tbuckley/cabot-search huggingface dataset:
Book: Clinical Governance: Making it Happen
Authors: P. Garside
Journal: BMJ (1999)

Eds Miriam Lugon, Jonathan Secker-Walker Royal Society of Medicine Press, £17.50, pp 222 ISBN 1853153834 Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img> This book comprises 13 chapters by various contributors addressing aspects of clinical governance. The chapters cover organisational, legal, educational, informational, and patient perspectives and an extremely useful guide to sources of information. The contributions are of a high standard, notwithstanding the different style and approach of each. To me, however, the book was missing two chapters—on professional self regulation as a critical component of clinical governance, … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
800. Generation of Recombinant Skin In Vitro by Adeno-Associated Virus Type 2 Vector Transduction
Authors: Nalini Agrawal, Yong Liu, Jawahar L. Mehta, Hong You, Paul L. Hermonat
Journal: Molecular Therapy (2004)

It has long been recognized that skin may be a particularly good target for pharmacologic gene therapy and as a platform for the secreting of systemically distributed molecules. Adeno-associated virus (AAV type 2) might be a useful vector for such skin gene therapy as skin is the natural host tissue for AAV in which it functions as an autonomous parvovirus. Here it is shown that recombinant (r)AAV vectors containing the granulocyte macrophage-colony stimulating factor (GM-CSF), human papillomavirus E6, or green fluorescent protein (GFP) transgenes could transduce primary human keratinocytes in ex vivo culture and that these transduced cells could then be used to form a transgene-positive recombinant skin using the organotypic epithelial raft culture system. Transduction of keratinocytes was demonstrated by six different techniques: reverse transcriptase-polymerase chain reaction (RT-PCR) for RNA expression, enzyme linked immunosorbant assay (ELISA) for product secretion, intracellular staining for protein expression, vector-chromosomal junction PCR and Southern blot analysis of proviral sequences, and in situ immunohistochemistry and ultraviolet light fluorescence for GFP protein expression. ELISA demonstrated that AAV/GM-CSF/Neo infected keratinocyte/raft skins secreted GM-CSF (measured as high as 25 ng/cm2 of skin) and maintained expression out to 60 days post-infection. These data support the utility and efficiency of AAV-based gene delivery to produce genetically altered keratinocytes and r-skin.
Quantitative Analysis of Friend's Disease in Two Inbred Strains of Mice with Emphasis on Bone Marrow Response
Authors: Frederic C. Ludwig, Warren L. Bostick, Mary L. Epling
Journal: Cancer Research (1964)

Summary  The anatomical expression of a murine viral leukemia depends on variables of the host as well as of the virus (20). After inoculating two inbred strains of mice with Friend9s virus, we compared numerical changes of the marrow cells, peripheral leukocytes, and organ weights at predetermined intervals.  Friend9s disease engenders measurable changes in the bone marrow that disclose significant differences between the two inbred strains. Although most stem cells of both strains proliferate, they proliferate at different rates. The erythroblasts show a qualitatively different response. Correlation between organ weights, marrow cell counts, and the time at which the peripheral blood becomes leukemic suggests that the leukemic blood cells in Friend9s disease are released by the spleen, despite conspicuous alterations of the bone marrow.  The experiments show that the progress of the leukemic process can be measured as a function of controllable host factors.
Comparative Study of Bone Marrow and Blood B Cells in Infantile and Acquired Agammaglobulinemia
Authors: Nabih I. Abdou, Salvatore R. Casella, Nancy L. Abdou, Ises A. Abrahamsohn
Journal: Journal of Clinical Investigation (1973)

