BACKGROUND Poor glycaemic control in patients with type 2 diabetes mellitus(T2DM)is often accompanied by multiple complications,including diabetic nephropathy(DN),diabetic retinopathy(DR),diabetic peripheral neuropath...BACKGROUND Poor glycaemic control in patients with type 2 diabetes mellitus(T2DM)is often accompanied by multiple complications,including diabetic nephropathy(DN),diabetic retinopathy(DR),diabetic peripheral neuropathy(DPN),and cardiac structural abnormality left ventricular hypertrophy(LVH).Early identification of high-risk populations for these complications and the implementation of intervention measures are crucial for improving patient outcomes.Serum alpha-1-microglobulin(α1-MG),a multifunctional protein synthesized by the liver and lymphocytes,has been considered a potential biomarker of diabetes-related diseases in recent years.AIM To investigate the associations of serumα1-MG with DN,DR,DPN,and LVH in T2DM patients and its predictive value.METHODS This retrospective study included 5045 T2DM patients.The study participants were stratified into quartiles according to their serumα1-MG levels.Multivariate logistic regression,restricted cubic spline,and explainable machine learning models were employed for risk assessment and feature importance evaluation.RESULTS Increasedα1-MG levels were observed in patients with DN,DR,DPN,and LVH(all P<0.001).Multivariate logistic regression revealed that each standard deviation increase inα1-MG was associated with an 84%increase in DN risk(OR:1.84,95%CI:1.62-2.10,P<0.001),a 17%increase in DR risk(OR:1.17,95%CI:1.07-1.28,P<0.001),a 14%increase in DPN risk(OR:1.14,95%CI:1.03-1.27,P=0.014),and a 28%increase in LVH risk(OR:1.28,95%CI:1.18-1.38,P<0.001).Subgroup analyses and machine learning confirmed the associations of elevatedα1-MG with these complications in T2DM patients.CONCLUSION Elevated serumα1-MG levels were independently associated with increased risks of DN,DR,DPN,and LVH in T2DM patients,suggesting its potential as a predictive biomarker.展开更多
Activation of inflammatory responses regulates the transmission of pain pathways through an integrated network in the peripheral and central nervous systems.The immunopotentiator thymosin alpha-1(Tal)has recently been...Activation of inflammatory responses regulates the transmission of pain pathways through an integrated network in the peripheral and central nervous systems.The immunopotentiator thymosin alpha-1(Tal)has recently been reported to have anti-inflammatory and neuroprotective functions in rodents.However,how Tα1 affects inflammatory pain remains unclear.In the present study,intraperitoneal injection of Tal attenuated complete Freund's adjuvant(CFA)-induced pain hypersensitivity,and decreased the up-regulation of pro-inflammatory cytokines(TNF-α,IL-1β,and IL-6)in inflamed skin and the spinal cord.We found that CFA-induced peripheral inflammation evoked strong microglial activation,but the effect was reversed by Tα1.Notably,Tα1 reversed the CFA-induced up-regulation of vesicular glutamate transporter(VGLUT)and down-regulated the vesicular γ-aminobutyric acid transporter(VGAT)in the spinal cord.Taken together,these results suggest that Tα1 plays a therapeutic role in inflammatory pain and in the modulation of microgliainduced pro-inflammatory cytokine production in addition to mediation of VGLUT and VGAT expression in the spinal cord.展开更多
AIM： To observe the efficiency and safety of thymosin-α1 treatment in patients with hepatitis B e antigen （HBeAg） and HBV DNA positive chronic hepatitis. METHODS： Sixty-two patients were randomly divided into gro...AIM： To observe the efficiency and safety of thymosin-α1 treatment in patients with hepatitis B e antigen （HBeAg） and HBV DNA positive chronic hepatitis. METHODS： Sixty-two patients were randomly divided into groups A and B. The patients in group A received subcutaneous injection of 1.6 mg thymosin-α1, twice a week （T-α1 group） for six months, and the patients in group B received 5 MU interferon alpha （IFN-α） each day for fifteen days, then three times weekly （IFN-α group） for six months. The results between two groups treated with and the group untreated with IFN-α which was followed up for 12 mo （historical control group consisting of 30 patients） were compared, and three groups were comparable between each other （P 〉 0.05） at baseline （age, sex, clinical history, biochemical, and serological parameters）. RESULTS： At the end of treatment, complete response, which was defined as alanine aminotransferase （ALT） normalization and HBV DNA and HBeAg loss, occurred in 9 of 29 （31.0%） patients in the T-α1 group and in 15 of 33 （45.5%） patients in the IFN-α group （χ^2= 1.36, P 〉 0.05）. After a follow-up period of six months, a complete response was observed in 14 of 29 （48.3%） patients in the T-α1 group and in 9 of 33 （27.3%） patients in the IFN-α group （χ^2= 2.93, P 〉 0.05）. Compared with the results observed in the historical control （HC） group untreated with IFN-α which was followed up for 12 mo, the rate of complete response was significantly higher in IFN-α group at the end of therapy （1 of 30 vs 15 of 33, 7：2 = 14.72, P 〈 0.001） and in the T-α1 group at the end of follow-up （1 of 30 vs 14 of 29,χ^2 = 15.71, P 〈 0.001）. In T-α1 and IFN-α treatment groups, the area under （the plasma concentration time） curve （AUC） of negative HBV DNA and HBeAg was 340, 17%, 31% and 19% smaller than that in the HC group. By the end of the follow-up period, the proportions of ALT normalization and negative HBV DNA in the T-α1 group were significantly higher than those in the IFN-α and HC groups. The odds of ALT normalization and negative HBV DNA at the end of the follow-up was three-fold higher in the T-α1 group than in the IFN-α group. Unlike IFN-α, T-α1 was well tolerated by all patients, and no side effects appeared in T-α1 group. CONCLUSION： The results suggest that a 6-too course of T-α1 therapy is effective and safe in patients with chronic hepatitis B. T-α1 is able to reduce HBV replication in patients with chronic hepatitis B. Furthermore, T-α1 is better tolerated than IFN-α and can gradually induce more sustained ALT normalization and HBV DNA and HBeAg loss. However, a response rate of 48.3% is still less ideal. A more effective therapeutic approach warrants further study.展开更多
