tbuckley/cabot-search huggingface dataset:
Suppression of idiotype and generation of suppressor T cells with idiotype-conjugated thymocytes.
Authors: Y Dohi, A Nisonoff
Journal: The Journal of Experimental Medicine (1979)

Inoculation of A/J mice with syngeneic thymocytes conjugated with specifically purified A/J anti-phenylarsonate (anti-Ar) antibodies, selectively suppressed the subsequent synthesis of those anti-Ar antibodies which carry the major cross-reactive idiotype. High titers of anti-Ar antibodies were produced upon subsequent immunization but in most mice the idiotype was undetectable. Suppression similarly occurred in F1(A/J X BALB/c) and in C.AL-20 mice. Although some mice were suppressed when unconjugated antibody was injected, the suppressive effect was much more pronounced, particularly in the F1 and C.AL-20 recipients, when the antibody was coupled to thymocytes. The state of suppression could be adoptively transferred with T cells to mildly irradiated syngeneic recipients. A population enriched for B cells had little if any suppressive effect. There was no requirement for antigen in the generation of suppressors. Thymocytes conjugated with antibody did not induce idiotype-specific suppression in mice that had been recently challenged with antigen. Thymocytes from BALB/c and C57BL/10 mice were effective carriers for the anti-Ar antibodies, i.e., there was no evidence for H-2 restriction. The experiments demonstrate the feasibility of suppressing idiotype production and generating idiotype-specific suppressor T cells without the use of anti-idiotypic antibody or antigen.
Intermittent Administration of MEK Inhibitor GDC-0973 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth Inhibition
Authors: Klaus P. Hoeflich, Mark Merchant, Christine Orr, Jocelyn Chan, Doug Den Otter, Leanne Berry, Ian Kasman, Hartmut Koeppen, Ken Rice, Nai-Ying Yang, Stefan Engst, Stuart Johnston, Lori S. Friedman, Marcia Belvin
Journal: Cancer Research (2011)

Combinations of MAP/ERK kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors have shown promise in preclinical cancer models, leading to the initiation of clinical trials cotargeting these two key cancer signaling pathways. GDC-0973, a novel selective MEK inhibitor, and GDC-0941, a class I PI3K inhibitor, are in early stage clinical trials as both single agents and in combination. The discovery of these selective inhibitors has allowed investigation into the precise effects of combining inhibitors of two major signaling branches downstream of RAS. Here, we investigated multiple biomarkers in the mitogen-activated protein kinase (MAPK) and PI3K pathway to search for points of convergence that explain the increased apoptosis seen in combination. Using washout studies in vitro and alternate dosing schedules in mice, we showed that intermittent inhibition of the PI3K and MAPK pathway is sufficient for efficacy in BRAF and KRAS mutant cancer cells. The combination of GDC-0973 with the PI3K inhibitor GDC-0941 resulted in combination efficacy in vitro and in vivo via induction of biomarkers associated with apoptosis, including Bcl-2 family proapoptotic regulators. Therefore, these data suggest that continuous exposure of MEK and PI3K inhibitors in combination is not required for efficacy in preclinical cancer models and that sustained effects on downstream apoptosis biomarkers can be observed in response to intermittent dosing.
Secretoglobins SCGB3A1 and SCGB3A2 Define Secretory Cell Subsets in Mouse and Human Airways
Authors: Susan D. Reynolds, Paul R. Reynolds, Gloria S. Pryhuber, Jonathan D. Finder, Barry R. Stripp
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Clara cell secretory protein (CCSP) is expressed abundantly within the conducting airway epithelium and is thought to have immunoregulatory functions. Differences in the localization of CCSP between mouse and human airways led us to hypothesize that functional homologues of CCSP may compensate for the lack of CCSP expression in proximal airway locations. We previously identified an expressed sequence tag (W82219) whose expression is induced within Clara cells of CCSP knockout mice. Expressed sequence tag W82219 is distantly related to CCSP and represents a member of a new subfamily of secretoglobins (MmSCGB3A2). Another member of the mouse SCGB3 family (MmSCGB3A1) as well as human orthologues (HsSCGB3A1 and HsSCGB3A2) that possess structural homology to CCSP were identified, suggesting they may share common functional properties. SCGB3A1 messenger RNA localizes to a subset of SCGB3A2-expressing cells within bronchi of both mouse and neonatal human lungs. CCSP, SCGB3A1, and SCGB3A2 were decreased in airways of neonates with bronchopulmonary dysplasia and in mice after airway injury. We conclude that secretory cells of the conducting airway epithelium express distinct members of the secretoglobin family in a partially overlapping fashion. Altered expression of secretoglobins in airway disease may contribute to immunoregulatory perturbations commonly seen in chronic airway disease.
Allergic Eosinophil-rich Inflammation Develops in Lungs and Airways of B Cell–deficient Mice
Authors: Magnus Korsgren, Jonas S. Erjef ält, Olle Korsgren, Frank Sundler, Carl G.A. Persson
Journal: The Journal of Experimental Medicine (1997)

