tbuckley/cabot-search huggingface dataset:
Antagonism of chemokine receptor CCR8 is ineffective in a primate model of asthma
Authors: Lin Wang, Tracy J Jenkins, Mingshi Dai, Wei Yin, Jacqueline C Pulido, Elise LaMantia-Martin, Martin R Hodge, Timothy Ocain, Roland Kolbeck
Journal: Thorax (2013)

Expression of the T-cell-associated chemokine receptor CCR8 and its ligand CCL1 have been demonstrated to be elevated in patients with asthma. CCR8 deficiency or inhibition in models of allergic airway disease in mice resulted in conflicting data.To investigate the effects of a selective small molecule CCR8 inhibitor (ML604086) in a primate model of asthma.ML604086 and vehicle were administered by intravenous infusion to 12 cynomolgus monkeys during airway challenge with Ascaris suum. Samples were collected throughout the study to measure pharmacokinetics (PK) and systemic CCR8 inhibition, as well as inflammation, T helper 2 (Th2) cytokines and mucus in bronchoalveolar lavage (BAL). Airway resistance and compliance were measured before and after allergen challenge, and in response to increasing concentrations of methacholine.ML604086 inhibited CCL1 binding to CCR8 on circulating T-cells>98% throughout the duration of the study. However, CCR8 inhibition had no significant effect on allergen-induced BAL eosinophilia and the induction of the Th2 cytokines IL-4, IL-5, IL-13 and mucus levels in BAL. Changes in airway resistance and compliance induced by allergen provocation and increasing concentrations of methacholine were also not affected by ML604086.These results clearly demonstrate a dispensable role for CCR8 in ameliorating allergic airway disease in atopic primates, and suggest that strategies other than CCR8 antagonism should be considered for the treatment of asthma.
Five-year Results of a Randomized Trial Comparing Retropubic and Transobturator Midurethral Slings for Stress Incontinence
Authors: Eija Laurikainen, Antti Valpas, Pauliina Aukee, Aarre Kivelä, Kirsi Rinne, Teuvo Takala, Carl Gustav Nilsson
Journal: European Urology (2014)
Time between onset of apoptosis and release of nucleosomes from apoptotic cells: putative implications for systemic lupus erythematosus
Authors: A E M van Nieuwenhuijze
Journal: Annals of the Rheumatic Diseases (2002)

<b>Objective:</b> To investigate the kinetics of nucleosome leakage from apoptotic cells in an in vitro system and extrapolate the results to autoimmune disease, in particular systemic lupus erythematosus. <b>Methods:</b> A sensitive nucleosome enzyme linked immunosorbent assay (ELISA) was developed, using a monoclonal antibody (mAb) against histone 3 and an mAb against nucleosomes. Nucleosome release during apoptotic cell death was studied in Jurkat cells. AnnexinV binding (early apoptosis) and propidium iodide positivity (late apoptosis) of the cells were compared with nucleosome release at different times after apoptosis induction. <b>Results:</b> Nucleosomes appeared in culture supernatant of Jurkat cells 24 to 48 hours after apoptosis induction, when the cells had been late apoptotic for more than 12 hours. <b>Conclusion:</b> Nucleosomes are released from late apoptotic Jurkat cells, with a 12 hour delay from the appearance of AnnexinV binding cells. This result suggests that in vivo scavenger mechanisms have 12 hours to remove apoptotic material from the circulation.
Natural killer (NK) cell-derived hematopoietic colony-inhibiting activity and NK cytotoxic factor. Relationship with tumor necrosis factor and synergism with immune interferon.
Authors: G Degliantoni, M Murphy, M Kobayashi, M K Francis, B Perussia, G Trinchieri
Journal: The Journal of Experimental Medicine (1985)