AIM:To evaluate the association between alpha-1 antitrypsin deficiency(A1ATD) and hepatocellular carcinoma(HCC) in patients with end-stage liver disease(ESLD).METHODS:Patients with cirrhosis and ESLD referred to the C...AIM:To evaluate the association between alpha-1 antitrypsin deficiency(A1ATD) and hepatocellular carcinoma(HCC) in patients with end-stage liver disease(ESLD).METHODS:Patients with cirrhosis and ESLD referred to the Cleveland Clinic Foundation for liver transplantation between 2003 and 2014 were included in the study(N = 675). ESLD was defined as having histological features of cirrhosis and/or radiological evidence of cirrhosis in the context of portal hypertension(ascites,variceal bleeding,thrombocytopenia,or hepatic encephalopathy). A1 ATD was diagnosed using phenotype characterization(MZ or ZZ),liver biopsy detection of PAS-positive diastaseresistant(PAS+) globules,or both. Patients with other causes of liver diseases such as hepatitis C virus(HCV),alcoholic liver disease and non-alcoholic steatohepatitis(NASH) or NASH were also included in the study. HCC was diagnosed by using imaging modalities,biopsy findings,or explanted liver inspection. Follow-up time was defined as the number of years from the diagnosis of cirrhosis to the diagnosis of hepatocellular carcinoma,or from the diagnosis of cirrhosis to the last follow up visit. The rate of HCC was assessed using time-tointerval analysis for interval censored data.RESULTS:This study included 675 patients. 7% of subjects had A1ATD(n = 47). Out of all subjects who did not have A1 ATD,46% had HCV,17% had alcoholic liver disease,19% had NASH and 18% had another primary diagnosis. Of the 47 subjects with A1 ATD,15 had a primary diagnosis of A1ATD(PI*ZZ phenotype and PAS+ globules),8 had a PI*MZ phenotype alone,14 had PAS+ alone,and 10 had both the PI*MZ phenotype and PAS+. Median follow-up time was 3.4(25th,75 th percentiles:1,5.2) years. The overall rate of hepatocellular carcinoma in all subjects was 29%(n = 199). In the A1 ATD group,the incidence rate of HCC was 8.5% compared to 31% in the group of patients with other causes of cirrhosis(P = 0.001). Patients with ESLD due to A1 ATD had the lowest yearly cumulative rate of hepatocellular carcinoma at 0.88% per year compared to 2.7% for those with HCV cirrhosis,1.5% in patients with NASH and 0.9% in alcohol-induced liver disease(P < 0.001).CONCLUSION:Within this group of patients with ESLD,there was no significant association between A1 ATD and increased risk of HCC.展开更多
Post-hepatectomy liver failure(PHLF) is a leading cause of morbidity and mortality following major liver resection. The development of PHLF is dependent on the volume of the remaining liver tissue and hepatocyte funct...Post-hepatectomy liver failure(PHLF) is a leading cause of morbidity and mortality following major liver resection. The development of PHLF is dependent on the volume of the remaining liver tissue and hepatocyte function. Without effective pre-operative assessment, patients with undiagnosed liver disease could be at increased risk of PHLF. We report a case of a 60-year-old male patient with PHLF secondary to undiagnosed alpha-1-antitrypsin deficiency(AATD) following major liver resection. He initially presented with acute large bowel obstruction secondary to a colorectal adenocarcinoma, which had metastasized to the liver. There was no significant past medical history apart from mild chronic obstructive pulmonary disease. After colonic surgery and liver directed neo-adjuvant chemotherapy, he underwent a laparoscopic partially extended right hepatectomy and radio-frequency ablation. Post-operatively he developed PHLF. The cause of PHLF remained unknown, prompting reanalysis of the histology, which showed evidence of AATD. He subsequently developed progressive liver dysfunction, portal hypertension, and eventually an extensive parastomal bleed, which led to his death; this was ultimately due to a combination of AATD and chemotherapy. This case highlights that formal testing for AATD in all patients with a known history of chronic obstructive pulmonary disease, heavy smoking, or strong family history could help prevent the development of PHLF in patients undergoing major liver resection.展开更多
One hundred and fifty-three consecutive cases of HCC and 25 controls from autopsy material were studied by immunohistochemical method in this paper. A review of the histopathology and demonstration of AFP, alpha- 1-an...One hundred and fifty-three consecutive cases of HCC and 25 controls from autopsy material were studied by immunohistochemical method in this paper. A review of the histopathology and demonstration of AFP, alpha- 1-antichymotrypsin (AACT), alpha 1-antitrypsin (AAT) and CEA were made.Among the tumor markers. AACT yielded the highest positive rate, 109 cases (71%) out of 153 HCC. CEA was the next, 95 cases (62%) .AFP and AAT gave the same result, 72 cases (47%) . AACT, AAT and CEA were not found in the controls. AFP was present in a few hepatocytes in 1 of 25 controls. The results were in keeping with serum tests so far as the highest positive rate being AACT was concerned. Therefore, combined determination of AACT and AFP would seem a better screening method than by that of AFP alone for survey of HCC.展开更多
