tbuckley/cabot-search huggingface dataset:
High rate of acute rejections in renal allograft recipients with thrombophilic risk factors.
Authors: S Heidenreich, C Dercken, C August, H G Koch, U Nowak-Göttl
Journal: Journal of the American Society of Nephrology (1998)

Inherited and acquired thrombophilic disorders predispose patients for thromboembolic and probably other occlusive vascular events that occur when additional risk factors play in concert. Because acute rejections in renal transplant recipients may reflect vascular events, and an impairment of the fibrinolytic system in immunosuppressed patients has been previously described, the implications of genetic or acquired risk factors of thrombophilia for the occurrence of early acute rejections after kidney transplantation were evaluated. The following risk factors of thrombophilia were determined in 97 patients after cadaveric kidney transplantation: factor V Leiden mutation, protein S, protein C, and antithrombin deficiency. In a retrospective analysis, the prevalence of acute rejections, the histologic classification when rejection episodes had been confirmed by biopsy, and other vascular complications were evaluated. In 21 of the 97 patients, an inherited or acquired risk factor of thrombophilia was detected. Prevalence of acute rejections was 71% in the first 6 mo after transplantation in patients with a thrombophilic disorder and significantly higher compared with patients without thrombophilia (41%; P = 0.017). The distribution of classic risk factors associated with acute rejections, such as number of human leukocyte antigen mismatches or percentage of panel-reactive antibodies, was similar in patients with and without thrombophilia. In the eight patients with thrombophilia and histologically proven acute rejection, four patients had an acute vascular rejection, and in two patients a vascular involvement was suspected. Furthermore, prevalence of cerebral or coronary vascular disease, or venous thromboembolic complications, was significantly higher in patients with a thrombophilic clotting defect (67%) compared with patients with normal hemostasis parameters (28%; P < 0.002). It is concluded that renal allograft recipients with thrombophilia are at risk of developing an acute rejection or other vascular event. Although the determination of thrombotic risk factors was performed at least 3 mo after an acute rejection episode, it can be presumed that acute rejection episodes are associated with subsequent coagulatory abnormalities with further consequences for transplant survival. Thus, pretransplant evaluation of genetic and acquired risk factors of thrombophilia is recommended.
Cost-Effectiveness Analysis of Different Screening Procedures for Type 2 Diabetes
Authors: Andrea Icks, Burkhard Haastert, Afschin Gandjour, Jürgen John, Hannelore Löwel, Rolf Holle, Guido Giani, Wolfgang Rathmann
Journal: Diabetes Care (2004)

OBJECTIVE—To compare the cost-effectiveness of different type 2 diabetes screening strategies using population-based data (KORA Survey; Augsburg, Germany; subjects aged 55–74 years), including participation data. RESEARCH DESIGN AND METHODS—The decision analytic model, which had a time horizon of 1 year, used the following screening strategies: fasting glucose testing, the oral glucose tolerance test (OGTT) following fasting glucose testing in impaired fasting glucose (IFG) (fasting glucose + OGTT), OGTT only, and OGTT if HbA1c was &amp;gt;5.6% (HbA1c + OGTT), all with or without first-step preselection (p). The main outcome measures were costs (in Euros), true-positive type 2 diabetic cases, incremental cost-effectiveness ratios (ICERs), third-party payers, and societal perspectives. RESULTS—After dominated strategies were excluded, the OGTT and HbA1c + OGTT from the perspective of the statutory health insurance remained, as did fasting glucose + OGTT and HbA1c + OGTT from the societal perspective. OGTTs (€4.90 per patient) yielded the lowest costs from the perspective of the statutory health insurance and fasting glucose + OGTT (€10.85) from the societal perspective. HbA1c + OGTT was the most expensive (€21.44 and €31.77) but also the most effective (54% detected cases). ICERs, compared with the next less effective strategies, were €771 from the statutory health insurance and €831 from the societal perspective. In the Monte Carlo analysis, dominance relations remained unchanged in 100 and 68% (statutory health insurance and societal perspective, respectively) of simulated populations. CONCLUSIONS—The most effective screening strategy was HbA1c combined with OGTT because of high participation. However, costs were lower when screening with fasting glucose tests combined with OGTT or OGTT alone. The decision regarding which is the most favorable strategy depends on whether the goal is to identify a high number of cases or to incur lower costs at reasonable effectiveness.
Mesenchymal stromal cells in the antimicrobial host response of hematopoietic stem cell recipients with graft-versus-host disease—friends or foes?
Authors: A Balan, G Lucchini, S Schmidt, A Schneider, L Tramsen, S Kuçi, R Meisel, P Bader, T Lehrnbecher
Journal: Leukemia (2014)
Increased exhaled nitric oxide on days with high outdoor air pollution is of endogenous origin
Authors: P.a. Steerenberg, J.b. Snelder, P.h. Fischer, J.g. Vos, H. van Loveren, J.G.c van Amsterdam
Journal: European Respiratory Journal (1999)