We characterize the natural killer (NK) cell colony-inhibiting activity (CIA) produced in supernatants from cultures of human peripheral blood lymphocytes (PBL) with NK-sensitive target cell lines, and study its relationship with NK cell-derived cytotoxic factor (NKCF). Using monoclonal antibodies (mAb) specific for NK cells or other lymphocyte populations, we unambiguously identify NK cells as the only PBL subset able to produce both NKCF and NK-CIA. We present functional and biochemical data suggesting that NKCF and NK-CIA represent the same molecule: (a) a highly significant positive correlation exists between the quantity of NKCF and NK-CIA in supernatants independently produced by different PBL subsets; (b) both NK-CIA and NKCF are induced by culture of PBL with NK-sensitive, but not with NK-insensitive cell lines, and with HLA-DR+ bone marrow cells; (c) both NKCF and NK-CIA are absorbed on the same cell lines or bone marrow cell types; (d) the two activities coelute in the same gel filtration fractions; (e) D-mannose-6-phosphate blocks both NKCF and NK-CIA activity, and prevents their absorption by K562 cells; and (f) both NKCF and NK-CIA activity are lost after 2 d at 37 degrees C. The NK-CIA-containing preparations are devoid of antiviral activity, and antiinterferon (anti-IFN) antibodies do not block the inhibitor activity of NK-CIA. The effect of NK-CIA on day 14 (early) colony-forming units of granulocytes and macrophages (CFU-GM) is synergistic with that of IFN-gamma, and this synergy is also evident on day 7 (late) CFU-GM growth. A combination of NK-CIA and IFN-gamma suppresses late CFU-GM, at concentrations of the two lymphokines that are completely ineffective when used independently. No synergy between NK-CIA and IFN-alpha or -beta was observed, due to a direct inhibitory effect of these two IFN types on late CFU-GM. Antibodies specific for tumor necrosis factor (TNF), but not those specific for lymphotoxins, inhibit both NK-CIA and NKCF activity in the NK cell-derived supernatant. Recombinant TNF, in the range of concentrations corresponding to that of the cytotoxic activity on L-929 cells present in supernatants, mediated both NKCF and NK-CIA activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Berson, Yalow, and the JCI: the agony and the ecstasy
Authors: C. Ronald Kahn, Jesse Roth
Journal: Journal of Clinical Investigation (2004)

The isolation of insulin in 1921 by Banting, Best, Collip, and Macleod stands as one of the most dramatic stories in modern medical investigation. Only two years passed between the initial experiments in dogs to widespread human application to the awarding of the Nobel Prize in 1923. Insulin-related research has also served as a focus, at least in part, for the work of three other Nobel Prize recipients: determination of the chemical structure of insulin by Frederick Sanger in 1958; determination of the three-dimensional structures of insulin and vitamin B12 by Dorothy Hodgkin in 1964; and finally, the development of immunoassay by Solomon Berson and Rosalyn Yalow in 1959–1960, which led to a Nobel Prize for Yalow in 1977 (five years after the untimely death of Berson). The history of Yalow and Berson’s discovery and its impact on the field is an illustration of the adage that every story has two sides.
Bad reporting does not mean bad methods for randomised trials: observational study of randomised controlled trials performed by the Radiation Therapy Oncology Group
Authors: H. P Soares
Journal: BMJ (2004)

