Blockade of fatty acid signalling inhibits lipopolysaccharide-induced macrophage recruitment and progression of apical periodontitis.

AIM: To examine the role of palmitic acid in lipopolysaccharide (LPS)-stimulated chemotaxis of macrophages and the potential contribution of saturated fatty acid in signalling during the pathogenesis of apical periodontitis. METHODOLOGY: J774, a mouse macrophage cell line, was used in the experiments. After treatment with LPS, proteolytic maturation of sterol regulatory element-binding protein-1c (SREBP-1c) and expression of fatty acid synthase (FASN) were examined by Western analysis. Levels of palmitic acid were measured by reverse phase-high performance liquid chromatography-mass spectrometry. Knockdown of SREBP-1c and FASN was accomplished by small interfering RNA technology. Secretion of CC-chemokine ligand 2 (CCL2) and cellular chemotaxis were assessed by enzyme-linked immunosorbent assay and transwell migration assay, respectively. Sulfo-N-succinimidyl oleate (SSO) treatment was used to inhibit fatty acid signalling in vitro and also in a rat model of apical periodontitis. All data were first subjected to Levene's test. In vitro data were then analysed using ANOVA followed by Tukey's multiple comparison test. Data from animal experiments were analysed by independent t-tests. The significant level was set at 0.05. RESULTS: LPS stimulated proteolytic maturation of SREBP-1c and FASN expression in macrophages and significantly enhanced palmitic acid synthesis (P < 0.05). Knockdown of SREBP-1c attenuated LPS-enhanced FASN expression. Knockdown of FASN significantly suppressed LPS-enhanced palmitic acid synthesis (P < 0.05). LPS and exogenous palmitic acid significantly enhanced CCL2 secretion and macrophage chemotaxis (all P < 0.05). Inhibition of FASN expression significantly alleviated LPS-augmented CCL2 secretion (P < 0.05). SSO significantly suppressed CCL2 secretion and macrophage chemotaxis augmented by LPS and palmitic acid (all P < 0.05). In a rat model of induced apical periodontitis, SSO treatment significantly attenuated progression of apical periodontitis and macrophage recruitment (all P < 0.05). CONCLUSIONS: LPS/SREBP-1c/FASN/palmitic acid signalling contributed to tissue destruction caused by bacterial infection. Modulation of lipid metabolism and signalling may be helpful for the management of apical periodontitis.

Increased risk of major depressive disorder among probands with psoriasis and unaffected siblings: a nationwide population-based study.

BACKGROUND: Previous studies have shown that patients with psoriasis have a higher risk of depression. However, the risk of major depressive disorder (MDD) among unaffected siblings of psoriasis probands remains unknown. This study aimed to investigate the risk of MDD among probands with psoriasis and unaffected siblings. METHODS: We selected subjects from the National Health Insurance Research Database (NHIRD) in Taiwan. Subjects were followed up from 01 January 1996 until a diagnosis of MDD, death or 31 December 2011. The Breslow-Cox model was used to calculate the adjusted relative risk (aRR). RESULTS: This study included 1094 probands with psoriasis, 1202 unaffected siblings and 4808 matched controls. Overall, 11.9% of the psoriasis probands (n = 130) and 2.5% of the unaffected siblings (n = 30) developed MDD, as compared with 1.1% of the controls (n = 52). Compared with controls, probands with psoriasis and unaffected siblings had aRRs of 10.60 [95% confidence interval (CI): 7.73-14.52] and 2.17 (95% CI: 1.44-3.28), respectively, for MDD. CONCLUSIONS: Probands with psoriasis and unaffected siblings have an increased risk of subsequently developing MDD. Further studies are needed to investigate the shared familial mechanisms underlying psoriasis and MDD.

Co-aggregation of major psychiatric disorders in individuals with first-degree relatives with schizophrenia: a nationwide population-based study.

