tbuckley/cabot-search huggingface dataset:
A Bimodal Association of Vitamin D Levels and Vascular Disease in Children on Dialysis
Authors: Rukshana Shroff, Martyn Egerton, Michala Bridel, Vanita Shah, Ann E. Donald, Tim J. Cole, Melanie P. Hiorns, John E. Deanfield, Lesley Rees
Journal: Journal of the American Society of Nephrology (2008)

In addition to its classical role in calcium-phosphate homeostasis, vitamin D has anti-inflammatory effects that may influence vascular disease. This study examined the impact of vitamin D levels on the vascular phenotype in 61 children who had been on dialysis for ≥3 mo and in 40 age-matched control subjects. All dialysis patients were prescribed daily oral 1-α hydroxyvitamin D3. 92% of patients were deficient in 25-hydroxyvitamin D [25(OH)D]. 1,25-dihydroxyvitamin D [1,25(OH)2D] levels were low in 36% and high in 11% of patients. There was a weak correlation between 1α-hydroxyvitamin D3 dosage and 1,25(OH)2D levels. Both carotid intima-media thickness and calcification scores showed a U-shaped distribution across 1,25(OH)2D levels: patients with both low and high 1,25(OH)2D had significantly greater carotid intima-media thickness (P < 0.0001) and calcification (P = 0.0002) than those with normal levels. Low 1,25(OH)2D levels were associated with higher high-sensitivity C-reactive protein (P < 0.0001). Calcification was most frequently observed in patients with the lowest 1,25(OH)2D and the highest high-sensitivity C-reactive protein. In contrast, 25(OH)D levels did not correlate with any vascular measure. In conclusion, both low and high 1,25(OH)2D levels are associated with adverse morphologic changes in large arteries, and this may be mediated through the effects of 1,25(OH)2D on calcium-phosphate homeostasis and inflammation. For optimization of strategies to protect the vasculature of dialysis patients, careful monitoring of 1,25(OH)2D levels may be required.
The Lipid Research Clinics Coronary Primary Prevention Trial
Authors: Kristan A. L'Abbe
Journal: JAMA (1985)

<h3>To the Editor.—</h3> We would like to point out a discrepancy between the final report of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT)<sup>1</sup>and the report on the design and implementation of this trial.<sup>2</sup>In the article on planning, the following statements appear in Appendix D under the heading, "Calculation of Sample Size": "Since the time, magnitude, and cost of this study make it unlikely that it could ever be repeated, it was essential to be sure that any observed beneficial effect of cholesterol lowering was a real one. Therefore, alpha was set at 0.01 rather than the usual 0.05." However, when the results appear for the primary end points and all-cause mortality, they are reported in relation to a level of significance of.05. We are concerned by this apparent post-hoc relaxation of the α-level used to judge the statistical significance of the LRC-CPPT results. Despite
Change in Quality Management in Diabetes Care Groups and Outpatient Clinics After Feedback and Tailored Support
Authors: Marjo J. Campmans-Kuijpers, Caroline A. Baan, Lidwien C. Lemmens, Guy E. Rutten
Journal: Diabetes Care (2014)

OBJECTIVE To assess the change in level of diabetes quality management in primary care groups and outpatient clinics after feedback and tailored support. RESEARCH DESIGN AND METHODS This before-and-after study with a 1-year follow-up surveyed quality managers on six domains of quality management. Questionnaires measured organization of care, multidisciplinary teamwork, patient centeredness, performance results, quality improvement policy, and management strategies (score range 0–100%). Based on the scores, responders received feedback and a benchmark and were granted access to a toolbox of quality improvement instruments. If requested, additional support in improving quality management was available, consisting of an elucidating phone call or a visit from an experienced consultant. After 1 year, the level of quality management was measured again. RESULTS Of the initially 60 participating care groups, 51 completed the study. The total quality management score improved from 59.8% (95% CI 57.0–62.6%) to 65.1% (62.8–67.5%; P &amp;lt; 0.0001). The same applied to all six domains. The feedback and benchmark improved the total quality management score (P = 0.001). Of the 44 participating outpatient clinics, 28 completed the study. Their total score changed from 65.7% (CI 60.3–71.1%) to 67.3% (CI 62.9–71.7%; P = 0.30). Only the results in the domain multidisciplinary teamwork improved (P = 0.001). CONCLUSIONS Measuring quality management and providing feedback and a benchmark improves the level of quality management in care groups but not in outpatient clinics. The questionnaires might also be a useful asset for other diabetes care groups, such as Accountable Care Organizations.
Cytokine-induced airway epithelial ICAM-1 upregulation: quantification by high-resolution scanning and transmission electron microscopy
Authors: J Zhu, A V Rogers, A Burke-Gaffney, P G Hellewell, P K Jeffery
Journal: European Respiratory Journal (1999)

