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"West, Michael R."
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لورنا دون
يحكي جون رد في هذه القصة الأحداث المثيرة التي وقعت معه في القرية التي يعيش فيها بإقليم \"سومرست\" بإنكلترا عندما تعرف على فتاة أحلامه الأميرة \"لورنا دوني\" عندما كان يصطاد سمك ال\"لوتش\" في أعلى ماء باجويرذي في وادي داوني وهو مكان خطر يسكنه الداونيين وهم قوم شرسين لصوص يترأسهم \"كارفر داوني\" الذي يسعى إلى الزواج من \"لورنا\" ولو بالقوة فهل سيستطيع \"جون ريد\" حماية لورنا داوني من عائلة داوني والدفاع عن أهل منطقته ؟
Book
Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease
Anti-TNFα and anti-IL-23 antibodies are highly effective therapies for Crohn’s disease or ulcerative colitis in a proportion of patients. V56B2 is a novel bispecific domain antibody in which a llama-derived IL-23p19-specific domain antibody, humanised and engineered for intestinal protease resistance, V900, was combined with a previously-described TNFα-specific domain antibody, V565. V56B2 contains a central protease-labile linker to create a single molecule for oral administration. Incubation of V56B2 with trypsin or human faecal supernatant resulted in a complete separation of the V565 and V900 monomers without loss of neutralising potency. Following oral administration of V900 and V565 in mice, high levels of each domain antibody were detected in the faeces, demonstrating stability in the intestinal milieu. In ex vivo cultures of colonic biopsies from IBD patients, treatment with V565 or V900 inhibited tissue phosphoprotein levels and with a combination of the two, inhibition was even greater. These results support further development of V56B2 as an oral therapy for IBD with improved safety and efficacy in a greater proportion of patients as well as greater convenience for patients compared with traditional monoclonal antibody therapies.
Journal Article
Preclinical Development of a Novel, Orally-Administered Anti-Tumour Necrosis Factor Domain Antibody for the Treatment of Inflammatory Bowel Disease
TNFα is an important cytokine in inflammatory bowel disease. V565 is a novel anti-TNFα domain antibody developed for oral administration in IBD patients, derived from a llama domain antibody and engineered to enhance intestinal protease resistance. V565 activity was evaluated in TNFα-TNFα receptor-binding ELISAs as well as TNFα responsive cellular assays and demonstrated neutralisation of both soluble and membrane TNFα with potencies similar to those of adalimumab. Although sensitive to pepsin, V565 retained activity after lengthy incubations with trypsin, chymotrypsin, and pancreatin, as well as mouse small intestinal and human ileal and faecal supernatants. In orally dosed naïve and DSS colitis mice, high V565 concentrations were observed in intestinal contents and faeces and immunostaining revealed V565 localisation in mouse colon tissue. V565 was detected by ELISA in post-dose serum of colitis mice, but not naïve mice, demonstrating penetration of disrupted epithelium. In an
ex vivo
human IBD tissue culture model, V565 inhibition of tissue phosphoprotein levels and production of inflammatory cytokine biomarkers was similar to infliximab, demonstrating efficacy when present at the disease site. Taken together, results of these studies provide confidence that oral V565 dosing will be therapeutic in IBD patients where the mucosal epithelial barrier is compromised.
