tbuckley/cabot-search huggingface dataset:
A Multiscale Mathematical Model for Oncolytic Virotherapy
Authors: Leticia R. Paiva, Christopher Binny, Silvio C. Ferreira, Marcelo L. Martins
Journal: Cancer Research (2009)

One of the most promising strategies to treat cancer is attacking it with viruses. Oncolytic viruses can kill tumor cells specifically or induce anticancer immune response. A multiscale model for virotherapy of cancer is investigated through simulations. It was found that, for intratumoral virus administration, a solid tumor can be completely eradicated or keep growing after a transient remission. Furthermore, the model reveals undamped oscillatory dynamics of tumor cells and virus populations, which demands new in vivo and in vitro quantitative experiments aiming to detect this oscillatory response. The conditions for which each one of the different tumor responses dominates, as well as the occurrence probabilities for the other nondominant therapeutic outcomes, were determined. From a clinical point of view, our findings indicate that a successful, single agent virotherapy requires a strong inhibition of the host immune response and the use of potent virus species with a high intratumoral mobility. Moreover, due to the discrete and stochastic nature of cells and their responses, an optimal range for viral cytotoxicity is predicted because the virotherapy fails if the oncolytic virus demands either a too short or a very large time to kill the tumor cell. This result suggests that the search for viruses able to destroy tumor cells very fast does not necessarily lead to a more effective control of tumor growth.
Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations
Authors: Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Xaver Baur, Graham L. Hall, Bruce H. Culver, Paul L. Enright, John L. Hankinson, Mary S.M. Ip, Jinping Zheng, Janet Stocks
Journal: European Respiratory Journal (2012)

The aim of the Task Force was to derive continuous prediction equations and their lower limits of normal for spirometric indices, which are applicable globally. Over 160,000 data points from 72 centres in 33 countries were shared with the European Respiratory Society Global Lung Function Initiative. Eliminating data that could not be used (mostly missing ethnic group, some outliers) left 97,759 records of healthy nonsmokers (55.3% females) aged 2.5-95 yrs. Lung function data were collated and prediction equations derived using the LMS method, which allows simultaneous modelling of the mean (mu), the coefficient of variation (sigma) and skewness (lambda) of a distribution family. After discarding 23,572 records, mostly because they could not be combined with other ethnic or geographic groups, reference equations were derived for healthy individuals aged 3-95 yrs for Caucasians (n=57,395), African-Americans (n=3,545), and North (n=4,992) and South East Asians (n=8,255). Forced expiratory value in 1 s (FEV(1)) and forced vital capacity (FVC) between ethnic groups differed proportionally from that in Caucasians, such that FEV(1)/FVC remained virtually independent of ethnic group. For individuals not represented by these four groups, or of mixed ethnic origins, a composite equation taken as the average of the above equations is provided to facilitate interpretation until a more appropriate solution is developed. Spirometric prediction equations for the 3-95-age range are now available that include appropriate age-dependent lower limits of normal. They can be applied globally to different ethnic groups. Additional data from the Indian subcontinent and Arabic, Polynesian and Latin American countries, as well as Africa will further improve these equations in the future.
Crosstalk Between Autophagy and Apoptosis in Heart Disease
Authors: Kazuhiko Nishida, Osamu Yamaguchi, Kinya Otsu
Journal: Circulation Research (2008)

Autophagy is a cell survival mechanism that involves degradation and recycling of cytoplasmic components, such as long-lived proteins and organelles. In addition, autophagy mediates cell death under specific circumstances. Apoptosis, a form of programmed cell death, has been well characterized, and the molecular events involved in apoptotic death are well understood. Damaged cardiomyocytes that show characteristics of autophagy have been observed during heart failure. However, it remains unclear whether autophagy is a sign of failed cardiomyocyte repair or is a suicide pathway for the failing cardiomyocytes. Although autophagy and apoptosis are markedly different processes, several pathways regulate both autophagic and apoptotic machinery and autophagy can cooperate with apoptosis. This review summarizes the evidence for crosstalk between autophagy and apoptosis.
Assembly of the cochlear gap junction macromolecular complex requires connexin 26
Authors: Kazusaku Kamiya, Sabrina W. Yum, Nagomi Kurebayashi, Miho Muraki, Kana Ogawa, Keiko Karasawa, Asuka Miwa, Xueshui Guo, Satoru Gotoh, Yoshinobu Sugitani, Hitomi Yamanaka, Shioko Ito-Kawashima, Takashi Iizuka, Takashi Sakurai, Tetsuo Noda, Osamu Minowa, Katsuhisa Ikeda
Journal: Journal of Clinical Investigation (2014)

