Crohn’s disease as the intestinal manifestation of pan-lymphatic dysfunction:An exploratory proposal based on basic and clinical data

Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biological and small-molecule drugs have advanced the treatment of CD;however,a considerable proportion of patients are non-responsive to all known drugs.To achieve a breakthrough in this field,innovations that could guide the further development of effective therapies are of utmost urgency.In this review,we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases,and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data.The supporting evidence is fully summarized,including the existence of lymphatic system dysfunction,recognition of the inside-out model,disorders of immune cells,changes in cell plasticity,partial overlap of the underlying mechanisms,and common gut-derived fatty and bile acid metabolism.Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases,especially CD,as this model is good at presenting and mimicking lymphatic dysfunction.More importantly,the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

De novo combined lamivudine and adefovir dipivoxil therapy vs entecavir monotherapy for hepatitis B virus-related decompensated cirrhosis

AIM:To compare efficacy of combined lamivudine(LAM)and adefovir dipivoxil(ADV)therapy with that of entecavir(ETV)monotherapy for hepatitis B virus(HBV)-related decompensated liver cirrhosis.METHODS:A total of 120 na ve patients with HBVrelated decompensated cirrhosis participated in this study.Sixty patients were treated with combined LAM and ADV therapy(LAM+ADV group),while the other60 were treated with ETV monotherapy(ETV group)for two years.Tests for liver and kidney function,alpha-fetoprotein,HBV serum markers,HBV DNA load,prothrombin time(PT),and ultrasonography or computed tomography scan of the liver were performed every1 to 3 mo.Repeated measure ANOVA and theχ2test were performed to compare the efficacy,side effects,and the cumulative survival rates at 48 and 96 wk.RESULTS:Forty-five patients in each group were observed for 96 wk.No significant differences in HBV DNA negative rates and alanine aminotransferase(ALT)normalization rates at weeks 48(χ2=2.12 and 2.88)and96(χ2=3.21 and 3.24)between the two groups were observed.Hepatitis B e antigen seroconversion rate in the LAM+ADV group at week 96 was significantly higher in the ETV group(43.5%vs 36.4%,χ2=4.09,P<0.05).Viral breakthrough occurred in 2 cases(4.4%)by week 48 and in 3 cases(6.7%)by week 96 in the LAM+ADV group,and no viral mutation was detected.In the ETV group,viral breakthrough occurred in 1 case(2.2%)at the end of week 96.An increase in albumin(F=18.9 and 17.3),decrease in total bilirubin and in ALT(F=16.5,17.1 and 23.7,24.8),reduced PT(F=22.7 and 24.5),and improved Child-Turcotte-Pugh and the model for end-stage liver disease scores(F=18.5,17.8,and 24.2,23.8)were observed in both groups.The cumulative rates of mortality and liver transplantation were 16.7%(10/60)and 18.3%(11/60)in the LAM+ADV and ETV groups,respectively.CONCLUSION:Both LAM+ADV combination therapy and ETV monotherapy can effectively inhibit HBV replication,improve liver function,and decrease mortality.

Early kidney injury during long-term adefovir dipivoxil therapy for chronic hepatitis B

AIM: To evaluate urine β2-microglobulin(β2-M), retinol-binding protein(RBP) excretion, and renal impairment with adefovir dipivoxil(ADV) for chronic hepatitis B. METHODS: We enrolled 165 patients with chronic hepatitis B infection who were treated with ADV monotherapy(n = 90) or ADV plus lamivudine combination therapy(n = 75). An additional 165 chronic hepatitis B patients treated with entecavir were recruited as controls. We detected serum creatinine, urine β2-M, and RBP levels, and estimated the glomerular filtration rate(e GFR) at the initiation of antiviral therapy and every 6 mo for a period of five years. RESULTS: Urine β2-M abnormalities were observed in patients during the first(n = 3), second(n = 7), third(n = 11), fourth(n = 16), and fifth(n = 21) year of ADV treatment. Urinary RBP abnormalities were observed in patients during the first(n = 2), second(n = 8), third(n = 12), fourth(n = 15), and fifth(n = 22) year of ADV treatment. e GFR decreased 20%-30% from baseline in 20 patients, 30%-50% in 12 patients, and > 50% in 3 patients during the five years of treatment. Further analysis indicated that decreases in e GFR of ≥ 30% relative to the baseline level correlated significantly with urine RBP and β2-M abnormalities. In contrast, both serum creatinine and e GFR remained stable in patients treated with entecavir, and only one of these patients developed a urine β2-M abnormality, and two developed urine RBP abnormalities during the five years of treatment. CONCLUSION: Urine RBP and β2-M are biomarkers of renal injury during long-term ADV treatment for chronic hepatitis B, and indicate when treatment should be switched to entecavir.

