Sorl1 knockout inhibits expression of brain-derived neurotrophic factor:involvement in the development of late-onset Alzheimer's disease

Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.

Early-onset gastrointestinal cancer:An epidemiological reality with great significance and implications

During the last few years,epidemiological data from many countries suggest that the incidence and prevalence of many cancers of the digestive system are shifting from the older to the younger ages,the so-called“early-onset cancer”.This is particularly evident in colorectal cancer and secondarily in other malignant digestive neoplasms,mainly stomach and in a lesser degree pancreas,and biliary tract.It should be emphasized that data concerning digestive neoplasms,except for those referring to the colon and stomach,could be characterized as rather insufficient.The exact magnitude of the shift in younger ages is expected to become clearer shortly,as long as relevant epidemiological data from many parts of the world would be available.The most important question concerns the etiology of this phenomenon,since its magnitude cannot be explained solely by the better diagnostic methodology and the preventive programs applied in many countries.The existing data support the assumption that a number of environ-mental factors may play a primary role in influencing carcinogenesis,sometimes from childhood.Changes that have appeared in the last decades related mainly to eating habits,consistency of gut microbiome and an increase of obese people interacting with genetic factors,ultimately favor the process of carcinogenesis.Even these factors however,are not entirely sufficient to explain the age-related changes in the frequency of digestive neoplasms.Studies of the individual effect of each of the already known factors or factors likely to be involved in the etiology of this phenomenon and studies using state-of-the-art technologies to accurately determine the degree of the population exposure to these factors are required.In this article,we attempt to describe the epidemiological data supporting the age-shifting of digestive malignancies and their possible pathogenesis.Finally,we propose some measures regarding the attitude of the scientific community to this alarming phenomenon.

Treatment patterns and survival outcomes in patients with nonmetastatic early-onset pancreatic cancer

BACKGROUND The incidence of patients with early-onset pancreatic cancer(EOPC;age≤50 years at diagnosis)is on the rise,placing a heavy burden on individuals,families,and society.The role of combination therapy including surgery,radiotherapy,and chemotherapy in non-metastatic EOPC is not well-defined.AIM To investigate the treatment patterns and survival outcomes in patients with non-metastatic EOPC.METHODS A total of 277 patients with non-metastatic EOPC who were treated at our institution between 2017 and 2021 were investigated retrospectively.Overall survival(OS),disease-free survival,and progression-free survival were estimated using the Kaplan-Meier method.Univariate and multivariate analyses with the Cox proportional hazards model were used to identify prognostic factors.RESULTS With a median follow-up time of 34.6 months,the 1-year,2-year,and 3-year OS rates for the entire cohort were 84.3%,51.5%,and 27.6%,respectively.The median OS of patients with localized disease who received surgery alone and adjuvant therapy(AT)were 21.2 months and 28.8 months,respectively(P=0.007).The median OS of patients with locally advanced disease who received radiotherapy-based combination therapy(RCT),surgery after neoadjuvant therapy(NAT),and chemotherapy were 28.5 months,25.6 months,and 14.0 months,respectively(P=0.002).The median OS after regional recurrence were 16.0 months,13.4 months,and 8.9 months in the RCT,chemotherapy,and supportive therapy groups,respectively(P=0.035).Multivariate analysis demonstrated that carbohydrate antigen 19-9 level,pathological grade,T-stage,N-stage,and resection were independent prognostic factors for non-metastatic EOPC.CONCLUSION AT improves postoperative survival in localized patients.Surgery after NAT and RCT are the preferred therapeutic options for patients with locally advanced EOPC.

