tbuckley/cabot-search huggingface dataset:
The IL-12Rβ2 gene functions as a tumor suppressor in human B cell malignancies
Authors: Irma Airoldi, Emma Di Carlo, Barbara Banelli, Lidia Moserle, Claudia Cocco, Annalisa Pezzolo, Carlo Sorrentino, Edoardo Rossi, Massimo Romani, Alberto Amadori, Vito Pistoia
Journal: Journal of Clinical Investigation (2004)

The IL-12Rβ2 gene is expressed in human mature B cell subsets but not in transformed B cell lines. Silencing of this gene may be advantageous to neoplastic B cells. Our objective was to investigate the mechanism(s) and the functional consequence(s) of IL-12Rβ2 gene silencing in primary B cell tumors and transformed B cell lines. Purified tumor cells from 41 patients with different chronic B cell lymphoproliferative disorders, representing the counterparts of the major mature human B cell subsets, tested negative for IL-12Rβ2 gene expression. Hypermethylation of a CpG island in the noncoding exon 1 was associated with silencing of this gene in malignant B cells. Treatment with the DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine restored IL-12Rβ2 mRNA expression in primary neoplastic B cells that underwent apoptosis following exposure to human recombinant IL-12 (hrIL-12). hrIL-12 inhibited proliferation and increased the apoptotic rate of IL-12Rβ2–transfected B cell lines in vitro. Finally, hrIL-12 strongly reduced the tumorigenicity of IL-12Rβ2–transfected Burkitt lymphoma RAJI cells in SCID-NOD mice through antiproliferative and proapoptotic effects, coupled with neoangiogenesis inhibition related to human IFN-γ–independent induction of hMig/CXCL9. The IL-12Rβ2 gene acts as tumor suppressor in chronic B cell malignancies, and IL-12 exerts direct antitumor effects on IL-12Rβ2–expressing neoplastic B cells.
Effect of sympathetic denervation on smooth muscle cell proliferation in the growing rabbit ear artery.
Authors: R D Bevan
Journal: Circulation Research (1975)

The effect of sympathetic denervation on the uptake of 3H-thymidine (3H-Tdr) into the ear artery of a growing rabbit was studied in vitro and in vivo. Uptake into the right artery was compared with that into the left 2 and 3 weeks after left superior cervical ganglionectomy in 4-week-old rabbits. Denervation was confirmed by the absence of catecholamine fluorescence. The total uptake of 3H--Tdr was determined by scintillation spectrometry, and its distribution in the artery wall was studied by light microscope autoradiography. The denervated ear artery took up significantly less DNA precursor and exhibited fewer labeled vascular smooth muscle cell nuclie in the tunica media than did the control artery. These findings suggest that sympathetic innervation influences the proliferation of vascular smooth muscle in growing rabbits.
Randomized Phase II Trial of First-Line Trastuzumab Plus Docetaxel and Capecitabine Compared With Trastuzumab Plus Docetaxel in <i>HER2</i>-Positive Metastatic Breast Cancer
Authors: Andrew M. Wardley, Xavier Pivot, Flavia Morales-Vasquez, Luis M. Zetina, Maria de Fátima Dias Gaui, Douglas Otero Reyes, Jacek Jassem, Claire Barton, Peter Button, Veronica Hersberger, Antonio Antón Torres
Journal: Journal of Clinical Oncology (2009)

Purpose To evaluate trastuzumab (H) and docetaxel (T) with or without capecitabine (X) as first-line combination therapy for human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. Patients and Methods Patients with HER2-positive locally advanced or metastatic breast cancer were randomly assigned to H (8 mg/kg loading; 6 mg/kg every 3 weeks) plus T (75 mg/m 2 in HTX arm, 100 mg/m 2 in HT arm, every 3 weeks) with or without X (950 mg/m 2 twice per day on days 1 to 14 every 3 weeks). The primary end point was overall response rate (ORR). Results In 222 patients, median follow-up was approximately 24 months. ORR was high with both regimens (70.5% with HTX; 72.7% with HT; P = .717); complete response rate was 23.2% with HTX compared with 16.4% with HT. HTX demonstrated significantly longer progression-free survival: median 17.9 months compared with 12.8 months with HT (hazard ratio, 0.72; P = .045), which translates to a gain of around 5 months. Two-year survival probability was 75% with HTX compared with 66% with HT. Febrile neutropenia (27% v 15%) and grade 3/4 neutropenia (77% v 54%) incidences were higher with HT than HTX. Treatment-related grade 3 hand-foot syndrome (17% v &lt; 1%) and grade 3/4 diarrhea (11% v 4%) occurred more commonly with HTX than HT. One case of congestive heart failure occurred in each arm. Conclusion HTX is an effective and feasible first-line therapy for HER2-positive locally advanced or metastatic breast cancer, although it should be reserved for patients with good performance status who are not receiving long-term steroids.
Human airway secretory cells during development and in mature airway epithelium
Authors: PK Jeffery, D Gaillard, S Moret
Journal: European Respiratory Journal (1992)