Efficacy of combined therapy in patients with hepatitis B virus-related decompensated cirrhosis

AIM: To investigate the efficacy and safety of combined de novo lamivudine (LAM) and adefovir dipivoxil (ADV) therapy in hepatitis B virus (HBV)-related decompensated liver cirrhosis patients. METHODS: One hundred and forty patients with HBVrelated decompensated cirrhosis were recruited, 70 patients were treated with combined LAM and ADV de novo therapy, and the other 70 patients were treated with LAM alone as controls. The follow-up period was 144 wk. All patients with LAM resistance were shifted to ADV. RESULTS: The percentage of HBV-related decompensated cirrhosis patients with undetectable HBV DNA inde novo combination group was 51.6% (33/64), 84.2% (48/57), and 92.3% (49/53) by weeks 48, 96, and 144, respectively. In monotherapy group, HBV DNA negativity rate was 46.1% (30/65), 56.1% (32/57), and 39.2% (20/51) by weeks 48, 96 and 144, respectively. There was a significant difference between the two groups by weeks 96 and 144 (P = 0.012 and 0.001). The hepatitis B e antigen seroconversion rate was 28.1% (9/32), 40.0% (12/30), and 53.6% (15/28) in the combination group by weeks 48, 96 and 144, respectively, and 24.2% (8/33), 31.0% (9/29), and 37.0% (10/27) by weeks 48, 96 and 144, respectively, in monotherapy group. A total of 68.6% (44/64), 84.2% (48/57), and 92.5% (49/53) patients achieved alanine aminotransferase (ALT) normalization by weeks 48, 96 and 144, respectively in the combination group. In monotherpy group, the ALT normalization rate was 64.6% (42/65) by week 48, 73.7% (42/57) by week 96, and 80.4% (41/51) by week 144. No patients in the combination group exhibited detectable resistance for at least 144 wk. The cumulative resistance rate in monotherapy group at weeks 48, 96, and 144 was 20.0%, 36.8%, and 56.9%. Both combination group and monotherapy group demonstrated an improvement in Child-Turcotte Pugh and Model for End-Stage Liver Disease scores at weeks 48, 96, and 144. All patients tolerated both combination and monotherapy. The ceratinine levels and glomerular filtration rate remained normal in all patients during the follow-up period. CONCLUSION: In HBV-related decompensated liver cirrhosis patients, the combined de novo LAM and ADV therapy is more efficacious and safer compared to LAM alone.

Helicobacter pylori and Crohn's disease: A retrospective single-center study from China

AIM: To investigate the association between Helicobacter pylori (H. pylori ) infection and the prevalence of Crohn's disease (CD). METHODS: Subjects were selected from patients admitted the gastrointestinal (GI) department at The First Affiliated Hospital School of Medicine (Zhejiang University)for abdominal pain, hematochezia, diarrhea and other GI symptoms between January 2008 and September 2012. CD was diagnosed by endoscopy and biopsy. H. pylori infection was detected by a 14 C-urea breath test and culturing of the biopsy sample. Demographic, anthropometric and serologic data were collected for each patient. H. pylori infection rate was compared between CD and control groups, followed by a subgroup analysis based on extent and severity of CD. Student's t , Mann-Whiney U , and χ 2 tests were used to analyze the data. RESULTS: A total of 447 patients were analyzed, including 229 in the CD group and 248 in the control group. There were no significant differences in age, sex, and rates of hypertension or diabetes. However, the CD group showed significantly higher rates of smoking history (34.9% vs 18.1%), alcohol intake (17.4% vs 8.1%), white blood cell count (9.7 ± 2.9 × 10 9 /L vs 4.3 ± 0.9 × 10 9 /L), and C-reactive protein (36.3 ± 20.8 mg/L vs 5.5 ± 2.3 mg/L) but lower body mass index (24.5 ± 2.0 kg/m 2 vs 26.0 ± 2.2 kg/m 2 ) than the control group. The H. pylori infection rate in the CD group was 27.1%, significantly lower than that of 47.9% in the control group. Furthermore, the H. pylori infection rates in patients with colonic, small intestine, ileocolonic and extensive CD were 31.1%, 28.9%, 26.8% and 25.9% respectively, all of which were significantly lower than in the control group. Finally, the H. pylori infection rates in patients with remission, moderate and severe CD were 34.3%, 30.7% and 22.0% respectively, which were also significantly lower than in the control group. CONCLUSION: Lower H. pylori infection in CD patients suggests a correlation between bacterial infection and CD, suggesting caution when considering H. pylori eradication in CD patients.