Serum ferritin and the risk of early-onset colorectal cancer

BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the indication for endoscopy in EO-CRC is unclear.AIM To compare serum ferritin between patients with EO-CRC and healthy controls(HCs),and examine the association of serum ferritin in EO-CRC with patient-and disease-specific characteristics.METHODS A retrospective study of patients<50 years with newly-diagnosed EO-CRC was conducted from 1/2013-12/2023.Patients were included if serum ferritin was measured within 2 years prior to 1 year following CRC histologic diagnosis.To supplement the analysis,a cohort of HCs meeting similar inclusion and exclusion criteria were identified for comparison.A sensitivity analysis including only patients with serum ferritin obtained at or before diagnosis was separately performed to minimize risk of confounding.RESULTS Among 85 patients identified with EO-CRC(48 females),the median serum ferritin level was 26 ng/mL(range<1-2759 ng/mL).Compared to HCs(n=80211),there were a higher proportion of individuals with EO-CRC with serum ferritin<20 ng/mL(female 65%,male 40%)versus HCs(female 32.1%,male 7.2%)age 29-39 years(P=0.002 and P<0.00001,respectively).Stage IV disease was associated with significantly higher serum ferritin compared to less advanced stages(P<0.001).Serum ferritin obtained before or at the time of diagnosis was lower than levels obtained after diagnosis.Similar findings were confirmed in the sensitivity analysis.CONCLUSION Severe iron deficiency may indicate an increased risk of EO-CRC,particularly at earlier stages.Further studies defining the optimal serum ferritin threshold and routine incorporation of serum ferritin in screening algorithms is essential to develop more effective screening strategies for EO-CRC.

Association of serum interleukin-6 with negative symptoms in stable early-onset schizophrenia

BACKGROUND Accumulating evidence suggests that the inflammatory cytokine interleukin-6(IL-6)contributes to the pathophysiology of psychiatric disorders.However,there was no study concerning the relationship between IL-6 concentrations and clinical features in the chronic phase of early-onset schizophrenia(EOS).AIM To investigate the relationship between serum IL-6 concentration and the clinical features of EOS.METHODS We measured serum IL-6 Levels from 74 patients with chronic schizophrenia,including 33 with age at onset<21 years(EOS group)and 41 with onset≥21 years in[adult-onset schizophrenia(AOS)group],and from 41 healthy controls.Symptom severities were evaluated using the Positive and Negative Syndrome Scale(PANSS).RESULTS Serum IL-6 concentrations were higher in both EOS and AOS groups than healthy controls(F=22.32,P<0.01),but did not differ significantly between EOS and AOS groups(P>0.05)after controlling for age,body mass index,and other covariates.Negative symptom scores were higher in the EOS group than the AOS group(F=6.199,P=0.015).Serum IL-6 concentrations in the EOS group were negatively correlated with both total PANSS-negative symptom score(r=-0.389,P=0.032)and avolition/asociality subscore(r=-0.387,P=0.026).CONCLUSION Patients with EOS may have more severe negative symptoms than those with adult-onset schizophrenia during the chronic phase of the illness.IL-6 signaling may regulate negative symptoms and its avolition/asociality subsymptoms among the early-onset chronic schizophrenic patients.

Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer's disease

Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals.The comorbidity of the two neurological disorders represents a grave health threat to older populations.This review presents a brief background of the development of novel concepts and their clinical potentials.The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal function.An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic site.This Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity.Furthermore,mild but sustained Ca^(2+)increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca^(2+)-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways.Based on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis.The N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity.Ischemic stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,although with much different time courses.It is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia.This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.

Salivary C-reactive protein and mean platelet volume as possible diagnostic markers for late-onset neonatal pneumonia

BACKGROUND Neonatal sepsis,a formidable threat to newborns,is a leading cause of neonatal mortality,with late-onset sepsis manifesting after 72 hours post-birth being particularly concerning.Pneumonia,a prevalent sepsis presentation,poses a significant risk,especially during the neonatal phase when lung defenses are compromised.Accurate diagnosis of pneumonia is imperative for timely and effective interventions.Saliva,a minimally invasive diagnostic medium,holds great promise for evaluating infections,especially in infants.AIM To investigate the potential of serum C-reactive protein(CRP),salivary CRP(sCRP),and mean platelet volume(MPV)as diagnostic markers for late-onset neonatal pneumonia(LONP).METHODS Eighty full-term neonates were systematically examined,considering anthropometric measurements,clinical manifestations,radiology findings,and essential biomarkers,including serum CRP,sCRP,and MPV.RESULTS The study reveals noteworthy distinctions in serum CRP levels,MPV,and the serum CRP/MPV ratio between neonates with LONP and healthy controls.MPV exhibited a robust discriminatory ability[area under the curve(AUC)=0.87]with high sensitivity and specificity at a cutoff value of>8.8.Correlations between serum CRP,sCRP,and MPV were also identified.Notably,sCRP demonstrated excellent predictive value for serum CRP levels(AUC=0.89),underscoring its potential as a diagnostic tool.CONCLUSION This study underscores the diagnostic promise of salivary and serum biomarkers,specifically MPV and CRP,in identifying and predicting LONP among neonates.These findings advocate for further research to validate their clinical utility in larger neonatal cohorts.