Hereditary deafness affects approximately 1 in 2,000 children. Mutations in the gene encoding the cochlear gap junction protein connexin 26 (CX26) cause prelingual, nonsyndromic deafness and are responsible for as many as 50% of hereditary deafness cases in certain populations. Connexin-associated deafness is thought to be the result of defective development of auditory sensory epithelium due to connexion dysfunction. Surprisingly, CX26 deficiency is not compensated for by the closely related connexin CX30, which is abundantly expressed in the same cochlear cells. Here, using two mouse models of CX26-associated deafness, we demonstrate that disruption of the CX26-dependent gap junction plaque (GJP) is the earliest observable change during embryonic development of mice with connexin-associated deafness. Loss of CX26 resulted in a drastic reduction in the GJP area and protein level and was associated with excessive endocytosis with increased expression of caveolin 1 and caveolin 2. Furthermore, expression of deafness-associated CX26 and CX30 in cell culture resulted in visible disruption of GJPs and loss of function. Our results demonstrate that deafness-associated mutations in CX26 induce the macromolecular degradation of large gap junction complexes accompanied by an increase in caveolar structures.
Studies on the density, distribution, and surface phenotype of intraepithelial class II major histocompatibility complex antigen (Ia)-bearing dendritic cells (DC) in the conducting airways.
Authors: M A Schon-Hegrad, J Oliver, P G McMenamin, P G Holt
Journal: The Journal of Experimental Medicine (1991)

Conventional immunohistochemical analysis of airway intraepithelial class II major histocompatibility complex (Ia) expression demonstrates a morphologically heterogeneous pattern of staining, suggestive of the presence of a mixed population of endogenous antigen presenting cells. Employing a novel tissue sectioning technique in conjunction with optimal surface antigen fixation, we now demonstrate that virtually all intraepithelial Ia staining throughout the respiratory tree in the normal rat, can be accounted for by a network of cells with classical dendritic cell (DC) morphology. The density of DC varies from 600-800 per mm2 epithelial surface in the large airways, to 75 per mm2 in the epithelium of the small airways of the peripheral lung. All the airway DC costain for CD4, with low-moderate expression of a variety of other leukocyte surface markers. Both chronic (eosinophilic) inflammation and acute (neutrophilic) inflammation, caused respectively by inhalation of chemical irritants in dust or aerosolised bacterial lipopolysaccharide (LPS), are shown to be accompanied by increased intraepithelial DC density in the large airways (in the order of 50%) and up to threefold increased expression of activation markers, including the beta chain of CD11/18. The kinetics of the changes in the DC network in response to LPS mirrored those of the transient neutrophil influx, suggesting that airway intraepithelial DC constitute a dynamic population which is rapidly upregulated in response to local inflammation. These findings have important theoretical implications for research on T cell activation in the context of allergic and infectious diseases in the respiratory tract.
Inhibition of binding of interferon-gamma to its receptor by salicylates used in inflammatory bowel disease.
Authors: B Crotty, W M Rosenberg, J K Aronson, D P Jewell
Journal: Gut (1992)

5-Aminosalicylic acid (5ASA), 4ASA, their N-acetylated metabolites N-acetyl-5ASA and N-acetyl-4ASA, olsalazine, and colchicine impair interferon-gamma (IFN gamma) induced HLA-DR expression on a colonic cell line, HT-29. The mechanism of this effect is now reported. HT-29 cells were cultured with 50 U/ml IFN gamma with or without drug, and northern blot analysis was performed using a probe for the beta chain of the DR molecule. IFN gamma led to a noticeable increase in HLA-DR mRNA which was attenuated by the drugs. Analysis of the specific binding of increasing concentrations of 125I-IFN gamma by non-linear regression showed a Kd of 1.35 x 10(-10) M and 2.3 x 10(5) binding sites per HT-29 cell. Binding of 125I-IFN gamma was reduced by incubation with increasing concentrations of unlabelled IFN gamma but not with IFN alpha. Incubation with therapeutic concentrations of drugs led to the following reductions in binding: 10 mM 5ASA, 20% (p < 0.001); 10 mM N-acetyl-5ASA, 24% (p < 0.01); 10 mM 4ASA, 21% (p < 0.005); 10 mM N-acetyl-4ASA, 29% (p < 0.001); and 1 mM olsalazine, 29% (p < 0.001). Colchicine (10(-7) M) and 10(-5) M prednisolone had no effect. Incubation with higher concentrations of the drugs revealed a dose-response effect on binding with complete inhibition by 100 mM 4ASA and 10 mM olsalazine, and lesser degrees of inhibition by 100 mM 5ASA, N-acetyl-5ASA, and N-acetyl-4ASA. At concentrations found in the rectal lumen, the salicylates used in inflammatory bowel disease impair the binding of IFN gamma to its receptor on colonic epithelial cells.
Geographic Variation in Medicare Drug Spending
Authors: Yuting Zhang, Katherine Baicker, Joseph P. Newhouse
Journal: New England Journal of Medicine (2010)

