tbuckley/cabot-search huggingface dataset:
Out with the old, in with the new
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Muraro et al., reporting on page 805, use stem cell transplants to suppress active multiple sclerosis (MS), and then show that the treatment increased the number of naive T cells at the expense of the memory T cells that are associated with disease.

Intense immunosuppression followed by stem cell transplantation has been shown to slow or stop the formation of new brain lesions in up to 95% of patients with aggressive MS. Yet it has been controversial and rarely used, mainly because immunosuppression is risky and because nothing was known about how transplantation induced remission. One proposed theory was that transplantation might change the composition of the T cell pool and bias it away from autoreactivity.






Figure 

An MS lesion (arrow) was resolved two years after stem cell transplantation.




Muraro and colleagues now provide the first evidence that stem cell transplantation allows patients to regenerate a new repertoire of T cells that are less activated and more diverse than their pretransplant repertoires. This suggests that many of the disease-causing T cells—most of which have a memory phenotype—were eliminated by the treatment.

However, concrete proof that autoreactive T cells are reduced or eliminated is difficult to obtain, partly because the specificities of the autoreactive T cells that invade the central nervous system are not well defined.

The difficulty in assessing the basis for treatment success is one problem. Another is the possibility that autoreactive cells will reemerge from the pool of transferred stem cells. The authors agree that these cells could eventually come back, but hope that resetting the immune system may improve the quality of life for patients with an otherwise poor prognosis.

They emphasize, however, that this intense therapy is probably only suited to a subset of MS patients who have active and aggressive disease and that its implementation will require careful patient selection.
Asthma Control Questionnaire in children: validation, measurement properties, interpretation
Authors: E.F. Juniper, K. Gruffydd-Jones, S. Ward, K. Svensson
Journal: European Respiratory Journal (2010)

The Asthma Control Questionnaire (ACQ) has been validated in adults to measure the primary goal of management (minimisation of symptoms, activity limitations, short-acting β 2 -agonist use and airway narrowing). The present study evaluated the validity, measurement properties and interpretability of the ACQ in children aged 6–16 yrs. 35 children attended clinic on three occasions (0, 1 and 4 weeks) and completed the ACQ, Mini Paediatric Asthma Quality of Life Questionnaire and the Royal College of Physicians’ “Three Questions”. Parents completed the Paediatric Asthma Caregiver’s Quality of Life Questionnaire. Between visits, children completed the Asthma Control Diary and measured peak expiratory flow. At weeks 1 and 4, clinicians and parents completed Global Rating of Change Questionnaires. All patients completed the study. 19 children were stable between two assessments and provided evidence of good test–retest reliability (intraclass correlation coefficient 0.79). The ACQ was responsive to change in asthma control (p = 0.026) and the mean± sd Minimal Important Difference was 0.52±0.45. Both cross-sectional and longitudinal correlations between the ACQ and the other outcomes were close to predicted and provided evidence that the ACQ measures asthma control in children. The ACQ has strong measurement properties and is valid for use in children aged 6–16 yrs. In children aged 6–10 yrs, it must be administered by a trained interviewer.
Racial Differences in Paranoid Ideation and Psychoses in an Older Urban Population
Authors: Carl I Cohen, Carol Magai, Robert Yaffee, Lorna Walcott-Brown
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: This study examined whether there are racial differences in the prevalence of paranoid ideation and psychotic symptoms in persons age ≥55 in an urban community. METHOD: Using 1990 census data for Brooklyn, N.Y., the authors attempted to interview all cognitively intact persons age ≥55 in randomly selected blocks. The final group consisted of 206 whites and 821 blacks. The authors used George's Social Antecedent Model for analyzing 21 independent and three dependent variables: paranoid ideation, psychotic symptoms, and psychotic symptoms/paranoid ideation. The group was weighted by race and gender. To control for intrablock clustering effects without replacement sampling, the authors used SUDAAN for data analysis. RESULTS: A significant difference in psychotic symptoms or paranoid ideation was found between blacks and whites (24% versus 10%) that was attenuated but not eliminated with logistic regression analyses. Blacks with psychotic symptoms or paranoid ideation, especially Caribbeans, had significantly lower receipt of mental health services and lower perceived service needs. With logistic regression, psychotic symptoms and paranoid ideation were associated with four variables among blacks and whites, although only one was significant in both groups. CONCLUSIONS: Racial differences in psychotic symptoms and paranoid ideation persist even after control for various clinical, social, and attitudinal effects. Among blacks, response to stressors may be expressed through increased paranoid ideation and psychotic symptoms. Stronger beliefs in spiritualism increase this expression in both races. The high prevalence of psychotic symptoms or paranoid ideation among this aging urban population, especially blacks, highlights a potential public health issue.
Basophil Histamine Release Induced by Leukocyte Nuclei in Patients with Rheumatoid Arthritis
Authors: Henrik Permin, Per Stahl Skov, Svend Norn
Journal: Allergy (1983)

