated with severe clinical status and poor survival of patients,suggesting that SCARNA16 pos-sesses potency as a novel biomarker for HCC.