Poorly controlled type II diabetes mellitus significantly enhances postoperative chemoresistance in patients with stage III colon cancer

BACKGROUND Type II diabetes mellitus(T2DM)has been associated with increased risk of colon cancer(CC)and worse prognosis in patients with metastases.The effects of T2DM on postoperative chemoresistance rate(CRR)and long-term disease-free survival(DFS)and overall survival(OS)in patients with stage III CC who receive curative resection remain controversial.AIM To investigate whether T2DM or glycemic control is associated with worse postoperative survival outcomes in stage III CC.METHODS This retrospective cohort study included 278 patients aged 40-75 years who underwent surgery for stage III CC from 2018 to 2021.Based on preoperative T2DM history,the patients were categorized into non-DM(n=160)and DM groups(n=118).The latter was further divided into well-controlled(n=73)and poorly controlled(n=45)groups depending on the status of glycemic control.DFS,OS,and CRR were compared between the groups and Cox regression analysis was used to identify risk factors.RESULTS Patients in the DM and non-DM groups demonstrated similar DFS,OS,and CRR(DFS:72.03%vs 78.75%,P=0.178;OS:81.36%vs 83.12%,P=0.638;CRR:14.41%vs 7.5%,P=0.063).Poorly controlled DM was associated with a significantly worse prognosis and higher CRR than well-controlled DM(DFS:62.22%vs 78.07%,P=0.021;OS:71.11%vs 87.67%,P=0.011;CRR:24.40%vs 8.22%,P=0.015).High preoperative fasting plasma glucose[DFS:Hazard ratio(HR)=2.684,P<0.001;OS:HR=2.105,P=0.019;CRR:HR=2.214,P=0.005]and glycosylated hemoglobin levels(DFS:HR=2.344,P=0.006;OS:HR=2.119,P=0.021;CRR:HR=2.449,P=0.009)indicated significantly poor prognosis and high CRR,while T2DM history did not(DFS:HR=1.178,P=0.327;OS:HR=0.933,P=0.739;CRR:HR=0.997,P=0.581).CONCLUSION Increased preoperative fasting plasma glucose and glycosylated hemoglobin levels,but not T2DM history,were identified as risk factors associated with poor postoperative outcomes and high CRR in patients with stage III CC.

Interleukin 1βreceptor and synaptic dysfunction in recurrent brain infection with Herpes simplex virus type-1

Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not completely understood.Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role.Here,we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain,highlighting the role of interleukins and,in particular,interleukin 1βas a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.

Retrospective analysis of pathological types and imaging features in pancreatic cancer: A comprehensive study

BACKGROUND Pancreatic cancer remains one of the most lethal malignancies worldwide,with a poor prognosis often attributed to late diagnosis.Understanding the correlation between pathological type and imaging features is crucial for early detection and appropriate treatment planning.AIM To retrospectively analyze the relationship between different pathological types of pancreatic cancer and their corresponding imaging features.METHODS We retrospectively analyzed the data of 500 patients diagnosed with pancreatic cancer between January 2010 and December 2020 at our institution.Pathological types were determined by histopathological examination of the surgical spe-cimens or biopsy samples.The imaging features were assessed using computed tomography,magnetic resonance imaging,and endoscopic ultrasound.Statistical analyses were performed to identify significant associations between pathological types and specific imaging characteristics.RESULTS There were 320(64%)cases of pancreatic ductal adenocarcinoma,75(15%)of intraductal papillary mucinous neoplasms,50(10%)of neuroendocrine tumors,and 55(11%)of other rare types.Distinct imaging features were identified in each pathological type.Pancreatic ductal adenocarcinoma typically presents as a hypodense mass with poorly defined borders on computed tomography,whereas intraductal papillary mucinous neoplasms present as characteristic cystic lesions with mural nodules.Neuroendocrine tumors often appear as hypervascular lesions in contrast-enhanced imaging.Statistical analysis revealed significant correlations between specific imaging features and pathological types(P<0.001).CONCLUSION This study demonstrated a strong association between the pathological types of pancreatic cancer and imaging features.These findings can enhance the accuracy of noninvasive diagnosis and guide personalized treatment approaches.