To determine whether poor reporting of methods in randomised controlled trials reflects on poor methods.Observational study.Reports of randomised controlled trials conducted by the Radiation Therapy Oncology Group since its establishment in 1968.The Radiation Therapy Oncology Group. Outcome measures Content of reports compared with the design features described in the protocols for all randomised controlled trials.The methodological quality of 56 randomised controlled trials was better than reported. Adequate allocation concealment was achieved in all trials but reported in only 42% of papers. An intention to treat analysis was done in 83% of trials but reported in only 69% of papers. The sample size calculation was performed in 76% of the studies, but reported in only 16% of papers. End points were clearly defined and alpha and beta errors were prespecified in 76% and 74% of the trials, respectively, but only reported in 10% of the papers. The one exception was the description of drop outs, where the frequency of reporting was similar to that contained in the original statistical files of the Radiation Therapy Oncology Group.The reporting of methodological aspects of randomised controlled trials does not necessarily reflect the conduct of the trial. Reviewing research protocols and contacting trialists for more information may improve quality assessment.
Certolizumab pegol plus methotrexate provides broad relief from the burden of rheumatoid arthritis: analysis of patient-reported outcomes from the RAPID 2 trial
Authors: Vibeke Strand, Josef S Smolen, Ronald F van Vollenhoven, Philip Mease, Gerd R Burmester, Falk Hiepe, Dinesh Khanna, Enkeleida Nikaï, Geoffroy Coteur, Michael Schiff
Journal: Annals of the Rheumatic Diseases (2011)

Objective To assess the impact of certolizumab pegol (CZP) on patient-reported outcomes (PROs) in rheumatoid arthritis (RA), and to interpret these results using number needed to treat (NNT), and associations between PRO responses and longer term outcomes. Methods A total of 619 patients with active RA were randomised to CZP 200 or 400 mg, or placebo plus methotrexate (MTX). PROs assessed included pain, patient's global assessment of disease activity (PtGA), physical function, fatigue and health-related quality of life. Treatment impact on PROs, NNT to achieve simultaneous improvements in multiple PROs and correlations between PROs were calculated. Times to onset of improvements greater than or equal to minimum clinically important differences (MCIDs) in pain as a determinant of clinical outcomes at week 24 were compared between week 6 and 12 responders, and in patients with improvements in pain ≥MCID at week 12 (week 12 responders/non-responders). Results CZP 200 and 400 mg plus MTX were associated with rapid, clinically meaningful improvements in all PROs. The NNT for subjects to report changes ≥MCID in up to five PROs was two to three, and five for all six PROs (pain, PtGA, physical function, fatigue and short-form 36-item Physical and Mental Component Summary Scores). More patients with improvements ≥MCID in pain at week 6 than those at week 12 had lower disease activity at week 24. Week 12 pain responders had better clinical outcomes at week 24 than non-responders. Conclusions The data demonstrate that CZP provides broad relief from the burden of RA. Trial registration number NCT00160602.
Secreted Molecules in Metanephric Induction
Authors: THOMAS J. CARROLL, ANDREW P. McMAHON
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Nearly 50 yr ago, Clifford Grobstein made the observation that the ureteric bud induced the nephrogenic mesenchyme to undergo tubulogenesis. Since that discovery, scientists have attempted to characterize the molecular nature of the inducer. To date, no single molecule that is both necessary and sufficient for nephric induction has been identified. Because of recent insights regarding the role of several secreted molecules in tubulogenesis, it has become necessary to revise the classic model of metanephric induction. The studies of the classic ureteric inducer performed to date have most likely been characterizations of a mesenchyme-specific inducer, Wnt-4, and its role in tubulogenesis. Ureteric induction most likely involves a series of distinct events that provide proliferative, survival, and condensation signals to the mesenchyme, integrating the growth of the ureteric system with tubulogenesis.
Dr. Archibald Arnott: surgeon to the 20th Foot and physician to Napoleon.
Authors: J B Wilson
Journal: BMJ (1975)

After qualifying in medicine at Edinburgh Arnott obtained an appointment through Lord Lindores as surgeon's mate in the 1 lth Dragoons.Eighteen months later he was promoted assistant surgeon in the same regiment and in 1799 he was appointed surgeon to the 20th Regiment of Foot
Carboplatin dosage: prospective evaluation of a simple formula based on renal function.
Authors: A H Calvert, D R Newell, L A Gumbrell, S O'Reilly, M Burnell, F E Boxall, Z H Siddik, I R Judson, M E Gore, E Wiltshaw
Journal: Journal of Clinical Oncology (1989)