A previous genetic study has suggested that schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) share common disease-associated genes. However, whether individuals with first-degree relatives (FDRs) with schizophrenia have a higher risk of these major psychiatric disorders requires further investigation. This study used Taiwan's National Health Insurance Research Database and identified 151 650 patients with schizophrenia and 227 967 individuals with FDRs with schizophrenia. The relative risks (RRs) of schizophrenia and other major psychiatric disorders were assessed in individuals with FDRs with schizophrenia. The individuals with FDRs with schizophrenia exhibited higher RRs (95% confidence interval) of major psychiatric disorders, namely schizophrenia (4.76, 4.65-4.88), bipolar disorder (3.23, 3.12-3.35), major depressive disorder (2.05, 2.00-2.10), ASD (2.55, 2.35-2.77) and ADHD (1.31, 1.25-1.37) than were found in the total population. Several sensitivity analyses were conducted to confirm these results. A dose-dependent relationship was observed between the risks of major psychiatric disorders and the numbers of FDRs with schizophrenia. The increased risks of major psychiatric disorders were consistent in different family relationships, namely among parents, offspring, siblings and twins. Our study supports the familial dose-dependent co-aggregation of schizophrenia, bipolar disorder, major depressive disorder, ASD and ADHD, and our results may prompt governmental public health departments and psychiatrists to focus on the mental health of individuals with FDRs with schizophrenia.

Analysis of serum metabolite profiles in syphilis patients by untargeted metabolomics.

BACKGROUND: Global metabolomics analysis can provide substantial information on energy metabolism, physiology, possible diagnostic biomarkers and intervention strategies for pathogens. OBJECTIVE: To gain a better understanding of the mechanisms of syphilis and analysis of serum metabolite profiles in syphilis patients. METHODS: We conducted an untargeted metabolomics analysis of serum from 20 syphilis patients and 20 healthy controls. RESULTS: A total of 2890 molecular features were extracted from each sample, and the peak intensity of each feature was obtained. Distinct differential metabolites were identified by principal component analysis, partial least squares-discriminant analysis and hierarchical clustering analysis. Furthermore, five metabolites were identified as significantly different by Student's t-test, including trimethylamine N-oxide, l-arginine, lysoPC(18:0), betaine and acetylcarnitine. KEGG analysis showed that these differential metabolites were in various pathways, including Chagas disease, fatty acid biosynthesis, primary bile acid biosynthesis, Salmonella infection, ABC transporters, glycerophospholipid metabolism and choline metabolism. Among them, trimethylamine N-oxide was 3.922 times in patients with syphilis than healthy controls. CONCLUSION: Trimethylamine N-oxide may be used as an indicator to distinguish between syphilis patients and healthy controls. The changes in these metabolites suggest that Treponema pallidum affects the normal metabolic activity of host cells, providing some clues for elucidating the pathogenesis of T. pallidum.

Simvastatin alleviates bone resorption in apical periodontitis possibly by inhibition of mitophagy-related osteoblast apoptosis.

AIM: To assess the connection between mitophagy and hypoxia-induced apoptosis in osteoblasts and whether simvastatin alleviates bone resorption in apical periodontitis through modulation of mitophagy-related apoptosis. METHODOLOGY: Hypoxia-induced generation of reactive oxygen species in mitochondria and changes in mitochondrial membrane potential were evaluated, respectively, by MitoSOX and JC-1 fluorescence dye signalling. Accumulation of mitophagy markers PTEN-induced putative kinase 1 (PINK1) and Parkin in mitochondria was examined by Western blotting and immunofluorescence microscopy. Osteoblast apoptosis was assessed by Western analysis of cleaved-poly (adenosine diphosphate ribose) polymerase (PARP). In a rat model of induced apical periodontitis, the therapeutic effect of simvastatin and its action on osteoblast mitophagy and apoptosis were examined. anova, Fisher's and Student's t-test were used for data analysis. RESULTS: Hypoxia-induced mitochondrial dysfunction and stimulated mitophagy in osteoblasts. Hypoxia also provoked apoptosis in osteoblasts and inhibition of mitophagy decreased hypoxia-augmented apoptotic activity. Simvastatin alleviated hypoxia-induced mitochondrial dysfunction, mitophagy and apoptosis. The protective action of simvastatin against apoptosis was related to its antimitophagy activity. Experiments in the rat model of induced apical periodontitis supported the laboratory findings. Simvastatin treatment mitigated periapical bone loss and reduced the activities of apoptosis and mitophagy in regional osteoblasts. CONCLUSIONS: The results suggest that modulation of osteoblast mitophagy may help diminish bone loss associated with inflammation and has potential as an auxiliary therapy for apical periodontitis.