Leukocyte suspensions containing basophils were obtained from 23 patients with rheumatoid arthritis (RA). When these cells were incubated with leukocyte nuclei from normal persons, histamine release was seen in 11 of the 15 patients with active disease, but not in the quiescent group or in normal individuals. The dose‐response cure for histamine release was similar to that obtained by specific antigen in type I allergy. By removal from and refixation to the cells of surface Ig, the release of histamine was respectively, abolished and restored, just as in similar experiments in hay lever patients. The dependence of pH for removal was also identical with that found in type 1 allergy. Antinuclear antibodies of the IgE class (IgE ANA) mainly directed against the granulocyte nuclei were often found in serum and on the cell surface of the RA patients, but not in normal individuals. A correlation was found between these titres in serum and on the cell surface on the correlation was found between ANA in serum and on the cell surface, on the one hand and disease activity and histamine release on the other. In a group of 12 patients with another Joint disease, osteoarthrosis, only two patients showed histamine release, and in contrast to the other patients they showed swelling of more than two joints. The present investigation supports our hypothesis of an involvement of an autoimmune type I reaction directed against nuclear components in the RA disease.
Clinical Characteristics of Patients With Lung Adenocarcinomas Harboring <i>BRAF</i> Mutations
Authors: Paul K. Paik, Maria E. Arcila, Michael Fara, Camelia S. Sima, Vincent A. Miller, Mark G. Kris, Marc Ladanyi, Gregory J. Riely
Journal: Journal of Clinical Oncology (2011)

Purpose BRAF mutations occur in non–small-cell lung cancer. Therapies targeting BRAF mutant tumors have recently been identified. We undertook this study to determine the clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. Patients and Methods We reviewed data from consecutive patients with lung adenocarcinoma whose tumors underwent BRAF, EGFR, and KRAS mutation testing as well as fluorescence in situ hybridization for ALK rearrangements. Patient characteristics including age, sex, race, performance status, smoking history, stage, treatment history, and overall survival were collected. Results Among 697 patients with lung adenocarcinoma, BRAF mutations were present in 18 patients (3%; 95% CI, 2% to 4%). The BRAF mutations identified were V600E (50%), G469A (39%), and D594G (11%). Mutations in EGFR were present in 24%, KRAS in 25%, and ALK translocations in 6%. In contrast to patients with EGFR mutations and ALK rearrangements who were mostly never smokers, all patients with BRAF mutations were current or former smokers (P &lt; .001). The median overall survival of advanced-stage patients with BRAF mutations was not reached. In comparison, the median overall survival of patients with EGFR mutations was 37 months (P = .73), with KRAS mutations was 18 months (P = .12), and with ALK rearrangements was not reached (P = .64). Conclusion BRAF mutations occur in 3% of patients with lung adenocarcinoma and occur more commonly in current and former smokers. The incidence of BRAF mutations other than V600E is significantly higher in lung cancer than in melanoma.
Improved Response With Higher Corticosteroid Dose in Children With Acute Lymphoblastic Leukemia
Authors: Cindy L. Schwartz, E. Brad Thompson, Richard D. Gelber, Mary L. Young, David Chilton, Harvey J. Cohen, Stephen E. Sallan
Journal: Journal of Clinical Oncology (2001)