Research Progress in Early-onset Colorectal Cancer

Colorectal cancer used to be a common disease among middle-aged and elderly people.In recent years,the incidence of colorectal cancer(Early-onset colorectal cancer,EOCRC)under 50 years old has increased year by year.Different from the traditional late-onset colon cancer(LOCRC),the diagnosis stage of EOCRC is mostly in the late stage,with poor cell differentiation and poor diagnosis,and there is a layer of consensus and guidance on the diagnosis,treatment or screening of EOCRC at presentation.Therefore,fully understanding the disease characteristics and risk exposure factors of EOCRC is helpful to guide early screening and treatment,which ultimately reduces the mortality of EOCRC.In this review article,we summarized the epidemiology,physiology,risk exposure factors and pathological diagnosis of EOCRC,and discussed the diagnosis and treatment prospect of EOCRC.

Early-onset colorectal cancer:A review of current knowledge

Colorectal cancer(CRC)is one of the most prevalent malignancies worldwide.Although most prevalent among older people,its incidence above 50 years old has been decreasing globally in the last decades,probably as a result of better screening.Paradoxically,its incidence in patients below 50 years old[early-onset CRC(EO-CRC)]has been increasing,for reasons not yet fully understood.EOCRC’s increasing incidence is genre independent but shows racial disparities and has been described to occur worldwide.It follows a birth-cohort effect which probably reflects a change in exposure to CRC risk factors.Its incidence is predicted to double until 2030,which makes EO-CRC a serious public health issue.Both modifiable and non-modifiable risk factors have been identified-some are potential targets for preventive measures.EO-CRC is often diagnosed at advanced stages and histological features associated with poor prognosis have been described.EO-CRC presents some distinctive features:Microsatellite instability is common,but another subtype of tumours,both microsatellite and chromosome stable also seems relevant.There are no age-specific treatment protocols and studies on EO-CRC survival rates have shown conflicting data.Due to the higher germline pathological mutations found in EO-CRC patients,an accurate genetic risk evaluation should be performed.In this review,we summarize the current evidence on epidemiological,clinical,histopathological and molecular features of EO-CRC and discuss the contribution of genetics and lifestyle risk factors.We further comment on screening strategies and specific dimensions to consider when dealing with a younger cancer patient.

Molecular genetics of early-onset colorectal cancer

Early-onset colorectal cancer(EOCRC)has been rising in global prevalence and incidence over the past several decades.Environmental influences,including generational lifestyle changes and rising obesity,contribute to these increased rates.While the rise in EOCRC is best documented in western countries,it is seen throughout the world,although EOCRC may have distinct genetic mutations in patients of different ethnic backgrounds.Pathological and molecular characterizations show that EOCRC has a distinct presentation compared with later-onset colorectal cancer(LOCRC).Recent studies have identified DNA,RNA,and protein-level alterations unique to EOCRC,revealing much-needed biomarkers and potential novel therapeutic targets.Many molecular EOCRC studies have been performed with Caucasian and Asian EOCRC cohorts,however,studies of other ethnic backgrounds are limited.In addition,certain molecular characterizations that have been conducted for LOCRC have not yet been repeated in EOCRC,including high-throughput analyses of histone modifications,mRNA splicing,and proteomics on large cohorts.We propose that the complex relationship between cancer and aging should be considered when studying the molecular underpinnings of EOCRC.In this review,we summarize current EOCRC literature,focusing on sporadic molecular alterations in tumors,and their clinical implications.We conclude by discussing current challenges and future directions of EOCRC research efforts.

