tbuckley/cabot-search huggingface dataset:
Regarding Formula One and global road safety
Authors: Matthew Ericson
Journal: Journal of the Royal Society of Medicine (2008)

In his passionate response to Ian Roberts1 (JRSM 2007;100:360-2), David Ward (JRSM 2007;100:412-3) did not declare all his competing interests. As well as being director general of the FIA Foundation, Mr Ward was appointed by the FIA (International Automobile Federation) from his FIA position, to manage the $300 million with which the FIA created the Foundation. Mr Ward also defended the Commission for Global Road Safety at length - but nowhere did he mention that he is the Commission's Secretary. In addition, Mr Ward neglected to declare that, as Director General of the FIA Foundation, he has a member's chair on the Executive Committee of the Global Road Safety Partnership (GRSP).

The complex links between these institutions - which Mr Ward's interests reflect - highlight Professor Roberts' point that motorists and the motor industry are powerful players in the international road safety debate. This is neither surprising nor necessarily a bad thing. Road transport plays a vital role in economic development, and the motoring industry has a legitimate role in road safety policy in the developing world. The auto industry has always lobbied governments to promote its own agenda3 and has considerable commercial interests in the emerging markets.4 In pursuing those interests, groups like the four that Mr Ward is involved in are doing precisely what they exist to do.5

A problem emerges, however, when such groups are able to steer the agenda in the direction favoured by just one or two stakeholders. At the national level in developed countries, interest groups compete with one another for influence; alongside motorists' groups and car manufacturers, there are vocal and well-organized groups representing cyclists, pedestrians, public transport users and others. Independent government institutions exist to make binding decisions when these competing interests are at odds.

At the global level, however, there is no government agency with the authority to weigh up competing claims. International NGOs like the World Bank and the World Health Organization may attempt to take on this role, but they are easily ‘captured’ by whoever can offer much-needed funding. In the sphere of road safety, this gives the FIA and the GRSP an extraordinary advantage.

Groups like the FIA Foundation and the GRSP have every right to advocate on their members' behalf, and as David Ward points out, they contribute desperately needed funds to road safety projects. But as representatives of motorists and of the motor industry, they necessarily prioritize the needs of these groups. In the absence of competing organizations, this threatens to narrow the scope of the policy debate and to exclude policies which might benefit other road users. The lack of a well-developed civil society at a global level is not the automotive industry's fault - but it would behove them to keep it in mind when exercising their considerable influence.
T cell receptor gene recombination patterns and mechanisms: cell death, rescue, and T cell production.
Authors: H T Petrie, F Livak, D Burtrum, S Mazel
Journal: The Journal of Experimental Medicine (1995)

The antigen-specific receptors of T and B lymphocytes are generated by somatic recombination between noncontiguous gene segments encoding the variable portions of these molecules. The semirandom nature of this process, while desirable for the generation of diversity, has been thought to exact a high price in terms of sterile (out-of-frame) products. Historically, the majority of T lymphocytes generated in mammals were thought to be useless, either because they generated such sterile rearrangements or because the receptors generated did not appropriately recognize self-molecules (i.e., positive and negative selection). In the studies described here, we characterize the onset of T cell receptor (TCR) alpha and beta chain gene rearrangements and quantitate their progression throughout T cell development. The results show that T cell production efficiency is enhanced through (a) rearrangement of TCR-beta chain genes early during T cell development, with selective expansion of those cells possessing in-frame rearrangements; (b) deletion of sterile rearrangements at the TCR-alpha chain locus through ordered (proximal to distal) sequential recombination; and (c) modification of nonselectable alpha/beta heterodimer specificities through generation and expression of new TCR-alpha chains. In addition, we demonstrate strict correlations between successful TCR-beta gene rearrangement, the onset of TCR-alpha gene rearrangement, rapid cell division, and programmed cell death, which together serve to maintain cell turnover and homeostasis during T cell development.
Survival Efficacy of Adjuvant Cytosine-Analogue CS-682 in a Fluorescent Orthotopic Model of Human Pancreatic Cancer
Authors: Matthew H. Katz, Michael Bouvet, Shinako Takimoto, Daniel Spivack, Abdool R. Moossa, Robert M. Hoffman
Journal: Cancer Research (2004)