PURPOSE: We investigated whether there was a dose-response relationship for the use of corticosteroids in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Three hundred sixty-nine patients, ages 1 to 18 years with ALL, were randomly assigned to receive one of four different doses of corticosteroid (prednisolone 40 mg/m 2 /d or dexamethasone 6, 18, or 150 mg/m 2 /d) administered as a 3-day, single-drug window before initiation of standard, multidrug induction chemotherapy. Corticosteroid drug response was measured by reduction in bone marrow blast counts and absolute peripheral blast counts after 3 days. Glucocorticoid receptor (GCR) number and the effective concentration of dexamethasone resulting in a 50% reduction of leukemic cell viability in vitro (EC-50) were evaluated at days 0 and 3. RESULTS: Increasing dexamethasone doses resulted in greater marrow blast response (P = .007), with a similar trend in peripheral-blood blast response. High-dose corticosteroid regimens (dexamethasone 18 or 150 mg/m 2 /d) elicited better responses than standard doses of dexamethasone or prednisone (bone marrow, P = .002; peripheral blasts, P = .05). Among patients treated with standard-dose corticosteroids, 38% with resistant (EC-50 &gt; 10 -7 ) peripheral blasts had a good response compared with 92% with sensitive (EC-50 &lt; 10 -7 ) peripheral blasts (P = .01). In contrast, there was no differential response according to EC-50 group after high-dose corticosteroids. Similarly, an association between response and GCR on peripheral-blood blasts was noted after standard-dose corticosteroid regimens but not after high-dose corticosteroid regimens. CONCLUSION: Response of ALL to glucocorticoid therapy increased with dose. Higher-dose corticosteroid treatment abrogated the effect of relative drug insensitivity and of low GCR on peripheral blasts.
Endothelin receptor blockade and nitric oxide bioactivity [Cardiovascular Research 2001;49:146–151]
Authors: M Barton
Journal: Cardiovascular Research (2001)

In a recent paper, Verma et al. reported abnormal endothelium-dependent relaxation to acetylcholine in isolated internal mammary arteries obtained from patients with coronary artery disease [1]. The authors also observed a moderate increase of the maximum response but not of the sensitivity of these relaxations after 20 min of incubation with micromolar concentrations of either bosentan, a non-selective ET receptor antagonist, BQ-123 (an ETA selective compound) or BQ-788 (an ETB selective compound at low concentrations). The improvement of endothelium-dependent relaxation averaged between 10 and 17% of complete relaxation compared to control experiments, and was not present in endothelium-denuded vessels and not evident in response to the endothelium-independent vasodilator sodium nitroprusside according to the authors’ unpublished data. The authors concluded that both ETA and ETB receptors contribute to ‘endothelial dysfunction’ and that blocking both the ETA and the ETB receptor may have endothelial protective effects in human internal mammary arteries. However, there are several issues that must be taken into account when interpreting these data.

First, the clinical characteristics and treatments of the study patients, a considerable number of which were women, deserve mentioning. More than half of the patients had a positive family history for coronary artery disease, were smokers, and/or had hypercholesterolemia. It is surprising to learn that despite the elevated plasma lipids and in view of the beneficial effects of statins in the secondary prevention of coronary artery disease, none of the patients was on statin therapy, a treatment that has also been shown to improve endothelium-dependent …
Mitochondrial complex II is essential for hypoxia-induced pulmonary vasoconstriction of intra- but not of pre-acinar arteries
Authors: Renate Paddenberg, Martina Tiefenbach, Petra Faulhammer, Anna Goldenberg, Barbara Gries, Uwe Pfeil, Katrin S. Lips, José I. Piruat, José López-Barneo, Ralph T. Schermuly, Norbert Weissmann, Wolfgang Kummer
Journal: Cardiovascular Research (2012)