The widespread geographic variation in Medicare spending has garnered a great deal of attention in the health care reform debate, both as a marker of inefficient resource use and as a window into potential strategies for improving the quality and value of U.S. health care. Analyses to date, however, have focused solely on inpatient and outpatient spending (Parts A and B) and have lacked information on pharmaceutical spending (Part D). With drug spending accounting for a rising share of total health care spending, these data limitations hinder interpretation of the variation in spending: do Medicare patients who spend more on . . .
Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study
Authors: T Card
Journal: Gut (2004)

<b>Background:</b> Inflammatory bowel disease (IBD) is known to be associated with reduced bone density but the extent to which this results in an increased risk of fracture and the contribution of corticosteroid therapy are unclear. We have conducted a large cohort study to address these issues. <b>Methods:</b> We selected subjects within the General Practice Research Database (GPRD) with a diagnosis of IBD and up to five matched controls for each patient. We derived dates of recorded hip fractures and also information on smoking, use of corticosteroids, and a number of other drugs. We calculated the absolute risk of fracture and the relative risk as a hazard ratio corrected for available confounders by Cox regression. <b>Results:</b> Seventy two hip fractures were recorded in 16 550 IBD cases and 223 in 82 917 controls. Cox modelling gave an unadjusted relative risk of hip fracture of 1.62 (95% confidence interval (CI) 1.24–2.11) for all IBD, 1.49 (1.04–2.15) for ulcerative colitis (UC) and 2.08 (1.36–3.18) for Crohn's disease (CD). Multivariate modelling showed that both current and cumulative use of corticosteroids and use of opioid analgesics confounded this relationship. After adjusting for confounding, the relative risk was 1.41 (0.94–2.11) for UC and 1.68 (1.01–2.78) for CD. <b>Conclusion:</b> The risk of hip fracture is increased approximately 60% in IBD patients. Corticosteroid use is a contributor to this, both in the long term as previously recognised and also in an acute reversible manner. The majority of hip fracture risk in IBD patients however cannot be attributed to steroid use.
Composition and replay of mnemonic sequences: The contributions of REM and slow-wave sleep to episodic memory
Authors: Sen Cheng, Markus Werning
Journal: Behavioral and Brain Sciences (2013)

Abstract We propose that rapid eye movement (REM) and slow-wave sleep contribute differently to the formation of episodic memories. REM sleep is important for building up invariant object representations that eventually recur to gamma-band oscillations in the neocortex. In contrast, slow-wave sleep is more directly involved in the consolidation of episodic memories through replay of sequential neural activity in hippocampal place cells.
The writing is on the wall for UNAIDS
Authors: Roger England
Journal: BMJ (2008)

The creation of UNAIDS, the joint United Nations programme on HIV and AIDS, was justified by the proposition that HIV is exceptional. The foundations of exceptionalism were laid when the “rights” arguments of gay men succeeded in making HIV a special case that demanded confidentiality and informed consent and discouraged routine testing and tracing of contacts, contrary to proved experience in public health.1 But exceptionalism grew—to encompass HIV as a disease of poverty, a developmental catastrophe, and an emergency demanding special measures, requiring multisectoral interventions beyond the leadership of the World Health Organization.

The exceptionality argument was used to raise international political commitment and large sums of money for the fight against HIV from, among others, the World Bank, through its multi-country AIDS programme, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and the US Presidents’ Emergency Plan for AIDS Relief. With its own UN agency, HIV has been treated like an economic sector rather than a disease.

