Autism-like behavior caused by deletion of vaccinia-related kinase 3 is improved by TrkB stimulation

Vaccinia-related kinases (VRKs) are multifaceted serine/threonine kinases that play essential roles in various aspects of cell signaling, cell cycle progression, apoptosis, and neuronal development and differentiation. However, the neuronal function of VRK3 is still unknown despite its etiological potential in human autism spectrum disorder (ASD). Here, we report that VRK3-deficient mice exhibit typical symptoms of autism-like behavior, including hyperactivity, stereotyped behaviors, reduced social interaction, and impaired context-dependent spatial memory. A significant decrease in dendritic spine number and arborization were identified in the hippocampus CA1 of VRK3-deficient mice. These mice also exhibited a reduced rectification of AMPA receptor-mediated current and changes in expression of synaptic and signaling proteins, including tyrosine receptor kinase B (TrkB), Arc, and CaMKII alpha. Notably, TrkB stimulation with 7,8-dihydroxyflavone reversed the altered synaptic structure and function and successfully restored autism-like behavior in VRK3-deficient mice. These results reveal that VRK3 plays a critical role in neurodevelopmental disorders and suggest a potential therapeutic strategy for ASD.112Ysciescopu

Beneficial Effect of Efonidipine, an L- and T-Type Dual Calcium Channel Blocker, on Heart Rate and Blood Pressure in Patients With Mild-to-Moderate Essential Hypertension

Background and Objectives: Efonidipine hydrochloride, an L- and T-type dual calcium channel blocker, is suggested to have a heart rate (HR)-slowing action in addition to a blood pressure (BP)-lowering effect. The aim of this study was to determine the effect of efonidipine on HR and BP in patients with mild-to-moderate hypertension. Subjects and Methods: In a multi-center, prospective, open-labeled, single-armed study, we enrolled 53 patients who had mild-to-moderate hypertension {sitting diastolic BP (SiDBP) 90-110 mmHg}. After a 2-week washout, eligible patients were treated with efonidipine (40 mg once daily for 12 weeks). The primary end point was the change in HR from baseline to week 12. The secondary end-point included the change in trough sitting BP and 24-hour mean BP between baseline and week 12. Laboratory and clinical adverse events were monitored at each study visit (4, 8, and 12 weeks). Results: Fifty-two patients were included in the intention-to-treat analysis. After 12 weeks of treatment with efonidipine, the resting HR decreased significantly from baseline to week 12 (from 81.5??5.3 to 71.8??9.9 beats/minute (difference, -9.9??9.0 beats/minute), p<0.0001}. The trough BP {sitting systolic blood pressure (SiSBP) and SiDBP} and 24-hour mean BP also decreased significantly (SiSBP: from 144.6??8.2 to 132.9??13.5 mmHg, p<0.0001; SiDBP: from 96.9??5.4 to 88.3??8.6 mmHg, p<0.0001, 24-hour mean systolic BP: from 140.4??13.5 to 133.8??11.6 mmHg, p<0.0001; 24-hour mean diastolic BP: from 91.7??8.7 to 87.5??9.5 mmHg, p<0.0001). Conclusion: Efonidipine was effective in controlling both HR and BP in patients with mild-to-moderate hypertension. Copyright ?? 2010 The Korean Society of Cardiology

DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load

Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy

Catalpol Modulates Lifespan via DAF-16/FOXO and SKN-1/Nrf2 Activation in

Catalpol is an effective component of rehmannia root and known to possess various pharmacological properties. The present study was aimed at investigating the potential effects of catalpol on the lifespan and stress tolerance using C. elegans model system. Herein, catalpol showed potent lifespan extension of wild-type nematode under normal culture condition. In addition, survival rate of catalpol-fed nematodes was significantly elevated compared to untreated control under heat and oxidative stress but not under hyperosmolality conditions. We also found that elevated antioxidant enzyme activities and expressions of stress resistance proteins were attributed to catalpol-mediated increased stress tolerance of nematode. We further investigated whether catalpol’s longevity effect is related to aging-related factors including reproduction, food intake, and growth. Interestingly, catalpol exposure could attenuate pharyngeal pumping rate, indicating that catalpol may induce dietary restriction of nematode. Moreover, locomotory ability of aged nematode was significantly improved by catalpol treatment, while lipofuscin levels were attenuated, suggesting that catalpol may affect age-associated changes of nematode. Our mechanistic studies revealed that mek-1, daf-2, age-1, daf-16, and skn-1 are involved in catalpol-mediated longevity. These results indicate that catalpol extends lifespan and increases stress tolerance of C. elegans via DAF-16/FOXO and SKN-1/Nrf activation dependent on insulin/IGF signaling and JNK signaling

Prescriptions patterns and appropriateness of usage of antibiotics in non-teaching community hospitals in South Korea: a multicentre retrospective study

