tbuckley/cabot-search huggingface dataset:
New diagnostic imaging tools for inflammatory bowel disease
Authors: B A MacKalski
Journal: Gut (2006)

The diagnosis of Crohn’s disease is established through an assessment of the clinical presentation with confirmatory evidence from radiographic, endoscopic, and pathological findings. As there is no known cure, and the condition runs a relapsing course, patients are recurrently reinvestigated. Although ultimately curable by colectomy, many patients with ulcerative colitis (UC) are managed medically for years, and require investigations to define the extent of disease, to re-examine diagnosis validity as clinical findings change, and to facilitate dysplasia surveillance. Imaging studies in these diseases serve to establish the primary diagnosis and to provide information for guiding the management of patients with known disease.1

Conventional investigations in patients with suspected or proven inflammatory bowel disease include colonoscopy, ileal intubation, and small bowel follow through (SBFT) or small bowel enteroclysis (SBE). It is recognised that these diagnostic modalities may not be uniformly confirmatory. Complete colonoscopy is not always possible due to technical difficulties, poor preparation, or patient intolerance. While the rate of ileal intubation by experienced endoscopists is reported to be 74%, that rate exceeds 90% when intubation is deemed necessary.2 A recent study reports that the rate of ileal intubation is low in the presence of an endoscopically normal colon, even when symptoms suggestive of inflammatory bowel disease are present.3 Of the 20 638 patients who underwent colonoscopy in the setting of an endoscopically normal colon for the indication of abdominal pain, diarrhoea, or anaemia, ileal intubation was performed only 18% of the time.

SBFT is considered a reliable approach to imaging the small bowel in inflammatory bowel disease, provided that it is a dedicated study, incorporating fluoroscopy with manual manipulation.4 The sensitivity and specificity of SBFT in terminal ileal disease is reported in the range of 85–95% and 89–94%, respectively, but these parameters are highly dependent on …
Cardioselective Infection With Coxsackievirus B3 Requires Intact Type I Interferon Signaling
Authors: Rainer Wessely, Karin Klingel, Kirk U. Knowlton, Reinhard Kandolf
Journal: Circulation (2001)

Background —Interferons (IFNs) play an important role in antiviral defense and have therapeutic potential in coxsackievirus heart disease. However, little is known about the relative contributions of type I and type II IFN signaling in coxsackievirus B3 (CVB3) infection or their role in the cardioselective nature of CVB3 infection. Methods and Results —Wild-type mice and mice deficient for either the type I or the type II IFN receptor (IFNR) were infected with CVB3. Infection of the type I IFNR–deficient mice with &gt;10 3 plaque-forming units (pfu) of CVB3 resulted in 100% mortality within 2 to 4 days after infection. Death was rare in wild-type and type II IFNR–deficient mice after inoculation with as much as 10 8 pfu of CVB3. Surprisingly, the early mortality in the type I IFNR–deficient mice was not accompanied by higher virus titers in the heart. Unexpectedly, a dramatic increase of viral RNA in the liver was found to correlate with early mortality in type I IFNR–deficient mice. Conclusions —Type I but not type II IFN signaling is essential for the prevention of early death due to CVB3 infection. Interestingly, neither type I or type II IFN signaling has a dramatic effect on early viral replication in the heart. However, lethal viral replication in the liver is controlled by type I IFNs. These results demonstrate that the IFN system is capable of modulating both viral pathogenicity and tissue tropism.
Off-Pump Coronary Artery Bypass (OPCAB) Surgery Reduces Risk-Stratified Morbidity and Mortality: A United Kingdom Multi-Center Comparative Analysis of Early Clinical Outcome
Authors: Sharif Al-Ruzzeh, Gareth Ambler, George Asimakopoulos, Rumana Z. Omar, Ragheb Hasan, Brian Fabri, Ahmed El-Gamel, Anthony DeSouza, Vipin Zamvar, Steven Griffin, Daniel Keenan, Uday Trivedi, Mark Pullan, Alex Cale, Michael Cowen, Kenneth Taylor, Mohamed Amrani
Journal: Circulation (2003)