The aim of this study was to investigate the variation of intercellular adhesion molecule (ICAM)-1 which occurs between individual airway epithelial cells of distinct phenotype. 16HBE14o- (16HBE) and BEAS-2B cell lines and human airway explants were cultured with medium alone or a mixture of tumour necrosis factor (TNF)-alpha (10 ng x mL(-1)) and interferon (IFN)-gamma (40 ng x mL(-1)) before being immunogold-labelled and examined quantitatively using sensitive high-resolution electron microscopic techniques. By enzyme-linked immunosorbent assay there was a 1.6-fold increase of ICAM-1 in the BEAS-2B cells following the cytokine mix which was not apparent in the 16HBE cells. However, high-resolution scanning electron microscopy demonstrated that an upregulation had occurred; median and ranges for gold particle number per 10 microm2 cell surface were: 7.9 (0-40) for nonstimulated and 19.1 (0-60 for stimulated) (p<0.01, Mann-Whitney U-test). The value for the nonstimulated BEAS-2B cells was 24.2 (0-60), 3-times higher that the constitutive expression in the 16HBE cells (p<0.01), whereas following stimulation, it was 68.5 (20-130) (p<0.01). Values for explant epithelial outgrowths were similar to the 16HBE cells. Immunohistochemistry of the explanted mucosa showed both constitutive and upregulated expression of epithelial ICAM-1 associated with basal and indeterminate cells rather than with ciliated or goblet cells. These results using high-resolution techniques indicate that there is marked cell-to-cell variation in cellular adhesion molecule expression and that it is the basal cells and less well differentiated (indeterminate) epithelial cells which are likely to play key roles in leukocyte retention via intercellular adhesion molecule-1.
Acute Neurocardiogenic Injury After Subarachnoid Hemorrhage
Authors: Nader M. Banki, Alexander Kopelnik, Michael W. Dae, Jacob Miss, Poyee Tung, Michael T. Lawton, Barbara J. Drew, Elyse Foster, Wade Smith, William W. Parmley, Jonathan G. Zaroff
Journal: Circulation (2005)

Left ventricular (LV) systolic dysfunction has been reported in humans with subarachnoid hemorrhage (SAH), and its underlying pathophysiology remains controversial. Possible mechanisms include myocardial ischemia versus excessive catecholamine release from sympathetic nerve terminals.For 38 months, echocardiography and myocardial scintigraphy with technetium sestamibi (MIBI) and meta-[(123)I]iodobenzylguanidine (MIBG) were performed on 42 patients admitted with SAH to assess myocardial perfusion and sympathetic innervation, respectively. A blinded observer interpreted the scintigraphic images. Cardiac troponin I (cTI) was measured to quantify the degree of myocyte necrosis. Blinded observers calculated the LV ejection fraction and graded each LV segment as normal (score=1), hypokinetic (score=2), or akinetic (score=3). A wall-motion score was calculated by averaging the sum of the 16 segments. All subjects with interpretable scans (N=41) had normal MIBI uptake. Twelve subjects had either global (n=9) or regional (n=3) absence of MIBG uptake. In comparison with patients with normal MIBG uptake, those with evidence of functional denervation were more likely to have LV regional wall-motion abnormalities (92% versus 52%, P=0.030) and cTI levels >1 microg/L (58% versus 21%, P=0.029).LV systolic dysfunction in humans with SAH is associated with normal myocardial perfusion and abnormal sympathetic innervation. These findings may be explained by excessive release of norepinephrine from myocardial sympathetic nerves, which could damage both myocytes and nerve terminals.
What Oncologists Believe They Said and What Patients Believe They Heard: An Analysis of Phase I Trial Discussions
Authors: Valerie Jenkins, Ivonne Solis-Trapala, Carolyn Langridge, Susan Catt, Denis C. Talbot, Lesley J. Fallowfield
Journal: Journal of Clinical Oncology (2010)