Abstract Background Although non-teaching community hospitals form the majority of healthcare providers in South Korea, there is limited data on antibiotic usage in them. To evaluate the pattern of antibiotic usage and its appropriateness in hospitals with < 400 beds in South Korea. Methods A multicentre retrospective study was conducted in 10 hospitals (six long-term care hospitals, three acute care hospitals, and one orthopaedic hospital), with < 400 beds in South Korea. We analysed patterns of antibiotic prescription in 2019, and their appropriateness in the participating hospitals. For the evaluation of the appropriateness of the prescription, 25 patients under antibiotic therapy were randomly selected at each hospital, over two separate periods. Due to the heterogeneity of their characteristics, the orthopaedics hospital was excluded from the analysis. Results The most commonly prescribed antibiotics in long-term care hospitals was fluoroquinolone, followed by beta-lactam/beta-lactamase inhibitor (anti-pseudomonal). In acute care hospitals, these were third generation cephalosporin, followed by first generation cephalosporin, and second generation cephalosporin. The major antibiotics that were prescribed in the orthopedics hospital was first generation cephalosporin Only 2.3% of the antibiotics were administered inappropriately. In comparison, 15.3% of patients were prescribed an inappropriate dose. The proportion of inappropriate antibiotic prescriptions was 30.6% of the total antibiotic prescriptions. Conclusions The antibiotic usage patterns vary between non-teaching community hospitals in South Korea. The proportion of inappropriate prescriptions exceeded 30% of the total antibiotic prescriptions

Development of key quality indicators for appropriate antibiotic use in the Republic of Korea: results of a modified Delphi survey

Background An effective antibiotic stewardship program relies on the measurement of appropriate antibiotic use, on which there is a lack of consensus. We aimed to develop a set of key quality indicators (QIs) for nationwide point surveillance in the Republic of Korea. Methods A systematic literature search of PubMed, EMBASE, and Cochrane Library (publications until 20th November 2019) was conducted. Potential key QIs were retrieved from the search and then evaluated by a multidisciplinary expert panel using a RAND-modified Delphi procedure comprising two online surveys and a face-to-face meeting. Results The 23 potential key QIs identified from 21 studies were submitted to 25 multidisciplinary expert panels, and 17 key QIs were retained, with a high level of agreement (13 QIs for inpatients, 7 for outpatients, and 3 for surgical prophylaxis). After adding up the importance score and applicability, six key QIs [6 QIs (Q 1–6) for inpatients and 3 (Q 1, 2, and 5) for outpatients] were selected. (1) Prescribe empirical antibiotic therapy according to guideline, (2) change empirical antibiotics to pathogen-directed therapy, (3) obtain culture samples from suspected infection sites, (4) obtain two blood cultures, (5) adapt antibiotic dosage to renal function, and (6) document antibiotic plan. In surgical prophylaxis, the QIs to prescribe antibiotics according to the guideline and initiate antibiotic therapy 1 h before incision were selected. Conclusions We identified key QIs to measure the appropriateness of antibiotic therapy to identify targets for improvement and to evaluate the effects of antibiotic stewardship intervention.This work was supported by a research program funded by the Korea Centers for Disease Control and Prevention (Grant No. 2019E280400). The funders had no role in the study design, data collection and analysis, preparation of the manuscript, or the decision to publish

Replication of a Glaucoma Candidate Gene on 5q22.1 for Intraocular Pressure in Mongolian Populations: The GENDISCAN Project