Objective— Off-Pump Coronary Artery Bypass (OPCAB) surgery is gaining more popularity worldwide. The aim of this United Kingdom (UK) multi-center study was to assess the early clinical outcome of the OPCAB technique and perform a risk-stratified comparison with the conventional Coronary Artery Bypass Grafting (CABG) using the Cardio-Pulmonary Bypass (CPB) technique. Methods— Data were collected on 5,163 CPB patients from the database of the National Heart and Lung institute, Imperial College, University of London, and on 2,223 OPCAB patients from eight UK cardiac surgical centers, which run established OPCAB surgery programs. All patients had undergone primary isolated CABG for multi-vessel disease through a midline sternotomy approach, between January 1997 and April 2001. Postoperative morbidity and mortality were compared between the CPB and OPCAB patients after adjusting for case-mix. The mortality of the OPCAB patients was also compared, using risk stratification, to the mortality figures reported by the Society of Cardiothoracic Surgeons of Great Britain and Ireland (SCTS) based on 28,018 patients in the national database who were operated on between January 1996 and December 1999. Results— Morbidity and mortality were significantly lower in the OPCAB patients compared with the CPB patients and the UK national database of CABG patients, over the same period of time, after adjusting for case-mix. Conclusion— This study demonstrates that risk stratified morbidity and mortality are significantly lower in OPCAB patients than CPB patients and patients in the UK national database.
The signature of long-standing balancing selection at the human defensin β-1 promoter
Authors: Rachele Cagliani, Matteo Fumagalli, Stefania Riva, Uberto Pozzoli, Giacomo P Comi, Giorgia Menozzi, Nereo Bresolin, Manuela Sironi
Journal: Genome biology (2008)

Defensins, small endogenous peptides with antimicrobial activity, are pivotal components of the innate immune response. A large cluster of defensin genes is located on human chromosome 8p; among them the beta defensin 1 (DEFB1) promoterhas been extensively studied since discovery that specific polymorphisms and haplotypes associate with asthma and atopy, susceptibility to severe sepsis, as well as HIV and Candida infection predisposition. Here, we characterize the sequence variation and haplotype structure of the DEFB1 promoter region in six human populations. In all of them, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, reduced population differentiation and a genealogy with common haplotypes separated by deep branches. Indeed, a significant departure from the expectation of evolutionary neutrality was observed in all populations and the possibility that this is due to demographic history alone was ruled out. Also, we verified that the selection signature is restricted to the promoter region and not due to a linked balanced polymorphism. A phylogeny-based estimation indicated that the two major haplotype clades separated around 4.5 million years ago, approximately the time when the human and chimpanzee lineages split. Altogether, these features represent strong molecular signatures of long-term balancing selection, a process that is thought to be extremely rare outside major histocompatibility complex genes. Our data indicate that the DEFB1 promoter region carries functional variants and support previous hypotheses whereby alleles predisposing to atopic disorders are widespread in modern societies because they conferred resistance to pathogens in ancient settings.
Interaction of Ipa proteins of Shigella flexneri with alpha5beta1 integrin promotes entry of the bacteria into mammalian cells.
Authors: M Watarai, S Funato, C Sasakawa
Journal: The Journal of Experimental Medicine (1996)