The status of immunoglobulin (Ig) receptors of the bone marrow dependent (B) cells present in either the bone marrow (BM) or peripheral blood (PB) of three patients with infantile agammaglobulinemia (I-AGG), or seven patients with acquired agammaglobulinemia (A-AGG) is compared with those of 12 controls. Quantitative and qualitative changes of the different classes of Ig receptors on B cells were evaluated by their capacity to bind [125I]anti-Ig, to be stained with fluorescinated anti-Ig and their in vitro proliferative capacity upon incubation with the anti-Ig. Patients with I-AGG lacked B cells in both the BM and PB. Whereas BM cells of patients with A-AGG carried receptors similar to control cells, their blood B cells had fewer IgM, IgG, and IgA cells which failed to proliferate in vitro in the presence of the anti-Ig. An anti-IgM of the IgG class was detected in the sera of patients with A-AGG but not in sera of I-AGG. The isolated anti-IgM agglutinated human red cells coated with IgM. The anti-IgM partially blocked the binding of fluorescinated or radiolabeled anti-IgM to IgM peripheral blood lymphocytes of normal controls. The eluted anti-IgM in presence of complement was partially cytotoxic to normal cells. It is concluded that I-AGG-B cell defect is due to failure of B cell development in the bone marrow compartment whereas the peripheral exclusion of IgM cells by an anti-IgM with the subsequent failure of differentiation of both IgG and IgA cells could be an important mechanism in A-AGG-B cell defect.
The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke
Authors: P Sandercock, R Collins, C Counsell, B Farrell, R Peto, J Slattery, C Warlow, S Anderson, A Bowie, J Boyle, A Brownlie, D Charlton, G Cranswick, L Day, M Dennis, P Dorman, H Fraser, M Kaye, R Lindley, M Liu, C MacDonald, I McCrindle, G Middleton, D Perry, V Scoltock, B Smith, H Taylor, F Waddell, J Wardlaw, J Crowther, J Heineman, S Knight, A Radley, R Ripley, S Richards, S Wilberforce, Z M Chen, J vanGijn, M Harrison, L Wilhelmsen
Journal: The Lancet (1997)
Abstract 280: Association of Bystander CPR Rates with County-Level Median Household Income in Pennsylvania
Authors: Kam Ching Li, Julie E Griff, Elizabeth K Heisler, Anne V Grossestreuer, Marion Leary, Benjamin S Abella, Lance B Becker
Journal: Circulation (2014)

Background: Each year, &gt;300,000 people suffer from out-of-hospital cardiac arrest (OHCA) in the U.S. Studies have shown that bystander CPR (BCPR) can greatly increase a victim’s chance of survival, yet the frequency of BCPR may vary as a byproduct of various demographic factors. Over 10,000 OHCAs occur in Pennsylvania each year across 67 counties. Objective: We sought to determine the association of bystander CPR rate with county-level median household income, as well as related factors, such as education level, persons below poverty status, and population density. Methods: Data were obtained from the Cardiac Arrest Registry to Enhance Survival (CARES) for Pennsylvania from 1/2012-12/2013 to determine rate of BCPR and return of spontaneous circulation (ROSC) by county. Demographic information regarding education level, median household income and population density were obtained from 2010 U.S. Census data. Counties were grouped into quartiles by lowest to highest rates of BCPR. Results from the lowest-performing were compared to the highest-performing quartile, with statistical analysis using STATA v11 (StataCorp, College Station, Texas). Results: A total of 7137 cases were included distributed across 47 counties. Mean age of patients was 63.7 years, 40.1% were female, and VF/VT was the initial rhythm in 19.7%. Median BCPR rate for the lowest-performing quartile was 7% (IQR 0%-26.5%). Median BCPR rate for the highest-performing quartile was 50.4% (IQR 46.95%-56%). Median ROSC rate for the lowest-performing quartile was 1.5% (IQR 0%-20%). Median ROSC rate for the highest-performing quartile was 23.3% (IQR 20.8%-33.3%). Median household income in the lowest-performing quartile was significantly lower than in the highest-performing quartile ($43611 ± $5038 v $50225 ± $6661, p = 0.023). Education level, persons below poverty status, and population density were not shown to have a significant association with BCPR rate. BCPR rate was positively associated with ROSC rate (p=0.001). Conclusions: BCPR rates are significantly higher in counties with higher median household income. Higher BCPR rates are associated with higher rates of ROSC. These findings have important implications for statewide public health efforts to improve arrest survival.
Detection of HER2 and CK-19 mRNA-positive circulating tumor cells (CTCs) in the peripheral blood of patients with early stage breast cancer.
Authors: D. Mavroudis, S. Apostolaki, M. Perraki, E. Politaki, N. Xenidis, A. Stathopoulou, E. Lianidou, V. Georgoulias.
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5148 