Application of peripherally inserted central catheter in acute myeloid leukaemia patients undergoing induction chemotherapy.

Increasingly, peripherally inserted central catheters (PICC) are applied in patients with haematological malignancies. The feasibility and safety of PICC for induction chemotherapy in acute myeloid leukaemia (AML) remain unclear. Medical records of 89 newly diagnosed adult de novo AML patients, who achieved complete remission, were retrospectively reviewed (PICC group, n = 43; intravenous [IV] line group, n = 46). Patients' clinical characteristics and the number of blind punctures for blood sampling were compared between these two groups, and risk factors associated with bacteraemia were identified by univariate analysis. Patients in the PICC group experienced significantly fewer blind punctures than those in the IV line group (3.3 ± 3.6 vs. 14.4 ± 6.0; p = .000); 20.9% of PICC patients had bacteraemia, compared with 23.9% in the IV line group (p = .803). Most patients (76.7%) removed their PICC because treatment was completed. PICC increased the quality of life in AML patients undergoing chemotherapy induction by reducing the number of blind blood punctures required. Bacteraemia in PICC patients was comparable to that in IV line patients. PICC is, therefore, a feasible and safe central venous device for use in AML patients.

Diagnostic uncertainty of herpangina and hand-foot-and-mouth disease and its impact on national enterovirus syndromic monitoring.

The community burden of enterovirus is often monitored through syndromic monitoring systems based on reported cases of enterovirus-related infection (EVI) diagnoses. The extent to which this is affected by under- and over-diagnosis has not been reported. In Taiwan, children often make more than one healthcare visit during an episode of infection. We used change of diagnosis within an episode of infection as a guide of diagnostic uncertainty in a nationally representative cohort of Taiwanese children (n = 13 284) followed from birth to the 9th birthday through electronic health records. We conducted a nested case-control analysis and estimated cross-diagnosis ratios (CDRs) as the observed proportion of acute respiratory infection (ARI) diagnoses following an EVI diagnosis in excess of background ARI burdens. With 19 357 EVI diagnoses in this cohort, the CDR within 7 days was 1·51 (95% confidence interval 1·45-1·57), confirming a significant excess of ARI diagnoses within the week following an EVI diagnosis. We used age-specific CDRs to calibrate the weekly EVI burden in children aged 3-5 years in 2008, and the difference between observed and calibrated weekly EVI burdens was small. Therefore, there was evidence suggesting a small uncertainty in EVI diagnosis, but the observed EVI burdens through syndromic monitoring were not substantially affected by the small uncertainty.

High PSA anxiety and low health literacy skills: drivers of early use of salvage ADT among men with biochemically recurrent prostate cancer after radiotherapy?

BACKGROUND: Although commonly used, early initiation of salvage androgen deprivation therapy (ADT) has not been proven to enhance survival. We evaluated whether prostate-specific antigen (PSA) anxiety or health literacy are associated with use of early salvage ADT among men with recurrent prostate cancer after radiotherapy. PATIENTS AND METHODS: The prospective Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma Registry was used to study 375 men with biochemically recurrent prostate cancer after external beam radiation or brachytherapy. Multivariable logistic regression was used to determine whether PSA anxiety and health literacy are associated with salvage ADT as initial management after biochemical recurrence. RESULTS: Sixty-eight men (18.1%) received salvage ADT as initial management for PSA recurrence. Men with high PSA anxiety were twice as likely to receive salvage ADT compared with men who did not have high PSA anxiety on both univariable [28.8% versus 13.1%; odds ratio (OR) 2.15; 95% confidence interval (CI) 1.16-4.00; P = 0.015] and multivariable analysis [adjusted OR (AOR) 2.36; 95% CI 1.21-4.62; P = 0.012]. Furthermore, men who had higher levels of health literacy were nearly half as likely to undergo salvage ADT compared with men who had lower levels of health literacy on univariable analysis (15.2% versus 26.3%; OR 0.50; 95% CI 0.29-0.88; P = 0.016), with a trend toward this association on multivariable analysis (AOR 0.58; 95% CI 0.32-1.05; P = 0.07). CONCLUSIONS: Among men with PSA recurrence after radiotherapy, odds of use of salvage ADT were nearly twice as great among men with high PSA anxiety or low health literacy, suggesting that these men are receiving higher rates of unproven treatment. Given that early salvage ADT is costly, worsens quality of life, and has not been shown to improve survival, quality improvement strategies are needed for these individuals.