Global trends and hotspots of type 2 diabetes in children and adolescents:A bibliometric study and visualization analysis

BACKGROUND Epidemiological surveys indicate an increasing incidence of type 2 diabetes mellitus(T2DM)among children and adolescents worldwide.Due to rapid disease progression,severe long-term cardiorenal complications,a lack of effective treatment strategies,and substantial socioeconomic burdens,it has become an urgent public health issue that requires management and resolution.Adolescent T2DM differs from adult T2DM.Despite a significant increase in our understanding of youth-onset T2DM over the past two decades,the related review and evidence-based content remain limited.AIM To visualize the hotspots and trends in pediatric and adolescent T2DM research and to forecast their future research themes.METHODS This study utilized the terms“children”,“adolescents”,and“type 2 diabetes”,retrieving relevant articles published between 1983 and 2023 from three citation databases within the Web of Science Core Collection(SCI,SSCI,ESCI).Utilizing CiteSpace and VoSviewer software,we analyze and visually represent the annual output of literature,countries involved,and participating institutions.This allows us to predict trends in this research field.Our analysis encompasses co-cited authors,journal overlays,citation overlays,time-zone views,keyword analysis,and reference analysis,etc.RESULTS A total of 9210 articles were included,and the annual publication volume in this field showed a steady growth trend.The United States had the highest number of publications and the highest H-index.The United States also had the most research institutions and the strongest research capacity.The global hot journals were primarily diabetes professional journals but also included journals related to nutrition,endocrinology,and metabolism.Keyword analysis showed that research related to endothelial dysfunction,exposure risk,cardiac metabolic risk,changes in gut microbiota,the impact on comorbidities and outcomes,etc.,were emerging keywords.They have maintained their popularity in this field,suggesting that these areas have garnered significant research interest in recent years.CONCLUSION Pediatric and adolescent T2DM is increasingly drawing global attention,with genes,behaviors,environmental factors,and multisystemic interventions potentially emerging as future research hot spots.

Intestinal glucagon-like peptide-1:A new regulator of impaired counterregulatory responses to hypoglycemia in type 1 diabetes mellitus

In this article,we review the study by Jin et al,which examined the role of intestinal glucagon-like peptide-1(GLP-1)in counterregulatory responses to hypoglycemia in patients with type 1 diabetes mellitus(T1DM).With the global rise of T1DM,there is an increased burden on society and healthcare systems.Due to insulin therapy and islet dysfunction,T1DM patients are highly vulnerable to severe hypoglycemia,a leading cause of mortality.In healthy individuals,counterregulatory mechanisms restore blood glucose during hypoglycemia,but repeated episodes impair these responses.Jin et al demonstrated that overexpression of GLP-1 attenuates the sympathetic-adrenal reflex and disrupts the secretion of counterregulatory hormones such as glucagon during hypoglycemia,leading to counterregulatory dysfunction.These findings highlight the critical role of GLP-1 in the impaired counterregulatory response to hypoglycemia in T1DM patients and provide new insights into the potential application of GLP-1-related therapies in T1DM patients.

Clinical study on the effect of jejunoileal side-to-side anastomosis on metabolic parameters in patients with type 2 diabetes