Purpose: To investigate the predictive and prognostic value of the simultaneous detection of HER2 and CK-19 mRNA-positive CTCs in the peripheral blood of patients with early stage breast cancer. Patients and Methods: Peripheral blood was obtained from 217 patients with stage I and II breast cancer after primary surgery and before the initiation of any systemic adjuvant therapy, and was analyzed for the presence of HER2 and CK-19 mRNA-positive CTCs using a nested RT-PCR and real time PCR, respectively. The association with known prognostic factors and the effect of HER2 and/or CK-19 mRNA-positive CTCs on patients’ prognosis was investigated. Results: HER2 and CK-19 mRNA-positive CTCs were detected in the blood of 64(29%) and 65(30%) of the 217 patients, respectively; 32(49%) of CK19-positive patients were also HER2-positive whereas 97(45%) of patients had CK19 and/or HER2 mRNA-positive CTCs. There was no correlation between the detection of CTCs and the different known pathologic and clinical prognostic factors. After a median follow up of 65 months, the incidence of recurrence was 52.3% and 11.8% for patients with CK19-positive and -negative CTCs, respectively (p=0.0001); similarly for patients with HER2-positive and -negative CTCs recurrence rates were 34.4% and 19.6%, respectively (p=0.02). The median disease-free interval as well as overall survival were significantly higher in patients with CK19/HER2-positive or CK19-positive/HER2-negative but not CK19-negative/HER2-positive CTCs as compared with those with non-detectable CTCs. Conclusion: The simultaneous detection of CK-19 and HER2 mRNA-positive CTCs provides clinically useful predictive and prognostic information for patients with early stage breast cancer.
14O_PR Biology of Breast Cancer Diagnosed in Young Women: Pooled Gene Expression Analysis From 3522 Patients
Authors: H.A. Azim, S. Michiels, P.L. Bedard, S.K. Singhal, C. Criscitiello, M. Ignatiadis, B. Haibe-Kains, M. Piccart, C. Sotiriou, S. Loi
Journal: Annals of Oncology (2012)
Abstract 11749: Cell-Specific Expression of Voltage-Sensitive Protein Confirms Cardiac Myocyte to Non-Myocyte Electrotonic Coupling in Healed Murine Infarct Border Tissue
Authors: T. Alexander Quinn, Patrizia Camelliti, Urszula Siedlecka, Tommaso Poggioli, Leslie M Loew, Thomas Knöpfel, Peter Kohl
Journal: Circulation (2014)

Introduction: Heterocellular electrotonic coupling of cardiac myocytes and non-myocytes is common in vitro , yet its presence, extent and role in vivo are debated. Optogenetic tools provide a unique means for cell-specific assessment of electrophysiology. Here, we utilise the genetically-encoded voltage-sensitive fluorescent protein 2.3 (VSFP2.3) to monitor transmembrane potential (Vm) in myocytes or fibroblasts of isolated murine hearts.

Methods: Transgenic mice expressing VSFP2.3 under the control of either alpha-myosin heavy chain promoter (αMHC; myocytes) or Wilm’s tumor promoter (WT1; fibroblasts) were generated by Cre-LoxP recombination. Infarcts (left ventricular freewall) were caused by cryoablation, followed by 8 weeks recovery. Vm was measured in mechanically-uncoupled (10μM blebbistatin) Langendorff-perfused hearts by simultaneous collection of VSFP2.3 donor (mCerulean; CFP) and acceptor (citrine; YFP), or of VSFP2.3 YFP and voltage-sensitive dye (di-4-ANBDQPQ) signals, using an EMCCD camera (128х128 pixels, 511Hz) on an upright microscope (10х water-immersion lens). Cell-specificity of transgene expression was confirmed post hoc by immunohistochemistry (myomesin for myocytes, vimentin for fibroblasts) using confocal microscopy.

Results: Cardiomyocyte action potentials (AP) were successfully measured in αMHC-VSFP2.3 mice by CFP/YFP ratiometry. After adding di-4-ANBDQPQ to these hearts, signal comparison reconfirmed slower AP upstroke and repolarisation kinetics of VSFP2.3 (Fig.A). Strikingly, myocyte-like AP were also recorded, in (dye-free) WT1-VSFP2.3 hearts, from fibroblasts at the infarct border zone (Fig.B).

Conclusions: Results demonstrate the utility of VSFP2.3 for cell-specific cardiac electrophysiology research. In addition, observation of AP-like potentials in non-excitable cells confirms in vivo electrotonic coupling of cardiac myocytes and non-myocytes in healed murine infarct border tissue.

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Abstract 1946: Inhibition of IKK/NF-κB impairs glioma stem cell function
Authors: Amanda L. Rinkenbaugh, Patricia C. Cogswell, Albert S. Baldwin
Journal: Cancer Research (2014)

