cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5123413
title: Supplementary Material for: Influence of Antipsychotic Agents on Heart Rate Variability in Male WKY Rats: Implications for Cardiovascular Safety

description: <b><i>Background:</i></b> Sudden cardiac death is higher among schizophrenic patients and is associated with parasympathetic hypoactivity. Antipsychotic agents are highly suspected to be a precipitating factor. Thus, we aimed to test if the antipsychotics haloperidol, risperidone and clozapine affect cardiac autonomic function, excluding the confounding effect of altered sleep structure by the drugs. <b><i>Methods:</i></b> In this study, haloperidol, risperidone and clozapine were given separately by intraperitoneal injection to male Wistar-Kyoto rats for 5 days. Electroencephalogram (EEG), electromyogram (EMG) and electrocardiographic signals were recorded at baseline and 5 days after drug treatments. Sleep scoring was based on EEG and EMG signals. Cardiac autonomic function was assessed using heart rate variability analysis. <b><i>Results:</i></b> Clozapine increased heart rate and suppressed cardiac sympathetic and parasympathetic activity. Cardiac acceleration was more severe during sleep. Haloperidol tended to decrease heart rate while risperidone mildly increased heart rate; however, their effects were less obvious than those of clozapine. There was a significant drug-by-stage interaction on several heart rate variability measures. <b><i>Conclusion:</i></b> Taking this evidence as a whole, we conclude that haloperidol has a better level of cardiovascular safety than either risperidone or clozapine. Application of this approach to other psychotropic agents in the future will be a useful and helpful way to evaluate the cardiovascular safety of the various psychotropic medications that are in clinical use.
DOI: 10.6084/m9.figshare.5123416
title: Supplementary Material for: Chronic Reduction of Nitric Oxide Level in Adult Spontaneously Hypertensive Rats Induces Aortic Stiffness Similar to Old Spontaneously Hypertensive Rats

description: <b><i>Introduction:</i></b> Age and hypertension are two major determinants of arterial stiffness, as well as endothelial dysfunction. The present study was designed to test whether a chronic reduction of endogenous nitric oxide (NO) produces arterial stiffening close to that observed in old spontaneously hypertensive rats (SHR), and also to study the effect of an acute or a chronic decrease in blood pressure (BP) on aortic distensibility. <b><i>Methods:</i></b> BP, aortic stiffness, endothelial dysfunction and remodelling were measured in male adult (20-week-old) SHR, in adult SHR treated with a nonspecific NO synthase inhibitor <i>L</i>-NAME (SHR/<i>L</i>-NAME) for 2 weeks, in adult SHR/<i>L</i>-NAME cotreated with perindopril (1 mg/kg/day) and in old SHR (55-week-old). Age-matched WKY were used as a normotensive group. <b><i>Results:</i></b> Aortic endothelial dysfunction, remodelling and stiffening appeared in old SHR. Reduction of NO production in adult SHR caused similar alterations. Acute decreases in BP in SHR/<i>L</i>-NAME did not improve isobaric aortic distensibility but a chronic reduction of BP prevented endothelial dysfunction, aortic remodelling and aortic wall stiffening. <b><i>Conclusion:</i></b> NO reduction in adult SHR induces aortic alterations similar to those observed during aging, which supports the major role of NO in the development of arterial stiffening. These aortic alterations can be prevented by angiotensin-converting enzyme inhibitor treatment.
DOI: 10.6084/m9.figshare.5123419.v1
title: Supplementary Material for: Acute Kidney Injury and Mortality in Hospitalized Patients

