tbuckley/cabot-search huggingface dataset:
Samuel Laird Galbraith
Authors: M. Limb
Journal: BMJ (2014)

<h3>Background:</h3> The ABCD<sup>2</sup> score predicts stroke risk within a few days of transient ischaemic attack (TIA). It is not clear whether the predictive value of the ABCD<sup>2</sup> score can be generalised to UK TIA services, where delayed presentation of TIA and minor stroke are common. We investigated prognosis, and the use of the ABCD<sup>2</sup> score, in patients attending TIA services in the North West of England with a diagnosis of TIA or minor stroke. <h3>Methods:</h3> 711 patients with TIA or minor stroke were prospectively recruited from five centres (median duration from index event to recruitment 15 days). The primary outcome was the composite of incident TIA, stroke, acute coronary syndrome or cardiovascular death at the 3 month follow-up. Prognostic factors were analysed using Cox proportional hazards regression. <h3>Results:</h3> The primary outcome occurred in 126 (18%) patients. Overall, there were 30 incident strokes. At least one incident TIA occurred in 100 patients (14%), but only four had a subsequent stroke. In multifactorial analyses, the ABCD<sup>2</sup> score was unrelated to the risk of the primary outcome, but predicted the risk of incident stroke: score 4–5: hazard ratio (HR) 3.4 (95% CI 1.0 to 12); score 6–7: HR 4.8 (1.3 to 18). Of the components of the ABCD<sup>2</sup> score, unilateral motor weakness predicted both the primary outcome (HR 1.8 (1.2 to 2.8)) and stroke risk (HR 4.2 (1.3 to 14)). <h3>Conclusions:</h3> In patients attending typical NHS TIA services, the risk of incident stroke was relatively low, probably reflecting delays to assessment. Current provision of TIA services, where delayed presentation to “rapid access” TIA clinics is common, does not appear to provide an appropriate setting for urgent evaluation, risk stratification or timely secondary prevention for those who may be at highest risk.
Autologous Stem-Cell Transplantation Without Hematopoietic Support for the Treatment of Hematologic Malignancies in Jehovah's Witnesses
Authors: Patricia A. Ford, Shakira J. Grant, Rosemarie Mick, Gina Keck
Journal: Journal of Clinical Oncology (2015)

Autologous stem-cell transplantation (ASCT) has shown to provide curative benefit in patients with relapsed lymphoma and multiple myeloma (MM), often requiring hematopoietic support until marrow engraftment. Because of Jehovah's Witnesses' (JW) refusal of blood products, treatment challenges arise. This study represents 125 JWs with lymphoma (n = 55), MM (n = 68), or amyloidosis (n = 2), treated with high-dose chemotherapy (HDC) and ASCT without transfusions.Priming with intravenous iron and erythropoietin occurred to increase hemoglobin (Hb) pretransplantation. Cytokine mobilization of stem-cells was used. Delay to HDC was done to allow Hb and platelets to approach 11 g/dL and 100 × 10(3)/μL, respectively. Patients with MM received a standard dose of melphalan 200 mg/m(2), with dose reduction for severe kidney dysfunction. Patients with lymphoma received carmustine 300 mg/m(2), cyclophosphamide 1,500 mg/m(2) on days 2 through 5 (total 6 g/m(2)), and etoposide 700 mg/m(2) per day on days 2 through 4 (total 2,100 mg/m(2)). Post-transplantation, a combination of granulocyte colony-stimulating factor, erythropoietin, aminocaproic acid, and phytonadione was administered.There were two major and 15 minor bleeding complications, none occurring at platelets less than 5.0 × 10(3)/μL, with six (4.8%) treatment-related mortalities. The median decrease in Hb was 5.0 g/dL, with median Hb nadir of 7.0 g/dL. The median number of days with platelet count less than 10 × 10(3)/μL was 3, with median platelet nadir of 5.0 × 10(3)/μL. Cardiac complications occurred in 40 patients (32%).ASCT can safely be performed without transfusion support. A platelet transfusion trigger of ≤ 5 × 10(3)/μL may be appropriate in select patients. Pharmacotherapy and cardiac monitoring are effective in the management of cardiac complications.
Epidermal Transglutaminase (TGase 3) Is the Autoantigen of Dermatitis Herpetiformis
Authors: Miklós Sárdy, Sarolta Kárpáti, Barbara Merkl, Mats Paulsson, Neil Smyth
Journal: The Journal of Experimental Medicine (2002)