Journal Article
Oral Anti-Tumour Necrosis Factor Domain Antibody V565 Provides High Intestinal Concentrations, and Reduces Markers of Inflammation in Ulcerative Colitis Patients
V565 is an engineered TNFα-neutralising single domain antibody formulated into enteric coated mini-tablets to enable release in the intestine after oral administration as a possible oral treatment for inflammatory bowel disease (IBD). Following oral administration, ileal recovery of V565 was investigated in four patients with terminal ileostomy. Intestinal and systemic pharmacokinetics were measured in six patients with Crohn’s disease and evidence of target engagement assessed in five patients with ulcerative colitis. Following oral administration, V565 was detected at micromolar concentrations in ileal fluid from the ileostomy patients and in stools of the Crohn’s patients. In four of the five ulcerative colitis patients, biopsies taken after 7d dosing demonstrated V565 in the lamina propria with co-immunostaining on CD3
+
T-lymphocytes and CD14
+
macrophages. Phosphorylation of signalling proteins in biopsies taken after 7d oral dosing was decreased by approximately 50%. In conclusion, enteric coating of V565 mini-tablets provided protection in the stomach with gradual release in intestinal regions affected by IBD. Immunostaining revealed V565 tissue penetration and association with inflammatory cells, while decreased phosphoproteins after 7d oral dosing was consistent with V565-TNFα engagement and neutralising activity. Overall these results are encouraging for the clinical utility of V565 in the treatment of IBD.
Journal Article
Full-time Orthopedic Traumatologists Enhance Value and Increase Pelvic Fracture Caseloads at a Rural Level I Trauma Center
Six years ago Holston Valley Medical Center in Kingsport, Tennessee, implemented a focused program commitment process for American College of Surgeons Committee on Trauma verification of a statedesignated Level I trauma center. Financial studies on the interdependent relationship between hospital-based orthopedic traumatologists and facility charges and revenues confirm a net revenue multiplier effect between orthopedic care and the hospital side of the ledger.2 Orthopedic trauma surgeons may therefore generate hospital revenues at a multiplier rate of seven times their own collection rates, enhanced by busy operating schedules.
Journal Article
Decreased Distribution of Lung Epithelial Junction Proteins after Intratracheal Antigen or Lipopolysaccharide Challenge: Correlation with Neutrophil Influx and Levels of BALF sE-Cadherin
Distribution of airway junctional complex proteins after antigen or lipopolysaccharide challenge in sensitized or naive mice, respectively, was investigated. E-cadherin immunoreactivity was detected continuously along neighboring epithelial cell borders and between adjacent alveolar epithelial cells in naive and saline-challenged mice. Occludin and ZO-1 immunoreactivity were observed in the tight junction areas. Both challenges induced changes in epithelial morphology and phenotype, accompanied initially by focal loss of epithelial E-cadherin that increased in size with time and number of allergen challenges. Allergen challenge also led to focal loss of occludin and ZO-1. Western blot analysis revealed increased levels of sE-cadherin in lavage fluid after either challenge, and this increase correlated with lavage neutrophil numbers (P = 0.002). Immunocytochemistry of lavage cells 6 h after either challenge revealed E-cadherin epitopes within cytoplasmic vacuoles of neutrophils, the major cell type. In contrast, peripheral blood neutrophils or tissue neutrophils before epithelial transmigration were negative, suggesting that in airway inflammation, E-cadherin extracellular domain is cleaved by neutrophils during epithelial penetration, instigating the destabilization of adherens and tight junctions. This junctional deterioration could lead to a progressive decrease in epithelial integrity and induce alterations in epithelial morphology, with consequent enhanced paracellular transit of antigens and pathogens.
Journal Article
Loss of Epithelial Integrity Resulting from E-Cadherin Dysfunction Predisposes Airway Epithelial Cells to Adenoviral Infection
Abstract
Epithelial intercellular adhesion is fundamental to the formation of the airway epithelial protective barrier. In this respect, cadherins are important because these adhesion molecules regulate formation and maintenance of epithelial intercellular junctions. To study the importance of airway epithelial integrity in determining susceptibility to virus infection, we used a replication-incompetent adenovirus, RAd35, and an E-cadherin specific function–blocking antibody, SHE78-7, to disrupt intercellular contacts in human bronchial epithelial cell line 16HBE14o–and primary bronchial epithelial cells. After exposure of 16HBE14o–cell cultures to SHE78-7, disruption of the transepithelial permeability barrier was indicated by a loss of transepithelial electrical resistance and an associated increase of mannitol, inulin, and dextran paracellular flux. Subsequent exposure of SHE78-7–treated cell cultures to RAd35 showed a remarkable increase in adenoviral infection as assessed by β-galactosidase reporter gene expression. In cultures exposed to SHE78-7, disruption of E-cadherin function resulted in infection equivalent to that in control cultures using 16-fold lower viral titers. These studies show that manipulation of E-cadherin function provides a specific means of altering epithelial integrity that in turn determines resistance of airway epithelia to adenoviral infection.