A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.
Molecular characterisation of non-absorptive and absorptive enterocytes in human small intestine
Authors: N Gassler
Journal: Gut (2005)

<b>Background and aims:</b> Perturbation of differentiation of the crypt-villus axis of the human small intestine is associated with several intestinal disorders of clinical importance. At present, differentiation of small intestinal enterocytes in the crypt-villus axis is not well characterised. <b>Subjects and methods:</b> Expression profiling of microdissected enterocytes lining the upper part of crypts or the middle of villi was performed using the Affymetrix X3P arrays and several methods for confirmation. <b>Results:</b> A total of 978 differentially expressed sequences representing 778 unique UniGene IDs were found and categorised into four functional groups. In enterocytes lining the upper part of crypts, cell cycle promoting genes and transcription/translation related genes were predominantly expressed, whereas in enterocytes lining the middle of villi, high expression of cell cycle inhibiting genes, metabolism related genes, and vesicle/transport related genes was found. <b>Conclusion:</b> Two types of enterocytes were dissected at the molecular level, the non-absorptive enterocyte located in the upper part of crypts and the absorptive enterocyte found in the middle of villi. These data improve our knowledge about the physiology of the crypt-villus architecture in human small intestine and provide new insights into pathophysiological phenomena, such as villus atrophy, which is clinically important.
High Frequency of Germline <i>SUFU</i> Mutations in Children With Desmoplastic/Nodular Medulloblastoma Younger Than 3 Years of Age
Authors: Laurence Brugières, Audrey Remenieras, Gaëlle Pierron, Pascale Varlet, Sébastien Forget, Véronique Byrde, Johny Bombled, Stéphanie Puget, Olivier Caron, Christelle Dufour, Olivier Delattre, Brigitte Bressac-de Paillerets, Jacques Grill
Journal: Journal of Clinical Oncology (2012)

Germline mutations of the SUFU gene have been shown to be associated with genetic predisposition to medulloblastoma, mainly in families with multiple cases of medulloblastoma and/or in patients with symptoms similar to those of Gorlin syndrome. To evaluate the contribution of these mutations to the genesis of sporadic medulloblastomas, we screened a series of unselected patients with medulloblastoma for germline SUFU mutations.A complete mutational analysis of the SUFU gene was performed on genomic DNA in all 131 consecutive patients treated for medulloblastoma in the pediatrics department of the Institut Gustave Roussy between 1972 and 2009 and for whom a blood sample was available.We identified eight germline mutations of the SUFU gene: one large genomic duplication and seven point mutations. Mutations were identified in three of three individuals with medulloblastoma with extensive nodularity, four of 20 with desmoplastic/nodular medulloblastomas, and one of 108 with other subtypes. All eight patients were younger than 3 years of age at diagnosis. The mutations were inherited from the healthy father in four of six patient cases in which the parents accepted genetic testing; de novo mutations accounted for the other two patient cases. Associated events were macrocrania in six patients, hypertelorism in three patients, and multiple basal cell carcinomas in the radiation field after age 18 years in one patient.These data indicate that germline SUFU mutations were responsible for a high proportion of desmoplastic medulloblastoma in children younger than 3 years of age. Genetic testing should be offered to all children diagnosed with sonic hedgehog-driven medulloblastoma at a young age.
Economic impact of a nationwide outbreak of salmonellosis: cost-benefit of early intervention.
Authors: J. A. Roberts, P. N. Sockett, O. N. Gill
Journal: BMJ (1989)