Gluten sensitivity typically presents as celiac disease, a common chronic small intestinal disorder. However, in certain individuals it is associated with dermatitis herpetiformis, a blistering skin disease characterized by granular IgA deposits in the papillary dermis. While tissue transglutaminase has been implicated as the major autoantigen of gluten sensitive disease, there has been no explanation as to why this condition appears in two distinct forms. Here we show that while sera from patients with either form of gluten sensitive disease react both with tissue transglutaminase and the related enzyme epidermal (type 3) transglutaminase, antibodies in patients having dermatitis herpetiformis show a markedly higher avidity for epidermal transglutaminase. Further, these patients have an antibody population specific for this enzyme. We also show that the IgA precipitates in the papillary dermis of patients with dermatitis herpetiformis, the defining signs of the disease, contain epidermal transglutaminase, but not tissue transglutaminase or keratinocyte transglutaminase. These findings demonstrate that epidermal transglutaminase, rather than tissue transglutaminase, is the dominant autoantigen in dermatitis herpetiformis and explain why skin symptoms appear in a proportion of patients having gluten sensitive disease.
Risks to patients in primary care need to be scrutinised
Authors: A. O'Dowd
Journal: BMJ (2009)

The extent of the risk to patient safety in primary care is unknown and badly in need of more scrutiny, MPs have heard.

Although patient safety has been on the hospital agenda for several years it is not clear to what extent it is embedded in NHS primary care services, expert witnesses told MPs on the parliamentary health select committee as part of its inquiry into patient safety.

Aneez Esmail, professor of general practice at the University of Manchester, who has led research in this area, gave evidence to the committee, which asked him about safety culture in the NHS.

“In terms of patient …
Altered Cellular and Humoral Immunity to Varicella‐Zoster Virus in Patients With Autoimmune Diseases
Authors: Christien Rondaan, Aalzen de Haan, Gerda Horst, J. Cordelia Hempel, Coretta van Leer, Nicolaas A. Bos, Sander van Assen, Marc Bijl, Johanna Westra
Journal: Arthritis & Rheumatology (2014)