Risk of developing Parkinson's disease among patients with asthma: a nationwide longitudinal study.

BACKGROUND: A cross-sectional retrospective study suggested a link between allergic diseases and Parkinson's disease. However, the temporal association between asthma and Parkinson's disease remains unknown. METHODS: From the Taiwan National Health Insurance Research Database, 10 455 patients who were diagnosed with asthma between 1998 and 2008 and aged ≥45 years and 41 820 age- and sex-matched controls were selected for our study and observed until the end of 2011. Those who developed Parkinson's disease during the follow-up period were identified. We also examined the asthma severity, as indicated by the frequency of admission (times per year) for asthma exacerbation, and the risk of subsequent Parkinson's disease. RESULTS: Patients with asthma had an increased risk of developing Parkinson's disease (hazard ratio [HR]: 3.10, 95% confidence interval [CI]: 2.20-4.36) after we adjusted for demographic data, health system use, medical comorbidities, and medication use. Sensitivity tests yielded consistent findings after we excluded observations on the first year (HR: 2.90, 95% CI: 2.04-4.13) and first 3 years (HR: 2.46, 95% CI: 1.64-3.69). Patients with asthma who had more frequent admissions (times per year) during the follow-up period exhibited a greater risk of subsequent Parkinson's disease (>2: HR: 16.42, 95% CI: 5.88-45.91; 1-2: 12.69, 95% CI: 5.03-31.71; 0-1: HR: 2.92, 95% CI: 1.91-4.49). CONCLUSION: Patients with asthma had an elevated risk of developing Parkinson's disease later in life, and we observed a dose-dependent relationship between greater asthma severity and a higher risk of subsequent Parkinson's disease.

Incidence and antiviral response of hepatitis C virus reactivation in lupus patients undergoing immunosuppressive therapy.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease and usually requires immunosuppressive therapy, which is a major cause of viral reactivation. The incidence and antiviral response in SLE patients with hepatitis C virus (HCV) reactivation is unclear and needs to be investigated. METHODS: One hundred and sixty-six SLE patients with antibody to HCV (anti-HCV) status were retrospectively reviewed regarding the events of HCV reactivation. Patients with HCV reactivation were treated with pegylated interferon plus ribavirin treatment. The virological response and relapse rate were evaluated. RESULTS: Twenty-six patients were positive for anti-HCV. During a mean 8.4 years of follow-up, 10 (38.5%) cases developed HCV reactivation. No clear relationship was noted between immunosuppressive therapy and the HCV reactivation. Eight patients underwent antiviral therapy and the rapid virological response (RVR), early virological response, and sustained virological response (SVR) rates were 37.5%, 87.5%, and 75.0%, respectively. However, late relapse (reappearance of HCV RNA in serum after archiving SVR) was found in two (33.3%) of six patients achieving SVR. The two cases were HCV genotype 1 b concurrent with corticosteroid treatment. CONCLUSIONS: HCV reactivation in anti-HCV-positive SLE patients was possibly associated with glucocorticoids. The virological response to interferon plus ribavirin treatment is not inferior to the general population. However, monitoring HCV RNA after SVR is necessary for patients concurrent with corticosteroid treatment due to the risk of late relapse.

Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and synergizes with current anti-myeloma agents.