Shigella is a genus of highly adapted bacterial pathogens that cause bacillary dysentery in humans. Bacteria reaching the colon invade intestinal epithelial cells by a process of bacterial-directed endocytosis mediated by the Ipa proteins: IpaB, IpaC, and IpaD of Shigella. The invasion of epithelial cells is thought to be a receptor-mediated phenomenon, although the cellular components of the host that interact with the Ipa proteins have not yet been identified. We report here that in a Shigella flexneri invasive system and Chinese hamster ovary (CHO) cell monolayers, the Ipa proteins were capable of interacting directly with alpha5beta1 integrin. The invasive capacity of S. flexneri for CHO cells increased as levels of alpha5beta1 integrin were elevated. When CHO cells were infected with S. flexneri, the tyrosine phosphorylation both of pp 125FAK, an integrin-regulated 125 K focal adhesion kinase, and of paxillin was stimulated. In contrast, an isogenic strain of S. flexneri that was defective in invasion owing to a mutation in its spa32 gene failed to induce such phosphorylation. Under in vitro and in vivo conditions, the released IpaB, IpaC, and IpaD proteins bound to alpha 5 beta 1 integrin in a manner different from that of soluble fibronectin but similar to that of the tissue form of fibronectin. At the site of attachment of S. flexneri to CHO cells, alpha5beta1 integrin converged with polymerization of actin. These data thus suggest that the capacity of Ipa proteins to interact with alpha5beta1 integrin may be an important Shigella factor in triggering the reorganization of actin cytoskeletons.
Concurrent interspecies and clonal dissemination of OXA-48 carbapenemase
Authors: D.M. Arana, D. Saez, P. García-Hierro, V. Bautista, S. Fernández-Romero, M. Ángel de la Cal, J.I. Alós, J. Oteo
Journal: Clinical Microbiology and Infection (2014)
Effect of a nicotine-free inhalator as part of a smoking-cessation programme
Authors: P. Caponnetto, F. Cibella, S. Mancuso, D. Campagna, G. Arcidiacono, R. Polosa
Journal: European Respiratory Journal (2011)

Smoking-cessation drugs are inadequate at addressing the behavioural component of tobacco dependence. Nicotine-free inhalators are plastic devices that may provide a coping mechanism for conditioned smoking by replacing some of the rituals associated with smoking gestures. This study assessed the effect of using a nicotine-free inhalator to improve success in a cessation programme. At baseline, 120 smokers attending a smoking-cessation programme were assessed for their sociodemographic factors, smoking history, depression, physical and behavioural dependence, and motivation. Participants were randomly assigned to two groups, nicotine-free inhalator group (PAIPO; Echos Srl, Milan, Italy) versus reference group. For the whole sample, no significant difference was found in quit rates at 24 weeks between the PAIPO group and the reference group. However, the quit rate in the PAIPO group (66.7%) was more than three-fold higher than the reference group (19.2%) for those individuals with high Glover–Nilsson Smoking Behavioural Questionnaire (GN-SBQ) scores at baseline. The results of the logistic model analysis indicate that a high GN-SBQ score is a strong independent predictor for successful quitting at 24 weeks (OR 8.88; 95% CI 2.08–37.94) in the PAIPO group. Nicotine-free inhalators may be beneficial when used in the context of smoking-cessation interventions, particularly for those smokers for whom handling and manipulation of their cigarettes plays an important part in the ritual of smoking.
Effective Immunoconjugate Therapy in Cancer Models Targeting a Serine Protease of Tumor Fibroblasts
Authors: Elinborg Ostermann, Pilar Garin-Chesa, Karl Heinz Heider, Milena Kalat, Herbert Lamche, Christina Puri, Dontscho Kerjaschki, Wolfgang J. Rettig, Guenther R. Adolf
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Invasion and metastasis of malignant epithelial cells into normal tissues is accompanied by adaptive changes in the mesenchyme-derived supporting stroma of the target organs. Altered gene expression in these nontransformed stromal cells provides potential targets for therapy. The present study was undertaken to determine the antitumor effects of an antibody-conjugate against fibroblast activation protein-α, a cell surface protease of activated tumor fibroblasts. Experimental Design: A novel antibody-maytansinoid conjugate, monoclonal antibody (mAb) FAP5-DM1, was developed to target a shared epitope of human, mouse, and cynomolgus monkey fibroblast activation protein-α, enabling preclinical efficacy and tolerability assessments. We have used stroma-rich models in immunodeficient mice, which recapitulate the histotypic arrangement found in human epithelial cancers. Results: Treatment with mAb FAP5-DM1 induced long-lasting inhibition of tumor growth and complete regressions in xenograft models of lung, pancreas, and head and neck cancers with no signs of intolerability. Analysis of chemically distinct conjugates, resistance models, and biomarkers implicates a unique mode of action, with mitotic arrest and apoptosis of malignant epithelial cells coupled to disruption of fibroblastic and vascular structures. Conclusions: We show that mAb FAP5-DM1 combines excellent efficacy and tolerability and provides a first assessment of the mode of action of a novel drug candidate for tumor stroma targeting, thus encouraging further development toward clinical testing of this treatment paradigm.
Neonatal Exposure to a Self-Peptide–Immunoglobulin Chimera Circumvents the Use of Adjuvant and Confers Resistance to Autoimmune Disease by a Novel Mechanism Involving Interleukin 4 Lymph Node Deviation and Interferon γ–mediated Splenic Anergy
Authors: Booki Min, Kevin L. Legge, Christopher Pack, Habib Zaghouani
Journal: The Journal of Experimental Medicine (1998)