Adjuvant treatment with the cytosine analogue 1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl)-N(4)-palmitoylcytosine (CS-682) results in a highly significant increase in survival in the aggressive orthotopic MIA-PaCa-2 human pancreatic cancer mouse model. Seven days after implantation, mice were randomized into eight groups, depending on whether they were to be treated by tumor resection, 5 weeks of CS-682 chemotherapy at 40-60 mg/kg once daily, or both. Throughout the course of treatment, noninvasive optical whole-body imaging based on brilliant red fluorescent protein expression of the tumor permitted visualization and quantification of primary, metastatic, and recurrent disease. Total tumor burden negatively correlated with survival. Untreated mice died of disseminated disease with a median survival of 26 days. Surgical resection alone conferred a small but significant survival advantage (median survival, 28 days, P = 0.03). Primary CS-682 treatment at all doses also significantly prolonged survival compared with untreated animals (P < 0.05) and was more effective than surgery alone at doses of 50 and 60 mg/kg (median survival, 34 days, P = 0.045, and 38.5 days, P = 0.03, respectively). Maximal survival (median, 48 days, with 30% of animals surviving longer than 60 days) was achieved by adjuvant CS-682 (50 mg/kg), given after surgical resection of the primary pancreatic tumor (P = 0.004 compared with surgery alone). The results demonstrate that adjuvant oral administration of CS-682 for pancreatic cancer is highly effective with acceptable toxicity, suggesting its potential for cure of this disease in appropriate combinations.
Phase III Comparison of Preoperative Chemotherapy Compared With Chemoradiotherapy in Patients With Locally Advanced Adenocarcinoma of the Esophagogastric Junction
Authors: Michael Stahl, Martin K. Walz, Martin Stuschke, Nils Lehmann, Hans-Joachim Meyer, Jorge Riera-Knorrenschild, Peter Langer, Rita Engenhart-Cabillic, Michael Bitzer, Alfred Königsrainer, Wilfried Budach, Hansjochen Wilke
Journal: Journal of Clinical Oncology (2009)

Preoperative chemotherapy is an accepted standard in the treatment of localized esophagogastric adenocarcinoma. Adding radiation therapy to preoperative chemotherapy appears promising, but its definitive value remains unknown.Patients with locally advanced (uT3-4NXM0) adenocarcinoma of the lower esophagus or gastric cardia were randomly allocated to one of two treatment groups: induction chemotherapy (15 weeks) followed by surgery (arm A); or chemotherapy (12 weeks) followed by chemoradiotherapy (3 weeks) followed by surgery (arm B). Primary outcome was overall survival time. A total of 354 patients were needed to detect a 10% increase in 3-year survival from 25% to 35% by addition of radiation therapy. The study was prematurely closed due to low accrual.The median observation time was 46 months. A total of 126 patients were randomly assigned and 119 eligible patients were evaluated. The number of patients undergoing complete tumor resection was not different between treatment groups (69.5% v 71.5%). Patients in arm B had a significant higher probability of showing pathologic complete response (15.6% v 2.0%) or tumor-free lymph nodes (64.4% v 37.7%) at resection. Preoperative radiation therapy improved 3-year survival rate from 27.7% to 47.4% (log-rank P = .07, hazard ratio adjusted for randomization strata variables 0.67, 95% CI, 0.41 to 1.07). Postoperative mortality was nonsignificantly increased in the chemoradiotherapy group (10.2% v 3.8%; P = .26).Although the study was closed early and statistical significance was not achieved, results point to a survival advantage for preoperative chemoradiotherapy compared with preoperative chemotherapy in adenocarcinomas of the esophagogastric junction.
CTLA-4 ligands are required to induce an in vivo interleukin 4 response to a gastrointestinal nematode parasite.
Authors: P Lu, X Zhou, S J Chen, M Moorman, S C Morris, F D Finkelman, P Linsley, J F Urban, W C Gause
Journal: The Journal of Experimental Medicine (1994)

