Geriatric conditions as predictors of increased number of hospital admissions and hospital bed days over one year: Findings of a nationwide cohort of older adults from Taiwan

The main aim of the present study was to determine whether geriatric conditions independently predict hospital utilizations after controlling for chronic diseases and disability among community dwelling older adults. We analyzed data from a nationally representative sample of older adults aged 65 years and above by linkage of 2005 Taiwan National Health Interview Survey data (including demographic characteristics, chronic diseases, disability, and geriatric conditions such as depressive symptoms, cognitive impairment, falls, and urinary incontinence), and 2006 National Health Insurance (NHI) claims data (including hospital admissions and hospital bed days). A total of 1598 participants who consented to data linkage, were successfully linked to NHI data, and had complete data for geriatric conditions were eligible for analysis. The prevalence of depressive symptoms, cognitive impairment, falls, and urinary incontinence were 20.6%, 26.1%, 21.3% and 23.9%, respectively. Overall, 18.2% (291/1598) of participants had at least one hospital admission during 2006. After adjustment for demographics, prior hospitalization, chronic diseases and functional disability, participants with geriatric conditions had significantly more hospital admissions (incidence rate ratio = 1.34; 95% confidence interval = [1.02–1.75]) and more hospital bed days (incidence rate ratio = 1.72; 95% confidence interval = [1.11–2.66]) than participants without geriatric conditions. Our results highlight the high prevalence (56.3%) of one or more geriatric conditions and their independent association with excess hospital utilizations. Thus, it is of critical importance to develop programs aimed at preventing or improving these conditions to reduce hospital use in this population.     

Domain within the helicase subunit Mcm4 integrates multiple kinase signals to control DNA replication initiation and fork progression

Eukaryotic DNA synthesis initiates from multiple replication origins and progresses through bidirectional replication forks to ensure efficient duplication of the genome. Temporal control of initiation from origins and regulation of replication fork functions are important aspects for maintaining genome stability. Multiple kinase-signaling pathways are involved in these processes. The Dbf4-dependent Cdc7 kinase (DDK), cyclin-dependent kinase (CDK), and Mec1, the yeast Ataxia telangiectasia mutated/Ataxia telangiectasia mutated Rad3-related checkpoint regulator, all target the structurally disordered N-terminal serine/threonine-rich domain (NSD) of mini-chromosome maintenance subunit 4 (Mcm4), a subunit of the mini-chromosome maintenance (MCM) replicative helicase complex. Using whole-genome replication profile analysis and single-molecule DNA fiber analysis, we show that under replication stress the temporal pattern of origin activation and DNA replication fork progression are altered in cells with mutations within two separate segments of the Mcm4 NSD. The proximal segment of the NSD residing next to the DDK-docking domain mediates repression of late-origin firing by checkpoint signals because in its absence late origins become active despite an elevated DNA damage-checkpoint response. In contrast, the distal segment of the NSD at the N terminus plays no role in the temporal pattern of origin firing but has a strong influence on replication fork progression and on checkpoint signaling. Both fork progression and checkpoint response are regulated by the phosphorylation of the canonical CDK sites at the distal NSD. Together, our data suggest that the eukaryotic MCM helicase contains an intrinsic regulatory domain that integrates multiple signals to coordinate origin activation and replication fork progression under stress conditions.Eukaryotic DNA replication initiates from multiple replication origins within each chromosome to duplicate the large genome efficiently. To ensure DNA synthesis occurs once and only once across the genome, cells adopt a two-step process to activate replication origins during two separate stages of the cell-division cycle. The first step is licensing of replication origins, which occurs only when cyclin-dependent kinase (CDK) activity is low. In Saccharomyces cerevisiae, origins of DNA replication are licensed in G1 by the formation of a prereplicative complex (pre-RC). The process begins with the origin recognition complex binding to replication origins and recruiting the licensing factor Cdc6, which facilitates loading of the Cdt1-bound minichromosome maintenance (MCM) complex composed of Mcm2–Mcm7 (Mcm2–7). The hexameric Mcm2–7 is the core of the replicative helicase that unwinds DNA during replication. Within the pre-RC Mcm2–7 is loaded as an inactive double hexamer. The next step, activation of licensed origins (origin firing), occurs throughout the S phase and requires the continuous presence of two kinases, the S phase CDKs and the Dbf4-dependent Cdc7 kinase (DDK). CDK phosphorylates Sld2 and Sld3 to allow their binding to Dpb11 (1, 2), facilitating recruitment of Cdc45 and GINS (composed of protein subunits Sld5, Psf1, Psf2 and Psf3; Go, Ichi, Nii, and San stand for five, one, two, and three in Japanese, respectively) to Mcm2–7 to create an active helicase. DDK phosphorylates Mcm2–7 and blocks an intrinsic initiation inhibitory activity residing in the N terminus of the Mcm4 subunit (3). The concerted action of these S-phase kinases transforms the inactive Mcm2–7 double hexamer into the active helicase complex composed of Cdc45, Mcm2-7, and GINS (the CMG complex) (4–6). Upon initiation, DNA polymerases and other components of the replication machinery are recruited to form replisomes and establish replication forks, where DNA synthesis ensues.Kinase-signaling pathways target various components of the replication machinery. Both CDK and DDK target replication proteins in addition to their essential targets described above. Furthermore, Ataxia telangiectasia mutated/Ataxia telangiectasia mutated Rad3-related (ATM/ATR) signaling targets components of the CMG helicase complex under replication stress (7–10). In the yeast S. cerevisiae, DNA damage activates the checkpoint kinase Rad53, which phosphorylates both Sld3 and Dbf4 to inhibit late origin firing (11, 12). The yeast ATM/ATR homolog Mec1 also targets Mcm4 (13). The stress-activated protein kinase Hog1 targets an auxiliary replisome component Mrc1 to regulate both origin firing and fork progression (14). Although we now have a better understanding of the essential functions of protein kinases in controlling the initiation of replication, we do not completely understand how the separate kinase signaling pathways are coordinated to regulate both initiation and replication fork progression.The structurally disordered N-terminal serine/threonine-rich domain (NSD) of Mcm4 is a target of multiple kinases, including DDK, CDK, and Mec1 (3, 13, 15, 16). Within this region we have identified two functionally distinct domains that exert different functions and are regulated by different kinase systems even though they overlap extensively in primary amino acid sequences. The segment of the Mcm4 NSD proximal to the DDK-docking domain (DDD) (15), and hence termed “proximal NSD,” blocks initiation until it is phosphorylated by DDK. In contrast, the distal segment of the NSD at the N terminus, away from the DDD, is targeted by additional kinases and contributes positively to promote S-phase progression. In this study we present a comprehensive analysis of the pattern of origin activation, replication fork progression, and the checkpoint response in cells under replication stress caused by the inhibition of ribonucleotide reductase (RNR). We show that the distal and proximal NSD segments contribute differently to origin activation and DNA replication fork progression. Furthermore, they exert opposing effects on checkpoint signaling under replication stress. All these effects are regulated by phosphorylation. We suggest that the Mcm4 NSD, a regulatory domain intrinsic to the replicative helicase, mediates the control of multiple aspects of DNA replication. Our data reveal a sophisticated mechanism to fine-tune S-phase progression in response to changing environments.     

