tbuckley/cabot-search huggingface dataset:
Serum house dust mite antibodies: predictor of increased bronchial responsiveness in adults of a community
Authors: E Omenaas, P Bakke, GE Eide, S Elsayed, A Gulsvik
Journal: European Respiratory Journal (1996)

The purpose of this study was to determine whether the presence of serum specific immunoglobulin E (IgE) antibodies was associated with increased bronchial responsiveness in adults. We studied cross-sectionally a random community sample of 18-73 year old adults, of whom 83% (n = 489) performed bronchial responsiveness testing as well as serum measurements of five specific IgE antibodies. In the crude data, 39% of those with house dust mite antibodies (n = 18) had a bronchial responsiveness &lt; or = 32 g.L-1 methacholine compared with 19% in subjects without any of the five specific IgE antibodies (n = 453). The corresponding percentages for subjects with timothy antibodies (n = 16) was 25%, birch antibodies (n = 13) 23%, cat antibodies (n = 10) 40% and mould antibodies (n = 2) 50%. When assessing the multivariate relationship between the presence of one specific IgE antibody and degree of bronchial responsiveness we used a semi-proportional hazards model with the response as a 20% fall in forced expiratory volume in one second (FEV1) from pretest value. Covariates included in the model were: gender, age, pretest FEV1, smoking habits, pack-years, season and other specific IgE antibodies than that examined. The presence of house dust mite antibodies was a significant predictor (p &lt; 0.01) of increased bronchial responsiveness in never- and ex-smokers. Indoor allergic sensitization (house dust mite, cat and mould) was a significant predictor of increased bronchial responsiveness, while outdoor allergic sensitization (timothy and birch) was not. Excluding subjects with obstructive lung disease (n = 39) or including the covariate log total serum IgE as a potential confounder yielded the same result. Thus, in this community, indoor allergic sensitization rather than allergic sensitization per se was related to increased bronchial responsiveness after adjusting for other relevant covariates.
Angiotensin II–Induced Transactivation of Epidermal Growth Factor Receptor Regulates Fibronectin and Transforming Growth Factor-β Synthesis via Transcriptional and Posttranscriptional Mechanisms
Authors: Yasutaka Moriguchi, Hiroaki Matsubara, Yasukiyo Mori, Satoshi Murasawa, Hiroya Masaki, Katsuya Maruyama, Yoshiaki Tsutsumi, Yasunobu Shibasaki, Yoko Tanaka, Takuma Nakajima, Kinichiro Oda, Toshiji Iwasaka
Journal: Circulation Research (1999)

Abstract —The signaling cascade elicited by angiotensin II (Ang II) resembles that characteristic of a growth factor, and recent evidence indicates transactivation of epidermal growth factor receptor (EGF-R) by G protein–coupled receptors. Here, we report the involvement of EGF-R in Ang II–induced synthesis of fibronectin and transforming growth factor-β (TGF-β) in cardiac fibroblasts. Ang II stimulated fibronectin mRNA levels dose dependently, with a maximal increase (≈5-fold) observed after 12 hours of incubation. Fibronectin synthesis induced by Ang II or calcium ionophore was completely abolished by tyrosine kinase inhibitors and intracellular Ca 2+ chelating agents. Ang II–induced fibronectin mRNA was not affected by protein kinase C inhibitors or protein kinase C depletion, whereas specific inhibition of EGF-R function by a dominant negative EGF-R mutant and tyrphostin AG1478 abolished induction of fibronectin mRNA. We isolated the rat fibronectin gene, including the 5′-flanking region, and found that the activator protein-1 (AP-1) binding site present in the promoter region was responsible for the Ang II responsiveness of this gene. A gel retardation assay revealed the binding of nuclear protein to the AP-1 site, which was supershifted with anti–c -fos and anti–c -jun but not anti–activating transcription factor (ATF)-2 antibodies. Conditioned medium from Ang II–treated cells contained TGF-β bioactivity, and addition of neutralizing TGF-β antibody modestly (46%) inhibited induction of fibronectin. Ang II–induced synthesis of TGF-β was also abolished by inhibition of EGF-R function. The effect of TGF-β was exerted by stabilizing fibronectin mRNA without affecting the promoter activity and required de novo protein synthesis. We concluded that Ang II–induced expression of fibronectin and TGF-β is mediated by downstream signaling of EGF-R transactivated by Ca 2+ -dependent tyrosine kinase and that Ang II–induced fibronectin mRNA expression is regulated by 2 different mechanisms, which are transcriptional control by binding of the c- fos /c- jun complex to the AP-1 site and posttranscriptional control by mRNA stabilization due to autocrine or paracrine effects of TGF-β. Thus, this study suggests that the action of Ang II on extracellular matrix formation should be interpreted in association with the EGF-R signaling cascade.
Distribution of peak expiratory flow variability by age, gender and smoking habits in a random population sample aged 20-70 yrs
Authors: HM Boezen, JP Schouten, DS Postma, B Rijcken
Journal: European Respiratory Journal (1994)

