tbuckley/cabot-search huggingface dataset:
Hyperemic Stenosis Resistance Index for Evaluation of Functional Coronary Lesion Severity
Authors: Martijn Meuwissen, Maria Siebes, Steven A.J. Chamuleau, Berthe L.F. van Eck-Smit, Karel T. Koch, Robbert J. de Winter, Jan G.P. Tijssen, Jos A.E. Spaan, Jan J. Piek
Journal: Circulation (2002)

Background — Both coronary blood flow velocity reserve (CFVR) and myocardial fractional flow reserve (FFR) are used to evaluate the hemodynamic severity of coronary lesions. However, discordant results between CFVR and FFR have been observed in 25% to 30% of intermediate coronary lesions. An index of stenosis resistance based on a combination of intracoronary pressure and flow velocity may improve the assessment of functional coronary lesion severity. Methods and Results — Single photon emission computed tomography (SPECT) was performed in 151 patients with angina to determine reversible perfusion defects within one-week before cardiac catheterization. Coronary pressure and flow velocity was measured distal to 181 single coronary lesions with a mean diameter stenosis of 56% (range: 32% to 85%). Maximum hyperemia was induced by 15 to 20 μg IC adenosine to determine CFVR, FFR, and the hyperemic stenosis resistance index (h-SRv), defined as the ratio of hyperemic stenosis pressure gradient (mean aorta pressure-mean distal pressure) and hyperemic average peak-flow velocity. Receiver-operating-characteristic curves of CFVR, FFR, and h-SRv were calculated to evaluate the predictive value for presence of reversible perfusion defects on SPECT with the use of the area under curve (AUC). The AUC was significantly higher for h-SRv (0.90±0.03) compared with those for CFVR (0.80±0.04; P =0.024) and FFR (0.82±0.03; P =0.018), respectively. Agreement with SPECT was particularly higher (73%) than for CFVR (49%, P =0.022) or FFR (51%, P =0.037) in the group of lesions showing discordant results between CFVR and FFR Conclusion — These results indicate that hyperemic stenosis resistance index is a more powerful predictor of reversible perfusion defects than CFVR or FFR.
Progress in the Estimation of Mortality due to Diabetes
Authors: Edward J. Boyko
Journal: Diabetes Care (2005)

In this issue, Roglic et al. (1) provide new estimates of the proportion of deaths worldwide attributable to diabetes. Their result is about three times as high as a prior estimate from the World Health Organization in 2002. The World Health Organization estimate was based on the underlying cause of death listed on death certificates and likely underestimated the contribution of this disorder to mortality, as underrecording of diabetes on death certificates has been demonstrated in several studies (2–4).

Further issues make use of death certificates to assess cause of mortality problematic. Recording of diabetes is likely to be inconsistent due to the lack of a standardized method for death certificate coding. Contrast this situation with a clinical research study that applied specific criteria to assign a cause of death. Such rigor would never be possible in the “real” world because of educational and practice differences regionally and nationally, as well as the current emphasis on the judgment of an individual physician in assigning cause of death. The idea of having a clinician assign cause of death seems sound, but the lack of standardization will lead to uncertainty about the meaning and inclusiveness of causes listed on death certificates.

Causal interpretations and competing causes of mortality also must be considered in interpreting and estimating causes of death. Diabetes may lead to the immediate cause of death by, for example, causing cardiovascular disease but remain unlisted on the death certificate since it was one or more steps removed from the terminal event. Conversely, the presence of diabetes in the deceased does not necessarily mean that diabetes contributed to mortality, as might be the case if death occurred due to non–hypoglycemia-related trauma, drowning, or another condition that is not likely …
<i>STAT4</i>and the Risk of Rheumatoid Arthritis and Systemic Lupus Erythematosus
Authors: Elaine F. Remmers, Robert M. Plenge, Annette T. Lee, Robert R. Graham, Geoffrey Hom, Timothy W. Behrens, Paul I.W. de Bakker, Julie M. Le, Hye-Soon Lee, Franak Batliwalla, Wentian Li, Seth L. Masters, Matthew G. Booty, John P. Carulli, Leonid Padyukov, Lars Alfredsson, Lars Klareskog, Wei V. Chen, Christopher I. Amos, Lindsey A. Criswell, Michael F. Seldin, Daniel L. Kastner, Peter K. Gregersen
Journal: New England Journal of Medicine (2007)

Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q.We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus.A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81x10(-7); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87x10(-9); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis.A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.
Optimal starting dose of inhaled corticosteroids in adult asthma: why has it taken so long?
Authors: M Masoli
Journal: Thorax (2005)

Start at a dose considered to be appropriate for the severity of the disease, usually 400 μg BDP or equivalent

It is disturbing to realise that, although inhaled corticosteroids have been prescribed for over three decades in the treatment of asthma, there are still major therapeutic issues associated with their use that have yet to be clearly determined. One of these issues is the optimal starting dose. This uncertainty is illustrated by the different approaches that have been proposed for starting inhaled corticosteroids in patients with asthma ranging from “start with a high dose then step down once control has been achieved”,1,2 “start with a dose of 400 µg3 or 200–500 µg per day beclomethasone dipropionate (BDP) or equivalent and then step up if required”,4 or “start at the dose considered to be appropriate for the severity of disease, usually 400 µg of BDP or equivalent”.5

To address this uncertainty and determine the optimal starting dose of inhaled corticosteroids in adults with asthma, Powell and Gibson have undertaken a systematic review and meta-analysis of randomised controlled trials that have investigated this issue. Their findings were reported in a recent issue of Thorax 6 and indicate that, for patients with asthma who require inhaled corticosteroids, there is no evidence of a difference in efficacy between commencing with a moderate dose (400 µg per day BDP or equivalent) compared with a high dose (⩾800 µg per day) and stepping down. An initial moderate dose of inhaled corticosteroids was more effective than an initial low dose (200 µg per day).

These findings are reassuring in that they do not support the “start high, step down” approach …
Weight Gain in Early Life Predicts Risk of Islet Autoimmunity in Children With a First-Degree Relative With Type 1 Diabetes
Authors: Jennifer J. Couper, Sarah Beresford, Craig Hirte, Peter A. Baghurst, Angie Pollard, Brian D. Tait, Leonard C. Harrison, Peter G. Colman
Journal: Diabetes Care (2008)

OBJECTIVE—In a prospective birth cohort study, we followed infants who had a first-degree relative with type 1 diabetes to investigate the relationship between early growth and infant feeding and the risk of islet autoimmunity. RESEARCH DESIGN AND METHODS—Infants with a first-degree relative with type 1 diabetes were identified during their mother's pregnancy. Dietary intake was recorded prospectively to determine duration of breast-feeding and age at introduction of cow's milk protein, cereals, meat, fruit, and vegetables. At 6-month reviews, length (or height) and weight, antibodies to insulin, GAD65, the tyrosine phosphatase-like insulinoma antigen, and tissue transglutaminase were measured. Islet autoimmunity was defined as persistent elevation of one or more islet antibodies at consecutive 6-month intervals, including the most recent measure, and was the primary outcome measure. RESULTS—Follow-up of 548 subjects for 5.7 ± 3.2 years identified 46 children with islet autoimmunity. Weight z score and BMI z score were continuous predictors of risk of islet autoimmunity (adjusted hazard ratios 1.43 [95% CI 1.10–1.84], P = 0.007, and 1.29 [1.01–1.67], P = 0.04, respectively). The risk of islet autoimmunity was greater in subjects with weight z score &amp;gt;0 than in those with weight z score ≤0 over time (2.61 [1.26–5.44], P = 0.01). Weight z score and BMI z score at 2 years and change in weight z score between birth and 2 years, but not dietary intake, also predicted risk of islet autoimmunity. CONCLUSIONS—Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes.
Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1α
Authors: Katherine A Gallagher, Zhao-Jun Liu, Min Xiao, Haiying Chen, Lee J Goldstein, Donald G Buerk, April Nedeau, Stephen R Thom, Omaida C Velazquez
Journal: Journal of Clinical Investigation (2007)