PURPOSE; Evaluation of the communication and informed consent process in phase I clinical trial interviews to provide authentic, practice-based content for inclusion in a communication skills training intervention for health care professionals.Seventeen oncologists and 52 patients from five United Kingdom cancer centers consented to recording of phase I trial discussions. Following each consultation, clinicians completed questionnaires indicating areas they felt they had discussed, and researchers conducted semistructured interviews with patients examining their recall and understanding. Patients and oncologists also completed the Life Orientation Test-Revised questionnaire, measuring predisposition toward optimism. Independent researchers coded the consultations identifying discussion of key information areas and how well this was done. Observed levels of agreement were analyzed for each consultation between oncologist-coder, oncologist-patient, and patient-coder pairs.In several key areas, information was either missing or had been explained but was interpreted incorrectly by patients. Discussion of prognosis was a frequent omission, with patients and coders significantly more likely to agree that oncologists had not discussed it (odds, 4.8; P < .001). In contrast, coders and oncologists were more likely to agree that alternate care plans to phase I trial entry had been explained (odds, 2.5; P = .023).These data indicate that fundamental components of communication and information sharing about phase I trial participation are often missing from interviews. Important omissions included discussion of prognosis and ensuring patient understanding about supportive care. These findings will inform educational initiatives to assist communication about phase I trials.
Re-estimated equations for 5th percentiles of lung function variables
Authors: O BRANDLI
Journal: Thorax (2000)

Xanthoma disseminatum (XD) is a rare mucocutaneous xanthomatosis classified as a benign form of non-Langerhans' cell histiocytosis.The case history is presented of a 61 year old woman with XD who developed dyspnoea and spirometric features of airflow obstruction.Bronchoscopy and computed tomography confirmed involvement of the large and medium sized bronchi and she subsequently died from acute respiratory failure.The post-mortem findings and the importance of respiratory tract disease in this unusual condition are discussed.
Bortezomib Primes Neuroblastoma Cells for TRAIL-Induced Apoptosis by Linking the Death Receptor to the Mitochondrial Pathway
Authors: Ivonne Naumann, Roland Kappler, Dietrich von Schweinitz, Klaus-Michael Debatin, Simone Fulda
Journal: Clinical Cancer Research (2011)

Searching for novel strategies to modulate apoptosis in neuroblastoma, we investigated the potential of the proteasome inhibitor bortezomib.The effect of bortezomib on TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis signaling pathways was analyzed in neuroblastoma cell lines, primary neuroblastoma cultures, and in an in vivo model.Bortezomib synergistically cooperates with TRAIL to induce apoptosis and to reduce colony formation of neuroblastoma cells (combination index: 0.5). Mechanistic studies reveal that bortezomib profoundly enhances TRAIL-induced cleavage of Bid into tBid, accumulation of tBid in the cytosol, and its insertion into mitochondrial membranes, pointing to a concerted effect on Bid cleavage (TRAIL) and stabilization of tBid (bortezomib), which links the death receptor to the mitochondrial pathway. In addition, bortezomib increases expression of p53 and Noxa. All these changes lead to increased activation of Bax and Bak, loss of the mitochondrial membrane potential, cytochrome c release, caspase activation, and caspase-dependent apoptosis on treatment with bortezomib and TRAIL. Knockdown of Bid, Noxa, or p53 significantly delays the kinetic of bortezomib- and TRAIL-induced apoptosis, whereas it does not confer long-term protection. By comparison, overexpression of Bcl-2, which simultaneously antagonizes tBid and p53, significantly inhibits bortezomib- and TRAIL-induced apoptosis and even rescues clonogenic survival. Importantly, bortezomib and TRAIL act in concert to trigger apoptosis and to suppress tumor growth in patient-derived primary neuroblastoma cells and in an in vivo model of neuroblastoma.Bortezomib represents a promising new approach to prime neuroblastoma cells toward TRAIL, which warrants further investigation.
Comparative transcriptome analysis of embryonic and adult stem cells with extended and limited differentiation capacity
Authors: Fernando Ulloa-Montoya, Benjamin L Kidder, Karen A Pauwelyn, Lucas G Chase, Aernout Luttun, Annelies Crabbe, Martine Geraerts, Alexei A Sharov, Yulan Piao, Minoru SH Ko, Wei-Shou Hu, Catherine M Verfaillie
Journal: Genome biology (2007)