Peak expiratory flow (PEF) variability can be considered as an index of bronchial lability. Population studies on PEF variability are few. The purpose of the current paper is to describe the distribution of PEF variability in a random population sample of adults with a wide age range (20-70 yrs), and to assess relationships to age, gender and smoking habits. PEF data were collected in 511 participants of the Dutch part of the European Community Respiratory Health Survey. A training effect was found, absolute PEF values on the first measurement day being significantly lower. Females had greater PEF variability (adjusted for age, height and pack-years) and lower absolute PEFs than males. The mean within-day variation (amplitude % mean) was 3.66% (SD 2.03%), whereas the mean day-to-day variation was relatively small: 0.08% (SD 1.53%). Absolute PEFs were lower and amplitude % mean were significantly higher in older age groups. Smoking was significantly associated with lower mean PEFs and greater amplitude % mean. We observed lower mean values of the amplitude % mean than other investigators, possibly related to lower frequency of PEF recording (twice daily). We conclude that PEF and PEF variability have a normal or log-normal distribution. When studying PEF variability, age, gender and smoking habits should be taken into account.
Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status
Authors: M Schmidt, J Rinke, V Schäfer, S Schnittger, A Kohlmann, E Obstfelder, C Kunert, J Ziermann, N Winkelmann, E Eigendorff, T Haferlach, C Haferlach, A Hochhaus, T Ernst
Journal: Leukemia (2014)
The distinction between gross negligence and recklessness in English criminal law
Authors: Peter Gooderham
Journal: Journal of the Royal Society of Medicine (2009)

Merry states that ‘in practice the distinction between gross negligence and recklessness may be very subtle’.1 I wonder if his discussion of both the law and the relevant medical errors is outdated.

Recklessness in English criminal law is advertent, and as Merry states, requires the conscious choice to take an unjustified risk. Criminal negligence is variously defined, but is usually regarded as not requiring advertence. One textbook definition is ‘… the inadvertent taking of an unjustifiable risk’.2

Historically, confusion has arisen from gross negligence manslaughter being sometimes known as reckless manslaughter. This should no longer be the case. The current leading cases, which Merry does not cite, are Adomako3 and Misra.4 Following these cases, a conviction for gross negligence manslaughter requires the existence of a duty of care, breach of that duty resulting in death and a risk of death which would be obvious to a reasonable prudent person. Additionally, the defendant's conduct must have fallen so far below the standard of a reasonable practitioner as to be grossly negligent in the view of the jury, and thereby warranting a criminal conviction for manslaughter.

Although there is overlap, reckless manslaughter has a distinctly different meaning.

Similarly, Merry's discussion of intrathecal vincristine administration would be enhanced by discussion of the incident at Nottingham in 2001. A junior doctor was prosecuted for gross negligence manslaughter, and pleaded guilty. However, an external inquiry identified over 50 other contributory factors to the fatal event.5

I hope this additional material may prove interesting and informative to JRSM readers.
IL-17A Produced by γδ T Cells Promotes Tumor Growth in Hepatocellular Carcinoma
Authors: Shoubao Ma, Qiao Cheng, Yifeng Cai, Huanle Gong, Yan Wu, Xiao Yu, Liyun Shi, Depei Wu, Chen Dong, Haiyan Liu
Journal: Cancer Research (2014)