Endothelial progenitor cells (EPCs) are essential in vasculogenesis and wound healing, but their circulating and wound level numbers are decreased in diabetes. This study aimed to determine mechanisms responsible for the diabetic defect in circulating and wound EPCs. Since mobilization of BM EPCs occurs via eNOS activation, we hypothesized that eNOS activation is impaired in diabetes, which results in reduced EPC mobilization. Since hyperoxia activates NOS in other tissues, we investigated whether hyperoxia restores EPC mobilization in diabetic mice through BM NOS activation. Additionally, we studied the hypothesis that impaired EPC homing in diabetes is due to decreased wound level stromal cell-derived factor-1alpha (SDF-1alpha), a chemokine that mediates EPC recruitment in ischemia. Diabetic mice showed impaired phosphorylation of BM eNOS, decreased circulating EPCs, and diminished SDF-1alpha expression in cutaneous wounds. Hyperoxia increased BM NO and circulating EPCs, effects inhibited by the NOS inhibitor N-nitro-L-arginine-methyl ester. Administration of SDF-1alpha into wounds reversed the EPC homing impairment and, with hyperoxia, synergistically enhanced EPC mobilization, homing, and wound healing. Thus, hyperoxia reversed the diabetic defect in EPC mobilization, and SDF-1alpha reversed the diabetic defect in EPC homing. The targets identified, which we believe to be novel, can significantly advance the field of diabetic wound healing.
Quality of Care for Uninsured Patients With Diabetes in a Rural Area
Authors: Deborah S. Porterfield, Linda Kinsinger
Journal: Diabetes Care (2002)

OBJECTIVE—We compared quality of care for uninsured patients with diabetes in private physician offices and community/migrant health centers (C/MHCs). RESEARCH DESIGN AND METHODS—We conducted a cross-sectional medical record review in a convenience sample of eight physician offices and three C/MHC sites in rural North Carolina. Billing systems generated lists of self-pay patients with diabetes. Abstraction of the medical records (n = 142) yielded data on process and intermediate outcome measures of diabetes care, which were derived from the Diabetes Quality Improvement Project. RESULTS—Medical records of patients in C/MHCs demonstrated higher rates on four of six process measures of quality of care, including measurement of HbA1c (98 vs. 75%; P &amp;lt; 0.001), cholesterol (82 vs. 51%; P &amp;lt; 0.001), and urine protein (90 vs. 25%; P &amp;lt; 0.001). Nonsignificant trends in documented eye examinations and the intermediate outcome of blood pressure control were found in medical records of C/MHC patients. No differences were seen in the intermediate outcomes of glucose or lipid control. Notable differences in provider type, time since training, and use of flow sheets were found. CONCLUSIONS—In our sample, uninsured patients with diabetes in C/MHCs had higher quality of care as suggested by higher rates of processes of care. Outcomes were similar in the two settings and well below targets. Further work is required to replicate these findings and to understand which features of C/MHCs may facilitate quality care for the uninsured and are replicable in other settings.
Preferential activation of microsomal diacylglycerol/protein kinase C signaling during glucose treatment (De Novo phospholipid synthesis) of rat adipocytes.
Authors: R V Farese, M L Standaert, T P Arnold, K Yamada, K Musunuru, H Hernandez, H Mischak, D R Cooper
Journal: Journal of Clinical Investigation (1994)

Glucose has been reported to increase the de novo synthesis of diacylglycerol (DAG) and translocate and activate protein kinase C (PKC) in rat adipocytes. Presently, we examined the major subcellular site of PKC translocation/activation in response to glucose-induced DAG. Glucose rapidly increased DAG content and PKC enzyme activity in microsomes, but not in plasma membranes or other membranes, during a 30-min treatment of rat adipocytes. This glucose-induced increase in microsomal DAG was attended by increases in immunoreactive PKC alpha, beta, and epsilon. Glucose-induced activation of DAG/PKC signaling in microsomes was not associated with a change in the translocation of Glut-4 transporters from microsomes to the plasma membrane, a biological response that is known to be stimulated by agonists, e.g., phorbol esters, which increase DAG/PKC signaling in plasma membranes, as well as in microsomes. In conclusion, an increase in de novo phospholipid synthesis, as occurs during glucose treatment of rat adipocytes, primarily activates DAG/PKC signaling in microsomes; moreover, this signaling response and biological consequences thereof may differ from those of agonists that primarily stimulate DAG/PKC signaling in the plasma membrane.
The Renal Mononuclear Phagocytic System
Authors: Peter J. Nelson, Andrew J. Rees, Matthew D. Griffin, Jeremy Hughes, Christian Kurts, Jeremy Duffield
Journal: Journal of the American Society of Nephrology (2011)