BACKGROUND At present,the existing internal medicine drug treatment can alleviate the high glucose toxicity of patients to a certain extent,to explore the efficacy of laparoscopic jejunoileal side to side anastomosis in the treatment of type 2 diabetes,the report is as follows.AIM To investigate the effect of jejunoileal side-to-side anastomosis on metabolic parameters in patients with type 2 diabetes mellitus(T2DM).METHODS We retrospectively analyzed the clinical data of 78 patients with T2DM who were treated via jejunoileal lateral anastomosis.Metabolic indicators were collected preoperatively,as well as at 3 and 6 months postoperative.The metabolic indicators analyzed included body mass index(BMI),systolic blood pressure(SBP),diastolic blood pressure(DBP),fasting blood glucose(FBG),2-hour blood glucose(PBG),glycated hemoglobin(HbA1c),fasting C-peptide,2-hour C-peptide(PCP),fasting insulin(Fins),2-hour insulin(Pins),insulin resistance index(HOMA-IR),βCellular function index(HOMA-β),alanine aminotransferase,aspartate aminotransferase,serum total cholesterol(TC),low-density lipoprotein cholesterol(L DL-C),triglycerides(TG),high-density lipoprotein,and uric acid(UA)levels.RESULTS SBP,DBP,PBG,HbA1c,LDL-C,and TG were all significantly lower 3 months postoperative vs preoperative values;body weight,BMI,SBP,DBP,FBG,PBG,HbA1c,TC,TG,UA,and HOMA-IR values were all significantly lower 6 months postoperative vs at 3 months;and PCP,Fins,Pins,and HOMA-βwere all significantly higher 6 months postoperative vs at 3 months(all P<0.05).CONCLUSION Side-to-side anastomosis of the jejunum and ileum can effectively treat T2DM and improve the metabolic index levels associated with it.

Influence of gut bacteria on type 2 diabetes:Mechanisms and therapeutic strategy

The onset and progression of type 2 diabetes mellitus(T2DM)are strongly associated with imbalances in gut bacteria,making the gut microbiome a new potential therapeutic focus.This commentary examines the recent publication in World Journal of Diabetes.The article explores the association between T2DM and gut microbiota,with a focus on the pathophysiological changes related to dysbiosis.It proposes innovative microbiome-targeted therapeutic strategies and evaluates the challenges and future directions of such approaches.This editorial summarizes the key points of their discussion of the role of the gut microbiome in T2DM and elaborates on the influence of specific gut microbial species on the disease through the host–microbiota metabolic axis.It provides new insights for future research on gut-microbiota-based interventions for T2DM.

Current perspectives and the future of disease-modifying therapies in type 1 diabetes

Use of immunomodulating agents to prevent the progression of autoimmuneβ-cell damage leading to type 1 diabetes mellitus(T1DM)is an interesting area for research.These include non-specific anti-inflammatory agents,immunologic vaccination and anti-inflammatory agents targeting specific immune cells or cytokines.Teplizumab is an anti-CD3-molecule that binds to and leads to the disappearance of the CD3/TCR complex and rendering the T cell anergic to its target antigen.Preclinical and clinical trials have demonstrated its efficacy in reducing the decline in serum C-peptide levels and the need for insulin therapy if used early in the disease process of T1DM.The benefits have been apparent as early as six months to as long as seven years after therapy.It has recently been approved by the Food and Drug Administration to delay the onset of clinical(stage 3)type 1 diabetes in children above 8 years of age.In their recent metaanalysis published in the World Journal of Diabetes,Ma et al found that those in the teplizumab treatment group have a greater likelihood of reduction in insulin use,change in C-peptide response,and better glycemic control compared to the control group with a good safety profile.However,all the included randomized control trials have been conducted in high-income countries.High cost of therapy and unknown utility of the molecule in stage 3 disease limit its widespread use.

Cardiovascular involvement in multisystem inflammatory syndrome in children and midterm follow-up from a pediatric tertiary center in India