description: <i>Background:</i> The objective of this study was to determine the incidence of acute kidney injury (AKI) and its relation with mortality among hospitalized patients. <i>Methods:</i> Analysis of hospital discharge and laboratory data from an urban academic medical center over a 1-year period. We included hospitalized adult patients receiving two or more serum creatinine (sCr) measurements. We excluded prisoners, psychiatry, labor and delivery, and transferred patients, ‘bedded outpatients’ as well as individuals with a history of kidney transplant or chronic dialysis. We defined AKI as (a) an increase in sCr of ≥0.3 mg/dl; (b) an increase in sCr to ≥150% of baseline, or (c) the initiation of dialysis in a patient with no known history of prior dialysis. We identified factors associated with AKI as well as the relationships between AKI and in-hospital mortality. <i>Results:</i> Among the 19,249 hospitalizations included in the analysis, the incidence of AKI was 22.7%. Older persons, Blacks, and patients with reduced baseline kidney function were more likely to develop AKI (all p &lt; 0.001). Among AKI cases, the most common primary admitting diagnosis groups were circulatory diseases (25.4%) and infection (16.4%). After adjustment for age, sex, race, admitting sCr concentration, and the severity of illness index, AKI was independently associated with in-hospital mortality (adjusted odds ratio 4.43, 95% confidence interval 3.68–5.35). <i>Conclusions:</i> AKI occurred in over 1 of 5 hospitalizations and was associated with a more than fourfold increased likelihood of death. These observations highlight the importance of AKI recognition as well as the association of AKI with mortality in hospitalized patients.
DOI: 10.6084/m9.figshare.5123422.v1
title: Supplementary Material for: Expression of the Sodium/Calcium/Potassium Exchanger, NCKX4, in Ameloblasts

description: Transcellular calcium transport is an essential activity in mineralized tissue formation, including dental hard tissues. In many organ systems, this activity is regulated by membrane-bound sodium/calcium (Na<sup>+</sup>/Ca<sup>2+</sup>) exchangers, which include the NCX and NCKX [sodium/calcium-potassium (Na<sup>+</sup>/Ca<sup>2+</sup>-K<sup>+</sup>) exchanger] proteins. During enamel maturation, when crystals expand in thickness, Ca<sup>2+</sup> requirements vastly increase but exactly how Ca<sup>2+</sup> traffics through ameloblasts remains uncertain. Previous studies have shown that several NCX proteins are expressed in ameloblasts, although no significant shifts in expression were observed during maturation which pointed to the possible identification of other Ca<sup>2+</sup> membrane transporters. NCKX proteins are encoded by members of the solute carrier gene family, Slc24a, which include 6 different proteins (NCKX1–6). NCKX are bidirectional electrogenic transporters regulating Ca<sup>2+</sup> transport in and out of cells dependent on the transmembrane ion gradient. In this study we show that all NCKX mRNAs are expressed in dental tissues. Real-time PCR indicates that of all the members of the NCKX group, NCKX4 is the most highly expressed gene transcript during the late stages of amelogenesis. In situ hybridization and immunolocalization analyses clearly establish that in the enamel organ, NCKX4 is expressed primarily by ameloblasts during the maturation stage. Further, during the mid-late maturation stages of amelogenesis, the expression of NCKX4 in ameloblasts is most prominent at the apical poles and at the lateral membranes proximal to the apical ends. These data suggest that NCKX4 might be an important regulator of Ca<sup>2+</sup> transport during amelogenesis.
DOI: 10.6084/m9.figshare.5123407
title: Supplementary Material for: Economics of Medically Unexplained Symptoms: A Systematic Review of the Literature

description: <b><i>Objective:</i></b> To review cost-of-illness studies (COI) and economic evaluations (EE) conducted for medically unexplained symptoms and to analyze their methods and results. <b><i>Methods:</i></b> We searched the databases PubMed, PsycINFO and National Health Service Economic Evaluations Database of the University of York. Cost data were inflated to 2006 using country-specific gross domestic product inflators and converted to 2006 USD purchasing power parities. <b><i>Results:</i></b> We identified 5 COI and 8 EE, of which 6 were cost-minimization analyses and 2 were cost-effectiveness analyses. All studies used patient level data collected between 1980 and 2004 and were predominantly conducted in the USA (n = 10). COI found annual excess health care costs of somatizing patients between 432 and 5,353 USD in 2006 values. Indirect costs were estimated by only one EE and added up to about 18,000 USD per year. In EE, educational interventions for physicians as well as cognitive-behavioral therapy approaches for patients were evaluated. For both types of interventions, effectiveness was either shown within EE or by previous studies. Most EE found (often insignificant) cost reductions resulting from the interventions, but only two studies explicitly combined changes in costs with data on effectiveness to cost-effectiveness ratios (ratio of additional costs to additional effects). <b><i>Conclusions:</i></b> Medically unexplained symptoms cause relevant annual excess costs in health care that are comparable to mental health problems like depression or anxiety disorders and which may be reduced by interventions targeting physicians as well as patients. More extensive research on indirect costs and cost-effectiveness is needed.
DOI: 10.6084/m9.figshare.5123410
title: Supplementary Material for: An Antagonist for CCR4 Alleviates Murine Allergic Rhinitis by Intranasal Administration