BACKGROUND: Small molecule MIRA-1 induced mutant p53-dependent apoptosis in several types of solid tumours. However, anti-tumour activity of MIRA-1 in haematological malignancies including multiple myeloma (MM) is unknown. In this study, we evaluated the effect of MIRA-1 in MM. METHODS: We examined the anti-tumour activity of MIRA-1 alone or in combination with current anti-myeloma agents in a panel of MM cell lines, primary MM samples, and in a mouse xenograft model of MM. RESULTS: MIRA-1 treatment resulted in the inhibition of viability, colony formation, and migration and increase in apoptosis of MM cells irrespective of p53 status accompanied by upregulation of Puma and Bax and downregulation of Mcl-1 and c-Myc. Genetic knockdown of p53 did not abrogate apoptotic response of MIRA-1. MIRA-1 triggered activation of PERK and IRE-α leading to splicing of XBP1 indicating an association of endoplasmic reticulum stress response. Furthermore, combined treatment of MIRA-1 with dexamethasone, doxorubicin or velcade displayed synergistic response in MM cells. Importantly, MIRA-1 alone or in combination with dexamethasone retarded tumour growth and prolonged survival without showing any untoward toxicity in the mice bearing MM tumour. CONCLUSIONS: Our data provide the preclinical framework for clinical evaluation of MIRA-1 as a novel therapeutic agent to improve patient outcome in MM.

Serum high-mobility group box 1 protein correlates with cognitive decline after gastrointestinal surgery.

BACKGROUND: Accumulating evidence has indicated that inflammation may act as a potential mechanism underlying post-operative cognitive dysfunction (POCD). High-mobility group box 1 (HMGB1), as a known late mediator of inflammation, is involved in the development of post-operative complications. Thus, we sought to determine the role of HMGB1 in reflecting POCD following major gastrointestinal surgery. METHODS: Fifty-three elderly patients undergoing gastrointestinal surgery were recruited, and 50 patients completed the study. Serum HMGB1 and interleukin (IL)-6 levels were measured pre-operatively and at 6 h, day 1 and day 3 post-operatively. Neuropsychological tests were administered before and 1 week after surgery. POCD was determined using a Z score ≥ 1.96. RESULTS: Seventeen (34%, 17/50) patients developed POCD at 1 week. The POCD group had higher serum HMGB1 levels at day 1 (12.15 ± 3.12 vs. 9.91 ± 3.15 ng/ml, P = 0.021) and day 3 (11.04 ± 2.88 vs. 8.52 ± 3.31 ng/ml, P = 0.011). IL-6 levels at 6 h (51.18 ± 15.22 vs. 39.20 ± 14.32 pg/ml, P = 0.009) and day 1 (41.59 ± 11.08 vs. 33.81 ± 11.42 pg/ml, P = 0.026) were significantly higher in POCD patients. Serum values of IL-6 at 6 h, HMGB1 at day 1 and levels of education showed positive correlations with Z scores. HMGB1 at day 3 and IL-6 at 6 h were independent risk factors. CONCLUSIONS: Serum HMGB1 and IL-6 levels increase significantly after major gastrointestinal surgery in elderly patients and such elevations are associated with the occurrence of cognitive decline after surgery.

Retraction Note: MicroRNA-199a regulates myocardial fibrosis in rats by targeting SFRP5.

The article "MicroRNA-199a regulates myocardial fibrosis in rats by targeting SFRP5", by M.-H. Chen, J.-C. Liu, Y. Liu, Y.-C. Hu, X.-F. Cai, D.-C. Yin, published in Eur Rev Med Pharmacol Sci 2019; 23 (9): 3976-3983-DOI: 10.26355/eurrev_201905_17827-PMID: 31115026 has been retracted by the authors. This paper has been questioned on PubPeer (https://pubpeer.com/publications/6417BECD38A43595A89D977A1CBDF8). In particular, concerns were raised about Figures 2C and 4C, potentially showing three panels with overlapping details of a single image. The corresponding author states they used the wrong figure during manuscript drafting, which led to picture reuse. For this reason, the authors decided to withdraw the manuscript. This article has been retracted. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/17827.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer (GC), published in late 2022 and the updated ESMO Gastric Cancer Living Guideline published in July 2023, were adapted in August 2023, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with GC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with GC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), coordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with GC across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Performance of imaging modalities in the diagnosis of hepatocellular carcinoma: a systematic review and meta-analysis.