The costimulatory signal provided to T cells through CTLA-4-ligand interactions is required for T cell activation resulting in increased interleukin 2 (IL-2) production in vitro, but its role in the production of IL-4 and other cytokines is unclear and few in vivo studies have been performed to confirm results of in vitro experiments. We have examined the in vivo effects of blocking CTLA-4 ligands on the T helper cell 2 (Th2)-associated mucosal immune response that follows oral infection of mice with the nematode parasite, Heligmosomoides polygyrus. CTLA-4Ig administration inhibited H. polygyrus-induced increases in mesenteric lymph node (MLN) B cell major histocompatibility complex class II expression and size and T cell-derived IL-4 gene expression. In addition, CTLA-4 immunoglobulin (Ig) partially blocked increased IL-3, IL-5, and IL-9 cytokine gene expression in Peyer's patch (PP) and MLN 8 d after primary inoculation of mice with the parasite. Increases in the number of IL-4- but not IL-5-secreting cells were also inhibited by CTLA-4Ig. H. polygyrus-induced elevations in serum IgE levels but not blood eosinophils, were markedly inhibited by CTLA-4Ig. These results suggest that stimulation of CD28 and/or CTLA-4 is required for T cell priming leading to IL-4 cytokine production, B cell activation, and IgE secretion during a Th2-like, mucosal immune response to a nematode parasite.
Glycophorin C (CD236R) mediates vivax malaria parasite rosetting to normocytes
Authors: Wenn-Chyau Lee, Benoit Malleret, Yee-Ling Lau, Marjorie Mauduit, Mun-Yik Fong, Jee Sun Cho, Rossarin Suwanarusk, Rou Zhang, Letusa Albrecht, Fabio T. M. Costa, Peter Preiser, Rose McGready, Laurent Renia, Francois Nosten, Bruce Russell
Journal: Blood (2014)
Human male infertility: chromosome anomalies, meiotic disorders, abnormal spermatozoa and recurrent abortion
Authors: S. Egozcue
Journal: Human Reproduction Update (2000)

Human male infertility is often related to chromosome abnormalities. In chromosomally normal infertile males, the rates of chromosome 21 and sex chromosome disomy in spermatozoa are increased. Higher incidences of trisomy 21 (seldom of paternal origin) and sex chromosome aneuploidy are also found. XXY and XYY patients produce increased numbers of XY, XX and YY spermatozoa, indicating an increased risk of production of XXY, XYY and XXX individuals. Since XXYs can reproduce using intracytoplasmic sperm injection (ICSI), this could explain the slight increase of sex chromosome anomalies in ICSI series. Carriers of structural reorganizations produce unbalanced spermatozoa, and risk having children with duplications and/or deficiencies. In some cases, this risk is considerably lower or higher than average. These patients also show increased diploidy, and a higher risk of producing diandric triploids. Meiotic disorders are frequent in infertile males, and increase with severe oligoasthenozoospemia (OA) and/or high follicle stimulating hormone (FSH) concentrations. These patients produce spermatozoa with autosomal and sex chromosome disomies, and diploid spermatozoa. Their contribution to recurrent abortion depends on the production of trisomies, monosomies and of triploids. The most frequent sperm chromosome anomaly in infertile males is diploidy, originated by either meiotic mutations or by a compromised testicular environment.
Duration and exclusiveness of breastfeeding and childhood asthma-related symptoms
Authors: A. M. M. Sonnenschein-van der Voort, V. W. V. Jaddoe, R. J. P. van der Valk, S. P. Willemsen, A. Hofman, H. A. Moll, J. C. de Jongste, L. Duijts
Journal: European Respiratory Journal (2011)

The aim of our study was to examine the associations of breastfeeding duration and exclusiveness with the risks of asthma-related symptoms in preschool children, and to explore whether these associations are explained by atopic or infectious mechanisms. This study was embedded in a population-based prospective cohort study of 5,368 children. Information on breastfeeding duration, exclusiveness and asthma-related symptoms, including wheezing, shortness of breath, dry cough and persistent phlegm, was obtained by questionnaires. Compared with children who were breastfed for 6 months, those who were never breastfed had overall increased risks of wheezing, shortness of breath, dry cough and persistent phlegm during the first 4 yrs (OR 1.44 (95% CI 1.24–1.66), 1.26 (1.07–1.48), 1.25 (1.08–1.44) and 1.57 (1.29–1.91), respectively). Similar associations were observed for exclusive breastfeeding. The strongest associations per symptom per year were observed for wheezing at 1 and 2 yrs. Additionally adjusted analyses showed that the associations of breastfeeding with asthma-related symptoms were not explained by eczema but partly by lower respiratory tract infections. Shorter duration and nonexclusivity of breastfeeding were associated with increased risks of asthma-related symptoms in preschool children. These associations seemed, at least partly, to be explained by infectious, but not by atopic, mechanisms.
Use of the Proton Pump Inhibitor Pantoprazole to Modify the Distribution and Activity of Doxorubicin: A Potential Strategy to Improve the Therapy of Solid Tumors
Authors: Krupa J. Patel, Carol Lee, Qian Tan, Ian F. Tannock
Journal: Clinical Cancer Research (2013)