Prognostic CpG Methylation Biomarkers Identified by Methylation Array in Esophageal Squamous Cell Carcinoma Patients

Background: Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients.Methods: Illumina''s GoldenGate methylation array, supervised principal components, Kaplan-Meier survival analyses and Cox regression model were conducted on dissected tumor tissues from a training cohort of 40 ESCC patients to identify potential CpG methylation biomarkers. Pyrosequencing quantitative methylation assay were performed to validate prognostic CpG methylation biomarkers in 61 ESCC patients. The correlation between DNA methylation and RNA expression of a validated marker, SOX17, was examined in a validation cohort of 61 ESCC patients.Results: We identified a panel of nine CpG methylation probes located at promoter or exon1 region of eight genes including DDIT3, FES, FLT3, NTRK3, SEPT5, SEPT9, SOX1, and SOX17, for prognosis prediction in ESCC patients. Risk score calculated using the eight-gene panel statistically predicted poor outcome for patients with high risk score. These eight-gene also showed a significantly higher methylation level in tumor tissues than their corresponding normal samples in all patients analyzed. In addition, we also detected an inverse correlation between CpG hypermethylation and the mRNA expression level of SOX17 gene in ESCC patients, indicating that DNA hypermethylation was responsible for decreased expression of SOX17.Conclusions: This study established a proof-of-concept CpG methylation biomarker panel for ESCC prognosis that can be further validated by multiple cohort studies. Functional characterization of the eight prognostic methylation genes in our biomarker panel could help to dissect the mechanism of ESCC tumorigenesis.     