Advantage of log odds of positive lymph nodes in prognostic evaluation of patients with early-onset colon cancer

BACKGROUND Colon cancer(CC)is one of the most common cancers of the digestive tract,the third most common cancer worldwide,and the second most common cause of cancer-related deaths.Previous studies have demonstrated a higher risk of lymph node metastasis(LNM)in young patients with CC.It might be reasonable to treat patients with early-onset locally advanced CC with extended lymph node dissection.However,few studies have focused on early-onset CC(ECC)patients with LNM.At present,the methods of predicting and evaluating the prognosis of ECC patients with LNM are controversial.From the data of patients with CC obtained from the Surveillance,Epidemiology,and End Results(SEER)database,data of young patients with ECC(≤50 years old)was screened.Patients with unknown data were excluded from the study,while the remaining patients were included.The patients were randomly divided into a training group(train)and a testing group(test)in the ratio of 7:3,while building the model.The model was constructed by the training group and verified by the testing group.Using multiple Cox regression models to compare the prediction efficiency of LNM indicators,nomograms were built based on the best model selected for overall survival(OS)and cause-specific survival(CSS).In the two groups,the performance of the nomogram was evaluated by constructing a calibration plot,time-dependent area under the curve(AUC),and decision curve analysis.Finally,the patients were grouped based on the risk score predicted by the prognosis model,and the survival curve was constructed after comparing the survival status of the high and low-risk groups.RESULTS Records of 26922 ECC patients were screened from the SEER database.N classification,positive lymph nodes(PLN),lymph node ratio(LNR)and log odds of PLN(LODDS)were considered to be independent predictors of OS and CSS.In addition,independent risk factors for OS included gender,race,marital status,primary site,histology,grade,T,and M classification,while the independent prognostic factors for CSS included race,marital status,primary site,grade,T,and M classification.The prediction model including LODDS is composed of minimal Akaike information criterion,maximal concordance indexes,and AUCs.Factors including gender,race,marital status,primary site,histology,grade,T,M classification,and LODDS were integrated into the OS nomogram,while race,marital status,primary site,grade,T,M classification,and LODDS were included into the CSS nomogram.The nomogram representing both cohorts had been successfully verified in terms of prediction accuracy and clinical practicability.CONCLUSION LODDS is superior to N-stage,PLN,and LNR of ECC.The nomogram containing LODDS might be helpful in tumor evaluation and clinical decision-making,since it provides an appropriate prediction of ECC.

When the vermiform appendix resembles a polyp: Be cautious of an intussuscepted appendix polypectomy

This article discusses a recently published case report on a rare instance of type IV appendiceal intussusception with a concurrent mucinous adenocarcinoma of the cecum in a young individual.The report highlights challenges in diagnosing ap-pendiceal intussusception,emphasizing the importance of endoscopic expertise in preventing impulsive decisions such as inappropriate polypectomies.The rarity of the concurrent intussuscepted appendix and mucinous cecal cancer is under-scored,prompting consideration of malignancy in appendiceal intussusception cases.Additionally,the report addresses the increasing incidence of early-onset colorectal cancer and the need for a revaluation of diagnostic paradigms in the context of evolving epidemiological trends.The awareness of potential misinter-pretations and the imperative for further investigation into this rare condition are emphasized.

Early-onset colorectal cancer:A sporadic or inherited disease?

Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a &#x0201c;sporadic&#x0201d; subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the &#x0201c;sporadic&#x0201d; subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this &#x0201c;sporadic&#x0201d; early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.

Survey for late-onset hypogonadism among old anti middle-aged males in Shanghai communities

This study sought to investigate late-onset hypogonadism （LOH） in old and middle-aged males in Shanghai communities, using symptom score evaluation systems and measurements of sex hormone levels. One thousand cases of males aged 40-70 years were investigated. The aging male symptoms （AMS） scale and androgen deficiency in aging males （ADAM） questionnaire were used at the beginning of the investigation, followed by measurement of the sex hormone-related factors （total testosterone （TT）, free testosterone （fT）, sex hormone-binding globulin （SHBG） and bioavailability of testosterone （Bio-T））. There were 977 valid questionnaires. The LOH-positive rates shown by AMS and ADAM were 59.88% and 84.65%, respectively; values increased with the age of the patients. There were 946 results related to sex hormone measurements, which showed the following results： TT was not related to aging （P〉O.05）; levels of SHBG increased with age; and fT and Bio-T decreased with age. There was a significant difference in fT between LOH-positive and LOH-negative patients, as shown by the ADAM. In summary, TT levels were not related to aging, even though SHBG did increase while fT and Bio-T decreased with aging. Clinically, the diagnosis of LOH cannot be based on serum TT level.

Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

Colorectal cancer(CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC(EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, Mut YH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach.

Clinical Features and Microvascular Complications Risk Factors of Early-onset Type 2 Diabetes Mellitus

The aim of this research was to study the clinical features and microvascular complications risk factors of early-onset type 2 diabetes mellitus(T2DM).We analyzed the clinical data from 1421 T2DM inpatients at Wuhan Union Hospital.Subjects were divided into early-onset T2DM group(diagnostic age<40 years)and late-onset T2DM group(diagnostic age>40 years).All subjects underwent a standardized assessment of microvascular complications.Data were compared with independent-samples t test or Chi-square test.Multiple logistic regression was used to determine the risk factors of microvascular complications.Patients with early-onset T2DM were more inclined to have a lower systolic blood pressure(SBP),a longer duration of diabetes and higher levels of body mass index(BM1),uric acid(UA),fasting plasma glucose(FPG),total cholesterol(TC),triglyceride(TG)and glycosylated hemoglobin(HbAlc)than those with lateonset T2DM(P<0.05).The prevalence of diabetic retinopathy(DR)was significantly higher and that of diabetic peripheral neuropathy(DPN)was significantly lower in early-onset group than in late-onset group(P<0.05).For DN,UA was an independent risk factor in early-onset T2DM.SBP and TG were independent risk factors in late-onset T2DM.For DR,duration of diabetes and SBP were independent risk factors in early-onset T2DM.Duration of diabetes,SBP and HbAlc were independent risk factors in late-onset T2DM.This study demonstrated that the clinical characteristics of early-onset T2DM were metabolic disorders,including glucose metabolism,lipid metabolism and amino acid metabolism.Early-onset T2DM was more likely to be associated with DR.The potential pathogenesis of early and late-onset T2DM might be different.The management of metabolic risk factors especially HbA1c,SBP,TG and UA is advised to be performed in the early stage of diabetes.

Circulating MicroRNAs as Novel Diagnostic Biomarkers for Very Early-onset(≤40 years) Coronary Artery Disease

Objective Very early-onset coronary artery disease （CAD） is a great challenge in cardiovascular medicine throughout the world, especially regarding its early diagnosis. This study explored whether circulating microRNAs （miRNAs） could be used as potential biomarkers for patients with very early-onset CAD. Methods We performed an initial screening of miRNA expression using RNA isolated from 20 patients with angiographically documented very early-onset CAD and 20 age- and sex-matched normal controls. For further confirmation, we prospectively examined the miRNAs selected from 40 patients with very early-onset CAD and 40 angiography-normal controls. Results A total of 22 overexpressed miRNAs and 22 underexpressed miRNAs were detected in the initial screening. RT-qPCR analysis of the miRNAs obtained from the initial screening revealed that four miRNAs including miR-196-5p, miR-3163-3p, miR-145-3p, and miR-190a-5p exhibited significantly decreased expression in patients compared with that in controls （P〈0.05）. The areas under the receiver operating characteristic curve for these miRNAs were 0.824 （95% CI, 0.731-0.917; P〈0.001）, 0.758 （95% CI, 0.651-0.864; P〈0.001）, 0.753 （95% CI, 0.643-0.863; P〈0.001）, and 0.782 （95% CI, 0.680-0.884; P〈0.001）, respectively, in the validation set. Conclusion To our knowledge, this is an advanced study to report about four serum miRNAs （miR-196-5p, miR-3163-3p, miR-145-3p, and miR-190a-5p） that could be used as novel biomarkers for the diagnosis of very early-onset CAD.