The proposition of exceptionality is now under stress. The poverty argument has been exposed as baseless. The country surveys carried out by Measure DHS (Demographic and Health Surveys) of, for example, Ethiopia, Kenya, and Tanzania show that prevalence is highest among the middle classes and more educated people.2 Although HIV can tip households into poverty and constrain national …
Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis
Authors: Marc Arbyn, Freija Verdoodt, Peter J F Snijders, Viola M J Verhoef, Eero Suonio, Lena Dillner, Silvia Minozzi, Cristina Bellisario, Rita Banzi, Fang-Hui Zhao, Peter Hillemanns, Ahti Anttila
Journal: The Lancet Oncology (2014)
Cases of Pelvic Abscess Treated by Abdominal Section
Authors: A. W. M. Robson
Journal: BMJ (1890)

no dilatation ensues under an antesthetic, the benefit of electro- lysis is most marked. Results of Fifty Cases of Urethral Stricture treated 15yElectrolysis.Date of No. Name.X Treat-Result.¢ merit. 1 D. C.
Applying Current Screening Tools for Gestational Diabetes Mellitus to a European Population: Is It Time for Change?
Authors: Gloria E. Avalos, Lisa A. Owens, Fidelma Dunne
Journal: Diabetes Care (2013)

The optimal screening regimen for gestational diabetes mellitus (GDM) remains controversial. Risk factors used in selective screening guidelines vary. Given that universal screening is not currently adopted in our European population, we aimed to evaluate which selective screening strategies were most applicable.Between 2007 and 2009, 5,500 women were universally screened for GDM, and a GDM prevalence of 12.4% using International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria was established. We retrospectively applied selective screening guidelines to this cohort.When we applied National Institute for Health and Clinical Excellence (NICE), Irish, and American Diabetes Association (ADA) guidelines, 54% (2,576), 58% (2,801), and 76% (3,656) of women, respectively, had at least one risk factor for GDM and would have undergone testing. However, when NICE, Irish, and ADA guidelines were applied, 20% (120), 16% (101), and 5% (31) of women, respectively, had no risk factor and would have gone undiagnosed. Using a BMI≥30 kg/m2 for screening has a specificity of 81% with moderate sensitivity at 48%. Reducing the BMI to ≥25 kg/m2 (ADA) increases the sensitivity to 80% with a specificity of 44%. Women with no risk factors diagnosed with GDM on universal screening had more adverse pregnancy outcomes than those with normal glucose tolerance.This analysis provides a strong argument for universal screening. However, if selective screening were adopted, the ADA guidelines would result in the highest rate of diagnosis and the lowest number of missed cases.
Longitudinal immunomonitoring following tocilizumab in rheumatoid arthritis
Authors: P. Louis-Plence, Y.-M. Pers, P. Portales, J. Quentin, S. Fabre, J.-F. Eliaou, C. Jorgensen
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Introduction</h3> Tocilizumab is a humanised anti-interleukin (IL)-6 receptor monoclonal antibody, which binds to circulating soluble IL-6 receptor and membrane-expressed IL-6 receptor, inhibiting IL-6 binding to both forms of IL-6 receptor. Tocilizumab is an efficient therapy for adults with moderate to severe rheumatoid arthritis (RA) in whom disease-modifying antirheumatic drugs or a tumour necrosis factor (TNF) inhibitor has failed. However, the impact of tocilizumab on several immune populations such as lymphocytes, monocytes, dendritic cells is still unknown. In order to longitudinally analyse the variations in frequencies as well as the activation status of these populations, the authors designed several panels specific for immune cells and performed immunomonitoring by FACSanalyses. <h3>Patients and methods</h3> 20 patients with severe and active RA, refractory to methotrexate or anti-TNF therapies were recruited and treated with 8 mg/kg of tocilizumab monthly. Peripheral blood was recovered for each patient at day 0, as well as 1 and 3 months after informed consents. Staining was performed on whole blood and peripheral blood mononuclear cells were purified for intracellular cytokine staining following CD3-CD28 overnight stimulation. The data were acquired on a FACS Canto II (eight colours) and analysed using DIVA software. Ten panels specific for subpopulations of T cells (Th1, Th2, Th17), B cells (naïve, memory and transitional), monocytes (classical, inflammatory and non-classical) dendritic cells (myeloid and plasmacytoid), Tregs (natural and induced) were designed. The activation status of the T, B and DC was also monitored. <h3>Results</h3> According to the cytokinic secretion of the T cells following ex vivo activation, the authors observed various profile of patients: Th1, Th17 or Th1/Th17. The frequencies of these proinflammatory cytokine secreting T cells were found to be decreased following treatment with tocilizumab. Concerning the longitudinal analyses of the B cell populations, an increase of the transitional B cells (CD24<sup>high</sup>CD38<sup>high</sup>) was observed in non-responder patients and in contrast an increase of non-classical monocytes was observed in good responders. Concerning the Treg population, the high heterogeneity of the patients before treatment was confirmed. However the CD4CD25FoxP3 staining was confined to CD127<sup>low</sup> and CD62L<sup>high</sup> suggesting the induction of induced Tregs following Tocilizumab treatment as observed after infliximab treatment. In conclusion, the design of specific panels to analyse the frequencies and the activation status of several subpopulation of immune cells, allows a longitudinal monitoring of the major effector populations in RA patients following cytokine blocade.
Obesity and risk of incident psoriatic arthritis in US women
Authors: Wenqing Li, Jiali Han, Abrar A Qureshi
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> Both overall and central obesity have been associated with the risk of psoriasis in a prospective study. Data on the association between obesity and psoriatic arthritis (PsA) have been sparse and no evidence on obesity measures and the risk of incident PsA is available now. This study aimed to evaluate the association between obesity and the risk of incident PsA in a large cohort of women. <h3>Methods</h3> 89 049 participants were included from the Nurses Health Study II over a 14-year period (1991–2005). Information on body mass index (BMI), weight change and measures of central obesity (waist circumference, hip circumference and waist–hip ratio) was collected during the follow-up. The incidence of clinician-diagnosed PsA was ascertained and confirmed by supplementary questionnaires. <h3>Results</h3> 146 incident PsA cases were identified during 1 231 693 person-years of follow-up. Among all participants, BMI was monotonically associated with an increased risk of incident PsA. Compared with BMI less than 25.0, the RR was 1.83 for BMI 25.0–29.9 (95% CI 1.15 to 2.89), 3.12 for BMI 30.0–34.9 (95% CI 1.90 to 5.11) and 6.46 for BMI over 35.0 (95% CI 4.11 to 10.16). There was a graded positive association between weight change from age 18 years, measures of central obesity and risk of PsA (p for trend &lt;0.001). The analysis among participants developing psoriasis during follow-up revealed a similar association (p for trend &lt;0.01), indicating an increased risk of PsA associated with obesity among patients with psoriasis. <h3>Conclusion</h3> This study provides further evidence linking obesity with the risk of incident PsA among US women.
Use of Antioxidants During Chemotherapy and Radiotherapy Should Be Avoided
Authors: G. M. D'Andrea
Journal: CA A Cancer Journal for Clinicians (2005)