Objective Patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and granulomatosis with polyangiitis (Wegener's) (GPA) have a 3–20‐fold increased risk of herpes zoster compared to the general population. The aim of this study was to evaluate if susceptibility is due to decreased levels of cellular and/or humoral immunity to the varicella‐zoster virus (VZV). Methods A cross‐sectional study of VZV‐specific immunity was performed in 38 SLE patients, 33 GPA patients, and 51 healthy controls. Levels of IgG and IgM antibodies to VZV were measured using an in‐house glycoprotein enzyme‐linked immunosorbent assay (ELISA). Cellular responses to VZV were determined by interferon‐γ (IFNγ) enzyme‐linked immunospot (ELISpot) assay and carboxyfluorescein succinimidyl ester (CFSE) dye dilution proliferation assay. Results Levels of IgG antibodies to VZV were increased in SLE patients as compared to healthy controls, but levels of IgM antibodies to VZV were not. Antibody levels in GPA patients did not differ significantly from levels in healthy controls. In response to stimulation with VZV, decreased numbers of IFNγ spot‐forming cells were found among SLE patients (although not GPA patients) as compared to healthy controls. Proliferation of CD4+ T cells in response to stimulation with VZV was decreased in SLE patients but not GPA patients. Conclusion SLE patients have increased levels of IgG antibodies against VZV, while cellular immunity is decreased. In GPA patients, antibody levels as well as cellular responses to VZV were comparable to those in healthy controls. These data suggest that increased prevalence of herpes zoster in SLE patients is due to a poor cellular response. Vaccination strategies should aim to boost cellular immunity against VZV.
Preparation and Biological Evaluation of Copper-64–Labeled Tyr3-Octreotate Using a Cross-Bridged Macrocyclic Chelator
Authors: Jennifer E. Sprague, Yijie Peng, Xiankai Sun, Gary R. Weisman, Edward H. Wong, Samuel Achilefu, Carolyn J. Anderson
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Somatostatin receptors (SSTr) are expressed on many neuroendocrine tumors, and several radiotracers have been developed for imaging these types of tumors. For this reason, peptide analogues of somatostatin have been well characterized. Copper-64 (t1/2 = 12.7 hours), a positron emitter suitable for positron emission tomography (PET) imaging, was shown recently to have improved in vivo clearance properties when chelated by the cross-bridged tetraazamacrocycle 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane (CB-TE2A) compared with 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA). Experimental Design: CB-TE2A and TETA were conjugated to the somatostatin analogue tyrosine-3-octreotate (Y3-TATE) for evaluation of CB-TE2A as a bifunctional chelator of 64Cu. The in vitro affinity of each compound for SSTr was determined using a homologous competitive binding assay. In vivo characteristics of both radiolabeled compounds were examined in biodistribution and microPET studies of AR42J tumor-bearing rats. Results: Cu-CB-TE2A-Y3-TATE (Kd = 1.7 nmol/L) and Cu-TETA-Y3-TATE (Kd = 0.7 nmol/L) showed similar affinities for AR42J derived SSTr. In biodistribution studies, nonspecific uptake in blood and liver was lower for 64Cu-CB-TE2A-Y3-TATE. Differences increased with time such that, at 4 hours, blood uptake was 4.3-fold higher and liver uptake was 2.4-fold higher for 64Cu-TETA-Y3-TATE than for 64Cu-CB-TE2A-Y3-TATE. In addition, 4.4-times greater tumor uptake was detected with 64Cu-CB-TE2A-Y3-TATE than with 64Cu-TETA-Y3-TATE at 4 hours postinjection. MicroPET imaging yielded similar results. Conclusions: CB-TE2A appears to be a superior in vivo bifunctional chelator of 64Cu for use in molecular imaging by PET or targeted radiotherapy due to both improved nontarget organ clearance and higher target organ uptake of 64Cu-CB-TE2A-Y3-TATE compared with 64Cu-TETA-Y3-TATE.
Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis
Authors: Dennis J Nieuwkamp, Larissa E Setz, Ale Algra, Francisca HH Linn, Nicolien K de Rooij, Gabriël JE Rinkel
Journal: The Lancet Neurology (2009)
A randomized trial of coronary stenting versus balloon angioplasty as a rescue intervention after failed thrombolysis in patients with acute myocardial infarction
Authors: Albert Schömig, Gjin Ndrepepa, Julinda Mehilli, Josef Dirschinger, Stefan G. Nekolla, Claus Schmitt, Stefan Martinoff, Melchior Seyfarth, Markus Schwaiger, Adnan Kastrati, Stopami Study Investigators
Journal: Journal of the American College of Cardiology (2004)
Contribution of six risk factors to achieving the 25×25 non-communicable disease mortality reduction target: a modelling study
Authors: Vasilis Kontis, Colin D Mathers, Jürgen Rehm, Gretchen A Stevens, Kevin D Shield, Ruth Bonita, Leanne M Riley, Vladimir Poznyak, Robert Beaglehole, Majid Ezzati
Journal: The Lancet (2014)
GLI1 Interferes with the DNA Mismatch Repair System in Pancreatic Cancer through BHLHE41-Mediated Suppression of MLH1
Authors: Shingo Inaguma, Miho Riku, Mitsuyoshi Hashimoto, Hideki Murakami, Shinsuke Saga, Hiroshi Ikeda, Kenji Kasai
Journal: Cancer Research (2013)