BACKGROUND In multisystem inflammatory syndrome in children(MIS-C)with coronavirus disease 2019,there was paucity of data from low-income and middle-income countries on cardiovascular involvement and its longitudinal outcomes.We planned to estimate the pattern of cardiovascular involvement among children with MIS-C and its mid-term outcomes.AIM To determine association between cardiovascular abnormalities and clinical and laboratory parameters.To study the time-line for resolution of various abnormalities.METHODS In this prospective study done in a tertiary care hospital,270 were recruited from June 2020 to January 2022.Baseline demographic data and clinical presentation were recorded.Laboratory parameters and echocardiography were done at admission.Follow-up was done at 2 weeks,3 months,6 months and 1 year after diagnosis.Descriptive statistics were used for parametric and non-parametric data.Risk factors were identified by multivariate regression analysis.RESULTS The 211(78.2%)had cardiac involvement and 102 needed intensive care unit(ICU)admission.Cardiovascular abnormalities observed were shock 123(45.6%),coronary dilatation 28(10.4%),coronary aneurysm 77(28.5%),left ventricular(LV)dysfunction 78(29.3%),mitral regurgitation(MR)77(28.5%)and pericardial effusion 98(36.3%).Coronary artery aneurysm/dilatation during follow-up at 2 weeks and 1 year were 25.7%and 0.9%respectively.Multivariate regression analysis revealed breathlessness[odds ratio(OR)=3.91,95%CI:1.25-12.21,P=0.019]and hi-flow nasal cannula(HFNC)support(OR=8.5,95%CI:1.06-68.38,P=0.044)as predictors of cardiovascular involvement.Higher mean age(OR=1.16,95%CI:1.02-1.32,P=0.026),breathlessness(OR=4.99,95%CI:2.05-12.20,P<0.001),gallop(OR=4.45,95%CI:0.41-2.52,P=0.016),MR(OR=3.61,95%CI:1.53-8.53,P=0.004)and invasive ventilation(OR=4.01,95%CI:1.28-12.58,P=0.017)were predictive of LV dysfunction.Altered sensorium(OR=4.96,95%CI:2.23-11.02,P<0.001),headache(OR=6.61,95%CI:1.46-29.92,P=0.014),HFNC(OR=7.03,95%CI:2.04-24.29,P=0.002),non-rebreathing mask usage(OR=21.13,95%CI:9.00-49.61,P<0.001)and invasive ventilation(OR=5.64,95%CI:1.42-22.45,P=0.014)were risk factors for shock.Anemia was a risk factor for coronary involvement(OR=3.09,95%CI:1.79-5.34,P<0.001).CONCLUSION Significant number of children with MIS-C had cardiovascular involvement contributing to higher ICU management.Although shock resolved quickly,resolution of ventricular function and coronary abnormalities were slower,and hence warrants a structured long-term follow-up protocol.

C-X-C chemokine receptor type 5+CD8+T cells as immune regulators in hepatitis Be antigen-positive chronic hepatitis B under interferonalpha treatment

BACKGROUND C-X-C chemokine receptor type 5(CXCR5)+CD8+T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5+CD8+T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5+CD8+T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5+CD8+T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×104 copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8+T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5+CD8+T cells compared to healthy controls(P<0.01).Notably,CXCR5+CD8+T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5+CD8+T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5+CD8+T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.

Application of Dorzagliatin in peritoneal dialysis patients with type 2 diabetes mellitus:A case report

BACKGROUND Treating diabetes in dialysis patients remains a challenge,with many hypoglycemic drugs requiring dose adjustments or avoidance in these patients.CASE SUMMARY This report describes an 83-year-old female patient with a 30-year history of type 2 diabetes(T2DM)who had struggled to control her blood sugar for more than a year.She had a history of high blood pressure for 30 years,had undergone continuous ambulatory peritoneal dialysis for more than two years,was 163 cm tall,weighed 77 kg,and had a body mass index of 28.98 kg/m2.Despite intensive insulin therapy at a daily dose of 150 units,adding Dorzagliatin at a dosage of 75 mg orally twice daily led to immediate blood sugar improvement and a gradual reduction in insulin dosage.After one month of follow-up,the fasting plasma glucose was 6-8 mmol/L,and the 2-hour postprandial glucose was 8-12 mmol/L.CONCLUSION To our knowledge,this report is the first to use Dorzagliatin to treat type 2 diabetes peritoneal dialysis patients with challenging glucose control.Dorzagliatin,a novel glucokinase activator primarily metabolized by the liver,exhibits no pharmacokinetic differences among patients with varying degrees of chronic kidney disease.It has a high plasma protein binding rate and may not be cleared by peritoneal dialysis,potentially offering a new glycemic control option for Type 2 diabetic patients on peritoneal dialysis.