Hepatitis B surface antigen levels during natural history of chronic hepatitis B: A Chinese perspective study

AIM: To determine the baseline hepatitis B surface antigen (HBsAg) levels during the different phases of chronic hepatitis B (CHB) patients in China.

HBsAg levels in HBeAg-positive chronic hepatitis B patients with different immune conditions

AIM: To investigate hepatitis B surface antigen (HBsAg) levels in patients with HBeAg-positive chronic hepatitis B (CHB) and different immune conditions.

Gene therapy: Regulations, ethics and its practicalities in liver disease

Gene therapy is a new and promising approach which opens a new door to the treatment of human diseases. By direct transfer of genetic materials to the target cells, it could exert functions on the level of genes and molecules. It is hoped to be widely used in the treatment of liver disease, especially hepatic tumors by using different vectors encoding the aim gene for anti-tumor activity by activating primary and adaptive immunity, inhibiting oncogene and angiogenesis. Despite the huge curative potential shown in animal models and some pilot clinical trials, gene therapy has been under fierce discussion since its birth in academia and the public domain because of its unexpected side effects and ethical problems. There are other challenges arising from the technique itself like vector design, administration route test and standard protocol exploration. How well we respond will decide the fate of gene therapy clinical medical practice.

Controlling hydrogenation of C=C and C=O bonds in cinnamaldehyde using Pt_(1)/Ni and Pt_(1)/Co single-atom alloy catalysts

Selective hydrogenation of C=C and C=O bonds in cinnamaldehyde(CAL)to produce desired products is a challenging task due to the complex conjugate system of the two unsaturated functional groups.In this study,a simple ball milling method is presented for synthesizing Pt-based single-atom alloy catalysts(SAAs)that can function as a control switch for the selective hydrogenation of CAL into highly valuable products.

Interferon-α2b spray inhalation did not shorten virus shedding time of SARS-CoV-2 in hospitalized patients: a preliminary matched case-control study

Background:Currently,there are no drugs that have been proven to be effective against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Because of its broad antiviral activity,interferon(IFN)should be evaluated as a potential therapeutic agent for treatment of coronavirus disease 2019(COVID-19),especially while COVID-19-specific therapies are still under development.Methods:Confirmed COVID-19 patients hospitalized in the First Affiliated Hospital,School of Medicine,Zhejiang University in Hangzhou,China,from January 19 to February 19,2020 were enrolled in a retrospective study.The patients were separated into an IFN group and a control group according to whether they received initial IFN-α2 b inhalation treatment after admission.Propensity-score matching was used to balance the confounding factors.Results:A total of 104 confirmed COVID-19 patients,68 in the IFN group and 36 in the control group,were enrolled.Less hypertension(27.9%vs.55.6%,P=0.006),dyspnea(8.8%vs.25.0%,P=0.025),or diarrhea(4.4%vs.19.4%,P=0.030)was observed in the IFN group.Lower levels of albumin and C-reactive protein and higher level of sodium were observed in the IFN group.Glucocorticoid dosage was lower in the IFN group(median,40 vs.80 mg/d,P=0.025).Compared to the control group,fewer patients in the IFN group were ventilated(13.2%vs.33.3%,P=0.015)and admitted to intensive care unit(ICU)(16.2%vs.44.4%,P=0.002).There were also fewer critical patients in the IFN group(7.4%vs.25.0%,P=0.017)upon admission.Although complications during admission process were comparable between groups,the discharge rate(85.3%vs.66.7%,P=0.027)was higher and the hospitalization time(16 vs.21 d,P=0.015)was shorter in the IFN group.When other confounding factors were not considered,virus shedding time(10 vs.13 d,P=0.014)was also shorter in the IFN group.However,when the influence of other factors was eliminated using propensity score matching,virus shedding time was not significantly shorter than that of the control group(12 vs.15 d,P=0.206).Conclusions:IFN-α2 b spray inhalation did not shorten virus shedding time of SARS-CoV-2 in hospitalized patients.