The aim of this study was to assess the effect of outdoor air pollution on exhaled levels of endogenously released nitric oxide. To exclude bias from exogenous NO in the recovered exhaled air (residual NO or NO in dead volume) an experimental design was used that sampled NO of endogenous origin only. The validity of the presented experimental design was established in experiments where subjects were exposed to high levels of exogenous NO (cigarette smoke or 480 microg x m(-3) synthetic NO). Subsequent 1 min breathing and a final inhalation of NO-free air proved to be sufficient to attain pre-exposure values. Using the presented method detecting only endogenous NO in exhaled air, 18 subjects were sampled on 4 separate days with different levels of outdoor air pollution (read as an ambient NO level of 4, 30, 138 and 246 microg x m(-3)). On the 2 days with highest outdoor air pollution, exhaled NO was significantly (p<0.001) increased (67-78%) above the mean baseline value assessed on 4 days with virtually no outdoor air pollution. In conclusion, the level of endogenous nitric oxide in exhaled air is increased on days with high outdoor air pollution. The physiological implications of this findings need to be investigated further.
An Ancient Fission of Mitochondrial cox1
Authors: R. M.R. Gawryluk, M. W. Gray
Journal: Molecular Biology and Evolution (2009)

Many genes inherited from the α-proteobacterial ancestor of mitochondria have undergone evolutionary transfer to the nuclear genome in eukaryotes. In some rare cases, genes have been functionally transferred in pieces, resulting in split proteins that presumably interact in trans within mitochondria, fulfilling the same role as the ancestral, intact protein. We describe a nucleus-encoded mitochondrial protein (here named Cox1-c) in the amoeboid protist Acanthamoeba castellanii that is homologous to the C-terminal portion of conventional mitochondrial Cox1, whereas the corresponding portion of the mitochondrion-encoded A. castellanii Cox1 is absent. Bioinformatics searches retrieved nucleus-encoded Cox1-c homologs in most major eukaryotic supergroups; in these cases, also, the mitochondrion-encoded Cox1 lacks the corresponding C-terminal motif. These data constitute the first report of functional relocation of a portion of cox1 to the nucleus. This transfer event was likely ancient, with the resulting nuclear cox1-c being differentially activated across the eukaryotic domain.
Increased plasma soluble CD40 ligand concentrations in systemic sclerosis and association with pulmonary arterial hypertension and digital ulcers
Authors: Y Allanore
Journal: Annals of the Rheumatic Diseases (2004)

Increased expression of CD40L has been reported on activated CD4+ T lymphocytes in systemic sclerosis. CD40L can be expressed in soluble form (sCD40L).To compare sCD40L concentrations in patients with systemic sclerosis and healthy controls.Quantitative sandwich ELISA was used to measure plasma sCD40L in systemic sclerosis (n = 50) and matched healthy controls (n = 20). Patients with systemic sclerosis had limited cutaneous disease (29), digital ulcers (14), pulmonary arterial hypertension (PAH) (10), pulmonary fibrosis on CT (23), positive anti-Scl70 (14), and anti-centromere antibodies (10). Calcium channel blockers were discontinued 72 hours before measurements.Median (range) sCD40L concentration (pg/ml) was higher in systemic sclerosis than in controls (495 (10 to 7720) v 79 (50 to 118); p = 0.003), in limited cutaneous disease v diffuse disease (620 (20 to 7720) v 250 (10 to 2690); p = 0.005), in patients with digital ulcers v those without (1430 (36 to 7720) v 370 (10 to 2320); p = 0.002), and in those with PAH v those without (995 (15 to 3850) v 400 (10 to 7720); p = 0.048). sCD40L correlated with pulmonary arterial pressure estimated by Doppler echocardiography (r = 0.41; p = 0.005).The soluble form of CD40L is increased in plasma in systemic sclerosis and may be associated with vascular complications of the disease.
Behavioral stress accelerates prostate cancer development in mice
Authors: Sazzad Hassan, Yelena Karpova, Daniele Baiz, Dana Yancey, Ashok Pullikuth, Anabel Flores, Thomas Register, J. Mark Cline, Ralph D’Agostino, Nika Danial, Sandeep Robert Datta, George Kulik
Journal: Journal of Clinical Investigation (2013)