Plasma D-dimer level in early and late-onset neonatal sepsis

BACKGROUND Neonatal sepsis is a life-threatening disease.Early diagnosis is essential,but no single marker of infection has been identified.Sepsis activates a coagulation cascade with simultaneous production of the D-dimers due to lysis of fibrin.Ddimer test reflects the activation of the coagulation system.AIM To assess the D-dimer plasma level,elaborating its clinicopathological value in neonates with early-onset and late-onset neonatal sepsis.METHODS The study was a prospective cross-sectional study that included ninety neonates;divided into three groups:Group I:Early-onset sepsis(EOS);Group II:Late-onset sepsis(LOS);and GroupⅢ:Control group.We diagnosed neonatal sepsis according to our protocol.C-reactive protein(CRP)and D-dimer assays were compared between EOS and LOS and correlated to the causative microbiological agents.RESULTS D-dimer was significantly higher in septic groups with a considerably higher number of cases with positive D-dimer.Neonates with LOS had substantially higher levels of D-dimer than EOS,with no significant differences in CRP.Neonates with LOS had a significantly longer hospitalization duration and higher gram-negative bacteriemia and mortality rates than EOS(P<0.01).Gramnegative bacteria have the highest D-dimer levels(Acinetobacter,Klebsiella,and Pseudomonas)and CRP(Serratia,Klebsiella,and Pseudomonas);while gram-positive sepsis was associated with relatively lower levels.D-dimer had a significant negative correlation with hemoglobin level and platelet count;and a significant positive correlation with CRP,hospitalization duration,and mortality rates.The best-suggested cut-off point for D-dimer in neonatal sepsis was 0.75 mg/L,giving a sensitivity of 72.7%and specificity of 86.7%.The D-dimer assay has specificity and sensitivity comparable to CRP in the current study.CONCLUSION The current study revealed a significant diagnostic value for D-dimer in neonatal sepsis.D-dimer can be used as an adjunct to other sepsis markers to increase the sensitivity and specificity of diagnosing neonatal sepsis.

Early-onset gastric cancer:Learning lessons from the young

There is by no means a clear-cut pattern of mutations contributing to gastric cancers,and gastric cancer research can be hampered by the diversity of factors that can induce gastric cancer,such as Helicobacter pylori infection,diet,ageing and other environmental factors.Tumours are unquestionably riddled with genetic changes yet we are faced with an unsolvable puzzle with respect to a temporal relationship.It is postulated that inherited genetic factors may be more important in early-onset gastric cancer (EOGC) than in gastric cancers found in older patients as they have less exposure to environmental carcinogens.EOGC,therefore,could provide a key to unravelling the genetic changes in gastric carcinogenesis.Gastric cancers occurring in young patients provide an ideal background on which to try and uncover the initiating stages of gastric carcinogenesis.This review summarizes the literature regarding EOGC and also presents evidence that these cancers have a unique molecular-genetic phenotype,distinct from conventional gastric cancer.

How to recognize late-onset hypogonadism in men wit sexual dysfunction

Late-onset hypogonadism （LOH） has been considered the most common form of male hypogonadism with a prevalence of approximately 1 in 100 men. Diagnosis of LOH should be made in symptomatic men with unequivocally low serum testosterone （T） levels. However, its clinical presentation is often insidious and difficult to recognize because it is characterized by nonspecific symptoms that make differential diagnosis with physiological ageing problematic. Sexual dysfunction is the most important determinant for medical consultation and the most specific symptom associated with low T. We therefore analysed a consecutive series of 1734 subjects who attended our unit for sexual dysfunction to investigate the associations between low T （different thresholds）, sexual parameters, medical history data （delayed puberty, pituitary disease or cryptorchidism） and their physical exam results. Metabolic parameters, in particular waist circumference, display the greatest accuracy in detecting low T. We found that only the association of several symptoms and signs could significantly raise the clinical suspicion of low T. Structured inventories, which cluster together symptoms and signs of hypogonadism, can help clinicians suspect androgen deficiency. In particular, structured interviews, such as ANDROTEST, have been demonstrated to have a greater accuracy when compared to self reported questionnaires in detecting low T levels.