The mismatch repair (MMR) system is indispensable for the fidelity of DNA replication, the impairment of which predisposes to the development and progression of many types of cancers. To date, GLI1 transcription factor, a key molecule of the Hedgehog signaling pathway, has been shown to regulate the expression of several genes crucial for a variety of cancer cell properties in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), but whether GLI1 could control the MMR system was not known. Here, we showed that GLI1 and GLI2 indirectly suppressed the expression of MLH1 in PDAC cells. Through GLI1 target gene screening, we found that GLI1 and GLI2 activated the expression of a basic helix-loop-helix type suppressor BHLHE41/DEC2/SHARP1 through a GLI-binding site in the promoter. Consistent with a previous report that BHLHE41 suppresses the MLH1 promoter activity, we found that the activation of GLI1 led to the BHLHE41-dependent suppression of MLH1, and a double knockdown of GLI1 and GLI2 conversely increased the MLH1 protein in PDAC cells. Using TALEN-based modification of the MLH1 gene, we further showed that GLI1 expression was indeed associated with an increased tolerance to a methylating agent, methylnitrosourea cooperatively with a lower copy number status of MLH1. Finally, GLI1 expression was immunohistochemically related positively with BHLHE41 and inversely with MLH1 in PDAC cells and precancerous lesions of the pancreas. On the basis of these results, we propose that GLI1 depresses the MMR activity and might contribute to the development and progression of PDAC.
A New Generation of Optical Diagnostics for Bladder Cancer: Technology, Diagnostic Accuracy, and Future Applications
Authors: Evelyne C.C. Cauberg, Daniël M. de Bruin, Dirk J. Faber, Ton G. van Leeuwen, Jean J.M.C.H. de la Rosette, Theo M. de Reijke
Journal: European Urology (2009)
Causes of death – other than progressive leukemia – in childhood acute lymphoblastic (ALL) and myeloid leukemia (AML): the Dutch Childhood Oncology Group experience
Authors: A M Slats, R M Egeler, A van der Does-van den Berg, C Korbijn, K Hählen, W A Kamps, A J P Veerman, C M Zwaan
Journal: Leukemia (2005)
Relaxin, a Pregnancy Hormone, Is a Functional Endothelin-1 Antagonist
Authors: Thomas Dschietzig, Cornelia Bartsch, Christoph Richter, Michael Laule, Gert Baumann, Karl Stangl
Journal: Circulation Research (2003)

We have recently demonstrated that relaxin (RLX) acts as compensatory mediator in human heart failure. RLX inhibits the stimulation of endothelin-1, the most potent vasoconstrictor in heart failure. Upregulation of the endothelin type-B receptor (ET B ), which mediates endothelin-1 clearance and endothelial release of NO, represents a pivotal mode of RLX action. However, signal transduction and abundance of this phenomenon are unknown. Therefore, we investigated RLX-induced regulation of ET B in human umbilical vein endothelial, epithelial (HeLa), and vascular smooth muscle cells. In human umbilical vein endothelial cells and HeLa cells, but not in human vascular smooth muscle cells, RLX upregulated ET B expression and activated extracellular signal–regulated kinase-1/2 (ERK-1/2) and nuclear factor-κB (NF-κB), a transcription factor. PD-98059, a selective inhibitor of the mitogen-activated protein kinase kinase-1 (MEK-1)–ERK-1/2 pathway, abolished ERK-1/2 and NF-κB activation and ET B upregulation. NF-κB inhibition also prevented RLX-mediated ET B stimulation. In NF-κB-luciferase reporter assays, we demonstrated complete inhibition of RLX-induced NF-κB activation in cells transfected with dominant-negative Raf-1, MEK-1, or ERK-1/2 constructs, whereas dominant-negative Ras had no effect. In rat aorta and mesenteric artery, RLX pretreatment, in an ET B -dependent fashion, mitigated the maximum contractile response to endothelin-1, by 38±4% and 43±6%, and the endothelin-1 sensitivity (−log[EC 50 ]: aorta, 8.2±0.2 for vehicle versus 7.2±0.2 for RLX; mesenteric artery, 8.0±0.2 for vehicle versus 7.1±0.1 for RLX). RLX pretreatment augmented the dilator effect of the ET B agonist endothelin-3 by 100±8% and 133±13%. In conclusion, RLX stimulates endothelial and epithelial ET B via a Ras-independent Raf-1–MEK-1–ERK-1/2 pathway that activates NF-κB. On vascular smooth muscle cells, ET B , a contributor to endothelin-mediated vasoconstriction, remains unaffected. This renders RLX a functional endothelin-1 antagonist.
Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing
Authors: Mitchell S Stark, Susan L Woods, Michael G Gartside, Vanessa F Bonazzi, Ken Dutton-Regester, Lauren G Aoude, Donald Chow, Chris Sereduk, Natalie M Niemi, Nanyun Tang, Jonathan J Ellis, Jeffrey Reid, Victoria Zismann, Sonika Tyagi, Donna Muzny, Irene Newsham, YuanQing Wu, Jane M Palmer, Thomas Pollak, David Youngkin, Bradford R Brooks, Catherine Lanagan, Christopher W Schmidt, Bostjan Kobe, Jeffrey P MacKeigan, Hongwei Yin, Kevin M Brown, Richard Gibbs, Jeffrey Trent, Nicholas K Hayward
Journal: Nature Genetics (2011)
Therapeutic Use of Calcimimetics
Authors: Steven C. Hebert
Journal: Annual Review of Medicine (2006)