Immunoglobulins (Ig), particularly IgE, are believed to be crucially involved in the pathogenesis of asthma and, equally, in allergic models of the disease. To validate this paradigm we examined homozygous mutant C57BL/6 mice, which are B cell deficient, lacking all Ig. Mice were immunized intraperitoneally with 10 μg ovalbumin (OVA) plus alum, followed by daily (day 14–20) 30 min exposures to OVA aerosol (OVA/OVA group). Three control groups were run: OVA intraperitoneally plus saline (SAL) aerosol (OVA/SAL group); saline intraperitoneally plus saline aerosol; saline intraperitoneally plus OVA aerosol (n = 6–7). Lung and large airway tissues obtained 24 h after the last OVA or SAL exposure were examined by light microscopy and transmission electron microscopy (TEM). The Ig-deficient mice receiving OVA/ OVA treatment had swollen and discolored lungs and exhibited marked eosinophilia both in large airway subepithelial tissue (49.2 ± 12.0 cells/mm basement membrane [BM] versus OVA/ SAL control 1.2 ± 0.3 cells/mm BM; P &amp;lt;0.001), and perivascularly and peribronchially in the lung (49.3 ± 9.0 cells/unit area versus OVA/SAL control 2.6 ± 0.6 cells/unit area; P &amp;lt;0.001). The eosinophilia extended to the regional lymph nodes. TEM confirmed the subepithelial and perivascular localization of eosinophils. Mucus cells in large airway epithelium increased from 1.5 ± 0.8 (OVA/SAL mice) to 39.5 ± 5.7 cells/mm BM in OVA/OVA treated mice (P &amp;lt;0.001). OVA/SAL mice never differed from the other control groups. Corresponding experiments in wild-type mice (n = 6–7 in each group) showed qualitatively similar but less pronounced eosinophil and mucus cell changes. Macrophages and CD4+ T cells increased in lungs of all OVA/OVA-treated mice. Mast cell number did not differ but degranulation was detected only in OVA/OVA-treated wild-type mice. Immunization to OVA followed by OVA challenges thus cause eosinophil-rich inflammation in airways and lungs of mice without involvement of B cells and Ig.
Antibody-independent Classical Pathway-mediated Opsonophagocytosis of Type Ia, Group B Streptococcus
Authors: Carol J. Baker, Morven S. Edwards, Bette J. Webb, Dennis L. Kasper
Journal: Journal of Clinical Investigation (1982)

The opsonophagocytic requirements of human sera containing endogenous complement for a variety of type Ia, and group B streptococcal strains were defined. Significant reduction (>==90%) in colony-forming units was noted after a 40-min incubation for the highly encapsulated, mouse-passed prototype strain 090 by sera containing moderate to high concentrations of antibody to type Ia polysaccharide (mean, 16.5 mug/ml), whereas bacterial growth occurred in 25 sera with low levels of specific antibody (mean, 2.1 mug/ml). This absolute requirement for a critical amount of specific antibody in promoting opsonophagocytic killing of strain 090 was not found when 18 fresh clinical type Ia isolates were tested. In antibody-deficient and agammaglobulinemic sera, respectively, mean reductions in colony-forming units of 94 and 95% were seen for fresh clinical isolates, whereas strain 090 was not killed by polymorphonuclear leukocytes in the presence of these sera. All strains required a considerable amount of specific antibody for alternative pathway-mediated opsonophagocytosis. That opsonophagocytic killing of clinical type Ia isolates was mediated by the classical pathway in a nonantibody-dependent fashion was shown when MgEGTA chelation of agammaglobulinemic serum or use of serum deficient in C2 resulted in bacterial growth. The addition of C2 to C2-deficient serum restored bactericidal activity of this serum. These experiments indicate that substances other than the exposed surface of the type Ia capsular polysaccharide initiate classical pathway-mediated opsonophagocytosis of clinical isolates of type Ia, group B streptococci by human sera in the absence of immunoglobulin. Perhaps, a deficiency in classical complement pathway function is critical to the susceptibility of neonates to type Ia, group B streptococcal disease.
CRF2 receptor activation prevents colorectal distension induced visceral pain and spinal ERK1/2 phosphorylation in rats
Authors: M Million
Journal: Gut (2005)