Objective:To analyze the application effect of Zhuang medicine aponeurotic system triple therapy in the treatment of lumbar disc herniation and its effect on the level of alpha-1 acid glycoprotein(alpha-1 AGP).Methods...Objective:To analyze the application effect of Zhuang medicine aponeurotic system triple therapy in the treatment of lumbar disc herniation and its effect on the level of alpha-1 acid glycoprotein(alpha-1 AGP).Methods:200 patients with lumbar disc herniation were selected and randomly divided into a treatment group and a control group,100 cases in each group.The control group was given conventional acupuncture,and the treatment group was treated with manipulation+fire needling+cupping.The alpha-1-AGP levels before and after treatment,as well as the lumbar spine function and pain scores before and after treatment,and the adverse reactions occurred during treatment between the two groups were compared.Results:Before treatment,there was no significant difference in alpha-1 AGP levels,lumbar function,and pain scores between the two groups(P>0.05).After treatment,the lumbar function scores of the two groups were significantly increased,with the treatment group having higher scores than the control group(P<0.05);the incidence of adverse reactions in the treatment group was 2.00%,which was much lower than the control group(P>0.05).Conclusion:Appropriate application of Zhuang medicine aponeurotic system triple therapy in the clinical treatment of lumbar disc herniation can promote the improvement of alpha-1 AGP index level,reduce the pain degree of patients,and improve their lumbar spine function.At the same time,Zhuang medicine also has significant advantages in terms of safety,while ensuring the efficacy and safety of the treatment.展开更多
The study was aimed at the evaluation of the effects of breed, age, different digestion stimulators, and dietary crude protein (CP) level on the activities of proteolytic enzymes in pancreatic tissue and duodenal chym...The study was aimed at the evaluation of the effects of breed, age, different digestion stimulators, and dietary crude protein (CP) level on the activities of proteolytic enzymes in pancreatic tissue and duodenal chymus (in vivo), serum trypsin and α1-proteinase inhibitor (A1PI) concentrations in meat-type chicks. The study of age dynamics of trypsin and A1PI concentrations was performed on the chicks of hybrid cross “Smena-8”and two parental lines (Plymouth Rock and Cornish) fed standard commercial corn-wheat-SBM diets. Twenty birds per breed were euthanized at 1, 7, 14, 21, 28 and 35 days of age to obtain blood samples and pancreatic homogenate. Experiments on the effects of different digestion promotors (probiotic, acidifier, phytobiotic, enzymatic preparation) and different CP levels (finisher diet, CP 20%, vs. ground corn, CP 8.5%) were performed on 12 hybrid chicks with fistulated duodenum from 14 to 50 days of age. The following conclusions were made: 1) At 1 day of age high proteolytic activity in pancreatic tissue and maximal serum concentrations of trypsin and A1PI were found in both hybrid and parental lines. Since 7 to 35 days of age A1PI concentration was nearly constant, serum trypsin concentration decreased while proteolytic activity in pancreatic tissue exhibited undulate increase;2) Proteolytic activity in pancreatic tissue was higher in hybrids compared to the parental lines from 7 to 35 days of age (p 0.05);3) Supplementation of diet with exogenous enzymes stimulated the digestion due to the increase in protease activity in duodenal chymus by 9.1% compared to unsupplemented control (p 0.05);4) Proteolytic activity in duodenal chymus significantly responded to the substitution of ground corn for the complete diet by 2-fold decrease while serum trypsin concentration responded by 2.5-fold increase (p 0.001). This fact can indicate that physiological functions of digestive proteases are not confined to the digestive processes.展开更多
GFAP is a specific antigen of glial element, but Alpha-1-antichymotrypsin has not been reported in the literature. Alpha-1-antichymotrypsin was guided by GFAP using PAP method to the astrocytes of 137 gliomas. 120 (87...GFAP is a specific antigen of glial element, but Alpha-1-antichymotrypsin has not been reported in the literature. Alpha-1-antichymotrypsin was guided by GFAP using PAP method to the astrocytes of 137 gliomas. 120 (87%) gliomas were positive for Alpha-1-antichymotrypsin. Of these 120 gliomas, 86 (72%) gave diffuse distribution, 17 (14%) gave focal distribution, and 17 (14%) gave scattered distributions. Alpha-1-antichymotrypsin in glioma tissue may be an important tumor marker for diagnosis.展开更多
BACKGROUND Alpha-1 antitrypsin deficiency(AATD)is a codominant autosomal hereditary condition that predisposes patients to the development of lung and/or liver disease,and Pi*Z allele is the most clinically relevant m...BACKGROUND Alpha-1 antitrypsin deficiency(AATD)is a codominant autosomal hereditary condition that predisposes patients to the development of lung and/or liver disease,and Pi*Z allele is the most clinically relevant mutation.AIM To evaluate the impact of clinical parameters and AATD phenotypes,particularly the Pi*Z allele,in liver fibrosis.METHODS Cross-sectional cohort study including consecutive patients with AATD followed in Pulmonology or Hepatology consultation.RESULTS Included 69 patients,49.3%had Pi*MZ phenotype and 10.1%Pi*ZZ.An age≥55 years,age at diagnosis≥41 years and AAT at diagnosis<77 mg/dL predicted a nonalcoholic fatty liver disease fibrosis score(NFS)not excluding advanced fibrosis[area under the curve(AUC)=0.840,P<0.001;AUC=0.836,P<0.001;AUC=0.681,P=0.025].An age≥50 years and age at diagnosis≥41 years predicted a fibrosis-4 index of moderate to advanced fibrosis(AUC=0.831,P<0.001;AUC=0.795,P<0.001).Patients with hypertension,type 2 diabetes mellitus(DM),dyslipidaemia,metabolic syndrome,and regular alcohol consumption were more likely to have a NFS not excluding advanced fibrosis(P<0.001,P=0.002,P=0.008,P<0.001,P=0.033).Patients with at least one Pi*Z allele and type 2 DM were 8 times more likely to have liver stiffness measurement≥7.1 kPa(P=0.040).CONCLUSION Risk factors for liver disease in AATD included an age≥50 years,age at diagnosis≥41 years,metabolic risk factors,regular alcohol consumption,at least one Pi*Z allele,and AAT value at diagnosis<77 mg/dL.We created an algorithm for liver disease screening in AATD patients to use in primary care,selecting those to be referred to Hepatology consultation.展开更多