It has long been recognized that the secretion of PTH by chief cells in the parathyroid gland is regulated by extracellular ionized calcium. The molecular mechanism by which extracellular Ca2+ performs this feat was deduced by the cloning of the extracellular calcium-sensing receptor (CaSR) in 1993 in the laboratories of Brown and Hebert. The CaSR is a G protein-coupled cell surface receptor that belongs to family 3 of the GPCR superfamily. The CaSR senses the extracellular ionic activity of the divalent minerals Ca2+ and Mg2+ and translates this information, via a complex array of cellular signaling pathways, to modify cell and tissue function. Genetic studies have demonstrated that the activity of this receptor determines the steady-state plasma calcium concentration in humans by regulating key elements in the calcium homeostatic system. CaSR agonists (calcimimetics) and antagonists (calcilytics) have been identified and have provided both current and potential therapies for a variety of disorders. Calcimimetics can effectively reduce PTH secretion in all forms of hyperparathyroidism. They are likely to become a major therapy for secondary hyperparathyroidism associated with renal failure and for treatment of certain patients with primary hyperparathyroidism. On the therapeutic horizon are calcilytics that can transiently increase PTH and may prove useful in the treatment of osteoporosis.
The Trifunctional Antibody Ertumaxomab Destroys Tumor Cells That Express Low Levels of Human Epidermal Growth Factor Receptor 2
Authors: Michael Jäger, Alexandra Schoberth, Peter Ruf, Jürgen Hess, Horst Lindhofer
Journal: Cancer Research (2009)