AimsAlveolar hypoxia acutely elicits contraction of pulmonary arteries, leading to a rise in pulmonary arterial pressure (PAP) and shifting blood to better ventilated areas of the lung. The molecular mechanisms underlying this hypoxic pulmonary vasoconstriction (HPV) are still incompletely understood. Here, we investigated the role of succinate dehydrogenase (SDH; synonymous to mitochondrial complex II) in HPV, with particular emphasis on regional differences along the vascular bed and consequences for PAP and perfusion-to-ventilation matching, using mutant mice heterozygous for the SDHD subunit of complex II (SDHD+/−).
Dual Disruption of DNA Repair and Telomere Maintenance for the Treatment of Head and Neck Cancer
Authors: Shayanne A. Lajud, Danish A. Nagda, Taku Yamashita, Jun Zheng, Nobuaki Tanaka, Waleed M. Abuzeid, Alyssa Civantos, Orysia Bezpalko, Bert W. O'Malley, Daqing Li
Journal: Clinical Cancer Research (2014)

Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a targeted molecular "hit" on the MRN complex, which is upstream of BRCA, can effectively sensitize BRCA-proficient head and neck squamous cell carcinoma (HNSCC) to PARP inhibitor (PARPi).Human HNSCC cell lines and a mouse model with HNSCC xenografts were used in this study. In vitro and in vivo studies were conducted to evaluate the effects and underlying mechanisms of dual molecular disruption of PARP and the MRN complex, using a pharmacologic inhibitor and a dominant-negative Nbs1 expression vector, respectively.Our findings demonstrate that downregulation of the MRN complex disrupts homologous recombination, and, when combined with PARPi, leads to accumulation of lethal DNA double-strand breaks. Moreover, we show that PARPi and MRN complex disruption induces significantly shortening telomere length. Together, our results demonstrate that dual disruption of these pathways causes significant cell death in BRCA-proficient tumor cells both in vitro and in vivo.Our study, for the first time, elucidates a novel mechanism for MRN complex and PARP inhibition beyond DNA repair, demonstrating the feasibility of a dual disruption approach that extends the utility of PARPi to the treatment of BRCA-proficient cancers.
Interaction of lymphokine-activated killer cells with susceptible targets does not induce second messenger generation and cytolytic granule exocytosis.
Authors: P Zanovello, A Rosato, V Bronte, V Cerundolo, S Treves, F Di Virgilio, T Pozzan, G Biasi, D Collavo
Journal: The Journal of Experimental Medicine (1989)

CTL activation by specific targets leads to a rapid rise of inositol phosphates (InsPs) and of cytoplasmic-free Ca2+ concentration ([Ca2+]i). While these events are considered necessary to trigger granule secretion, Ca2+-independent cytolytic mechanisms have been recently proposed in addition or as an alternative to the classical Ca2+-dependent exocytosis model. We observed that lymphokine-activated killer (LAK) cells, obtained after stimulation with supraoptimal concentrations of IL-2 in short- or long-term cultures, kill susceptible targets in the absence of a [Ca2+]i rise and InsP3 formation. Moreover, LAK cell-mediated lysis was not associated with an increase in cytotoxic granule exocytosis, as evaluated by BLT-esterase release into the culture supernatant. Furthermore, using an antigen-specific CTL clone, which acquires LAK-like activity when cultured in medium containing high IL-2 doses, second messenger generation and cytolytic granule content secretion were not detected during lysis of unrelated target cells, while killing of specific targets triggered both these processes. These findings suggest that two lytic pathways may coexist in the same effector cells: a second messenger-dependent pathway involving degranulation, which is activated after TCR interaction with specific targets, and another pathway, independent of any known second messenger generation, responsible for unrelated target cell lysis.
CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group
Authors: Michael Pfreundschuh, Lorenz Trümper, Anders Österborg, Ruth Pettengell, Marek Trneny, Kevin Imrie, David Ma, Devinder Gill, Jan Walewski, Pier-Luigi Zinzani, Rolf Stahel, Stein Kvaloy, Ofer Shpilberg, Ulrich Jaeger, Mads Hansen, Tuula Lehtinen, Armando López-Guillermo, Claudia Corrado, Adriana Scheliga, Noel Milpied, Myriam Mendila, Michelle Rashford, Evelyn Kuhnt, Markus Loeffler
Journal: The Lancet Oncology (2006)
Patient Selection for Oncology Phase I Trials: A Multi-Institutional Study of Prognostic Factors
Authors: David Olmos, Roger P. A'Hern, Silvia Marsoni, Rafael Morales, Carlos Gomez-Roca, Jaap Verweij, Emile E. Voest, Patrick Schöffski, Joo Ern Ang, Nicolas Penel, Jan H. Schellens, Gianluca del Conte, Andre T. Brunetto, T.R. Jeffry Evans, Richard Wilson, Elisa Gallerani, Ruth Plummer, Josep Tabernero, Jean-Charles Soria, Stan B. Kaye
Journal: Journal of Clinical Oncology (2012)