PURPOSE: The recent guidelines published in 2011 suggest the use of only one imaging method for the final imaging diagnosis of hepatocellular carcinoma. To evaluate the methods in the context of the available literature evidence, this systematic review aimed at assessing the relative performance of different imaging techniques currently used in clinical practice. MATERIALS AND METHODS: MEDLINE and EMBASE were searched from January 1996 to June 2011, with no language limitation. Eligible trials had to be conducted in patients with suspicion or diagnosis of hepatocellular carcinoma; compare at least two of the following imaging modalities: magnetic resonance imaging, computed tomography, ultrasound; have pathological findings as a reference standard. An analysis also including non-comparative studies was performed as a validation of the main comparison results. RESULTS: Of 5,144 screened papers, 16 studies fulfilled the eligibility criteria for the comparative analysis and 65 were eligible for the non-comparative analysis. The overall sensitivity and specificity derived by the pooled analysis were 0.78 and 0.77 for computed tomography, 0.84 and 0.84 for magnetic resonance imaging and 0.86 and 0.77 for ultrasound, respectively. In the pair-wise comparisons, ultrasound showed a statistically better specificity than magnetic resonance imaging (0.86 vs. 0.78; p = 0.014) and a statistically better sensitivity than computed tomography (0.88 vs. 0.78; p = 0.030). CONCLUSION: The present systematic review did not show an obvious superiority of one imaging method. Since their accuracy is not completely overlapping, the possibility of reaching better performance by combining methods should be considered in future prospective trials.

Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver--update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.

Partial cellular reprogramming stably restores the stemness of senescent epidermal stem cells.

OBJECTIVE: Adult stem cell senescence and exhaustion are important drivers of organismal age. Restored stem cell self-renewal has revealed novel therapeutic targets for decreasing the incidence of age-associated diseases (AADs) and prolonging the human health span. Transient ectopic expression of the reprogramming factors Oct3/4, Sox2, Klf4 and c-Myc (collectively known as OSKM) in somatic cells can induce partial cellular reprogramming and effectively ameliorate their age-associated hallmarks. However, how this form of rejuvenation is applied to senescent stem cells remains unknown. MATERIALS AND METHODS: The Integrin-α6highCD71high epidermal stem cells (ESCs) with low self-renewal ability were sorted by flow cytometry and then treated by the interrupted reprogramming induced by transient expression of OSKM. The ability of secondary clones' generation and self-proliferation in vitro, as well as stem cell marker p63, were detected to determine their self-renewal ability. Besides, gene and protein of epidermal cell markers were detected to determine whether their cell identities were retained. Finally, DNA methylation age (eAge) and DNA dehydroxymethylase/methyltransferase were analyzed to explore the alternation of their global DNA methylation pattern during this rejuvenation. RESULTS: The partial reprogramming restored the youthful self-renewal and proliferation in senescent ESCs, including larger secondary clone generation, higher expression of stem cell marker p63 and proliferation marker Ki67, and faster proliferation speed, in each case without abolishing epithelial cellular identity. Moreover, the rejuvenation of adult stem cells could be maintained for 2 weeks after reprogramming factor withdrawal, which was more stable than that of differentiated somatic cells. Additionally, we found that partial reprogramming counteracted the acceleration of eAge in senescent epidermal stem cells and DNA methyltransferase 1 (DNMT1) may play a crucial role in this process. CONCLUSIONS: Partial reprogramming has high therapeutic potential for reversing adult stem cell age, providing an advanced way to treat AADs.

Detection of patients presenting with adverse drug events in the emergency department.

BACKGROUND: Adverse drug events (ADE) have been studied widely in hospitalised and emergency department (ED) patients. Less is known about the ED visits of drug-related injury in Taiwan. This study seeks to determine the incidence, risk and patient outcomes of ADE in an ED population. METHODS: We conducted a prospective observational cohort study of patients 18 years and older presenting to the ED of an urban, tertiary medical centre. ED visits between 1 March 2009 and 28 February 2010 identified by investigators for suspected ADE were further assessed by using the Naranjo Adverse Drug Reaction probability scale. Outcomes (ED disposition, injury severity and preventability) and associated variables (triage, gender, drug category, number of drugs, Charlson comorbidity index score and ADE mechanism) were measured. RESULTS: Of 58,569 ED visits, 452 patients (0.77%) had physician-documented ADE. 24% of patients with ADE were hospitalised with life-threatening conditions, with a mortality rate of 10.0%. The majority of ADE were considered preventable (73.4%), and the unintentional overdose was the most common cause. Cardiovascular agents accounted for the most ADE (25.8%) and consisted of 65.3% of ADE in patients aged 65,years and older. Risk factors for ADE-related hospitalisation were elderly age (odds ratio (OR) 1.9, 95% confidence interval (CI) 1.1-3.4), severity of ADE (OR 6.9, 95% CI 3.3-14.5) and higher Charlson comorbidity index scores (OR 3.4, 95% CI 2.0-5.7). CONCLUSION: ADE-related ED visits are not uncommon in Taiwan and many cases are preventable. ED-based surveillance may provide useful information for monitoring outpatient ADE.