Limited drug distribution within solid tumors is an important cause of drug resistance. Basic drugs (e.g., doxorubicin) may be sequestered in acidic organelles, thereby limiting drug distribution to distal cells and diverting drugs from their target DNA. Here we investigate the effects of pantoprazole, a proton pump inhibitor, on doxorubicin uptake, and doxorubicin distribution and activity using in vitro and murine models.Murine EMT-6 and human MCF-7 cells were treated with pantoprazole to evaluate changes in endosomal pH using fluorescence spectroscopy, and uptake of doxorubicin using flow cytometry. Effects of pantoprazole on tissue penetration of doxorubicin were evaluated in multilayered cell cultures (MCC), and in solid tumors using immunohistochemistry. Effects of pantoprazole to influence tumor growth delay and toxicity because of doxorubicin were evaluated in mice.Pantoprazole (>200 μmol/L) increased endosomal pH in cells, and also increased nuclear uptake of doxorubicin. Pretreatment with pantoprazole increased tissue penetration of doxorubicin in MCCs. Pantoprazole improved doxorubicin distribution from blood vessels in solid tumors. Pantoprazole given before doxorubicin led to increased growth delay when given as single or multiple doses to mice bearing MCF7 xenografts.Use of pantoprazole to enhance the distribution and cytotoxicity of anticancer drugs in solid tumors might be a novel treatment strategy to improve their therapeutic index.
Access to Care and the Incidence of End-Stage Renal Disease Due to Diabetes
Authors: Michael M. Ward
Journal: Diabetes Care (2009)

Low socioeconomic status (SES) is associated with an increased risk of end-stage renal disease (ESRD) due to diabetes. Because ESRD is a preventable complication of diabetes, the association with SES may be related to limited access to treatment.In this population-based ecological study, I examined the association between the incidence of ESRD attributed to diabetes and the proportion of hospitalizations with no insurance, Medicaid, or managed care insurance; residence in a primary care provider shortage area or rural area; and rate of hospitalizations for hyperglycemic complications, by ZIP code in California in 2001-2004.The incidence of ESRD attributed to diabetes was higher in ZIP codes with higher proportions of hospitalizations with no insurance (r = 0.45; P < 0.0001) or Medicaid (r = 0.69; P < 0.0001) and in ZIP codes with higher rates of hospitalizations for hyperglycemic complications (r = 0.27; P < 0.0001). The incidence was lower in ZIP codes with higher proportions of hospitalizations with managed care insurance (r = -0.37; P < 0.0001) and was lower in primary care provider shortage areas and rural locations. In contrast, there were only weak associations between measures of access to care and the incidence of ESRD attributed to polycystic kidney disease, a condition that is not treatable.The incidence of ESRD attributed to diabetes is strongly associated with area-based measures of access to care, suggesting that access to treatment partly mediates the association between SES and the incidence of ESRD.
Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells
Authors: Lee-Hwa Tai, Christiano Tanese de Souza, Simon Bélanger, Lundi Ly, Almohanad A. Alkayyal, Jiqing Zhang, Julia L. Rintoul, Abhirami A. Ananth, Tiffany Lam, Caroline J. Breitbach, Theresa J. Falls, David H. Kirn, John C. Bell, Andrew P. Makrigiannis, Rebecca A. Auer
Journal: Cancer Research (2012)

Natural killer (NK) cell clearance of tumor cell emboli following surgery is thought to be vital in preventing postoperative metastases. Using a mouse model of surgical stress, we transferred surgically stressed NK cells into NK-deficient mice and observed enhanced lung metastases in tumor-bearing mice as compared with mice that received untreated NK cells. These results establish that NK cells play a crucial role in mediating tumor clearance following surgery. Surgery markedly reduced NK cell total numbers in the spleen and affected NK cell migration. Ex vivo and in vivo tumor cell killing by NK cells were significantly reduced in surgically stressed mice. Furthermore, secreted tissue signals and myeloid-derived suppressor cell populations were altered in surgically stressed mice. Significantly, perioperative administration of oncolytic parapoxvirus ovis (ORFV) and vaccinia virus can reverse NK cell suppression, which correlates with a reduction in the postoperative formation of metastases. In human studies, postoperative cancer surgery patients had reduced NK cell cytotoxicity, and we show for the first time that oncolytic vaccinia virus markedly increases NK cell activity in patients with cancer. These data provide direct in vivo evidence that surgical stress impairs global NK cell function. Perioperative therapies aimed at enhancing NK cell function will reduce metastatic recurrence and improve survival in surgical cancer patients.
Determinations of Penicilloyl Specific IgE Antibodies for the Evaluation of Hypersensitivity against Penicillin
Authors: P. Spath, H. Huber, M. Ludvan, A. Roth, S. Schwarz, J. Zelger
Journal: Allergy (1979)