PURPOSE. Glaucoma is the second most frequent cause of visual impairment worldwide. Elevated intraocular pressure (IOP) causes glaucomatous optic nerve damage, especially in the primary open-angle glaucoma (POAG) subtype. As most previous studies on IOP genetics were analyses of glaucomatous families, a study of general pedigrees will provide additional information on genetic etiology. METHODS. This work was part of the GENDISCAN study (Gene Discovery for Complex Traits in Isolated Large Families of Asians of the Northeast), which recruited families from population isolates in Mongolia. IOP (obtained by a noncontact method), epidemiologic, and clinical information were collected from 1451 healthy individuals of 142 families. From these individuals, 390 genome-wide short tandem repeat markers were genotyped. Variance component-based linkage analysis was applied to pursue candidate loci explaining IOP variation. RESULTS. The mean IOP was 13.6 mm Hg in the men and 13.7 mm Hg in the women, inversely associated with aging (beta = -0.05; P < 0.0001). The heritability of IOP was 0.48. Suggestive linkage evidence was found on the 5q22.1 region (LOD score, 2.4), which harbors WDR36, a candidate gene for POAG. In addition, possible linkage evidence was found on 2q37.1, 7p15.3, 17q25.3, and 20p13. CONCLUSIONS. The findings support evidence that IOP regulation is associated with the 5q22.1 region, along with four other candidate regions. The present results further indicate that genetic factors regulating IOP in the general Mongolian population are linked to regions harboring POAG genes, suggesting that common genetic factors influence both normal IOP variation and POAG occurrence. In addition, the replication of previous findings concerning POAG regions from the white and African populations implies that the mutations regulating IOP levels did not occur recently. (Invest Ophthalmol Vis Sci. 2010;51:1335-1340) DOI:10.1167/iovs.09-3979Pasutto F, 2008, INVEST OPHTH VIS SCI, V49, P270, DOI 10.1167/iovs.07-0500Miyazawa A, 2007, MOL VIS, V13, P1912Chen CY, 2007, INVEST OPHTH VIS SCI, V48, P4433, DOI 10.1167/iovs.06-1188Forsman E, 2007, ACTA OPHTHALMOL SCAN, V85, P500, DOI 10.1111/j.1600-0420.2007.00978.xvan Koolwijk LME, 2007, INVEST OPHTH VIS SCI, V48, P3669, DOI 10.1167/iovs.06-1519Duggal P, 2007, ARCH OPHTHALMOL-CHIC, V125, P74Zara F, 2006, NAT GENET, V38, P1111, DOI 10.1038/ng1870Kramer PL, 2006, ARCH OPHTHALMOL-CHIC, V124, P1328Ogbuehi KC, 2006, CLIN EXP OPTOM, V89, P310, DOI 10.1111/j.1444-0938.2006.00068.xRotimi CN, 2006, INVEST OPHTH VIS SCI, V47, P3262, DOI 10.1167/iovs.05-1537Franceschini N, 2006, HYPERTENSION, V48, P266, DOI 10.1161/01.HYP.0000231651.91523.7eGrant SFA, 2006, NAT GENET, V38, P320, DOI 10.1038/ng1732Quigley HA, 2006, BRIT J OPHTHALMOL, V90, P262, DOI 10.1136/bjo.2005.081224GUPTA V, 2006, INDIAN J OPHTHALMOL, V54, P261Charlesworth JC, 2005, INVEST OPHTH VIS SCI, V46, P3723, DOI 10.1167/iovs.05-0312Tonnu PA, 2005, BRIT J OPHTHALMOL, V89, P851, DOI 10.1136/bjo.2004.056622Chang TC, 2005, OPHTHALMOLOGY, V112, P1186, DOI 10.1016/j.ophtha.2005.03.006Paluru PC, 2005, INVEST OPHTH VIS SCI, V46, P2300, DOI 10.1167/iovs.04-1423Hashemi H, 2005, BRIT J OPHTHALMOL, V89, P652, DOI 10.1136/bjo.2004.058057Klein RJ, 2005, SCIENCE, V308, P385, DOI 10.1126/science.1109557Monemi S, 2005, HUM MOL GENET, V14, P725, DOI 10.1093/hmg/ddi068Lin HY, 2005, ARCH OPHTHALMOL-CHIC, V123, P381Duggal P, 2005, INVEST OPHTH VIS SCI, V46, P555, DOI 10.1167/iovs.04-0729Varilo T, 2004, CURR OPIN GENET DEV, V14, P316Klein BEK, 2004, INVEST OPHTH VIS SCI, V45, P59, DOI 10.1167/iovs.03-0516Hennis A, 2003, OPHTHALMOLOGY, V110, P908, DOI 10.1016/S0161-6420(03)00075-7Lee JS, 2002, CLIN EXP OPHTHALMOL, V30, P237, DOI 10.1046/j.1442-9071.2002.00527.xRochtchina E, 2002, CLIN EXP OPHTHALMOL, V30, P173Weih LM, 2001, ARCH OPHTHALMOL-CHIC, V119, P875Blangero J, 2001, ADV GENET, V42, P151Rao DC, 2001, ADV GENET, V42, P487Mori K, 2000, INT J EPIDEMIOL, V29, P661, DOI 10.1093/ije/29.4.661Wiggs JL, 2000, HUM MOL GENET, V9, P1109McPeek MS, 2000, AM J HUM GENET, V66, P1076Blangero J, 2000, GENET EPIDEMIOL, V19, pS8Mitchell P, 1999, OPHTHALMOLOGY, V106, P2010Foster PJ, 1998, OPHTHALMOLOGY, V105, P969Almasy L, 1998, AM J HUM GENET, V62, P1198Sarfarazi M, 1998, AM J HUM GENET, V62, P641Quigley HA, 1997, INVEST OPHTH VIS SCI, V38, P83Foster PJ, 1996, ARCH OPHTHALMOL-CHIC, V114, P1235Quigley HA, 1996, BRIT J OPHTHALMOL, V80, P389LANDER E, 1995, NAT GENET, V11, P241WEEKS DE, 1995, AM J HUM GENET, V56, P1506DIELEMANS I, 1995, OPHTHALMOLOGY, V102, P54VANDEVELDE T, 1995, B SOC BELGE OPHTALMO, V255, P19SHEFFIELD VC, 1993, NAT GENET, V4, P47KLEIN BEK, 1992, INVEST OPHTH VIS SCI, V33, P2224ELSTON RC, 1992, HUM HERED, V42, P16TIELSCH JM, 1991, JAMA-J AM MED ASSOC, V266, P369SHIOSE Y, 1991, JPN J OPHTHALMOL, V35, P133HU Z, 1989, CHIN J OPHTHALMOL, V25, P115KAHN HA, 1977, AM J EPIDEMIOL, V106, P17HOLLOWS FC, 1966, BRIT J OPHTHALMOL, V50, P570