AIM To systematically review literature for management of alpha-1 antitrypsin deficiency(AATD) panniculitis. METHODS Multiple databases were searched using combinations of pertinent terms. Articles were selected descr...AIM To systematically review literature for management of alpha-1 antitrypsin deficiency(AATD) panniculitis. METHODS Multiple databases were searched using combinations of pertinent terms. Articles were selected describing panniculitis treatment in patients with AAT < 11 μmol and/or PiZZ genotype, with no language limitation. All relevant articles were accessed in full text. Independent review of abstracts and full manuscripts was conducted by 2 reviewers, and quality assessment by one reviewer(checked by a second). Data extraction was conducted byone reviewer(checked by a second). Narrative synthesis only was conducted, as data were unsuitable for metaanalysis.RESULTS Thirty-two case reports and 4 case series were found. Augmentation therapy(infusions of plasma-derived AAT) was the most successful, with complete resolution of symptoms in all patients. Dapsone is a less expensive option, and it achieved clinical resolution in 62% of patients, but it is very poorly tolerated. Among other single-agent antibiotics, doxycycline was the most successful with complete clinical resolution seen in 33% of patients. Immunosuppressants were largely unsuccessful; 80% of patients exhibited no response. Liver transplantation and therapeutic plasma exchange displayed complete resolution in 66% of patients. Other strategies, such as non-steroidal anti-inflammatory drugs or antibiotics other than dapsone did not show sufficient response rates to recommend their use. Authors note the risk of bias imposed by the type of evidence(case reports, case series) available in this field.CONCLUSION Dapsone is the recommended first line therapy for AATD panniculitis, followed by augmentation therapy. Plasma exchange may be an alternative in the setting of rapidly progressive disease.展开更多
Green tea (Camellia sinensis)-associated hepatotoxicity is reported. However, the presence of alpha-1 antitrypsin MZ phenotype as a predisposing factor to green tea-associated drug-induced liver injury (DILI) is unkno...Green tea (Camellia sinensis)-associated hepatotoxicity is reported. However, the presence of alpha-1 antitrypsin MZ phenotype as a predisposing factor to green tea-associated drug-induced liver injury (DILI) is unknown. A previously healthy woman with alpha-1 antitrypsin MZ phenotype who took SlimQuick?, an herbal supplement containing green tea extract, developed severe hepatotoxicity requiring corticosteroid treatment. Green tea-associated hepatotoxicity is reviewed and alpha-1 antitrypsin MZ phenotype as a predisposing factor to green tea-associated DILI is discussed. Liver biopsy demonstrated marked inflammation with necrosis suggestive of toxic injury with diffuse alpha-1 antitrypsin globule deposition on immunostaining. Corticosteroid therapy resulted in rapid clinical improvement. Alpha-1 antitrypsin MZ phenotype may increase vulnerability to herbal hepatotoxicity.展开更多
According to the latest World Health Organization report 64 million people suffer from Chronic Obstructive Pulmonary Disease （COPD）, 3 million people died from COPD and it is predicted that COPD will become the thir...According to the latest World Health Organization report 64 million people suffer from Chronic Obstructive Pulmonary Disease （COPD）, 3 million people died from COPD and it is predicted that COPD will become the third leading cause of death worldwide by 2030. The alpha-1 antitrypsin deficiency is a rarely diagnosed hereditary disease caused by a genetic mutation and it is one of the most prevalent genetic disorders primarily affecting the lungs, especially in the form of COPD or emphysema, but in some cases also the liver or skin. The Global Initiative for Chronic Obstructive Lung Disease recommends all patients with COPD at a young age or significant family history to be examined for alpha-1 antitrypsin deficiency. This article presents the case of a 42 year old, female patient, Portuguese, with history of Chronic Obstructive Pulmonary Disease, 40 pack units/year smoker, with unknown family history, coming to her family doctor with breath shortness, especially during physical activities, with unsatisfying response to pharmacological prescribed therapy. Physical examination was normal. Alpha- 1 antitrypsin deficiency was confirmed by blood testing. All patient＇s first degree relatives were investigated showing low alpha-1 antitrypsin blood concentrations thus genetic tests were later performed. This case reinforces the need for primary care physicians to be aware of alphal-antitrypsin deficit as an underdiagnosed clinical entity.展开更多
Background and Aims:Alpha-1 antitrypsin deficiency(AATD)is a genetic disorder associated with liver disease,ranging from fibrosis to hepatocellular carcinoma.The disease remains asymptomatic until its final stages whe...Background and Aims:Alpha-1 antitrypsin deficiency(AATD)is a genetic disorder associated with liver disease,ranging from fibrosis to hepatocellular carcinoma.The disease remains asymptomatic until its final stages when liver transplantation is the only available therapy.Biomarkers offer an advantage for disease evaluation.The presence of microRNAs(miRNAs)in plasma extracellular vesicles(EVs)presents a noninvasive approach to assess the molecular signatures of the disease.In this study,we aimed to identify miRNA biomarkers to distinguish molecular signatures of the liver disease associated with AATD in AATD individuals.Methods:Using small RNA sequencing and qPCR,we examined plasma EV miRNAs in healthy controls(n=20)and AATD patients(n=17).We compared the EV miRNAs of AATD individuals with and without liver disease,developing an approach for detecting liver disease.A set of miRNAs identified in the AATD testing cohort was validated in a separate cohort of AATD patients(n=45).Results:We identified differential expression of 178 EV miRNAs in the plasma of the AATD testing cohort compared to controls.We categorized AATD individuals into those with and without liver disease,identifying 39 differentially expressed miRNAs.Six miRNAs were selected to test their ability to discriminate liver disease in AATD.These were validated for their specificity and sensitivity in an independent cohort of 45 AATD individuals.Our logistic model established composite scores with threeand four-miRNA combinations,achieving areas under the curve of 0.737 and 0.751,respectively,for predicting AATD liver disease.Conclusions:We introduce plasma EV-derived miRNAs as potential biomarkers for evaluating AATD liver disease.Plasma EV-associated miRNAs may represent a molecular signature of AATD liver disease and could serve as valuable tools for its detection and monitoring.展开更多