Induction of neonatal T cell tolerance to soluble antigens requires the use of incomplete Freund's adjuvant (IFA). The side effects that could be associated with IFA and the ill-defined mechanism underlying neonatal tolerance are setbacks for this otherwise attractive strategy for prevention of T cell–mediated autoimmune diseases. Presumably, IFA contributes a slow antigen release and induction of cytokines influential in T cell differentiation. Immunoglobulins (Igs) have long half-lives and could induce cytokine secretion by binding to Fc receptors on target cells. Our hypothesis was that peptide delivery by Igs may circumvent the use of IFA and induce neonatal tolerance that could confer resistance to autoimmunity. To address this issue we used the proteolipid protein (PLP) sequence 139–151 (hereafter referred to as PLP1), which is encephalitogenic and induces experimental autoimmune encephalomyelitis (EAE) in SJL/J mice. PLP1 was expressed on an Ig, and the resulting Ig–PLP1 chimera when injected in saline into newborn mice confers resistance to EAE induction later in life. Mice injected with Ig–PLP1 at birth and challenged as adults with PLP1 developed T cell proliferation in the lymph node but not in the spleen, whereas control mice injected with Ig–W, the parental Ig not including PLP1, developed T cell responses in both lymphoid organs. The lymph node T cells from Ig–PLP1 recipient mice were deviated and produced interleukin (IL)-4 instead of IL-2, whereas the spleen cells, although nonproliferative, produced IL-2 but not interferon (IFN)-γ. Exogenous IFN-γ, as well as IL-12, restored splenic proliferation in an antigen specific manner. IL-12–rescued T cells continued to secrete IL-2 and regained the ability to produce IFN-γ. In vivo, administration of anti–IL-4 antibody or IL-12 restored disease severity. Therefore, adjuvant-free induced neonatal tolerance prevents autoimmunity by an organ-specific regulation of T cells that involves both immune deviation and a new form of cytokine- dependent T cell anergy.
Technologies for Micromanipulating, Imaging, and Phenotyping Small Invertebrates and Vertebrates
Authors: Mehmet Fatih Yanik, Christopher B. Rohde, Carlos Pardo-Martin
Journal: Annual Review of Biomedical Engineering (2011)

Small multicellular model organisms such as the invertebrate nematode C. elegans and the vertebrate zebrafish provide unique opportunities for both basic science and pharmaceutical discovery. In recent years, there have been significant breakthroughs in technologies to manipulate and image these organisms for a variety of purposes ranging from behavioral studies of neuronal circuits to high-throughput screening. Here, we review these advancements with a particular focus on the optically transparent model organisms C. elegans and zebrafish.
Direct Translation of a Protracted Irinotecan Schedule From a Xenograft Model to a Phase I Trial in Children
Authors: Wayne L. Furman, Clinton F. Stewart, Catherine A. Poquette, Charles B. Pratt, Victor M. Santana, William C. Zamboni, Laura C. Bowman, Margaret K. Ma, Fredrick A. Hoffer, William H. Meyer, Alberto S. Pappo, Andrew W. Walter, Peter J. Houghton
Journal: Journal of Clinical Oncology (1999)