<b>Background and aims:</b> Activation of corticotropin releasing factor 1 (CRF<sub>1</sub>) receptors is involved in stress related responses and visceral pain, while activation of CRF<sub>2</sub> receptors dampens the endocrine and some behavioural stress responses. We hypothesised that CRF<sub>2</sub> receptor activation may influence visceral pain induced by colorectal distension (CRD) in conscious rats, and assessed the possible sites and mechanisms of action. <b>Methods:</b> Male Sprague-Dawley rats were exposed to CRDs (60 mm Hg, 10 minutes twice, with a 10 minute rest interval). Visceromotor responses (VMR) were measured by electromyography or visual observation. Spinal (L6–S1) extracellular signal regulated kinase 1/2 (ERK 1/2) activation following in vivo CRD and CRF<sub>2</sub> receptor gene expression in the T13–S1 dorsal root ganglia (DRG) and spinal cord were determined. Inferior splanchnic afferent (ISA) activity to CRD (0.4 ml, 20 seconds) was assessed by electrophysiological recording in an in vitro ISA nerve-inferior mesenteric artery (intra-arterial)-colorectal preparation. <b>Results:</b> In controls, VMR to the second CRD was mean 31 (SEM 4)% higher than that of the first (p&lt;0.05). The selective CRF<sub>2</sub> agonist, human urocortin 2 (hUcn 2, at 10 and 20 μg/kg), injected intravenous after the first distension, prevented sensitisation and reduced the second response by 8 (1)% and 30 (5)% (p&lt;0.05) compared with the first response, respectively. RT-PCR detected CRF<sub>2</sub> receptor gene expression in the DRG and spinal cord. CRD (60 mm Hg for 10 minutes) induced phosphorylation of ERK 1/2 in neurones of lumbosacral laminae I and IIo and the response was dampened by intravenous hUcn 2. CRD, in vitro, induced robust ISA spike activity that was dose dependently blunted by hUcn 2 (1–3 μg, intra-arterially). The CRF<sub>2</sub> receptor antagonist, astressin<sub>2</sub>-B (200 μg/kg subcutaneously or 20 μg intra-arterially) blocked the hUcn 2 inhibitory effects in vivo and in vitro. <b>Conclusions:</b> Peripheral injection of hUcn 2 blunts CRD induced visceral pain, colonic afferent, and spinal L6-S1 ERK 1/2 activity through CRF<sub>2</sub> receptor activation in rats.
Review of prevalence data in, and evaluation of methods for cross cultural adaptation of, UK surveys on tobacco and alcohol in ethnic minority groups
Authors: R. Bhopal
Journal: BMJ (2004)

Objective To assess the adequacy of cross cultural adaptations of survey questions on self reported tobacco and alcohol consumption in the United Kingdom.Design Assessment of consistency of data between studies identified through literature review.Studies evaluated with 12 guidelines developed from the research literature on achieving cross cultural comparability. ResultsThe literature review identified 18 key studies, five of them on national samples.Survey instruments were obtained for 15 of these.The comparison of prevalence data in national surveys showed some important discrepancies, greater for tobacco than for alcohol.For example, prevalence of cigarette smoking in Bangladeshi women was 6% in a national survey in 1994 and 1% in a national survey in 1999; in Chinese men it was 31% in a survey in 1993-4 and 17% in one in 1999; in African-Caribbean men it was 29% in a 1992 survey and 42% in one in 1993-4.The most guidelines met by any study was three, although one study partly met a fourth.Two studies met no guidelines.Only four studies consulted with ethnic minority communities in developing the questionnaire, none checked each language version with all others, and two stated the questionnaire had not been validated.Conclusions Surveys have not followed best practice in relation to measurement of risk factors in cross cultural settings.There is inconsistency in the prevalence data on smoking provided by different major national UK studies.Users of such data should be aware of their limitations.Research is needed to help achieve linguistic equivalence of survey questions in cross cultural research.
MAGNITUDE AND PATTERN OF THYMIC LYMPHOCYTE MIGRATION IN NEONATAL MICE
Authors: D. D. Joel, M. W. Hess, H. Cottier
Journal: The Journal of Experimental Medicine (1972)