Associations of a family history of lupus with the risks of lupus and major psychiatric disorders in first-degree relatives.

BACKGROUND: Genetic factors link psychiatric disorders, particularly major depressive disorder (MDD), bipolar disorder, and obsessive-compulsive disorder (OCD), with systemic lupus erythematosus (SLE). Additionally, maternal SLE is a risk factor for long-term developmental problems, particularly learning disabilities, attention disorders, autism spectrum disorder (ASD) and speech disorders, in children. AIM: We aimed to determine whether first-degree relatives (FDRs) of patients with SLE have increased risks of SLE and major psychiatric disorders. DESIGN AND METHODS: Using the Taiwan National Health Insurance Research Database, we recruited 40 462 FDRs of patients with SLE as well as 161 848 matched controls. The risks of major psychiatric disorders, including schizophrenia, bipolar disorder, OCD, MDD, ASD and attention-deficit/hyperactivity disorder (ADHD), were assessed. RESULTS: The FDRs of patients with SLE had higher risks of SLE (reported as the adjusted relative risk and 95% confidence interval: 14.54; 12.19-17.34), MDD (1.23; 1.12-1.34), ADHD (1.60; 1.55-1.65), OCD (1.41; 1.14-1.74) and bipolar disorder (1.18; 1.01-1.38) compared with controls. Specifically, male FDRs of patients with SLE had higher risks of SLE and bipolar disorder, whereas female FDRs of patients with SLE had higher risks of MDD and OCD. Differences in the familial relationship (i.e. parents, children, siblings and twins) were consistently associated with higher risks of these disorders compared with controls. CONCLUSIONS: The FDRs of patients with SLE had higher risks of SLE, MDD, ADHD, OCD and bipolar disorder than the controls.

Inhibition of extracellular signal-regulated kinase downregulates endoplasmic reticulum stress-induced apoptosis and decreases brain injury in a cardiac arrest rat model.

Cerebral ischemia-reperfusion injury (CIRI) is the predominant cause of neurological disability after cardiac arrest/cardiopulmonary resuscitation (CA/CPR). The endoplasmic reticulum stress (ERs)-induced apoptosis plays an important role in neuronal survival/death in CIRI. Our previous studies reported that the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, alleviates CIRI after CA/CPR. Whether ERs-induced apoptosis is involved in the neuroprotection of PD98059 remains unknown. This study aims to investigate the effects of ERK inhibition by PD98059 on ERs-induced apoptosis after CIRI in the CA/CPR rat model. The baseline characteristics of male adult Sprague-Dawley (SD) rats in all groups were evaluated before CA/CPR. The SD rats that survived from CA/CPR were randomly divided into 3 groups (n=12/group): normal saline group (1 ml/kg), dimethylsulfoxide (DMSO, the solvent of PD98059, 1 ml/kg) group, PD98059 group (0.3 mg/kg). Another 12 SD rats were randomly selected as the Sham group. Twenty-four hours after resuscitation, neural injury was assessed by survival rate, neurological deficit scores (NDS) and Nissl staining; apoptosis of brain cells was detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining; mRNA expression and protein levels of ERs-related protein BIP, PERK, ATF4 and CHOP were checked with RT-PCR and Western Blot. The results showed that there were no significant differences in baseline characteristics before CA/CPR among all groups. PD98059 significantly improved survival rate and NDS, increased the Nissl bodies in neurons, reduced apoptosis, downregulated the mRNA transcription and expression levels of BIP, PERK, ATF4 and CHOP at 24 h after CA/CPR. Our results demonstrate that inhibition of ERK by PD98059 alleviates ERs-induced apoptosis via BIP-PERK-ATF4-CHOP signaling pathway and mitigates CIRI in the CA/CPR rat model.