Journal Article
Online Dynamic Parameter Estimation of Synchronous Machines
Traditionally, synchronous machine parameters are determined through an offline characterization procedure. The IEEE 115 standard suggests a variety of mechanical and electrical tests to capture the fundamental characteristics and behaviors of a given machine. These characteristics and behaviors can be used to develop and understand machine models that accurately reflect the machine’s performance. To perform such tests, the machine is required to be removed from service. Characterizing a machine offline can result in economic losses due to down time, labor expenses, etc. Such losses may be mitigated by implementing online characterization procedures. Historically, different approaches have been taken to develop methods of calculating a machine’s electrical characteristics, without removing the machine from service. Using a machine’s input and response data combined with a numerical algorithm, a machine’s characteristics can be determined. This thesis explores such characterization methods and strives to compare the IEEE 115 standard for offline characterization with the least squares approximation iterative approach implemented on a 20 h.p. synchronous machine. This least squares estimation method of online parameter estimation shows encouraging results for steady-state parameters, in comparison with steady-state parameters obtained through the IEEE 115 standard.
Dissertation
Booker T. Washington and the Struggle against White Supremacy: The Southern Educational Tours, 1908-1912
[...] there is a long tradition of giving Washington more credit than is his due regarding economics; after all, he neither invented black entrepreneurialism nor effected any significant transfer of capital into black hands, except what went into the coffers of his patronage and propaganda enterprise, the Tuskegee machine.
Book Review
Teachers versus the Public
A comprehensive exploration of 21st Century school politics,Teachers versus the Publicoffers the first comparison of the education policy views of both teachers and the public as a whole, and reveals a deep, broad divide between the opinions held by citizens and those who teach in the public schools. Among the findings:
• Divisions between teachers and the public are wider and deeper than differences between other groups often thought to contest school policy, such as Republicans and Democrats, the young and the old, the rich and the poor, or African Americans and whites.
• The teacher-public gap is widest on such issues as merit pay, teacher tenure reform, impact of teacher unions, school vouchers, charter schools, and requirements to test students annually.
• Public support for school vouchers for all students, charter schools, and parent trigger laws increases sharply when people are informed of the national ranking of student performance in their local school district.
• Public willingness to give local schools high marks, its readiness to support higher spending levels, and its support for teacher unions all decline when the public learns the national ranking of their local schools.
• On most issues, teacher opinion does not change in response to new information nearly as much as it does for the public as a whole. In fact, the gap between what teachers and the public think about school reform grows even wider when both teachers and the public are given more information about current school performance, current expenditure levels, and current teacher pay.
The book provides the first experimental study of public and teacher opinion. Using a recently developed research strategy, the authors ask differently worded questions about the same topic to randomly chosen segments of representative groups of citizens. This approach allows them to identify the impact on public opinion of new information on issues such as student performance and school expenditures in each respondent's community.
The changes in public opinion when citizens receive information about school performance are largest in districts that perform below the national average. Altogether, the results indicate that support for many school reforms would increase if common core state standards were established and implemented in such a way as to inform the public about the quality of their local schools. These and many other findings illuminate the distance between teacher opinions and those of the public at large.
About the Research:In partnership with the Harvard Program on Education Policy and Governance and the journal, Education Next, authors Paul E. Peterson, Martin West and Michael Henderson surveyed nationally representative samples of teachers and the public as a whole annually between 2007 and 2013.
eBook