Purpose The appropriate selection of patients for early clinical trials presents a major challenge. Previous analyses focusing on this problem were limited by small size and by interpractice heterogeneity. This study aims to define prognostic factors to guide risk-benefit assessments by using a large patient database from multiple phase I trials. Patients and Methods Data were collected from 2,182 eligible patients treated in phase I trials between 2005 and 2007 in 14 European institutions. We derived and validated independent prognostic factors for 90-day mortality by using multivariate logistic regression analysis. Results The 90-day mortality was 16.5% with a drug-related death rate of 0.4%. Trial discontinuation within 3 weeks occurred in 14% of patients primarily because of disease progression. Eight different prognostic variables for 90-day mortality were validated: performance status (PS), albumin, lactate dehydrogenase, alkaline phosphatase, number of metastatic sites, clinical tumor growth rate, lymphocytes, and WBC. Two different models of prognostic scores for 90-day mortality were generated by using these factors, including or excluding PS; both achieved specificities of more than 85% and sensitivities of approximately 50% when using a score cutoff of 5 or higher. These models were not superior to the previously published Royal Marsden Hospital score in their ability to predict 90-day mortality. Conclusion Patient selection using any of these prognostic scores will reduce non–drug-related 90-day mortality among patients enrolled in phase I trials by 50%. However, this can be achieved only by an overall reduction in recruitment to phase I studies of 20%, more than half of whom would in fact have survived beyond 90 days.
Margaret McCartney: Have we given guidelines too much power?
Authors: M. McCartney
Journal: BMJ (2014)

“Guidelines, not tramlines,” said David Haslam, chair of the National Institute for Health and Care Excellence (NICE), at its conference this year. Amen to that, but for those of us in primary care, how well do guidelines fit our patients?

Guidelines should be a good idea. It’s impossible to keep on top of all new research, to assess its relevance, outcomes, and biases, and to systematically review and meta-analyse it. We require experts to pull research together and then pick it apart. But is the end result reliable? 

Researchers from Norwich Medical School assessed the 22 pieces of NICE guidance in 2011-12 that were relevant to primary care (from a total of 45). These contained 495 recommendations for primary care, based on …
An Experimental Investigation of the Cervical and Thoracic Nerve Roots in Relation to the Subject of Wry-Neck
Authors: J. S. R. Russell
Journal: BMJ (1897)

rOCT. 2, 2 b7 rtilust be obtained by induction; and that these principles, when of the mf)bt general kind, are axioms."Then he quotes passages in proof from Aristotle's writings.It is, howeer, pretty evident that Aristotle's reve- ) ence for facts was no more than a pious opinion, which he habitiially ig'oored in the actual handling of questions of natural knowledge.His treatise "On the Parts of Animals" bristles with errors of observation whicha very moderate amount of painstaking would have rectified.Had the ancient Greeks, and their successors in the Middle Ages, been more accurate observers of facts, and had they sought for and invented instru- ments for the more exact observation of facts, they would not have so '-onspicuously failed to establish at least thefoundations of exact science.The historian of the inductive sciences, however, will have it otherwise.Hie sums up his argument thus: "The defect was that, although they had in their possession Facts and Ideas, the Ideas were not distinct and appropriate to the Facts."Is it not rather the case that the "1ideas were not distinct and appropriate to the Facts," precisely because the " Facts " were indistinctly seen and imperfectly apprehended?aMr.Mulhall ealculates that "our steam power in the United Kingdom is equal to the forzte of x6g,0oo,0oo able-bodied men, a number greater than the whole population of Europe could supply.-NationalProgress during the Queen's Reign, p. 22.