description: <b><i>Background:</i></b> CCR4 is highly expressed on Th2 cells. These cells play an important role in acute inflammatory responses, including those involved in allergic rhinitis. We determined whether disrupting the CCR4 ligand interaction with CCR4 antagonist could alleviate allergic rhinitis in a mouse model.<b><i> Methods:</i></b> BALB/c mice were sensitized with ovalbumin and alum by intraperitoneal injection and challenged with intranasally administered ovalbumin. Compound 22, which has been reported as a novel small-molecule antagonist of CCR4, was also administered intranasally. In addition, budesonide, an efficient glucocorticoid, was used as a positive control. The effects of compound 22 were quantified by multiple parameters of allergic responses in both nasal and pulmonary tissues. <b><i>Results:</i></b> Compound 22 significantly improved symptoms of allergic rhinitis and suppressed levels of total IgE of serum. It dramatically reduced the levels of IL-4 in bronchoalveolar lavage fluid and also decreased the number of inflammatory cells in the fluid. The infiltration of inflammatory cells, especially eosinophils, was markedly reduced in the nasal and pulmonary tissues. The number of IL-4+ cells was also significantly reduced in these tissues. Moreover, the numbers of Foxp3+ cells and IL-17+ cells were reduced, though not to a statistically significant degree. <b><i>Conclusions:</i></b> In our research, CCR4 antagonists such as compound 22 were proven for the first time to alleviate murine allergic rhinitis when administered nasally. CCR4 antagonists may have therapeutic potential for the treatment of allergic rhinitis.
DOI: 10.6084/m9.figshare.5123401
title: Supplementary Material for: Two-Stage Extreme Phenotype Sequencing Design for Discovering and Testing Common and Rare Genetic Variants: Efficiency and Power

description: Next-generation sequencing technology provides an unprecedented opportunity to identify rare susceptibility variants. It is not yet financially feasible to perform whole-genome sequencing on a large number of subjects, and a two-stage design has been advocated to be a practical option. In stage I, variants are discovered by sequencing the whole genomes of a small number of carefully selected individuals. In stage II, the discovered variants of a large number of individuals are genotyped to assess associations. Individuals with extreme phenotypes are typically selected in stage I. Using simulated data for unrelated individuals, we explore two important aspects of this two-stage design: the efficiency of discovering common and rare single-nucleotide polymorphisms (SNPs) in stage I and the impact of incomplete SNP discovery in stage I on the power of testing associations in stage II. We applied a sum test and a sum of squared score test for gene-based association analyses evaluating the power of the two-stage design. We obtained the following results from extensive simulation studies and analysis of the GAW17 dataset. When individuals with trait values more extreme than the 99.7–99th quantile were included in stage I, the two-stage design could achieve the same power as or even higher than the one-stage design if the rare causal variants had large effect sizes. In such design, fewer than half of the total SNPs including more than half of the causal SNPs were discovered, which included nearly all SNPs with minor allele frequencies (MAFs) ≥5%, more than half of the SNPs with MAFs between 1% and 5%, and fewer than half of the SNPs with MAFs &lt;1%. Although a one-stage design may be preferable to identify multiple rare variants having small to moderate effect sizes, our observations support using the two-stage design as a cost-effective option for next-generation sequencing studies.
DOI: 10.6084/m9.figshare.5123404
title: Supplementary Material for: Osteopontin Plays a Critical Role in Interstitial Fibrosis but Not Glomerular Sclerosis in Diabetic Nephropathy

description: <i>Background/Aims:</i> Osteopontin (OPN) has been implicated in the pathology of several renal conditions. The aim of this study was to clarify the roles of OPN in diabetic nephropathy. <i>Methods:</i> Diabetes mellitus (DM) was induced in wild-type (WT) and OPN knockout (KO) mice by injecting streptozotocin. The mice were killed 20 weeks after induction of DM and their kidneys removed. <i>Results:</i> Renal mRNA expression of OPN was increased in WT-DM mice compared to WT-sham mice. Immunohistochemistry showed high levels of OPN expression in the proximal tubules of WT-DM mice. Kidney weight and urinary albumin excretion increased to similar levels in the WT-DM and KO-DM mice. Interstitial fibrosis was increased in WT-DM mice compared to KO-DM mice. However, there were no differences in the degree of mesangial expansion or glomerular hypertrophy between the two groups. F4/80-positive cells (macrophages) and FSP-1-positive cells (fibroblasts) showed significantly higher infiltration in WT-DM mice than in KO-DM mice. Renal mRNA expression of NADPH oxidase subunits and urinary 8-isoprostane excretion were also increased in WT-DM mice. <i>Conclusions:</i> These results indicated that OPN is a key molecule that induces interstitial fibrosis in the diabetic kidney, but does not induce glomerular sclerosis.
DOI: 10.6084/m9.figshare.5123410.v1
title: Supplementary Material for: An Antagonist for CCR4 Alleviates Murine Allergic Rhinitis by Intranasal Administration