Human epidermal growth factor receptor 2 (HER2/neu) is an important target for the treatment of the breast cancers in which it is overexpressed. However, no approved anti-HER2/neu therapy is available for the majority of breast cancer patients, who express HER2/neu at low levels (with scores of 1+ or 2+/fluorescence in situ hybridization-negative). The trifunctional antibody ertumaxomab targets HER2/neu, CD3, and activating Fcgamma receptors. In presence of ertumaxomab, tri-cell complexes consisting of tumor cells, T cells, and accessory cells form to cause tumor cell lysis. In a phase I trial with metastatic breast cancer patients, ertumaxomab could be applied safely and resulted in radiographically confirmed clinical responses. In this study, we compare ertumaxomab- and trastuzumab-mediated killing of cancer cell lines that express HER2/neu at low and high levels. Under optimal conditions for trastuzumab-mediated destruction of HER2/neu-overexpressing cells, only ertumaxomab was able to mediate the elimination of tumor cell lines that express HER2/neu at low levels (1+). Ertumaxomab-mediated activity was accompanied by a Th1-based cytokine release, a unique mode of action of trifunctional antibodies. Competitive binding studies with trastuzumab and 520C9 mapped the binding site of ertumaxomab to the extracellular regions II and III of the HER2/neu ectodomain. This site is distinct from the binding site of trastuzumab, so that HER2/neu-expressing tumor cells can be eliminated by ertumaxomab in the presence of high amounts of trastuzumab. The ability of ertumaxomab to induce cytotoxicity against various tumor cell lines, including those with low HER2/neu antigen density, may provide a novel therapeutic option for breast cancer patients who are not eligible for trastuzumab treatment.
Corneal Confocal Microscopy Shows an Improvement in Small-Fiber Neuropathy in Subjects With Type 1 Diabetes on Continuous Subcutaneous Insulin Infusion Compared With Multiple Daily Injection
Authors: Shazli Azmi, Maryam Ferdousi, Ioannis N. Petropoulos, Georgios Ponirakis, Hassan Fadavi, Mitra Tavakoli, Uazman Alam, Wendy Jones, Andrew Marshall, Maria Jeziorska, Andrew J.M. Boulton, Nathan Efron, Rayaz A. Malik
Journal: Diabetes Care (2014)

Improved glycemic control is the only treatment that has been shown to be effective for diabetic peripheral neuropathy in patients with type 1 diabetes (1). Continuous subcutaneous insulin infusion (CSII) is superior to multiple daily insulin injection (MDI) for reducing HbA1c and hypoglycemic events (2). Here, we have compared the benefits of CSII compared with MDI for neuropathy over 24 months.

A total of 49 subjects with T1DM (18 on CSII vs. 31 on MDI) and 40 age-matched control subjects underwent assessment of vibration perception threshold (VPT), cold threshold (CT), warm threshold (WT), neurophysiology, deep breathing heart rate variability (DB-HRV), intraepidermal nerve fiber density (IENFD), and corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) at baseline and after 24 months.

At baseline, subjects on CSII and MDI were …
Autocrine Stimulation of Cardiac Na <sup>+</sup> -Ca <sup>2+</sup> Exchanger Currents by Endogenous Endothelin Released by Angiotensin II
Authors: Ernesto A. Aiello, María C. Villa-Abrille, Horacio E. Cingolani
Journal: Circulation Research (2002)

The goal of the present study was to evaluate the effects of Ang II on the current produced by the Na + -Ca 2+ exchanger ( I NCX ) working in the reverse mode and the possible autocrine role played by the release of endothelin (ET) in these actions. I NCX was studied in isolation in cat cardiac myocytes. Angiotensin II (Ang II) (100 nmol/L) increased I NCX at potentials higher than 0 mV (at +60 mV: 2.07±0.22 pA/pF in control versus 2.73±0.22 pA/pF in Ang II, n=9; P &lt;0.05). The increase in I NCX induced by Ang II was prevented by the treatment of the cells with the unspecific blocker of the ET receptors, TAK 044 (1 μmol/L) (at +60 mV: 2.15±0.27 pA/pF in control versus 2.01±0.26 pA/pF in Ang II, n=5, NS). These results show, for the first time, that the effect of Ang II on I NCX is the result of the autocrine actions of ET released by the octapeptide.
Early Risk Factors and Developmental Pathways to Chronic High Inhibition and Social Anxiety Disorder in Adolescence
Authors: Marilyn J. Essex, Marjorie H. Klein, Marcia J. Slattery, H. Hill Goldsmith, Ned H. Kalin
Journal: American Journal of Psychiatry (2009)

Evidence suggests that chronic high levels of behavioral inhibition are a precursor of social anxiety disorder. The authors sought to identify early risk factors for, and developmental pathways to, chronic high inhibition among school-age children and the association of chronic high inhibition with social anxiety disorder by adolescence.