The recognition and investigation of an outbreak of food poisoning in 1982 due to chocolate contaminated with Salmonella napoli enabled the food that carried the salmonella to be identified and four fifths of the implicated consignment of chocolate to be withdrawn. The economic benefits of prompt intervention in the outbreak have been assessed. The cost of the outbreak was over 0.5 pounds m. It is estimated that five deaths were prevented by the intervention and that 185 admissions to hospital and 29,000 cases of S napoli enteritis were avoided. This successful investigation yielded a 3.5-fold rate of return to the public sector and a 23.3-fold return to society on an investment in public health surveillance. A methodology is described that can be used to estimate the benefits of early intervention in outbreaks of foodborne illness and topics for further research are suggested. It is concluded that public health authorities and industry have much to gain by collaborating in the research into the design of cost effective programmes to prevent foodborne infections.
Uncoupling of Proliferative Potential and Gain of Effector Function by CD8+ T Cells Responding to Self-Antigens
Authors: Javier Hernández, Sandra Aung, Kristi Marquardt, Linda A. Sherman
Journal: The Journal of Experimental Medicine (2002)

Professional antigen-presenting cells (APCs) are capable of transporting self-antigens from peripheral tissues to secondary lymphoid organs where they are presented to potentially autoreactive CD8(+) T cells. In the absence of an inflammatory response, this results in immune tolerance. The presence of activated, antigen-specific CD4(+) T cells converts this tolerogenic encounter into an immunogenic one by promoting extensive proliferation of CD8(+) T cells and their development into effectors. Surprisingly, activation of APCs with an agonistic antibody specific for CD40 could not substitute for CD4(+) help in this task. Anti-CD40 induced recruitment of dendritic cells expressing high levels of B7 costimulatory molecules into the lymph nodes, which in turn, greatly enhanced activation and expansion of CD8(+) T cells. However, these activated CD8(+) cells did not demonstrate effector function. We conclude that proliferative potential and gain of effector function are separable events in the differentiation program of CD8(+) T cells.
Glycogen Synthase Kinase-3α Limits Ischemic Injury, Cardiac Rupture, Post–Myocardial Infarction Remodeling and Death
Authors: Hind Lal, Jibin Zhou, Firdos Ahmad, Raihana Zaka, Ronald J. Vagnozzi, Morgan DeCaul, James Woodgett, Erhe Gao, Thomas Force
Journal: Circulation (2011)

The molecular pathways that regulate the extent of ischemic injury and post-myocardial infarction (MI) remodeling are not well understood. We recently demonstrated that glycogen synthase kinase-3α (GSK-3α) is critical to the heart's response to pressure overload. However, the role, if any, of GSK-3α in regulating ischemic injury and its consequences is not known.MI was induced in wild-type (WT) versus GSK-3α((-/-)) (KO) littermates by left anterior descending coronary artery ligation. Pre-MI, WT, and KO hearts had comparable chamber dimensions and ventricular function, but as early as 1 week post-MI, KO mice had significantly more left ventricular dilatation and dysfunction than WT mice. KO mice also had increased mortality during the first 10 days post-MI (43% versus 22%; P=0.04), and postmortem examination confirmed cardiac rupture as the cause of most of the deaths. In the mice that survived the first 10 days, left ventricular dilatation and dysfunction remained worse in the KO mice throughout the study (8 weeks). Hypertrophy, fibrosis, and heart failure were all increased in the KO mice. Given the early deaths due to rupture and the significant reduction in left ventricular function evident as early as 1 week post-MI, we examined infarct size following a 48-hour coronary artery ligation and found it to be increased in the KO mice. This was accompanied by increased apoptosis in the border zone of the MI. This increased susceptibility to ischemic injury-induced apoptosis was also seen in cardiomyocytes isolated from the KO mice that were exposed to hypoxia. Finally, Bax translocation to the mitochondria and cytochrome C release into the cytosol were increased in the KO mice.GSK-3α confers resistance to ischemic injury, at least in part, via limiting apoptosis. Loss of GSK-3α promotes ischemic injury, increases risk of cardiac rupture, accentuates post-MI remodeling and left ventricular dysfunction, and increases the progression to heart failure. These findings are in striking contrast to multiple previous reports in which deletion or inhibition of GSK-3β is protective.