文摘BACKGROUND Poor glycaemic control in patients with type 2 diabetes mellitus(T2DM)is often accompanied by multiple complications,including diabetic nephropathy(DN),diabetic retinopathy(DR),diabetic peripheral neuropathy(DPN),and cardiac structural abnormality left ventricular hypertrophy(LVH).Early identification of high-risk populations for these complications and the implementation of intervention measures are crucial for improving patient outcomes.Serum alpha-1-microglobulin(α1-MG),a multifunctional protein synthesized by the liver and lymphocytes,has been considered a potential biomarker of diabetes-related diseases in recent years.AIM To investigate the associations of serumα1-MG with DN,DR,DPN,and LVH in T2DM patients and its predictive value.METHODS This retrospective study included 5045 T2DM patients.The study participants were stratified into quartiles according to their serumα1-MG levels.Multivariate logistic regression,restricted cubic spline,and explainable machine learning models were employed for risk assessment and feature importance evaluation.RESULTS Increasedα1-MG levels were observed in patients with DN,DR,DPN,and LVH(all P<0.001).Multivariate logistic regression revealed that each standard deviation increase inα1-MG was associated with an 84%increase in DN risk(OR:1.84,95%CI:1.62-2.10,P<0.001),a 17%increase in DR risk(OR:1.17,95%CI:1.07-1.28,P<0.001),a 14%increase in DPN risk(OR:1.14,95%CI:1.03-1.27,P=0.014),and a 28%increase in LVH risk(OR:1.28,95%CI:1.18-1.38,P<0.001).Subgroup analyses and machine learning confirmed the associations of elevatedα1-MG with these complications in T2DM patients.CONCLUSION Elevated serumα1-MG levels were independently associated with increased risks of DN,DR,DPN,and LVH in T2DM patients,suggesting its potential as a predictive biomarker.
基金supported by the Foundation for Distinguished Young Talents in Higher Education of Guangdong Province, China (2016KQNCX019 and 2016KQNCX027)the National Natural Science Foundation of China (31571041)+1 种基金the Guangdong Provincial Department of Education Innovating Strong National Engineering Major Project (2014GKXM031)Guangdong Provincial Universities and Colleges Pearl River Scholar Funded Scheme (2016)
文摘Activation of inflammatory responses regulates the transmission of pain pathways through an integrated network in the peripheral and central nervous systems.The immunopotentiator thymosin alpha-1(Tal)has recently been reported to have anti-inflammatory and neuroprotective functions in rodents.However,how Tα1 affects inflammatory pain remains unclear.In the present study,intraperitoneal injection of Tal attenuated complete Freund's adjuvant(CFA)-induced pain hypersensitivity,and decreased the up-regulation of pro-inflammatory cytokines(TNF-α,IL-1β,and IL-6)in inflamed skin and the spinal cord.We found that CFA-induced peripheral inflammation evoked strong microglial activation,but the effect was reversed by Tα1.Notably,Tα1 reversed the CFA-induced up-regulation of vesicular glutamate transporter(VGLUT)and down-regulated the vesicular γ-aminobutyric acid transporter(VGAT)in the spinal cord.Taken together,these results suggest that Tα1 plays a therapeutic role in inflammatory pain and in the modulation of microgliainduced pro-inflammatory cytokine production in addition to mediation of VGLUT and VGAT expression in the spinal cord.
文摘AIM： To observe the efficiency and safety of thymosin-α1 treatment in patients with hepatitis B e antigen （HBeAg） and HBV DNA positive chronic hepatitis. METHODS： Sixty-two patients were randomly divided into groups A and B. The patients in group A received subcutaneous injection of 1.6 mg thymosin-α1, twice a week （T-α1 group） for six months, and the patients in group B received 5 MU interferon alpha （IFN-α） each day for fifteen days, then three times weekly （IFN-α group） for six months. The results between two groups treated with and the group untreated with IFN-α which was followed up for 12 mo （historical control group consisting of 30 patients） were compared, and three groups were comparable between each other （P 〉 0.05） at baseline （age, sex, clinical history, biochemical, and serological parameters）. RESULTS： At the end of treatment, complete response, which was defined as alanine aminotransferase （ALT） normalization and HBV DNA and HBeAg loss, occurred in 9 of 29 （31.0%） patients in the T-α1 group and in 15 of 33 （45.5%） patients in the IFN-α group （χ^2= 1.36, P 〉 0.05）. After a follow-up period of six months, a complete response was observed in 14 of 29 （48.3%） patients in the T-α1 group and in 9 of 33 （27.3%） patients in the IFN-α group （χ^2= 2.93, P 〉 0.05）. Compared with the results observed in the historical control （HC） group untreated with IFN-α which was followed up for 12 mo, the rate of complete response was significantly higher in IFN-α group at the end of therapy （1 of 30 vs 15 of 33, 7：2 = 14.72, P 〈 0.001） and in the T-α1 group at the end of follow-up （1 of 30 vs 14 of 29,χ^2 = 15.71, P 〈 0.001）. In T-α1 and IFN-α treatment groups, the area under （the plasma concentration time） curve （AUC） of negative HBV DNA and HBeAg was 340, 17%, 31% and 19% smaller than that in the HC group. By the end of the follow-up period, the proportions of ALT normalization and negative HBV DNA in the T-α1 group were significantly higher than those in the IFN-α and HC groups. The odds of ALT normalization and negative HBV DNA at the end of the follow-up was three-fold higher in the T-α1 group than in the IFN-α group. Unlike IFN-α, T-α1 was well tolerated by all patients, and no side effects appeared in T-α1 group. CONCLUSION： The results suggest that a 6-too course of T-α1 therapy is effective and safe in patients with chronic hepatitis B. T-α1 is able to reduce HBV replication in patients with chronic hepatitis B. Furthermore, T-α1 is better tolerated than IFN-α and can gradually induce more sustained ALT normalization and HBV DNA and HBeAg loss. However, a response rate of 48.3% is still less ideal. A more effective therapeutic approach warrants further study.