Interleukin (IL)-17A is expressed in the tumor microenvironment where it appears to contribute to tumor development, but its precise role in tumor immunity remains controversial. Here, we report mouse genetic evidence that IL-17A is critical for tumor growth. IL-17A-deficient mice exhibited reduced tumor growth, whereas systemic administration of recombinant mouse IL-17A promoted the growth of hepatocellular carcinoma. The tumor-promoting effect of IL-17A was mediated through suppression of antitumor responses, especially CD8(+) T-cell responses. Furthermore, we found that IL-17A was produced mainly by Vγ4 γδ T cells, insofar as depleting Vγ4 γδ T cells reduced tumor growth, whereas adoptive transfer of Vγ4 γδ T cells promoted tumor growth. Mechanistic investigations showed that IL-17A induced CXCL5 production by tumor cells to enhance the infiltration of myeloid-derived suppressor cells (MDSC) to tumor sites in a CXCL5/CXCR2-dependent manner. IL-17A also promoted the suppressive activity of MDSC to reinforce suppression of tumoral immunity. Moreover, we found that MDSC could induce IL-17A-producing γδ T cells via production of IL-1β and IL-23. Conversely, IL-17A could also enhance production of IL-1β and IL-23 in MDSC as a positive feedback. Together, our results revealed a novel mechanism involving cross-talk among γδ T cells, MDSCs, and tumor cells through IL-17A production. These findings offer new insights into how IL-17A influences tumor immunity, with potential implications for the development of tumor immunotherapy.
Recombinant Vesicular Stomatitis Virus Transduction of Dendritic Cells Enhances Their Ability to Prime Innate and Adaptive Antitumor Immunity
Authors: Jeanette E Boudreau, Byram W Bridle, Kyle B Stephenson, Kristina M Jenkins, Jérôme Brunellière, Jonathan L Bramson, Brian D Lichty, Yonghong Wan
Journal: Molecular Therapy (2009)

Dendritic cell (DC)–based vaccines are a promising strategy for tumor immunotherapy due to their ability to activate both antigen-specific T-cell immunity and innate immune effector components, including natural killer (NK) cells. However, the optimal mode of antigen delivery and DC activation remains to be determined. Using M protein mutant vesicular stomatitis virus (ΔM51-VSV) as a gene-delivery vector, we demonstrate that a high level of transgene expression could be achieved in ∼70% of DCs without affecting cell viability. Furthermore, ΔM51-VSV infection activated DCs to produce proinflammatory cytokines (interleukin-12, tumor necrosis factor-α, and interferon (IFN)α/β), and to display a mature phenotype (CD40highCD86high major histocompatibility complex (MHC II)high). When delivered to mice bearing 10-day-old lung metastatic tumors, DCs infected with ΔM51-VSV encoding a tumor-associated antigen mediated significant control of tumor growth by engaging both NK and CD8+ T cells. Importantly, depletion of NK cells completely abrogated tumor destruction, indicating that NK cells play a critical role for this DC vaccine-induced therapeutic outcome. Our findings identify ΔM51-VSV as both an efficient gene-delivery vector and a maturation agent allowing DC vaccines to overcome immunosuppression in the tumor-bearing host. Dendritic cell (DC)–based vaccines are a promising strategy for tumor immunotherapy due to their ability to activate both antigen-specific T-cell immunity and innate immune effector components, including natural killer (NK) cells. However, the optimal mode of antigen delivery and DC activation remains to be determined. Using M protein mutant vesicular stomatitis virus (ΔM51-VSV) as a gene-delivery vector, we demonstrate that a high level of transgene expression could be achieved in ∼70% of DCs without affecting cell viability. Furthermore, ΔM51-VSV infection activated DCs to produce proinflammatory cytokines (interleukin-12, tumor necrosis factor-α, and interferon (IFN)α/β), and to display a mature phenotype (CD40highCD86high major histocompatibility complex (MHC II)high). When delivered to mice bearing 10-day-old lung metastatic tumors, DCs infected with ΔM51-VSV encoding a tumor-associated antigen mediated significant control of tumor growth by engaging both NK and CD8+ T cells. Importantly, depletion of NK cells completely abrogated tumor destruction, indicating that NK cells play a critical role for this DC vaccine-induced therapeutic outcome. Our findings identify ΔM51-VSV as both an efficient gene-delivery vector and a maturation agent allowing DC vaccines to overcome immunosuppression in the tumor-bearing host.
THE GENETIC CONTROL OF ANTIBODY SPECIFICITY
Authors: Edna Mozes, Hugh O. McDevitt, Jean-Claude Jaton, Michael Sela
Journal: The Journal of Experimental Medicine (1969)