Prostate cancer patients have increased levels of stress and anxiety. Conversely, men who take beta blockers, which interfere with signaling from the stress hormones adrenaline and noradrenaline, have a lower incidence of prostate cancer; however, the mechanisms underlying stress–prostate cancer interactions are unknown. Here, we report that stress promotes prostate carcinogenesis in mice in an adrenaline-dependent manner. Behavioral stress inhibited apoptosis and delayed prostate tumor involution both in phosphatase and tensin homolog–deficient (PTEN-deficient) prostate cancer xenografts treated with PI3K inhibitor and in prostate tumors of mice with prostate-restricted expression of c-MYC (Hi-Myc mice) subjected to androgen ablation therapy with bicalutamide. Additionally, stress accelerated prostate cancer development in Hi-Myc mice. The effects of stress were prevented by treatment with the selective β2-adrenergic receptor (ADRB2) antagonist ICI118,551 or by inducible expression of PKA inhibitor (PKI) or of BCL2-associated death promoter (BAD) with a mutated PKA phosphorylation site (BADS112A) in xenograft tumors. Effects of stress were also blocked in Hi-Myc mice expressing phosphorylation-deficient BAD (BAD3SA). These results demonstrate interactions between prostate tumors and the psychosocial environment mediated by activation of an adrenaline/ADRB2/PKA/BAD antiapoptotic signaling pathway. Our findings could be used to identify prostate cancer patients who could benefit from stress reduction or from pharmacological inhibition of stress-induced signaling.
Beyond Metformin: Safety Considerations in the Decision-Making Process for Selecting a Second Medication for Type 2 Diabetes Management
Authors: William T. Cefalu, John B. Buse, Stefano Del Prato, Philip D. Home, Derek LeRoith, Michael A. Nauck, Itamar Raz, Julio Rosenstock, Matthew C. Riddle
Journal: Diabetes Care (2014)

The trend toward personalized management of diabetes has focused attention on the differences among available pharmacological agents in terms of mechanisms of action, efficacy, and, most important, safety. Clinicians must select from these features to develop individualized therapy regimens. In June 2013, a nine-member Diabetes Care Editors’ Expert Forum convened to review safety evidence for six major diabetes drug classes: insulin, sulfonylureas (SUs), thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium glucose cotransporter 2 inhibitors. This article, an outgrowth of the forum, summarizes well-delineated and theoretical safety concerns related to these drug classes, as well as the panelists’ opinions regarding their best use in patients with type 2 diabetes. All of the options appear to have reasonably wide safety margins when used appropriately. Those about which we know the most—metformin, SUs, insulin, and perhaps now also TZDs—are efficacious in most patients and can be placed into a basic initial algorithm. However, these agents leave some clinical needs unmet. Selecting next steps is a more formidable process involving newer agents that are understood less well and for which there are unresolved questions regarding risk versus benefit in certain populations. Choosing a specific agent is not as important as implementing some form of early intervention and advancing rapidly to some form of combination therapy as needed. When all options are relatively safe given the benefits they confer, therapeutic decision making must rely on a personalized approach, taking into account patients’ clinical circumstances, phenotype, pathophysiological defects, preferences, abilities, and costs.
Community-Based Study of Prevalence of NIDDM in Older Adults
Authors: Deborah L Wingard, Peter Sinsheimer, Elizabeth L Barrett-Connor, Janice B McPhillips
Journal: Diabetes Care (1990)