文摘AIM:To evaluate the association between alpha-1 antitrypsin deficiency(A1ATD) and hepatocellular carcinoma(HCC) in patients with end-stage liver disease(ESLD).METHODS:Patients with cirrhosis and ESLD referred to the Cleveland Clinic Foundation for liver transplantation between 2003 and 2014 were included in the study(N = 675). ESLD was defined as having histological features of cirrhosis and/or radiological evidence of cirrhosis in the context of portal hypertension(ascites,variceal bleeding,thrombocytopenia,or hepatic encephalopathy). A1 ATD was diagnosed using phenotype characterization(MZ or ZZ),liver biopsy detection of PAS-positive diastaseresistant(PAS+) globules,or both. Patients with other causes of liver diseases such as hepatitis C virus(HCV),alcoholic liver disease and non-alcoholic steatohepatitis(NASH) or NASH were also included in the study. HCC was diagnosed by using imaging modalities,biopsy findings,or explanted liver inspection. Follow-up time was defined as the number of years from the diagnosis of cirrhosis to the diagnosis of hepatocellular carcinoma,or from the diagnosis of cirrhosis to the last follow up visit. The rate of HCC was assessed using time-tointerval analysis for interval censored data.RESULTS:This study included 675 patients. 7% of subjects had A1ATD(n = 47). Out of all subjects who did not have A1 ATD,46% had HCV,17% had alcoholic liver disease,19% had NASH and 18% had another primary diagnosis. Of the 47 subjects with A1 ATD,15 had a primary diagnosis of A1ATD(PI*ZZ phenotype and PAS+ globules),8 had a PI*MZ phenotype alone,14 had PAS+ alone,and 10 had both the PI*MZ phenotype and PAS+. Median follow-up time was 3.4(25th,75 th percentiles:1,5.2) years. The overall rate of hepatocellular carcinoma in all subjects was 29%(n = 199). In the A1 ATD group,the incidence rate of HCC was 8.5% compared to 31% in the group of patients with other causes of cirrhosis(P = 0.001). Patients with ESLD due to A1 ATD had the lowest yearly cumulative rate of hepatocellular carcinoma at 0.88% per year compared to 2.7% for those with HCV cirrhosis,1.5% in patients with NASH and 0.9% in alcohol-induced liver disease(P < 0.001).CONCLUSION:Within this group of patients with ESLD,there was no significant association between A1 ATD and increased risk of HCC.
文摘Post-hepatectomy liver failure(PHLF) is a leading cause of morbidity and mortality following major liver resection. The development of PHLF is dependent on the volume of the remaining liver tissue and hepatocyte function. Without effective pre-operative assessment, patients with undiagnosed liver disease could be at increased risk of PHLF. We report a case of a 60-year-old male patient with PHLF secondary to undiagnosed alpha-1-antitrypsin deficiency(AATD) following major liver resection. He initially presented with acute large bowel obstruction secondary to a colorectal adenocarcinoma, which had metastasized to the liver. There was no significant past medical history apart from mild chronic obstructive pulmonary disease. After colonic surgery and liver directed neo-adjuvant chemotherapy, he underwent a laparoscopic partially extended right hepatectomy and radio-frequency ablation. Post-operatively he developed PHLF. The cause of PHLF remained unknown, prompting reanalysis of the histology, which showed evidence of AATD. He subsequently developed progressive liver dysfunction, portal hypertension, and eventually an extensive parastomal bleed, which led to his death; this was ultimately due to a combination of AATD and chemotherapy. This case highlights that formal testing for AATD in all patients with a known history of chronic obstructive pulmonary disease, heavy smoking, or strong family history could help prevent the development of PHLF in patients undergoing major liver resection.
文摘One hundred and fifty-three consecutive cases of HCC and 25 controls from autopsy material were studied by immunohistochemical method in this paper. A review of the histopathology and demonstration of AFP, alpha- 1-antichymotrypsin (AACT), alpha 1-antitrypsin (AAT) and CEA were made.Among the tumor markers. AACT yielded the highest positive rate, 109 cases (71%) out of 153 HCC. CEA was the next, 95 cases (62%) .AFP and AAT gave the same result, 72 cases (47%) . AACT, AAT and CEA were not found in the controls. AFP was present in a few hepatocytes in 1 of 25 controls. The results were in keeping with serum tests so far as the highest positive rate being AACT was concerned. Therefore, combined determination of AACT and AFP would seem a better screening method than by that of AFP alone for survey of HCC.