The immune response to a synthetic polypeptide built on multichain polyproline, poly-L-(Tyr,Glu)-poly-L-Pro-poly-L-Lys [(T,G)-Pro--L], in the offspring of a cross between DBA/1 and SJL mice is under a genetic control superficially similar to the one operating for the immune response to a similar synthetic polypeptide built on multichain polyalanine, poly-L-(Tyr,Glu)-poly-D,L-Ala-poly-L-Lys [(T,G)-A--L], in the offspring of a cross between CBA and C57 mice. In both cases, the genetic control is a quantitative trait in which the major gene(s) is (are) dominant and the trait is not linked to any of the known structural genes coding for mouse immunoglobulin heavy chains. However, the genetic control of response to (T, G)-Pro--L, designated immune response-3 (Ir-3), is qualitatively different from the one operating for (T,G)-A--L [immune response-1 (Ir-1)] in that it is not linked to the histocompatibility-2 (H-2) locus. A study of the immune response to a related polypeptide built on multichain polyproline, poly-L-(Phe,Glu)-poly-L-Pro-poly-L--Lys [(Phe, G)-Pro--L], in the DBA/1 x SJL cross has shown a genetic control of antibody specificity. F(1) x DBA/1 backcross anti-(Phe, G)-Pro--L sera segregate in their ability to bind (T,G)-Pro--L, and there is no linkage of anti-(T,G)-Pro--L binding capacity with the H-2(s) allele of the SJL grandparent. F(1) x SJL anti-(Phe, G)-Pro-L sera segregate in their capacity to bind poly-L-(Phe,Glu)-poly-D,L-Ala-poly-L-Lys [(Phe, G)-A--L] and the ability to bind (Phe, G)-A--L is clearly linked to the H-2(q) allele from the DBA/1 grandparent. Thus, in mice all responding well to a given antigen [(Phe, G)-Pro--L], the specificity of the antibodies produced [i.e., anti-(Phe,G) or anti-prolyl] is genetically determined. Cross-inhibition of binding m (DBA/1 x SJL)F(1) anti-(Phe,G)-Pro--L antisera indicates that the anti-(Phe,G) and anti-prolyl specificities are a function of two separate and largely non-crossreacting antibody populations.
Phase I Safety, Pharmacokinetics, and Inhibition of Src Activity Study of Saracatinib in Patients with Solid Tumors
Authors: José Baselga, Andres Cervantes, Erika Martinelli, Isabel Chirivella, Klaas Hoekman, Herbert I. Hurwitz, Duncan I. Jodrell, Paul Hamberg, Esther Casado, Paul Elvin, Alan Swaisland, Renee Iacona, Josep Tabernero
Journal: Clinical Cancer Research (2010)

This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors.Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing.In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and C(max) of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours.Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d.
Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp.
Authors: R N Bergman, R Prager, A Volund, J M Olefsky
Journal: Journal of Clinical Investigation (1987)

Studies were done to determine whether the minimal model approach and the glucose clamp measure equivalent indices of insulin action. Euglycemic glucose clamps (glucose, G: 85 mg/dl) were performed at two rates of insulin (I) infusion (15 and 40 mU/min per m2) in 10 subjects (body mass index, BMI, from 21 to 41 kg/m2). Insulin sensitivity index (SI) from clamps varied from 0.15 to 3.15 (mean: 1.87 +/- 0.36 X 10(-2) dl/[min per m2] per microU/ml), and declined linearly with increasing adiposity (versus BMI: r = -0.97; P less than 0.001). SI from modeling the modified frequently sampled intravenous tolerance test varied from 0.66 to 7.34 X 10(-4) min-1 per microU/ml, and was strongly correlated with SIP(clamp) (r = 0.89; P less than 0.001). SI and SIP(clamp) were similar (0.046 +/- 0.008 vs. 0.037 +/- 0.007 dl/min per microU/ml, P greater than 0.35); the relation had a slope not different from unity (1.05 P greater than 0.70) and passed through the origin (P greater than 0.40). However, on a period basis, SI exceeded SIP(clamp) slightly, due to inhibition of hepatic glucose output during the FSIGT, not included in SIP(clamp). These methods are equivalent for assessment of overall insulin sensitivity in normal and insulin-resistant nondiabetic subjects.
Sympathoadrenergic mechanisms in functional regulation and development of cardiac hypertrophy and failure: findings from genetically engineered mice
Authors: X Du
Journal: Cardiovascular Research (2001)

Time for primary review 33 days. 

Sympathoadrenergic signals to the heart are detected and processed by a group of membrane proteins converting external signals to alterations in intracellular properties. In recent years, our understanding of β- and α-adrenergic signaling has been significantly improved. It is beyond the scope of this review to discuss the adrenergic signaling pathways and several excellent reviews are available [1–5].