The renal mononuclear phagocytic system, conventionally composed of macrophages (Mø) and dendritic cells (DCs), plays a central role in health and disease of the kidney. Overlapping definitions of renal DCs and Mø, stemming from historically separate research tracks and the lack of experimental tools to specifically study the roles of these cells in vivo, have generated confusion and controversy, however, regarding their immunologic function in the kidney. This brief review provides an appraisal of the current state of knowledge of the renal mononuclear phagocytic system interpreted from the perspective of immunologic function. Physical characteristics, ontogeny, and known functions of the main subsets of renal mononuclear phagocytes as they relate to homeostasis, surveillance against injury and infection, and immune-mediated inflammatory injury and repair within the kidney are described. Gaps and inconsistencies in current knowledge are used to create a roadmap of key questions to be answered in future research.
TTI-237: A Novel Microtubule-Active Compound with <i>In vivo</i> Antitumor Activity
Authors: Carl F. Beyer, Nan Zhang, Richard Hernandez, Danielle Vitale, Judy Lucas, Thai Nguyen, Carolyn Discafani, Semiramis Ayral-Kaloustian, James J. Gibbons
Journal: Cancer Research (2008)

Abstract 5-Chloro-6-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine butanedioate (TTI-237) is a microtubule-active compound of novel structure and function. Structurally, it is one of a class of compounds, triazolo[1,5a]pyrimidines, previously not known to bind to tubulin. Functionally, TTI-237 inhibited the binding of [3H]vinblastine to tubulin, but it caused a marked increase in turbidity development that more closely resembled the effect observed with docetaxel than that observed with vincristine. The morphologic character of the presumptive polymer is unknown at present. When applied to cultured human tumor cells at concentrations near its IC50 value for cytotoxicity (34 nmol/L), TTI-237 induced multiple spindle poles and multinuclear cells, as did paclitaxel, but not vincristine or colchicine. Flow cytometry experiments revealed that, at low concentrations (20–40 nmol/L), TTI-237 produced sub-G1 nuclei and, at concentrations above 50 nmol/L, it caused a strong G2-M block. The compound was a weak substrate of multidrug resistance 1 (multidrug resistance transporter or P-glycoprotein). In a cell line expressing a high level of P-glycoprotein, the IC50 of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold, respectively. TTI-237 was not recognized by the MRP or MXR transporters. TTI-237 was active in vivo in several nude mouse xenograft models of human cancer, including LoVo human colon carcinoma and U87-MG human glioblastoma, when dosed i.v. or p.o. Thus, TTI-237 has a set of properties that distinguish it from other classes of microtubule-active compounds. [Cancer Res 2008;68(7):2292–300]
Lower Linkage Disequilibrium at CNVs is due to Both Recurrent Mutation and Transposing Duplications
Authors: D. R. Schrider, M. W. Hahn
Journal: Molecular Biology and Evolution (2009)

Copy number variants (CNVs) within humans can have both adaptive and deleterious effects. Because of their phenotypic significance, researchers have attempted to find single nucleotide polymorphisms (SNPs) in high linkage disequilibrium (LD) with CNVs to use in genomewide association studies. However, studies have found that CNVs are less likely to be in strong LD with flanking markers. We hypothesized that this “taggability gap” can be explained by duplication events that place paralogous sequences far apart. In support of our hypothesis, we find that duplications are significantly less likely than deletions to have a “tag” SNP, even after controlling for CNV length, allele frequency, and availability of appropriate flanking SNPs. Using a novel likelihood method, we are able to show that many complex CNVs—those due to multiple duplication or deletion polymorphisms—are made up of two loci with little LD between them. Additionally, we find that many polymorphic duplications detected in a recent clone-based study are located far from their parental loci. We also examine two other common hypotheses for the taggability gap, and find that recurrent mutation of both deletions and duplications appears to have an effect on LD, but that lower SNP density around CNVs has no effect. Overall, our results suggest that a substantial fraction of CNVs caused by duplication cannot be tagged by markers flanking the parental locus because they have changed genomic location.
Bifurcation lesions: two stents versus one stent—immediate and follow-up results
Authors: Takehiro Yamashita, Takahiro Nishida, Milena G Adamian, Carlo Briguori, Marco Vaghetti, Nicola Corvaja, Remo Albiero, Leo Finci, Carlo Di Mario, Jonathan M Tobis, Antonio Colombo
Journal: Journal of the American College of Cardiology (2000)
MicroRNAs and their role in gynecological tumors
Authors: Anna Torres, Kamil Torres, Ryszard Maciejewski, William H. Harvey
Journal: Medicinal Research Reviews (2010)