Prevalence rates of non-insulin-dependent diabetes mellitus (NIDDM) based on an oral glucose tolerance test, history, and medication use were evaluated in an upper-middle-class community of older White adults in southern California between 1984 and 1987. By World Health Organization (WHO) criteria, 14.7% of the 997 men and 11.3% of the 1243 women 50–89 yr of age had NIDDM. Of those classified as having diabetes by WHO criteria, 55.8% of the men and 73.8% of the women met the criteria solely by their postchallenge glucose (PCG) levels. Prevalence rates of diabetes were substantially lower when based on fasting hyperglycemia (5.0% of men and 2.2% of women) or a history of diabetes (5.7% of men and 3.1% of women). When all criteria were considered, 16.5% of the men and 12.7% of the women had NIDDM, and 89.2% of those classified as having diabetes by any criteria met the WHO criteria for diabetes. Prevalence of NIDDM based on WHO criteria or PCG level alone increased systematically with age (P &amp;lt; 0.001), and at each decade for every criterion the prevalence of NIDDM was more common among men than women. By these criteria, NIDDM is one of the most common chronic diseases associated with aging.
Some Aspects of the Role of Folic Acid in Nucleic Acid Synthesis in a Neoplastic C3H Mouse Cell Strain
Authors: Jean Rotherham, Floyd M. Price, Virginia J. Evans
Journal: JNCI Journal of the National Cancer Institute (1968)

A neoplastic murine cell strain, NCTC 3681, in culture in chemically defined medium for several years, requires thymidine for continued growth. The thymidine requirement could be replaced by deoxycytidine or 5-methyldeoxycytidine or by increasing the folate content of the medium. Labeled thymidine or deoxycytidine was used for DNA-thymidine synthesis to a greater extent than cytidine, uridine, deoxy-uridine, or orotic acid. The relative extent of utilization of these precursors for DNA-deoxycytidine and DNA-thymidine synthesis is indicated by the specific activity ratios of DNA-deoxycytidine to DNA-thymidine for each precursor used: deoxycytidine, 1; cytidine, 5; uridine, 10. When the folate content of the medium was increased tenfold, there was a greater utilization of cytidine for both DNA pyrimidines and, to a lesser extent, an increase in the utilization of deoxycytidine, deoxyuridine, and uridine for DNA-thymidine. A cell strain was derived from strain NCTC 3681 by growing these cells for 13 transplant generations in medium containing the tenfold higher level of folate. There was a marked increase in the extent of utilization of cytidine, uridine, and deoxyuridine for DNA-thymidine by the derived cells and the specific activity ratios of DNA-deoxycytidine to DNA-thymidine decreased: deoxycytidine 0.3, cytidine 1, uridine 1. The utilization of orotic acid remained comparatively low.
Effect of K <sup>+</sup> <sub>ATP</sub> Channel and Adenosine Receptor Blockade During Rest and Exercise in Congestive Heart Failure
Authors: Jay H. Traverse, YingJie Chen, MingXiao Hou, Yunfang Li, Robert J. Bache
Journal: Circulation Research (2007)

K + ATP channels are important metabolic regulators of coronary blood flow (CBF) that are activated in the setting of reduced levels of ATP or perfusion pressure. In the normal heart, blockade of K + ATP channels results in a ≈20% reduction in resting CBF but does not impair the increase in CBF that occurs during exercise. In contrast, adenosine receptor blockade fails to alter CBF or myocardial oxygen consumption (MVO 2 ) in the normal heart but contributes to the increase in CBF during exercise when vascular K + ATP channels are blocked. Congestive heart failure (CHF) is associated with a decrease in CBF that is matched to a decrease in MVO 2 suggesting downregulation of myocardial energy utilization. Because myocardial ATP levels and coronary perfusion pressure are reduced in CHF, this study was undertaken to examine the role of K + ATP channels and adenosine in dogs with pacing-induced CHF. Myocardial blood flow (MBF) and MVO 2 were measured during rest and treadmill exercise before and after K + ATP channel blockade with glibenclamide (50 μg/kg/min ic) or adenosine receptor blockade with 8-phenyltheophylline (8-PT; 5 mg/kg iv). Inhibition of K + ATP channels resulted in a decrease in CBF and MVO 2 at rest and during exercise without a change in the relationship between CBF and MVO 2 . In contrast, adenosine receptor blockade caused a significant increase in CBF that occurred secondary to an increase of MVO 2 . These findings demonstrate that coronary K + ATP channel activity contribute to the regulation of resting MBF in CHF, and that endogenous adenosine may act to inhibit MVO 2 in the failing heart.
Specific up-regulation of FAK expression in primary breast cancer as a marker for malignant transformation
Authors: E. Stickeler, D. O. Watermann, B. Gabriel, M. Jäger, G. Gitsch
Journal: Journal of Clinical Oncology (2005)