基金General Project of First-Class Discipline Construction Project of Guangxi University of Traditional Chinese Medicine(Project number:GJKY2019XK043)National Key R&D Program:Excavation and Collation of Ethnic Medicine and Research on Academic Inheritance(Project number:2017YFC1703903)+7 种基金Guangxi Key R&D Program Project:Research and Demonstration of Key Technologies of Zhuang Medicine Health Care and Pension(Project number:GKAB17195017)Guangxi Traditional Chinese Medicine Key Discipline Construction Project:Zhuang Medicine Meridian Tuina(Project number:GZXK-Z-20-61)Guangxi key research and development plan project:Research and application of key technologies for prevention and treatment of lumbago and leg pain in Zhuang medicine(Project number:GKAB21196035).Gui School TCM Master Training Project(Wei Yingcai)(Project Number:GZKJF No.6)Self-Funded Scientific Research Project of Guangxi Zhuang Autonomous Region Administration of Traditional Chinese Medicine(Project number:GZZC2020076)Key Laboratory of Guangxi Zhuang Autonomous Region,DNA barcode identification of Zhuang medicine Dripping Avalokitesvara(Project number:GXZYKF2020-10)Guangxi Education Department Guangxi College Young and Middle-Aged Teachers Basic Ability Improvement Project(Project number:2023KY0301)Guangxi University of Traditional Chinese Medicine,Guangxi School of Traditional Chinese Medicine Inheritance and Innovation Team-Traditional Chinese Medicine Master Huang Jinming Academic Thought and Clinical Treatment Inheritance and Development Research Center(Project number:04B22058V2)。
文摘Objective:To analyze the application effect of Zhuang medicine aponeurotic system triple therapy in the treatment of lumbar disc herniation and its effect on the level of alpha-1 acid glycoprotein(alpha-1 AGP).Methods:200 patients with lumbar disc herniation were selected and randomly divided into a treatment group and a control group,100 cases in each group.The control group was given conventional acupuncture,and the treatment group was treated with manipulation+fire needling+cupping.The alpha-1-AGP levels before and after treatment,as well as the lumbar spine function and pain scores before and after treatment,and the adverse reactions occurred during treatment between the two groups were compared.Results:Before treatment,there was no significant difference in alpha-1 AGP levels,lumbar function,and pain scores between the two groups(P>0.05).After treatment,the lumbar function scores of the two groups were significantly increased,with the treatment group having higher scores than the control group(P<0.05);the incidence of adverse reactions in the treatment group was 2.00%,which was much lower than the control group(P>0.05).Conclusion:Appropriate application of Zhuang medicine aponeurotic system triple therapy in the clinical treatment of lumbar disc herniation can promote the improvement of alpha-1 AGP index level,reduce the pain degree of patients,and improve their lumbar spine function.At the same time,Zhuang medicine also has significant advantages in terms of safety,while ensuring the efficacy and safety of the treatment.
文摘The study was aimed at the evaluation of the effects of breed, age, different digestion stimulators, and dietary crude protein (CP) level on the activities of proteolytic enzymes in pancreatic tissue and duodenal chymus (in vivo), serum trypsin and α1-proteinase inhibitor (A1PI) concentrations in meat-type chicks. The study of age dynamics of trypsin and A1PI concentrations was performed on the chicks of hybrid cross “Smena-8”and two parental lines (Plymouth Rock and Cornish) fed standard commercial corn-wheat-SBM diets. Twenty birds per breed were euthanized at 1, 7, 14, 21, 28 and 35 days of age to obtain blood samples and pancreatic homogenate. Experiments on the effects of different digestion promotors (probiotic, acidifier, phytobiotic, enzymatic preparation) and different CP levels (finisher diet, CP 20%, vs. ground corn, CP 8.5%) were performed on 12 hybrid chicks with fistulated duodenum from 14 to 50 days of age. The following conclusions were made: 1) At 1 day of age high proteolytic activity in pancreatic tissue and maximal serum concentrations of trypsin and A1PI were found in both hybrid and parental lines. Since 7 to 35 days of age A1PI concentration was nearly constant, serum trypsin concentration decreased while proteolytic activity in pancreatic tissue exhibited undulate increase;2) Proteolytic activity in pancreatic tissue was higher in hybrids compared to the parental lines from 7 to 35 days of age (p 0.05);3) Supplementation of diet with exogenous enzymes stimulated the digestion due to the increase in protease activity in duodenal chymus by 9.1% compared to unsupplemented control (p 0.05);4) Proteolytic activity in duodenal chymus significantly responded to the substitution of ground corn for the complete diet by 2-fold decrease while serum trypsin concentration responded by 2.5-fold increase (p 0.001). This fact can indicate that physiological functions of digestive proteases are not confined to the digestive processes.
文摘GFAP is a specific antigen of glial element, but Alpha-1-antichymotrypsin has not been reported in the literature. Alpha-1-antichymotrypsin was guided by GFAP using PAP method to the astrocytes of 137 gliomas. 120 (87%) gliomas were positive for Alpha-1-antichymotrypsin. Of these 120 gliomas, 86 (72%) gave diffuse distribution, 17 (14%) gave focal distribution, and 17 (14%) gave scattered distributions. Alpha-1-antichymotrypsin in glioma tissue may be an important tumor marker for diagnosis.
文摘BACKGROUND Alpha-1 antitrypsin deficiency(AATD)is a codominant autosomal hereditary condition that predisposes patients to the development of lung and/or liver disease,and Pi*Z allele is the most clinically relevant mutation.AIM To evaluate the impact of clinical parameters and AATD phenotypes,particularly the Pi*Z allele,in liver fibrosis.METHODS Cross-sectional cohort study including consecutive patients with AATD followed in Pulmonology or Hepatology consultation.RESULTS Included 69 patients,49.3%had Pi*MZ phenotype and 10.1%Pi*ZZ.An age≥55 years,age at diagnosis≥41 years and AAT at diagnosis<77 mg/dL predicted a nonalcoholic fatty liver disease fibrosis score(NFS)not excluding advanced fibrosis[area under the curve(AUC)=0.840,P<0.001;AUC=0.836,P<0.001;AUC=0.681,P=0.025].An age≥50 years and age at diagnosis≥41 years predicted a fibrosis-4 index of moderate to advanced fibrosis(AUC=0.831,P<0.001;AUC=0.795,P<0.001).Patients with hypertension,type 2 diabetes mellitus(DM),dyslipidaemia,metabolic syndrome,and regular alcohol consumption were more likely to have a NFS not excluding advanced fibrosis(P<0.001,P=0.002,P=0.008,P<0.001,P=0.033).Patients with at least one Pi*Z allele and type 2 DM were 8 times more likely to have liver stiffness measurement≥7.1 kPa(P=0.040).CONCLUSION Risk factors for liver disease in AATD included an age≥50 years,age at diagnosis≥41 years,metabolic risk factors,regular alcohol consumption,at least one Pi*Z allele,and AAT value at diagnosis<77 mg/dL.We created an algorithm for liver disease screening in AATD patients to use in primary care,selecting those to be referred to Hepatology consultation.