description: <b><i>Background:</i></b> CCR4 is highly expressed on Th2 cells. These cells play an important role in acute inflammatory responses, including those involved in allergic rhinitis. We determined whether disrupting the CCR4 ligand interaction with CCR4 antagonist could alleviate allergic rhinitis in a mouse model.<b><i> Methods:</i></b> BALB/c mice were sensitized with ovalbumin and alum by intraperitoneal injection and challenged with intranasally administered ovalbumin. Compound 22, which has been reported as a novel small-molecule antagonist of CCR4, was also administered intranasally. In addition, budesonide, an efficient glucocorticoid, was used as a positive control. The effects of compound 22 were quantified by multiple parameters of allergic responses in both nasal and pulmonary tissues. <b><i>Results:</i></b> Compound 22 significantly improved symptoms of allergic rhinitis and suppressed levels of total IgE of serum. It dramatically reduced the levels of IL-4 in bronchoalveolar lavage fluid and also decreased the number of inflammatory cells in the fluid. The infiltration of inflammatory cells, especially eosinophils, was markedly reduced in the nasal and pulmonary tissues. The number of IL-4+ cells was also significantly reduced in these tissues. Moreover, the numbers of Foxp3+ cells and IL-17+ cells were reduced, though not to a statistically significant degree. <b><i>Conclusions:</i></b> In our research, CCR4 antagonists such as compound 22 were proven for the first time to alleviate murine allergic rhinitis when administered nasally. CCR4 antagonists may have therapeutic potential for the treatment of allergic rhinitis.
DOI: 10.6084/m9.figshare.5123413.v1
title: Supplementary Material for: Influence of Antipsychotic Agents on Heart Rate Variability in Male WKY Rats: Implications for Cardiovascular Safety

description: <b><i>Background:</i></b> Sudden cardiac death is higher among schizophrenic patients and is associated with parasympathetic hypoactivity. Antipsychotic agents are highly suspected to be a precipitating factor. Thus, we aimed to test if the antipsychotics haloperidol, risperidone and clozapine affect cardiac autonomic function, excluding the confounding effect of altered sleep structure by the drugs. <b><i>Methods:</i></b> In this study, haloperidol, risperidone and clozapine were given separately by intraperitoneal injection to male Wistar-Kyoto rats for 5 days. Electroencephalogram (EEG), electromyogram (EMG) and electrocardiographic signals were recorded at baseline and 5 days after drug treatments. Sleep scoring was based on EEG and EMG signals. Cardiac autonomic function was assessed using heart rate variability analysis. <b><i>Results:</i></b> Clozapine increased heart rate and suppressed cardiac sympathetic and parasympathetic activity. Cardiac acceleration was more severe during sleep. Haloperidol tended to decrease heart rate while risperidone mildly increased heart rate; however, their effects were less obvious than those of clozapine. There was a significant drug-by-stage interaction on several heart rate variability measures. <b><i>Conclusion:</i></b> Taking this evidence as a whole, we conclude that haloperidol has a better level of cardiovascular safety than either risperidone or clozapine. Application of this approach to other psychotropic agents in the future will be a useful and helpful way to evaluate the cardiovascular safety of the various psychotropic medications that are in clinical use.
DOI: 10.6084/m9.figshare.5123395
title: Supplementary Material for: Mesenchymal Stem Cells Provide an Advantageous Tumor Microenvironment for the Restoration of Cancer Stem Cells