Unveiling mitochondrial mysteries:Exploring novel tRNA variants in type 2 diabetes mellitus

The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY)variants in type 2 diabetes mellitus(T2DM).This editorial explores their findings,highlighting the role of mitochondrial dysfunction in the pathogenesis of T2DM.By examining the molecular mechanisms through which these tRNA variants contribute to disease progression,the study introduces new targets for therapeutic strategies.We discuss the broader implications of these results,emphasizing the importance of understanding mitochondrial genetics in addressing T2DM.

Impact of community public health care on treatment effect,health cognition,and self-management in patients with type 2 diabetes

BACKGROUND At present,China has become the country with the largest number of individuals with diabetes mellitus(DM)in the world,with a total of approximately 140 million patients,the majority of whom have type 2 DM(T2DM).Based on conven-tional nursing methods,community home care has important clinical significance in controlling blood sugar and disease progression.AIM To explore the impact of community public health nursing on treatment effect,health cognition,and self-management in patients with T2DM.METHODS One hundred patients with T2DM were selected as the research subjects.The patients were divided into either a conventional nursing group or community nursing(CN)group using the random number table method.The conventional nursing group(50 cases)received routine care,while the CN group(50 cases)received community public health care in addition to routine care as that for the conventional nursing group.The rate of excellent and good blood glucose control,fasting blood glucose before and after care,2-h postprandial blood glucose,health cognition,and self-management ability,and patient satisfaction were compared between the two groups.RESULTS The CN group had a higher rate of excellent blood sugar control than the conventional nursing group(88%vs 70%,P<0.05).Before care,there was no significant difference in fasting blood glucose or 2-h postprandial blood glucose between the two groups of patients(P>0.05).After nursing,fasting blood glucose and 2-h postprandial blood glucose were reduced to varying degrees in both groups,and both blood glucose levels in the CN group were lower than those of the conventional nursing group(P<0.05).Compared with the scores before care,the cognitive level score for diabetes and self-management ability score improved after care in both groups.The cognitive level and self-management ability of patients in the CN group were higher than those of the conventional nursing group(P<0.05).The overall satisfaction of the CN group was better than that of the conventional nursing group(98%vs 86%,P<0.05).CONCLUSION Community public health care based on conventional care of T2DM can achieve better blood sugar control,and improve patients’health cognitive level and self-management ability.

Association of the glycemic background patterns and the diabetes management efficacy in poorly controlled type 2 diabetes

BACKGROUND Inadequate glycemic control in patients with type 2 diabetes(T2DM)is a major public health problem and a significant risk factor for the progression of diabetic complications.AIM To evaluate the effects of intensive and supportive glycemic management strategies over a 12-month period in individuals with T2DM with glycated hemoglobin(HbA1c)≥10%and varying backgrounds of glycemic control.METHODS This prospective observational study investigated glycemic control in patients with poorly controlled T2DM over 12 months.Participants were categorized into four groups based on prior glycemic history:Newly diagnosed,previously well controlled with recent worsening,previously off-target but now worsening,and HbA1c consistently above 10%.HbA1c levels were monitored quarterly,and patients received medical,educational,and dietary support as needed.The analysis focused on the success rates of good glycemic control and the associated factors within each group.RESULTS The study showed significant improvements in HbA1c levels in all participants.The most significant improvement was observed in individuals newly diagnosed with diabetes:65%achieved an HbA1c target of≤7%.The results varied between participants with different glycemic control histories,followed by decreasing success rates:39%in participants with previously good glycemic control,21%in participants whose glycemic control had deteriorated compared to before,and only 10%in participants with persistently poor control,with mean HbA1c levels of 6.3%,7.7%,8.2%,and 9.7%,respectively.After one year,65.2%of the“newly diagnosed patients”,39.3%in the“previously controlled group”,21.9%in the“previously off-target but now worsened'”group and 10%in the“poorly controlled from the start”group had achieved HbA1c levels of 7 and below.CONCLUSION In poorly controlled diabetes,the rate at which treatment goals are achieved is associated with the glycemic background characteristics,emphasizing the need for tailored strategies.Therefore,different and comprehensive treatment approaches are needed for patients with persistent uncontrolled diabetes.