There have been only few events in the history of molecular biology that could be compared to the discovery of microRNAs and their role in cell physiology and pathology. MicroRNAs are small, single-stranded, noncoding RNAs composed of 19-25 nucleotides (∼22 nt), which have been proven to regulate gene expression at the posttranscriptional level. The regulatory function of microRNAs was demonstrated in normal and diseased conditions. In particular, it has been linked to cell cycle regulation, cell proliferation and differentiation, inflammatory response, and apoptosis. Altered expression profiles of microRNA have been observed in many pathologies, including diabetes, rheumatoid arthritis, and several cancers. To date, more than 700 human microRNAs have been identified and in silico-based analyses estimate at least 500 more to be identified. The purpose of this review is to present the current perspective on microRNAs structure and biogenesis as well as their contribution to the etiopathogenesis of gynecological tumors. We discuss results of the recent publications that indicate possibilities of microRNAs use as novel markers for tumors screening, early diagnosis, and treatment monitoring. The possible utilization of microRNAs as prognostic factors and specific therapy targets is also reviewed.
Herceptin Down-Regulates HER-2/<i>neu</i> and Vascular Endothelial Growth Factor Expression and Enhances Taxol-Induced Cytotoxicity of Human Ewing's Sarcoma Cells <i>In vitro</i> and <i>In vivo</i>
Authors: Hui Guan, Shu-Fang Jia, Zhichao Zhou, John Stewart, Eugenie S. Kleinerman
Journal: Clinical Cancer Research (2005)

Abstract We have previously shown that high levels of HER-2/neu protein were overexpressed in human Ewing's sarcoma cells (TC71, SK-ES1) relative to normal human osteoblasts. The purpose of this study was to determine whether herceptin alone or in combination with chemotherapeutic agents could inhibit the growth of Ewing's sarcoma in vitro and in vivo. Western blot analysis showed that the protein levels of HER-2/neu were decreased following herceptin treatment. Cell growth was also inhibited by herceptin in a dose-dependent manner with an IC50 of 4 mg/mL in TC71 and SK-ES1 cell line, whereas human immunoglobin had no effect. Northern blot and ELISA showed the RNA expression and protein levels of vascular endothelial growth factor were also inhibited by herceptin treatment with no alteration in HIF-1α protein and topoisomerase IIα expression. Furthermore, Ewing's sarcoma tumor growth was significantly delayed by 100 mg/kg herceptin treatment in our Ewing's sarcoma xenograft mouse model. Combining taxol with herceptin resulted in additive cytotoxicity, whereas herceptin-etoposide, doxorubicin, and 9-nitrocamptothecin combinations did not. Taxol-herceptin enhanced growth inhibition in TC71 cells in vitro compared with either agent alone. Ewing's sarcoma growth was also delayed in vivo and mean tumor size was significantly lower in mice treated with herceptin plus taxol than in those receiving taxol or herceptin alone. These data suggest that herceptin in combination with taxol may be a therapeutic option in the treatment of Ewing's sarcoma.
Oral C-Met Inhibitor MSC2156119J as Monotherapy Versus Sorafenib in First-Line Treatment of Asian Patients with Met-Positive Advanced Hepatocellular Carcinoma and Child-Pugh Class a Liver Function: Phase IB/II, Multicenter, Randomized Trial
Authors: Cheng Ann-Lii, Lim Ho Yeong, Xu Lianzhe, Li Cindy, Massimini Giorgio, Qin Shukui
Journal: Annals of Oncology (2014)