Abstract Glioma, the most frequently occurring primary brain tumor, has a median survival of less than 15 months, despite multimodal treatment combining surgery, radiation, and chemotherapy. It has been suggested that the presence of cancer stem cells (CSCs) within these tumors are responsible for resistance to treatment and high probability of recurrence. As a result, there is increasing interest in specifically targeting CSCs with new therapies to improve treatment of this disease. NF-κB has been implicated in numerous forms of cancer, as its target genes regulate hallmarks of cancer such as cell proliferation, survival, and invasion. Both glioma cell lines and tumor samples show high levels of phosphorylated p65, a marker of NF-κB activation. When comparing populations from tumor explants, NF-κB is preferentially activated in the CSC subset. We are examining the effects of IKK/NF-κB inhibition on both heterogeneous glioma explants and purified (CD133+) CSCs from these explants. Inhibition of NF-κB through either genetic or pharmacological means abrogates neurosphere formation, an in vitro measure of stem cell function. Additionally, real-time PCR analysis indicates that inhibition of NF-κB leads to a decrease in target genes implicated in glioma CSC biology, such as A20 and IL-6. We have also studied our glioma explants in both subcutaneous and intracranial xenografts to examine the role of NF-κB in vivo. We are utilizing microarrays to define the NF-κB-dependent gene expression signature in CD133+ cells. Our studies indicate a significant role for the NF-κB pathway in the biology of glioma CSCs, with possible parallels in CSCs of other tumor types. Citation Format: Amanda L. Rinkenbaugh, Patricia C. Cogswell, Albert S. Baldwin. Inhibition of IKK/NF-κB impairs glioma stem cell function. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1946. doi:10.1158/1538-7445.AM2014-1946
Parenteral treprostinil for significant pulmonary arterial hypertension associated with pulmonary fibrosis: A safety study
Authors: Rajeev Saggar, Dinesh Khanna, John Belperio, Shelley Shapiro, Rajan Saggar
Journal: European Respiratory Journal (2011)

Objectives: Safety & efficacy of treprostinil (IV/SQ) in patients with pulmonary fibrosis (PF) and PAH.

Methods: Prospective, open label trial of patients referred for lung transplantation with PF/PAH (mean PA >35 mmHg & PVR >3 WU), treated treprostinil × 12 weeks.

Results: N=14 received treprostinil (18-97 ng/kg/min). The hemodynamics, 6MW, BNP, and UCSD/SF 36 significantly improved. No significant changes were seen in peripheral oxygen at rest or during 6MW.

View this table:

Table 1 Baseline characteristics





![Figure][1] 



![Figure][1] 



Conclusions: Chronic administration of treprostinil is well tolerated in patients with PF/PAH. Prospective, multicenter, randomized-controlled studies are warranted to verify these results

 [1]: pending:yes
Myosin Light Chain Kinase Signaling in Endothelial Barrier Dysfunction
Authors: Robert R. Rigor, Qiang Shen, Christopher D. Pivetti, Mack H. Wu, Sarah Y. Yuan
Journal: Medicinal Research Reviews (2012)

Microvascular barrier dysfunction is a serious problem that occurs in many inflammatory conditions, including sepsis, trauma, ischemia-reperfusion injury, cardiovascular disease, and diabetes. Barrier dysfunction permits extravasation of serum components into the surrounding tissue, leading to edema formation and organ failure. The basis for microvascular barrier dysfunction is hyperpermeability at endothelial cell-cell junctions. Endothelial hyperpermeability is increased by actomyosin contractile activity in response to phosphorylation of myosin light chain by myosin light chain kinase (MLCK). MLCK-dependent endothelial hyperpermeability occurs in response to inflammatory mediators (e.g., activated neutrophils, thrombin, histamine, tumor necrosis factor alpha, etc.), through multiple cell signaling pathways and signaling molecules (e.g., Ca(++) , protein kinase C, Src kinase, nitric oxide synthase, etc.). Other signaling molecules protect against MLCK-dependent hyperpermeability (e.g., sphingosine-1-phosphate or cAMP). In addition, individual MLCK isoforms play specific roles in endothelial barrier dysfunction, suggesting that isoform-specific inhibitors could be useful for treating inflammatory disorders and preventing multiple organ failure. Because endothelial barrier dysfunction depends upon signaling through MLCK in many instances, MLCK-dependent signaling comprises multiple potential therapeutic targets for preventing edema formation and multiple organ failure. The following review is a discussion of MLCK-dependent mechanisms and cell signaling events that mediate endothelial hyperpermeability.
Abstract 603: TNFR1 is indispensable in the development of spontaneous lung squamous cell carcinomas
Authors: Zuoxiang Xiao, Jami Willette-Brown, Yinling Hu, Sichuan Xi
Journal: Cancer Research (2014)