9647 Background: The focal adhesion kinase (FAK) is a protein tyrosine kinase linked to integrin mediated cell-cell and cell- matrix signalling and overexpressed in a variety of human solid tumors. FAK expression might be correlated to the invasive and metastatic capability of tumor cells. The data on breast cancer are inconclusive. To determine whether FAK is up-regulated, we analyzed FAK protein levels and expression patterns in primary breast cancer and normal tissue. Methods: To analyze the expression changes of FAK in breast cancer development we determined FAK in 55 matched pairs of breast cancer and corresponding normal tissue of the same patient by Western Blot and immunohistochemistry, using a FAK specific monoclonal antibody. Results: Using a score ranging from 0 to +5 for western blots, we found in normal breast tissue a low median score of 1,00, which was strongly induced up to 3,0 in invasive breast cancers. The medium score was 1,51 ⦡ 0,836 in physiological tissue versus 2,91 ⦡ 1,221 in tumors. A more detailed analysis revealed, that 50 out of 55 normal tissue specimen (90,9%) were valued with a score of 0 to +2. Interestingly, score +1 was given in 30/55 probes or 54,5% of all physiological tissue specimen. Only 5 (9,1%) samples were detected with a score of +3 or +5. In contrast, invasive breast cancer displayed a strong FAK expression. Score +3 to +5 was found in 33/55 (60%) specimen, with 17/55 (30,9%) in the highest two score ranks +4 and +5. Only 7/55 tumors (12,7%) got a score of +1.Overall, 45 out of 55 corresponding tissue pairs (81,8%) were found to show an upregulation of p125FAK protein expression in the tumors in direct comparison to the normal surrounding breast tissue. Immunohistochemistry confirmed the findings of Western Blot analysis. Conclusion: FAK is specifically upregulated in breast cancer in comparison to matched normal breast tissue. These results provide evidence on a large number of specimen that induction of FAK is a frequent and relatively constant event in breast cancer development. FAK might serve as a marker for malignant transformation. No significant financial relationships to disclose.
Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes.
Authors: A K Matsumoto, D R Martin, R H Carter, L B Klickstein, J M Ahearn, D T Fearon
Journal: The Journal of Experimental Medicine (1993)

The CD21/CD19/TAPA-1 complex of B lymphocytes amplifies signal transduction through membrane immunoglobulin (mIg), recruits phosphatidylinositol 3-kinase (PI3-kinase), and induces homotypic cellular aggregation. The complex is unique among known membrane protein complexes of the immune system because its components represent different protein families, and can be expressed individually. By constructing chimeric molecules replacing the extracellular, transmembrane, and cytoplasmic regions of CD19 and CD21 with those of HLA-A2 and CD4, we have determined that CD19 and TAPA-1 interact through their extracellular domains, CD19 and CD21 through their extracellular and transmembrane domains, and, in a separate complex, CD21 and CD35 through their extracellular domains. A chimeric form of CD19 that does not interact with CD21 or TAPA-1 was expressed in Daudi B lymphoblastoid cells and was shown to replicate two functions of wild-type CD19 contained within the complex: synergistic interaction with mIgM to increase intracellular free calcium and tyrosine phosphorylation and association with the p85 subunit of PI3-kinase after ligation of mIgM. The chimeric CD19 lacked the capacity of the wild-type CD19 to induce homotypic cellular aggregation, a function of the complex that can be ascribed to the TAPA-1 component. The CD21/CD19/TAPA-1 complex brings together independently functioning subunits to enable the B cell to respond to low concentrations of antigen.