Sympathetic activation serves to maintain cardiac output by enhancing inotropy, relaxation and chronotropy. Under conditions of heart failure (HF), the sympathetic nervous system is activated chronically and enhanced cardiac sympathetic drive frequently precedes the onset of overt clinic symptoms and is one of the fundamental abnormalities in HF [6]. In the hypertrophied and failing heart, there occurs profound desensitization of β-adrenergic receptor (AR) signaling due to decreased β1AR density, uncoupling of βAR to stimulatory G-protein (Gs), diminished adenylyl cyclase (AC) activity, increased βAR kinase (βARK) activity, and elevated content and function of inhibitory G-protein (Gi) [1,4,7]. The pathophysiological implications of these alterations are only partially understood.

Numerous mouse strains have recently been created that target key components in the signaling pathways as well as these components involved in sympathetic activity (Table 1) [8–47]. These genes are either overexpressed in the heart, mostly under the α-myosin heavy chain promoter, or are disrupted or modified. These strains provide us with systematic tools and novel opportunities to address a number of fundamental questions crucial to our understanding of the contribution by the sympathoadrenergic system to cardiac physiology and pathophysiology. These questions include the difference in signaling mediated by β1AR and β2AR, roles of βARK1 in βAR signaling and functional regulation, activities of α1AR subtypes in cardiac function and hypertrophic growth, contributions of heterotrimeric G-proteins (like Gq and … 

* Tel.: +61-3-9522-4333; fax: +61-3-9521-1362 xiaojun.du{at}baker.edu.au
How objective are systematic reviews?
Authors: E. Ernst
Journal: Journal of the Royal Society of Medicine (2003)

Dr Linde and Dr Willich (January 2003 JRSM1) have done a great service to the medical community by showing us how systematic reviews (SRs) can differ confusingly regarding a range of methodological aspects. As they point out, SRs are designed to avoid biases and make conclusions as objective as possible. Given the diversity of the SRs analysed, I was impressed with the level of agreement many of them reached in their conclusions. Table 1 summarizes five subject areas where our own SRs were cited. The concordance of the conclusions is stunning.
Early Increases in Multiple Biomarkers Predict Subsequent Cardiotoxicity in Patients With Breast Cancer Treated With Doxorubicin, Taxanes, and Trastuzumab
Authors: Bonnie Ky, Mary Putt, Heloisa Sawaya, Benjamin French, James L. Januzzi, Igal A. Sebag, Juan Carlos Plana, Victor Cohen, Jose Banchs, Joseph R. Carver, Susan E. Wiegers, Randolph P. Martin, Michael H. Picard, Robert E. Gerszten, Elkan F. Halpern, Jonathan Passeri, Irene Kuter, Marielle Scherrer-Crosbie
Journal: Journal of the American College of Cardiology (2013)
Peanut allergen Ara h 3: Isolation from peanuts and biochemical characterization
Authors: S. J. Koppelman, E. F. Knol, R. A. A. Vlooswijk, M. Wensing, A. C. Knulst, S. L. Hefle, H. Gruppen, S. Piersma
Journal: Allergy (2003)

Peanut allergen Ara h 3 has been the subject of investigation for the last few years. The reported data strongly depend on recombinant Ara h 3, since a purification protocol for Ara h 3 from peanuts was not available.Peanut allergen Ara h 3 (glycinin), was purified and its posttranslational processing was investigated. Its allergenic properties were determined by studying IgE binding characteristics of the purified protein.Ara h 3 consists of a series of polypeptides ranging from approximately 14 to 45 kDa that can be classified as acidic and basic subunits, similar to the subunit organization of soy glycinin. N-terminal sequences of the individual polypeptides were determined, and using the cDNA deduced amino-acid sequence, the organization into subunits was explained by revealing posttranslational processing of the different polypeptides. IgE-binding properties of Ara h 3 were investigated using direct elisa and Western blotting with sera from peanut-allergic individuals. The basic subunits, and to a lesser extent the acidic subunits, bind IgE and may act as allergenic peptides.We conclude that peanut-derived Ara h 3, in contrast to earlier reported recombinant Ara h 3, resembles, to a large extent, the molecular organization typical for proteins from the glycinin family. Furthermore, posttranslational processing of Ara h 3 affects the IgE-binding properties and is therefore an essential subject of study for research on the allergenicity of Ara h 3.