首乌芪灵胶囊质量控制方法的研究

目的建立首乌芪灵胶囊的质量控制方法。方法薄层色谱法（TLC）鉴别制剂中何首乌、黄芪、淫羊霍和紫河车;高效液相色谱法（HPLC）测定何首乌的主要成分2,3,5,4：四羟基二苯乙烯-2-O—β-D-葡萄糖苷（二苯乙烯苷）的含量。结果定性鉴别方法重现性好,专属性强;二苯乙烯苷的回收率为100．13％,RSD为0．85％。结论方法操作简便,快速,准确,能够有效地控制首乌芪灵胶囊的质量。     

Usefulness of Upstroke Time per Cardiac Cycle for Cardiovascular and All-Cause Mortality Prediction in Patients with Normal Ankle-Brachial Index

Aim: Abnormal ankle-brachial index (ABI) is regarded as peripheral artery disease and can be used to predict cardiovascular (CV) outcomes. However, the usefulness of ABI for the prediction of CV outcome in patients with normal ABI is limited. Upstroke time per cardiac cycle (UTCC) is recently reported to be associated with mortality in patients with acute myocardial infarction and the elderly. Therefore, we aimed to evaluate UTCC, left ventricular ejection fraction (LVEF), brachial-ankle pulse wave velocity (baPWV), and ABI for the prediction of mortality in patients with normal ABI. Methods: Patients arranged for echocardiographic examinations were enrolled, and 1076 patients with normal ABI were included. ABI, baPWV, and UTCC were measured by an ABI-form device. Results: The median follow-up to mortality was 95 months. There were 88 CV and 244 all-cause deaths. After multivariate analysis, UTCC was associated with increased CV and all-cause mortality ( P ≤ 0.004). Age, diabetes, heart failure, left ventricular hypertrophy, baPWV, and LVEF were also independent predictors of CV and all-cause mortality, but ABI was not. Furthermore, UTCC had a better additive predictive value than ABI, baPWV, and LVEF for CV mortality ( P ≤ 0.012). It also had a better additive predictive value than ABI and LVEF for all-cause mortality ( P ≤ 0.013). Conclusions: UTCC is an independent predictor for CV and all-cause mortality in patients with normal ABI. It also has a better additive predictive value of CV and all-cause mortality than ABI and LVEF. Therefore, UTCC is a simple, novel, and useful parameter for identifying high-risk patients with normal ABI.     

Successful retrieval of dislodged paclitaxel-eluting stent with a nitinol loop snare: a case report

Coronary stent dislodgment or embolization before deployment is a rare but challenging complication in interventional cardiology. Intracoronary embolization of the dislodged stent is associated with a high risk of coronary occlusion, due to thrombus formation and subsequent myocardial infarction. Furthermore, systemic embolization may cause severe cerebrovascular events. Nonsurgical retrieval strategies for this complication have been suggested, but bailout cardiac surgery may be indicated if percutaneous retrieval attempts fail. To our knowledge, this is the first case report of intracoronary drug-eluting stent dislodgment, and successful retrieval was accomplished by a loop snare technique. With the increasing trend of using drug-eluting stents in percutaneous coronary intervention, the likelihood of stent dislodgment or embolization may increase. It should be kept in mind, especially by coronary interventionists, how to manage this complication.     

Different roles of host and bacterial factors in Escherichia coli extra-intestinal infections

Many host and bacterial factors contribute to the development of different Escherichia coli extra-intestinal infections. The aim of this study was to evaluate the roles of host and bacterial factors in different extra-intestinal E. coli infections. A total of 221 E. coli isolates collected from urine, bile and peritoneal fluid were included in this retrospective study. Four main phylogenetic groups of E. coli , 14 genetic determinants, static biofilm formation and antimicrobial resistance data were assessed, as well as the immunological status of the hosts. Group B2 was the most common phylogenetic group (30%), especially in cases of asymptomatic bacteriuria (ABU), urinary tract infection (UTI), acute appendicitis/gastrointestinal perforation, and spontaneous bacterial peritonitis (SBP), and was associated with elevated prevalence of papG  III , fimH , sfa , iha , hlyA , cnf1 , ompT and usp . Phylogenetic group A was most common in the isolates from asymptomatic bacteriocholia, biliary tract infection, and peritoneal dialysis (PD)-related peritonitis. There was similarity with respect to both phylogenetic groups and virulence factors in strains from faeces and ABU, and in strains from faeces and SBP/PD-related peritonitis. Host characteristics were important in patients with ABU, UTI, and SBP/PD-related peritonitis. Immunocompetence of hosts was associated with a relatively high prevalence of papG  II , afa and iha , and relatively low antimicrobial resistance to fluoroquinolones. This study demonstrates that, in most E. coli extra-intestinal infections, phylogenetic group B2 was predominant and was more virulent than the three other phylogenetic groups in the Taiwanese population studied. The diverse patterns of host and bacterial factors demonstrate that there were different host and bacterial factors dominating in different extra-intestinal E. coli infections.