Neonatal mice were given a subcapsular, intrathymic injection of thymidine-3H using a modified microneedle technique, and the migration of labeled cells to spleen, lymph nodes, Peyer's patches, and bone marrow was followed radioautographically with time. Assuming that nonlabeled lymphocytes migrated in the same manner as labeled lymphocytes, it can be concluded that the majority of lymphocytes present within mesenteric lymph nodes (74%) and Peyer's patches (61%), and a large proportion of those located in popliteal lymph nodes (40%) and the spleen (26%), were of thymic origin. Evidence is presented indicating that these are minimum values. The difference in the magnitude of thymic cell migration to gut-associated lymphoid tissue on the one hand and to the spleen and popliteal lymph node on the other hand was tentatively attributed to antigenic stimulation from the intestinal flora which develops during the first days of life. Thymus-derived lymphocytes were scattered throughout the lymph node cortex and splenic follicles. No noticeable thymic cell migration to the bone marrow was found. Labeling indices in the peripheral lymphoid organs paralleled those of cortical thymic lymphocytes suggesting the thymic cortex as the major source of migrants. By 2 days postinjection, the mean grain counts of labeled lymphocytes in all peripheral lymphoid tissues were higher than the mean grain counts of labeled lymphocytes in the thymus. At 7 days postinjection heavily labeled cells constituted 11–16% of the labeled population in peripheral tissues while they were absent from the thymic cortex. These results indicate that a fraction of thymus-derived cells, upon settling in the periphery, remained in, or reentered, a nonproliferative phase for at least 7 days. Conversely, many thymus-derived lymphocytes underwent division in the periphery and/or penetrated the intestinal epithelium. Since the relative number of thymus-derived cells found in the mesenteric lymph nodes of 1- and 2-day old mice was considerably higher than the percentage of cells at this site having the theta (θ) alloantigen, as reported by other authors, the possibility exists that θ-antigen on thymus-derived lymphocytes may, at least in a fraction of these cells, no longer be detectable as they reach the peripheral organs.
Reduced lung function and the risk of out-of-hospital sudden cardiac death
Authors: Sudhir Kurl, Sae Young Jae, Jari A. Laukkanen
Journal: European Respiratory Journal (2014)

In conclusion, we have shown that in adult asthmatics who have a preserved FEV1, the presence of persistent small airway dysfunction was associated with poorer control, perhaps suggesting the presence of a defined small airway asthma phenotype.In asthmatics with preserved FEV1, small airway dysfunction was associated with poorer long-term control http://ow.
Is ski helmet legislation more effective than education?
Authors: Gerhard Ruedl, Martin Kopp, Martin Burtscher
Journal: British Journal of Sports Medicine (2012)

Annually, several hundred million people worldwide enjoy alpine skiing and snowboarding.1 Besides the well-known beneficial effects related to exercise, these snow sports are also associated with a certain risk of injury. Head injuries account for 9–19% of all winter sport injuries reported by ski patrols and emergency departments.1 ,2 However, the use of ski helmets has been shown to reduce the head injury risk up to 60% among children and adults.1 ,2 While in recent years ski helmet use has become mandatory for children in Italy and in most Austrian provinces,3 ,4 the worldwide first mandatory ski helmets for all ages was introduced in Nova Scotia (East Canada) in 2011.5 Although over the last 10 years ski helmet use has steadily increased worldwide, for example, up to 70% in Canada, Austria and Switzerland in 2010,4 ,5  there is an ongoing debate in various countries about the introduction of mandatory ski helmets.4 ,6 Therefore, question arises as to whether ski helmet legislation is more effective regarding an increasing helmet use than education.

To our knowledge, only one study has investigated the impact of mandatory ski helmets on …
Non-invasive ventilation in acute exacerbations of COPD: what happens after hospital discharge?
Authors: M W Elliott
Journal: Thorax (2004)

The role of domiciliary NIV in patients with COPD

Now that non-invasive ventilation (NIV) is well established in clinical practice, particularly for chronic obstructive pulmonary disease (COPD),1,2 it is likely that more patients will survive an acute exacerbation, especially in countries such as the UK where comparatively few patients with COPD are ventilated invasively. However, it is possible that some patients are now just being saved for a future life of poor quality at home, punctuated by recurrent admissions to hospital because their respiratory reserve is so marginal that even trivial exacerbations are sufficient to provoke life threatening ventilatory failure.