Comparison of epidemiological and clinical characteristics of COVID-19 patients with and without Wuhan exposure history in Zhejiang Province,China

Background:A novel coronavirus called severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),first identified in Wuhan,China,has been rapidly spreading around the world.This study investigates the epidemiological and clinical characteristics of coronavirus disease 2019(COVID-19)patients in Zhejiang Province who did or did not have a history of Wuhan exposure.Methods:We collected data from medical records of confirmed COVID-19 patients in Zhejiang Province from Jan.17 to Feb.7,2020 and analyzed epidemiological,clinical,and treatment data of those with and without recorded recent exposure in Wuhan.Results:Patients in the control group were older than those in the exposure group((48.19±16.13)years vs.(43.47±13.12)years,P<0.001),and more were over 65 years old(15.95%control vs.5.60%exposure,P<0.001).The rate of clustered onset was also significantly higher in the control group than in the exposure group(31.39%vs.18.66%,P<0.001).The symptom of a sore throat in patients in the exposure group was significantly higher than that in the control group(17.30%vs.10.89%,P=0.01);however,headache in the exposure group was significantly lower than that in the control group(6.87%vs.12.15%,P=0.015).More patients in the exposure group had a significantly lower level of lactate dehydrogenase(LDH)and aspartate aminotransferase(AST)than those in the control group.There was no significant difference in any degree of COVID-19 including mild,severe,and critical between the two groups.Conclusions:From the perspective of epidemiological and clinical characteristics,there was no significant difference between COVID-19 patients with and without Wuhan exposure history.

Clinical characteristics of different subtypes and risk factors for the severity of illness in patients with COVID-19 in Zhejiang, China

Background The outbreak of coronavirus disease 2019(COVID-19)is now becoming an enormous threat to public health.The clinical spectrum of COVID-19 is extensive,of which critical cases are with rapid disease progression and high mortality.The aim of our study is to summarize the characteristics of different subtypes and explore risk factors of illness severity for early identification and prompt treatment.Methods In this retrospective study,we collected data of patients confirmed COVID-19 in Zhejiang Province from 17 January to 12 February 2020.According to the definition of clinical classification,we divided confirmed cases into four types,and summarize epidemiological and clinical characteristics,laboratory and radiograph findings,treatments,and outcomes,respectively.Moreover,we used univariate and multivariate ordinal logistic regression models to explore risk factors for the severity of illness in patients with COVID-19.Results A total of 788 patients were enrolled in our study,of whom 52 cases(6.6%)were mild type,658 cases(83.5%)were common type,61 cases(7.2%)were severe type,and 17 cases(2.2%)were critical type.Multivariate ordinal logistic regression demonstrated increasing odds of the severity of illness in patients with COVID-19 associated with male(odds ratio[OR]=1.7,95%confidence interval[CI]:1.2–2.6 P=0.008),fever(OR=3.6,95%CI:2.1–6.3,P<0.001),cough(OR=1.7,95%CI:1.0–2.9,P=0.041),hemoptysis(OR=3.4,95%CI:1.1–10.3,P=0.032),gastrointestinal symptoms(OR=1.9,95%CI:1.0–3.5,P=0.047),hypertension(OR=2.6,95%CI:1.2–5.6,P=0.013).With the increase of age-grading,risk for the severity of illness was gradually higher(≤18 years[OR=1.0],19–40 years[OR=12.7,95%CI:4.5–36.0,P<0.001],41–65 years[OR=14.8,95%CI:5.2–42.1,P<0.001],≥66 years[OR=56.5,95%CI:17.1–186.5,P<0.001]).Conclusions Clinicians should pay close attention to these features in patients with COVID-19 including older age,male,fever,cough,hemoptysis,gastrointestinal symptoms and hypertension to identify the severity of illness as early as possible.