Many patients being treated for cancer use dietary supplements, particularly antioxidants, in the hope of reducing the toxicity of chemotherapy and radiotherapy. Some researchers have claimed, furthermore, that antioxidants also increase the effectiveness of cytotoxic therapy and have explicitly recommended their use. However, mechanistic considerations suggest that antioxidants might reduce the effects of conventional cytotoxic therapies. Preclinical data are currently inconclusive and a limited number of clinical studies have not found any benefit. Clinicians should advise their patients against the use of antioxidant dietary supplements during chemotherapy or radiotherapy. Such caution should be seen as the standard approach for any unproven agent that may be harmful.
Is mitochondrial antibody diagnostic of primary biliary cirrhosis?
Authors: L E Munoz, H C Thomas, P J Scheuer, D Doniach, S Sherlock
Journal: Gut (1981)

In a series of 218 patients diagnosed as having primary biliary cirrhosis only nine exhibited a negative serum mitochondrial antibody. On examining additional specimens from these patients, seven were found to be positive, giving a final incidence of greater than 99%. The two patients whose sera remained negative for the mitochondrial antibody had liver histology compatible with the diagnosis of primary biliary cirrhosis, but a firm diagnosis could not be reached. Three additional mitochondrial antibody positive subjects who were asymptomatic and exhibited normal serum alkaline phosphatase were shown on liver biopsy to have stage I primary biliary cirrhosis. The presence of a positive serum mitochondrial antibody in a patient with or without abnormalities in liver function tests strongly suggests the diagnosis of primary biliary cirrhosis.