Activin A receptor type 1C single nucleotide polymorphisms associated with esophageal squamous cell carcinoma risk in Chinese population

BACKGROUND Transforming growth factor-β(TGF-β)superfamily plays an important role in tumor progression and metastasis.Activin A receptor type 1C(ACVR1C)is a TGF-βtype I receptor that is involved in tumorigenesis through binding to dif-ferent ligands.AIM To evaluate the correlation between single nucleotide polymorphisms(SNPs)of ACVR1C and susceptibility to esophageal squamous cell carcinoma(ESCC)in Chinese Han population.METHODS In this hospital-based cohort study,1043 ESCC patients and 1143 healthy controls were enrolled.Five SNPs(rs4664229,rs4556933,rs77886248,rs77263459,rs6734630)of ACVR1C were assessed by the ligation detection reaction method.Hardy-Weinberg equilibrium test,genetic model analysis,stratified analysis,linkage disequi-librium test,and haplotype analysis were conducted.RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC,and those with rs77886248 TA mutant were related with higher risk,especially in older male smokers.In the haplotype analysis,ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC,while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC,which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.

Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

Drosophila models used to simulate human ATP1A1 gene mutations that cause Charcot-Marie-Tooth type 2 disease and refractory seizures

Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.

A population-based follow-up study on gallstone disease among type 2 diabetics in Kinmen,Taiwan

AIM： To assess the incidence of and risk factors for gallstone disease （GSD） among type 2 diabetics in Kinmen, Taiwan. METHODS： A screening program for GSD was performed by two specialists who employed real-time abdominal ultrasound to examine the abdominal region after patients had fasted for at least eight hours. Screening, which was conducted in 2001, involved 848 patients diagnosed with type 2 diabetes. After exclusion of 63 subjects with prevalent GSD, 377 participants without GSD were invited in 2002 for a second round of screening. A total of 281 （74.5%） subjects were re-examined. RESULTS： Among the 281 type 2 diabetics who had no GSD at the first screening, 10 had developed GSD by 2002. The incidence was 3.56% per year （95%CI： 1.78% per year-6.24% per year）. Using a Cox regression model, age （RR = 1.07, 95% CI： 1.00-1.14）, waist circumference （RR = 1.12, 95% CI： 1.01-1.29）, and ALT （RR = 1.13, 95%CI： 1.01-1.26） appeared to be significantly correlated with development of GSD. CONCLUSION： Older age is a known risk factor for the development of GSD. Our study shows that greater waist circumference and elevated ALT levels are also associated with the development of GSD among type 2 diabetics in Kinmen.

Long-term Follow-up Study on Gastric Intestinal Metaplasia Subtype and Its Relation to Expression of P53,Bcl-2 and PCNA