description: <b><i>Objective:</i></b> Accumulating evidences suggest that cancer-associated fibroblasts are provided from bone-marrow-derived mesenchymal stem cells (BM-MSCs); however, little is known about the mechanism(s) by which BM-MSCs accelerate cancer aggressiveness. <b><i>Methods:</i></b> Gastric carcinoma (GC)-derived MKN-7 cells were cocultured with UE6E7T-12 BM-MSCs. The gene expression profile in MKN-7 cells was investigated by microarray analysis. Between two major types of GCs (intestinal- and diffuse-type), the expression of genes was detected by immunohistochemistry. <b><i>Results:</i></b> We found that direct attachment to UE6E7T-12 induced proliferation and cluster formation of MKN-7 cells. Coculture with UE6E7T-12 increased the population of CD133+ MKN-7 cells in vitro and coimplantation of these in mice resulted in subcutaneous tumors in vivo. The <i>wingless-type MMTV integration site (WNT) family member 5A (WNT5A)</i> and <i>transforming growth factor-</i>β<i> (TGF-</i>β<i>)-induced (TGFBI) </i>genes were found to be upregulated in MKN-7 cells directly attached to UE6E7T-12. Recruitment of CD271+ BM-MSC was detected preferentially in the stroma of the diffuse-type GC and this type of GC cell also showed frequent expression of WNT5A, TGF-β type I receptor and CD133. <b><i>Conclusion:</i></b> BM-MSC-mediated activations of the WNT and TGF-β signaling pathways were thought to provide advantageous microenvironments for cancer progression by supporting the reacquisition and maintenance of cancer stem cells.
DOI: 10.6084/m9.figshare.5123398
title: Supplementary Material for: Integrated Analysis of Gene Copy Number, Copy Neutral LOH, and microRNA Profiles in Adult Acute Lymphoblastic Leukemia

description: We adopted an integrated analysis of gene copy number alterations (CNAs), copy number neutral loss of heterozygosity (CNN LOH), and microRNA (miRNA) profiling in 21 adult acute lymphoblastic leukemia (ALL) patients. This study revealed the most frequent CNAs to be at chromosomes 9p, 7, and 17 and recurrent CNN LOH at 5p, 9p, and Xq. As for the most differentially expressed miRNAs, they included 8 upregulated and 14 downregulated miRNAs, of which miR-148a at 7p15.2, miR-22 at 17p13.3, miR-223 at Xq12, as well as miR-101-2 at 9p24.1 exhibited recurrent CNAs or CNN LOH. miR-101-2 was recurrently downregulated, and although the related CNN LOH was detected only in <i>BCR-ABL1</i> negative cases (2/14), deletions of miR-101-2 were observed solely in <i>BCR-ABL1</i> positive cases (4/7). Finally, <i>BCR-ABL1</i> positive cases, in contrast to negative ones, were characterized by slightly, but still significantly, higher expression levels of miR-29b.
DOI: 10.6084/m9.figshare.5123401.v1
title: Supplementary Material for: Two-Stage Extreme Phenotype Sequencing Design for Discovering and Testing Common and Rare Genetic Variants: Efficiency and Power

description: Next-generation sequencing technology provides an unprecedented opportunity to identify rare susceptibility variants. It is not yet financially feasible to perform whole-genome sequencing on a large number of subjects, and a two-stage design has been advocated to be a practical option. In stage I, variants are discovered by sequencing the whole genomes of a small number of carefully selected individuals. In stage II, the discovered variants of a large number of individuals are genotyped to assess associations. Individuals with extreme phenotypes are typically selected in stage I. Using simulated data for unrelated individuals, we explore two important aspects of this two-stage design: the efficiency of discovering common and rare single-nucleotide polymorphisms (SNPs) in stage I and the impact of incomplete SNP discovery in stage I on the power of testing associations in stage II. We applied a sum test and a sum of squared score test for gene-based association analyses evaluating the power of the two-stage design. We obtained the following results from extensive simulation studies and analysis of the GAW17 dataset. When individuals with trait values more extreme than the 99.7–99th quantile were included in stage I, the two-stage design could achieve the same power as or even higher than the one-stage design if the rare causal variants had large effect sizes. In such design, fewer than half of the total SNPs including more than half of the causal SNPs were discovered, which included nearly all SNPs with minor allele frequencies (MAFs) ≥5%, more than half of the SNPs with MAFs between 1% and 5%, and fewer than half of the SNPs with MAFs &lt;1%. Although a one-stage design may be preferable to identify multiple rare variants having small to moderate effect sizes, our observations support using the two-stage design as a cost-effective option for next-generation sequencing studies.