Recently, several populations of postnatal stem cells, such as multipotent adult progenitor cells (MAPCs), have been described that have broader differentiation ability than classical adult stem cells. Here we compare the transcriptome of pluripotent embryonic stem cells (ESCs), MAPCs, and lineage-restricted mesenchymal stem cells (MSCs) to determine their relationship.Applying principal component analysis, non-negative matrix factorization and k-means clustering algorithms to the gene-expression data, we identified a unique gene-expression profile for MAPCs. Apart from the ESC-specific transcription factor Oct4 and other ESC transcripts, some of them associated with maintaining ESC pluripotency, MAPCs also express transcripts characteristic of early endoderm and mesoderm. MAPCs do not, however, express Nanog or Sox2, two other key transcription factors involved in maintaining ESC properties. This unique molecular signature was seen irrespective of the microarray platform used and was very similar for both mouse and rat MAPCs. As MSC-like cells isolated under MAPC conditions are virtually identical to MSCs, and MSCs cultured in MAPC conditions do not upregulate MAPC-expressed transcripts, the MAPC signature is cell-type specific and not merely the result of differing culture conditions.Multivariate analysis techniques clustered stem cells on the basis of their expressed gene profile, and the genes determining this clustering reflected the stem cells' differentiation potential in vitro. This comparative transcriptome analysis should significantly aid the isolation and culture of MAPCs and MAPC-like cells, and form the basis for studies to gain insights into genes that confer on these cells their greater developmental potency.
Are large compensation payouts for negligence good for medicine in India?
Authors: K. Saha, D. Shetty
Journal: BMJ (2014)

The Indian Supreme Court recently awarded a record compensation payout for medical negligence that resulted in the death of a patient. <b>Kunal Saha</b> says such payments are essential when other accountability is lacking, but <b>Devi Shetty </b>fears the emergence of a US style compensation culture that stifles doctors
CX3CR1 Is Expressed by Prostate Epithelial Cells and Androgens Regulate the Levels of CX3CL1/Fractalkine in the Bone Marrow: Potential Role in Prostate Cancer Bone Tropism
Authors: Whitney L. Jamieson, Saori Shimizu, Julia A. D'Ambrosio, Olimpia Meucci, Alessandro Fatatis
Journal: Cancer Research (2008)

Abstract We have previously shown that the chemokine fractalkine promotes the adhesion of human prostate cancer cells to bone marrow endothelial cells as well as their migration toward human osteoblasts in vitro. Thus, the interaction of fractalkine with its receptor CX3CR1 could play a crucial role in vivo by directing circulating prostate cancer cells to the bone. We found that although CX3CR1 is minimally detectable in epithelial cells of normal prostate glands, it is overexpressed upon malignant transformation. Interestingly, osteoblasts, stromal and mesenchymal cells derived from human bone marrow aspirates express the cell-bound form of fractalkine, whereas the soluble form of the chemokine is detected in bone marrow supernatants. To investigate the mechanisms regulating the levels of soluble fractalkine in the bone marrow, we focused on androgens, which play a critical role in both prostate cancer progression and skeletal metastasis. Here, we show that dihydrotestosterone dramatically increases the cleavage of fractalkine from the plasma membrane of bone cells and its action is reversed by nilutamide—an antagonist of the androgen receptor—as well as the wide-spectrum inhibitor of matrix metalloproteases, GM6001. However, dihydrotestosterone was unable to induce fractalkine-cleavage from human bone marrow endothelial cells. Thus, androgens could promote the extravasation of CX3CR1-bearing cancer cells on a fractalkine concentration gradient, while leaving unaltered their ability to adhere to the bone marrow endothelium. In conclusion, our results indicate that CX3CR1, fractalkine, and the enzymes responsible for its cleavage might represent suitable targets for therapies aiming to counteract skeletal secondary tumors from prostate adenocarcinoma. [Cancer Res 2008;68(6):1715–22]
Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na+-K+-2Cl− Cotransporter
Authors: Aljona Borschewski, Nina Himmerkus, Christin Boldt, Katharina I Blankenstein, James A McCormick, Rebecca Lazelle, Thomas E Willnow, Vera Jankowski, Allein Plain, Markus Bleich, David H Ellison, Sebastian Bachmann, Kerim Mutig
Journal: Journal of the American Society of Nephrology (2015)