Objective： To investigate the correlation of typies of gastric intestinal metaplasia（IM）, expression of p53, bcl-2 and the proliferating cell nuclear antigen（PCNA）, with the lesion＇s evolution. Methods： A total of 80 patients with IM（53 male and 27 female, 35-64 years old） from an area with high-risk of gastric cancer（GC） in China were enrolled into this prospective study, including 28 cases of type Ⅰ （complete）, 25 cases of type Ⅱ （incomplete） , and 27 cases of type Ⅲ （incomplete）. Of the 80 cases, 62 cases including 19 cases of type Ⅰ, 22 type Ⅱ and 21 type Ⅲ, were followed up for 5-14 years（49 cases for 14 years, 6 for 10 years, and 7 for 5 years）. All of the 80 cases were studied immunohistochemically for the expression of p53, bcl-2 and PCNA. Results： The rate of p53-expressing cases was higher in type Ⅲ（25.9%） than in type Ⅰ（10.7%） and type Ⅱ （12.0%）, but without statistical significance（P=0.3070）. The positive rate of bcl-2 was obviously lower in type Ⅰ （21.4%） and type Ⅱ （24.0%） than in type Ⅲ（37.0%）, but not statistically significant（P=0.4223）. We observed difference in PCNA labelling index （LI） between type Ⅱ and type Ⅲ（P=0.0037）, and the difference was particularly significant in type Ⅰ as compared with type Ⅲ（P〈0.0001）. There was no statistical significance between type I and type II （P=0.0616）. Evolution into GC was detected in 0%, 4.5%, and 14.3% of type Ⅰ, type Ⅱ, and type Ⅲ IM cases, respectively. Progression to dysplasia was detected in 31.6%, 18.2%, and 14.3% of type Ⅰ, type Ⅱ, and type Ⅲ IM cases, respectively. Persistence of IM was documented in 31.6%, 45.5%, and 42.9% of type Ⅰ, type Ⅱ, and type Ⅲ IM cases, respectively. Regression of IM was documented in 36.8%, 31.8%, and 28.6% of type Ⅰ, type Ⅱ, and type ⅢIM cases, respectively. In progressive, persistent and regressive groups, the positive rates of p53 were 17.6%, 16.0% and 15.0%, bcl-2 were 29.4%, 36.0% and 25.0%, and PCNA LIs were 24.953±14.477, 23.752±12.934 and 25.105±10.055, respectively. There were no significant differences between the groups. Conclusion： The present follow-up study indicated that type Ⅲ had a higher risk for development of cancer than type Ⅰ or Ⅱ. PCNA LI was significantly higher in type Ⅲthan in type Ⅰ and Ⅱ, suggesting that cell proliferation in type Ⅲwas more active. Our data also indicated that the expression of p53 and bcl-2 had no apparent association with the particular type and the expression of p53, bcl-2 and PCNA had no apparent correlation with evolution of IM. Further studies with a larger sample size are needed to verify present observation.

Association of extraintestinal manifestations of inflammatory bowel disease in a province of western Hungary with disease phenotype:Results of a 25-year follow-up study

AIM:IBD is a systemic disease associated with a large number of extraintestinal manifestations (EIMs).Our aim was to determine the prevalence of EIMs in a large IBD cohort in Veszprem Province in a 25-year follow-up study. METHODS:Eight hundred and seventy-three IBD patients were enrolled (ulcerative colitis/UC/:619,m/f:317/302, mean age at presentation:38.3 years,average disease duration:11.2 years;Crohn's disease/CD/:254,m/f:125/129, mean age at presentation:32.5 years,average disease duration:9.2 years).Intestinal,extraintestinal signs and laboratory tests were monitored regularly.Any alteration suggesting an EIMs was investigated by a specialist. RESULTS:A total of 21.3% of patients with IBD had EIM (UC:15.0%,CD:36.6%).Age at presentation did not affect the likelihood of EIM.Prevalence of EIMs was higher in women and in CD,ocular complications and primary sclerosing cholangitis (PSC) were more frequent in UC.In UC there was an increased tendency of EIM in patients with a more extensive disease.Joint complications were more frequent in CD (22.4% vsUC 10.2%,P<0.01).In UC positive family history increased the risk of joint complications (OR:3.63).In CD the frequency of type-1 peripheral arthritis was increased in patients with penetrating disease (P=0.028).PSC was present in 1.6% in UC and 0.8% in CD.Dermatological complications were present in 3.8% in UC and 10.2% in CD,the rate of ocular complications was around 3% in both diseases.Rare complications were glomerulonephritis,autoimmune hemolytic anaemia and celiac disease. CONCLUSION:Prevalence of EIM in Hungarian IBD patients is in concordance with data from Western countries.The high number of EIM supports a role for complex follow-up in these patients.