Results from skin tests and radioallergosorbent test (penicilloyl G and penicilloyl V) were compared in 76 patients with suspected penicillin hypersensitivity and in 22 control subjects without such clinical symptoms. The test results were also correlated to the clinical history of adverse reactions and to the levels of total serum IgE. The overall agreement between skin test and RAST results was 89% in the patient group. Two of the control subjects without symptoms were professionally employed with penicillin production; one of them had circulating IgE-antibodies and the other exhibited positive skin tests. The skin tests were more frequently positive than the RAST test. By means of skin titration some of the skin tests were demonstrated to be false positive. The discrepancy can also be explained by the fact that skin reactions also occur in other situations than IgE-mediated adverse reactions. Circulating IgE-antibodies were not found in any of 23 cases where adverse reactions appeared later than 24 h after the latest penicillin administration. It is concluded that the measurement of circulating IgE-antibodies is a valuable aid in the diagnosis of penicillin allergy.
Dispersion of the HIV-1 Epidemic in Men Who Have Sex with Men in the Netherlands: A Combined Mathematical Model and Phylogenetic Analysis
Authors: Daniela Bezemer, Anne Cori, Oliver Ratmann, Ard van Sighem, Hillegonda S. Hermanides, Bas E. Dutilh, Luuk Gras, Nuno Rodrigues Faria, Rob van den Hengel, Ashley J. Duits, Peter Reiss, Frank de Wolf, Christophe Fraser
Journal: PLoS Medicine (2015)

The HIV-1 subtype B epidemic amongst men who have sex with men (MSM) is resurgent in many countries despite the widespread use of effective combination antiretroviral therapy (cART). In this combined mathematical and phylogenetic study of observational data, we aimed to find out the extent to which the resurgent epidemic is the result of newly introduced strains or of growth of already circulating strains.As of November 2011, the ATHENA observational HIV cohort of all patients in care in the Netherlands since 1996 included HIV-1 subtype B polymerase sequences from 5,852 patients. Patients who were diagnosed between 1981 and 1995 were included in the cohort if they were still alive in 1996. The ten most similar sequences to each ATHENA sequence were selected from the Los Alamos HIV Sequence Database, and a phylogenetic tree was created of a total of 8,320 sequences. Large transmission clusters that included ≥10 ATHENA sequences were selected, with a local support value ≥ 0.9 and median pairwise patristic distance below the fifth percentile of distances in the whole tree. Time-varying reproduction numbers of the large MSM-majority clusters were estimated through mathematical modeling. We identified 106 large transmission clusters, including 3,061 (52%) ATHENA and 652 Los Alamos sequences. Half of the HIV sequences from MSM registered in the cohort in the Netherlands (2,128 of 4,288) were included in 91 large MSM-majority clusters. Strikingly, at least 54 (59%) of these 91 MSM-majority clusters were already circulating before 1996, when cART was introduced, and have persisted to the present. Overall, 1,226 (35%) of the 3,460 diagnoses among MSM since 1996 were found in these 54 long-standing clusters. The reproduction numbers of all large MSM-majority clusters were around the epidemic threshold value of one over the whole study period. A tendency towards higher numbers was visible in recent years, especially in the more recently introduced clusters. The mean age of MSM at diagnosis increased by 0.45 years/year within clusters, but new clusters appeared with lower mean age. Major strengths of this study are the high proportion of HIV-positive MSM with a sequence in this study and the combined application of phylogenetic and modeling approaches. Main limitations are the assumption that the sampled population is representative of the overall HIV-positive population and the assumption that the diagnosis interval distribution is similar between clusters.The resurgent HIV epidemic amongst MSM in the Netherlands is driven by several large, persistent, self-sustaining, and, in many cases, growing sub-epidemics shifting towards new generations of MSM. Many of the sub-epidemics have been present since the early epidemic, to which new sub-epidemics are being added.