Abstract We recently reported that kinase-dead IKKα knockin mice, in which an ATP binding site of IKKα, Lys 44 was replaced by alanine (IkkαKA/KA), develop spontaneous lung SCCs that were closely associated with lung inflammatory microenvironment. This mouse model resembles human lung SCCs, sheds light on the mechanisms underlying lung malignancy development, and identifies targets for therapy of lung SCCs (Xiao et al. Cancer Cell 23(4):527-40, 2013). To further elucidate what and how the inflammatory stimuli contribute to the tumorigenesis, we generated bitransgenic mice harboring IkkαKA/KA and tnfrsf1-/- (KALTFR). It was identified that the KALTFR mice display lung tumor-free even the lung inflammations are still severe, while almost all of the littermate IkkαKA/KA mice developed lung SCCs. Interestingly, we found a noticeably increased TNFR1 expression in the lung SCCs of IkkαKA/KA mice compared to normal lung tissues. It has also been detected that the TNFR1 expressions are significantly higher in both transcript and protein levels in human lung SCCs with the compare to their adjacent tissues. These findings indicate that TNFR1 may play a crucial role in the development of lung SCC in either IkkαKA/KA mice or humans. Further investigation demonstrated that TNFR1 is a critical factor to regulate nuclear transcriptional factors and oncogenes including C-Myc, through one bromodomain (BRD) proteins- containing complex. These findings broaden our understanding about how inflammatory microenvironment contributes to tumorigenesis through TNFα-TNFRs engagements. Citation Format: Zuoxiang Xiao, Jami Willette-Brown, Yinling Hu, Sichuan Xi. TNFR1 is indispensable in the development of spontaneous lung squamous cell carcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 603. doi:10.1158/1538-7445.AM2014-603
Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia
Authors: Ashkan Emadi, Rawan Faramand, Brandon Carter‐Cooper, Seda Tolu, Laurie A. Ford, Rena G. Lapidus, Meir Wetzler, Eunice S. Wang, Arash Etemadi, Elizabeth A. Griffiths
Journal: American Journal of Hematology (2015)

Mutations in IDH1 and IDH2 occur in 15-20% of AML cases, resulting in the production of 2-hydroxyglutarate, which promotes aberrant hypermethylation of DNA in leukemic cells. Although these mutations have been shown to have prognostic implications for patients with AML, optimal treatment strategies have yet to be defined. We retrospectively identified forty-two patients with AML treated with DNA methyltransferase inhibitors (DNMTIs) decitabine (n = 36) or azacitidine (n = 6) and performed analysis of stored samples for the presence of IDH1 and IDH2 mutations. Of the forty-two samples analyzed, seven (16.7%) had IDH mutations. Thirteen patients (31%) achieved remission [(complete remission (CR)/complete remission with incomplete count recovery (CRi)/partial response (PR)] after treatment with a DNMTI, five of seven (71.4%) with IDH mutations and eight of thirty-five (22.9%) without IDH mutations (P = 0.01). When adjusted for age at diagnosis, sex, bone marrow blast percentage and cytogenetic, the odds of achieving response after administration of a DNMTI among patients with an IDH mutation was 14.2 when compared to patients without an IDH mutation (95%CI: 1.3-150.4). IDH1 and IDH2 mutations may predict a favorable response to DNMTI in patients with AML.
Lesson of the week: Unsuspected nephrogenic diabetes insipidus
Authors: A Waise, R A Fisken
Journal: BMJ (2001)

Long term treatment with lithium can lead to nephrogenic diabetes insipidus by making distal renal tubules resistant to the action of vasopressin.1–3 Polyuria and polydipsia are the likely clinical features, but the condition may not always be clinically apparent; especially when the underlying condition has not been recognised. We report two cases, seen between 1991 and 1995, in which severe and potentially life threatening water depletion and hypernatraemia became apparent when the patients were admitted to hospital.
Cholic Acid Biosynthesis
Authors: Gerald Salen, S. Shefer, F. W. Cheng, B. Dayal, A. K. Batta, G. S. Tint
Journal: Journal of Clinical Investigation (1979)

Cholic acid biosynthesis is defective in individuals with cerebrotendinous xanthomatosis (CTX) and is associated with the excretion of 5β-cholestane-3α,7α, 12α,25-tetrol, an intermediate in the 25-hydroxylation pathway of cholic acid in CTX. To define the enzymatic defect in CTX, two suspected precursors of cholic acid, namely 5β-[7β-3H]cholestane-3α,7α, 12α-triol and 5β-[24-14C]cholestane-3α,7α, 12α,24S,25-pentol were examined by both in vivo and in vitro experiments. A third precursor, 5β-[7β-3H]-cholestane-3α,7α, 12α,25-tetrol, was compared with them in vitro.