PURPOSE: In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd × 5] × 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children. PATIENTS AND METHODS: Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m 2 (qd × 5) × 2 every 21 days. RESULTS: The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m 2 , despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m 2 /d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL). CONCLUSION: This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd × 5) × 2 schedule, beginning at a dose of 20 mg/m 2 . These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.
Consumer, carer, provider, purchaser--developing care for adults with cystic fibrosis: a specialist service.
Authors: A K Webb
Journal: Thorax (1994)

EditorialsConsumer, carer, provider, purchaser -developing care for adults with cystic fibrosis: a specialist service A successful structure for the care of adults with cystic fibrosis must be devised within the framework of the current NHS reforms.By the year 2000 there will be over 3000 adults with the disease -equal to the number of paediatric patients; thereafter there will be more adult than paediatric patients because of the longer survival which it has been predicted will extend into the fourth decade,' and the reduction in the birth rate.Respiratory physicians need to develop this area of growth in their specialty.Over the next decade all respira- tory physicians will, of necessity, acquire practical experi- ence of cystic fibrosis -either during training or as consultants -because of the increasing size of the adult population with the disease.This will test the clinical and personal skills of carers where the end point will remain death of a young adult from pulmonary sepsis.Addition- ally, cystic fibrosis will provide clinical and scientific research potential for decades to come.Cystic fibrosis is distinguished from other respiratory diseases by the ability of young adults, with a sharply focused and limited future, to enunciate their perceived
A randomised trial of sheathed versus standard forceps for obtaining uncontaminated biopsy specimens of microbiota from the terminal ileum
Authors: M. Dave, L. A. Johnson, S. T. Walk, V. B. Young, R. W. Stidham, M. N. Chaudhary, J. FunNell, P. D. R. Higgins
Journal: Gut (2011)

<h3>Background</h3> The study of intestinal microbiota has been revolutionised by the use of molecular methods, including terminal restriction fragment length polymorphism (T-RFLP) analysis. Microbiota studies of Crohn9s disease patients have examined samples from stool or from the neoterminal ileum with a standard biopsy forceps, which could be contaminated by colonic bacteria when the forceps passes through the colonoscope channel. <h3>Objective</h3> To determine whether sheathed biopsy forceps are able to obtain terminal ileal microbiota samples with less colonic bacterial contamination compared with unsheathed (standard) biopsy forceps. <h3>Design</h3> Prospective randomised single-centre study. <h3>Patients and methods</h3> Four (paired) biopsy specimens were obtained from adjacent locations in the terminal ileum using the sheathed and standard forceps of 27 consecutive subjects undergoing colonoscopy and the microbiota were characterised using T-RFLP. The Bray–Curtis similarity index between samples (sheathed vs unsheathed forceps) was calculated within patients and significant differences were tested for across all patients. <h3>Results</h3> There was not a significant difference in the microbial diversity of samples obtained using sheathed versus unsheathed forceps. The difference in microbial diversity between patients was much greater than the variability within patients by proximal versus distal site or by forceps type. <h3>Limitations</h3> T-RFLP is based on PCR amplification, so it is not always sensitive to rare bacterial species. <h3>Conclusion</h3> Standard unsheathed forceps appear to be sufficient for microbiota sample collection from the terminal ileum.
Innate talents: Reality or myth?
Authors: Michael J. A. Howe, Jane W. Davidson, John A. Sloboda
Journal: Behavioral and Brain Sciences (1998)

Talents that selectively facilitate the acquisition of high levels of skill are said to be present in some children but not others. The evidence for this includes biological correlates of specific abilities, certain rare abilities in autistic savants, and the seemingly spontaneous emergence of exceptional abilities in young children, but there is also contrary evidence indicating an absence of early precursors of high skill levels. An analysis of positive and negative evidence and arguments suggests that differences in early experiences, preferences, opportunities, habits, training, and practice are the real determinants of excellence.