Before NIV was widely available, Connors et al 3 showed that hypercapnia during an admission with an acute exacerbation of COPD was a poor prognostic indicator. In a prospective study of a cohort of 1016 patients who were admitted with an exacerbation of COPD and a Paco2 of 50 mm Hg (6.6 kPa) or more, they found that 11% of the patients died during the index hospital stay. The 60 day (20%), 180 day (33%), 1 year (43%), and 2 year (49%) mortality rates were all high; 446 patients (44%) were readmitted 754 times in the following 6 months. At 6 months only 26% of the cohort were both alive and able to report a “good”, “very good”, or “excellent” quality of life. Survival time was independently related to severity of illness, body mass index (BMI), age, prior functional status, Pao2/Fio2, congestive heart failure, serum albumin, and the presence of cor pulmonale. Given that current recommendations state that patients with an acute respiratory acidosis (pH <7.35) after initial treatment and a Paco2 above 6 kPa should be offered NIV,4 all patients who have received NIV acutely fall …
Translational research and sport sciences
Authors: Giuseppe Lippi
Journal: British Journal of Sports Medicine (2010)

As a habitual reader and former contributor of the British Journal of Sports Medicine , I am delighted to know that the Editor-in-Chief transitions from Paul McCrory to Karim Khan will not change substantially the essence of this exciting journal. Rephrasing the three foremost tasks of BMJ editors on the type of manuscripts submitted (Is it new? Is it true? Will it change what doctors do?), the new Editor-in-Chief, Karim Khan, stated that the new editorial board ‘will aim to accept and solicit material that is new, true and has the potential to change the things you do.’1 This is reasonable from the Editor's prominent perspective. However, there is something more in science that does not necessarily fulfil any of the three above-mentioned BMJ criteria: basic, experimental research. Translational medicine, which is defined as the translation of basic research into practical clinical applications, has a great potential to develop and deliver new information that may …
Beta 1-adrenoceptor stimulation and beta 2-adrenoceptor stimulation differ in their effects on contraction, cytosolic Ca2+, and Ca2+ current in single rat ventricular cells.
Authors: R P Xiao, E G Lakatta
Journal: Circulation Research (1993)

The effects of beta 2- and beta 1-adrenoceptor (beta 2AR and beta 1AR, respectively) agonists on the cytosolic Ca2+ (Cai) transient (indexed by the transient increase in indo-1 fluorescence ratio after excitation), twitch amplitude (measured via photodiode array), membrane potential, and L-type sarcolemmal Ca2+ current (ICa, measured by whole-cell patch electrode) were assessed in single rat ventricular myocytes. The selective beta 2AR agonist Zinterol increased the amplitudes of both the Cai transient and twitch in a concentration-dependent manner. Similar results were obtained when beta 2ARs were stimulated with isoproterenol in the presence of the selective beta 1AR antagonist CGP 20712A. beta 1AR stimulation induced by norepinephrine increased twitch amplitude to about the same extent as did beta 2AR stimulation. However, several striking differences between response to beta 1AR and beta 2AR stimulation were observed. beta 1AR stimulation had the potent effect of abbreviating the time course of the contraction and Cai transient, and beta 2AR stimulation did not reduce the time course of the Cai transient and had only a minor effect on the twitch duration. For a given increase in twitch amplitude, beta 1AR stimulation caused a greater increase in Cai transient, suggesting a diminished Cai-myofilament interaction. beta 1AR, but not beta 2AR, stimulation evoked spontaneous Cai oscillations, increased the diastolic indo fluorescence level, and caused a decline in resting cell length. beta 1AR and beta 2AR also differed in their effects on ICa. Whereas both beta 1AR and beta 2AR stimulation increased the peak ICa amplitude, beta 2AR stimulation markedly prolonged the ICa inactivation time. Accordingly, beta 2AR stimulation prolonged the action potential duration to a greater extent than did beta 1AR stimulation. 8-(4-Chlorophenylthio)cAMP mimicked the effects of beta 1AR stimulation by norepinephrine but not those due to beta 2AR stimulation. These results clearly indicate that both beta 2ARs and beta 1ARs functionally coexist in rat ventricular myocytes but that stimulation of these receptor subtypes elicits qualitatively different cell responses at the levels of ionic channels, the myofilaments, and sarcoplasmic reticulum.