文摘AIM To systematically review literature for management of alpha-1 antitrypsin deficiency(AATD) panniculitis. METHODS Multiple databases were searched using combinations of pertinent terms. Articles were selected describing panniculitis treatment in patients with AAT < 11 μmol and/or PiZZ genotype, with no language limitation. All relevant articles were accessed in full text. Independent review of abstracts and full manuscripts was conducted by 2 reviewers, and quality assessment by one reviewer(checked by a second). Data extraction was conducted byone reviewer(checked by a second). Narrative synthesis only was conducted, as data were unsuitable for metaanalysis.RESULTS Thirty-two case reports and 4 case series were found. Augmentation therapy(infusions of plasma-derived AAT) was the most successful, with complete resolution of symptoms in all patients. Dapsone is a less expensive option, and it achieved clinical resolution in 62% of patients, but it is very poorly tolerated. Among other single-agent antibiotics, doxycycline was the most successful with complete clinical resolution seen in 33% of patients. Immunosuppressants were largely unsuccessful; 80% of patients exhibited no response. Liver transplantation and therapeutic plasma exchange displayed complete resolution in 66% of patients. Other strategies, such as non-steroidal anti-inflammatory drugs or antibiotics other than dapsone did not show sufficient response rates to recommend their use. Authors note the risk of bias imposed by the type of evidence(case reports, case series) available in this field.CONCLUSION Dapsone is the recommended first line therapy for AATD panniculitis, followed by augmentation therapy. Plasma exchange may be an alternative in the setting of rapidly progressive disease.
基金Supported by in part by Grant Number 1 K23 DK089008-01 from the National Institutes of Health(NIH)National Institute of Diabetes and Digestive and Kidney Diseases to Ayse L Mindikoglu,MD,MPH and its contents are solely the responsibility of the authors and do not necessarily represent the off icial views of the National Institute of Diabetes and Digestive and Kidney Diseases or the NIH
文摘Green tea (Camellia sinensis)-associated hepatotoxicity is reported. However, the presence of alpha-1 antitrypsin MZ phenotype as a predisposing factor to green tea-associated drug-induced liver injury (DILI) is unknown. A previously healthy woman with alpha-1 antitrypsin MZ phenotype who took SlimQuick?, an herbal supplement containing green tea extract, developed severe hepatotoxicity requiring corticosteroid treatment. Green tea-associated hepatotoxicity is reviewed and alpha-1 antitrypsin MZ phenotype as a predisposing factor to green tea-associated DILI is discussed. Liver biopsy demonstrated marked inflammation with necrosis suggestive of toxic injury with diffuse alpha-1 antitrypsin globule deposition on immunostaining. Corticosteroid therapy resulted in rapid clinical improvement. Alpha-1 antitrypsin MZ phenotype may increase vulnerability to herbal hepatotoxicity.
文摘According to the latest World Health Organization report 64 million people suffer from Chronic Obstructive Pulmonary Disease （COPD）, 3 million people died from COPD and it is predicted that COPD will become the third leading cause of death worldwide by 2030. The alpha-1 antitrypsin deficiency is a rarely diagnosed hereditary disease caused by a genetic mutation and it is one of the most prevalent genetic disorders primarily affecting the lungs, especially in the form of COPD or emphysema, but in some cases also the liver or skin. The Global Initiative for Chronic Obstructive Lung Disease recommends all patients with COPD at a young age or significant family history to be examined for alpha-1 antitrypsin deficiency. This article presents the case of a 42 year old, female patient, Portuguese, with history of Chronic Obstructive Pulmonary Disease, 40 pack units/year smoker, with unknown family history, coming to her family doctor with breath shortness, especially during physical activities, with unsatisfying response to pharmacological prescribed therapy. Physical examination was normal. Alpha- 1 antitrypsin deficiency was confirmed by blood testing. All patient＇s first degree relatives were investigated showing low alpha-1 antitrypsin blood concentrations thus genetic tests were later performed. This case reinforces the need for primary care physicians to be aware of alphal-antitrypsin deficit as an underdiagnosed clinical entity.
基金supported by a grant from the Alpha One Foundation(AGR00019116)the recipient of a Research Career Scientist Award from the Department of Veterans Affairs(IK6BX004477).
文摘Background and Aims:Alpha-1 antitrypsin deficiency(AATD)is a genetic disorder associated with liver disease,ranging from fibrosis to hepatocellular carcinoma.The disease remains asymptomatic until its final stages when liver transplantation is the only available therapy.Biomarkers offer an advantage for disease evaluation.The presence of microRNAs(miRNAs)in plasma extracellular vesicles(EVs)presents a noninvasive approach to assess the molecular signatures of the disease.In this study,we aimed to identify miRNA biomarkers to distinguish molecular signatures of the liver disease associated with AATD in AATD individuals.Methods:Using small RNA sequencing and qPCR,we examined plasma EV miRNAs in healthy controls(n=20)and AATD patients(n=17).We compared the EV miRNAs of AATD individuals with and without liver disease,developing an approach for detecting liver disease.A set of miRNAs identified in the AATD testing cohort was validated in a separate cohort of AATD patients(n=45).Results:We identified differential expression of 178 EV miRNAs in the plasma of the AATD testing cohort compared to controls.We categorized AATD individuals into those with and without liver disease,identifying 39 differentially expressed miRNAs.Six miRNAs were selected to test their ability to discriminate liver disease in AATD.These were validated for their specificity and sensitivity in an independent cohort of 45 AATD individuals.Our logistic model established composite scores with threeand four-miRNA combinations,achieving areas under the curve of 0.737 and 0.751,respectively,for predicting AATD liver disease.Conclusions:We introduce plasma EV-derived miRNAs as potential biomarkers for evaluating AATD liver disease.Plasma EV-associated miRNAs may represent a molecular signature of AATD liver disease and could serve as valuable tools for its detection and monitoring.