The furosemide-sensitive Na(+)-K(+)-2Cl(-)-cotransporter (NKCC2) is crucial for NaCl reabsorption in kidney thick ascending limb (TAL) and drives the urine concentrating mechanism. NKCC2 activity is modulated by N-terminal phosphorylation and dephosphorylation. Serine-threonine kinases that activate NKCC2 have been identified, but less is known about phosphatases that deactivate NKCC2. Inhibition of calcineurin phosphatase has been shown to stimulate transport in the TAL and the distal convoluted tubule. Here, we identified NKCC2 as a target of the calcineurin Aβ isoform. Short-term cyclosporine administration in mice augmented the abundance of phospho-NKCC2, and treatment of isolated TAL with cyclosporine increased the chloride affinity and transport activity of NKCC2. Because sorting-related receptor with A-type repeats (SORLA) may affect NKCC2 phosphoregulation, we used SORLA-knockout mice to test whether SORLA is involved in calcineurin-dependent modulation of NKCC2. SORLA-deficient mice showed more calcineurin Aβ in the apical region of TAL cells and less NKCC2 phosphorylation and activity compared with littermate controls. In contrast, overexpression of SORLA in cultured cells reduced the abundance of endogenous calcineurin Aβ. Cyclosporine administration rapidly normalized the abundance of phospho-NKCC2 in SORLA-deficient mice, and a functional interaction between calcineurin Aβ and SORLA was further corroborated by binding assays in rat kidney extracts. In summary, we have shown that calcineurin Aβ and SORLA are key components in the phosphoregulation of NKCC2. These results may have clinical implications for immunosuppressive therapy using calcineurin inhibitors.
Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study
Authors: Richard G Grundy, Sophie A Wilne, Claire L Weston, Kath Robinson, Linda S Lashford, James Ironside, Tim Cox, W Kling Chong, Richard HA Campbell, Cliff C Bailey, Rao Gattamaneni, Sue Picton, Nicky Thorpe, Conor Mallucci, Martin W English, Jonathan AG Punt, David A Walker, David W Ellison, David Machin
Journal: The Lancet Oncology (2007)
Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells
Authors: Bernadette Pöllinger, Gurumoorthy Krishnamoorthy, Kerstin Berer, Hans Lassmann, Michael R. Bösl, Robert Dunn, Helena S. Domingues, Andreas Holz, Florian C. Kurschus, Hartmut Wekerle
Journal: The Journal of Experimental Medicine (2009)

We describe new T cell receptor (TCR) transgenic mice (relapsing-remitting [RR] mice) carrying a TCR specific for myelin oligodendrocyte glycoprotein (MOG) peptide 92–106 in the context of I-As. Backcrossed to the SJL/J background, most RR mice spontaneously develop RR experimental autoimmune encephalomyelitis (EAE) with episodes often altering between different central nervous system tissues like the cerebellum, optic nerve, and spinal cord. Development of spontaneous EAE depends on the presence of an intact B cell compartment and on the expression of MOG autoantigen. There is no spontaneous EAE development in B cell–depleted mice or in transgenic mice lacking MOG. Transgenic T cells seem to expand MOG autoreactive B cells from the endogenous repertoire. The expanded autoreactive B cells produce autoantibodies binding to a conformational epitope on the native MOG protein while ignoring the T cell target peptide. The secreted autoantibodies are pathogenic, enhancing demyelinating EAE episodes. RR mice constitute the first spontaneous animal model for the most common form of multiple sclerosis (MS), RR MS.
Childhood tuberculosis: progress requires an advocacy strategy now
Authors: Andreas Sandgren, Luis E. Cuevas, Masoud Dara, Robert P. Gie, Malgorzata Grzemska, Anthony Hawkridge, Anneke C. Hesseling, Beate Kampmann, Christian Lienhardt, Davide Manissero, Claire Wingfield, Stephen M. Graham
Journal: European Respiratory Journal (2012)

Childhood tuberculosis (TB) is a preventable and curable infectious disease that remains overlooked by public health authorities, health policy makers and TB control programmes. Childhood TB contributes significantly to the burden of disease and represents the failure to control transmission in the community. Furthermore, the pool of infected children constitutes a reservoir of infection for the future burden of TB. It is time to prioritise childhood TB, advocate for addressing the challenges and grasp the opportunities in its prevention and control. Herein, we propose a scientifically informed advocacy agenda developed at the International Childhood TB meeting held in Stockholm, Sweden, from March 17 to 18, 2011, which calls for a renewed effort to improve the situation for children affected by <i>Mycobacterium tuberculosis</i> exposure, infection or disease. The challenges and needs in childhood TB are universal and apply to all settings and must be addressed more effectively by all stakeholders.