The combined secretions of distinct secretory cells of the airway lining mucosa serve to keep the inspired air moist and free of potentially harmful dust particles, organisms and adsorbed gases. Apart from their role in protecting the respiratory zone of the lung, mucus-secreting cells act as pluripotential stem cells during foetal development and, in the adult, following mucosal injury. The variety of secretory cells include the mucous and serous cells of the surface and glandular epithelium, the non-ciliated bronchiolar (Clara) cell and the less frequent dense-core granulated (neuroendocrine) cell. The last-mentioned is the first type to differentiate at about 10 weeks of gestation; mucus-secreting cells are present from the 13th week of gestation, when mature ciliated cells are already present, and Clara cells begin to mature during the 19th week of human development. The alteration of secretory cell number and chemical composition of their secretions during the second trimester of foetal life is similar to that which occurs in chronic bronchitis in the adult. However, in hypersecretory disease the extent and site of the major change appear to be inappropriate to the defence of the lung.
Primary diffuse large B-cell lymphoma of the breast: prognostic factors and outcomes of a study by the International Extranodal Lymphoma Study Group
Authors: G. Ryan, G. Martinelli, M. Kuper-Hommel, R. Tsang, G. Pruneri, K. Yuen, D. Roos, A. Lennard, L. Devizzi, S. Crabb, D. Hossfeld, G. Pratt, M. Dell’Olio, S.P. Choo, R.G. Bociek, J. Radford, S. Lade, A.M. Gianni, E. Zucca, F. Cavalli, J.F. Seymour
Journal: Annals of Oncology (2007)
Surface-associated heparin inhibits zymosan-induced activation of the human alternative complement pathway by augmenting the regulatory action of the control proteins on particle-bound C3b.
Authors: M D Kazatchkine, D T Fearon, J E Silbert, K F Austen
Journal: The Journal of Experimental Medicine (1979)

Discrimination by the human alternative pathway between activating and nonactivating particles occurs after deposition of C3b by the continuous low-grade interaction of the alternative pathway components in biologic fluids and is dependent on the modulation by surface constituents of the interaction of bound C3b with the control proteins, beta 1H, and C3b inactivator (C3bINA). When heparin glycosaminoglycan was coupled to activating particles, such as zymosan or Sepharose, by cyanogen bromide activation, their capacity to activate the human alternative pathway was inhibited. The loss of alternative pathway-activating capacity was directly correlated to the number of heparin molecules bound/zymosan particle, whether the ratio was varied by increasing the amounts of heparin in the initial coupling reactions or by treating a fully inhibited particle with incremental concentrations of heparinase. Analysis by linear regression of the inhibitory effect of each procedure (r = 0.97, r = 0.98, respectively) for adjusting the number of heparin molecules/particle revealed that the dose-response relationships were identical and that complete inhibition occurred with greater than 12 X 10(8) molecules of heparin/zymosan particle. The coupling of heparin to zymosan did not impair the uptake of C3b from the fluid-phase interaction of C3, B, and D, and did not alter the capacity of bound C3b to associate with B so as to permit its inactivation by D. Although the regulatory proteins present in normal serum chelated with EDTA or presented as a combination of purified C3bINA and beta 1H were relatively inefficient in inactivating C3b function on an activating particle of the alternative pathway such as zymosan or zymosan-cyanogen bromide, the control proteins rapidly inactivated C3b on a nonactivating particle wuch as a sheep erythrocyte or zymosan with coupled heparin. The increased numbers of C3b sites susceptible to inactivation by C3bINA in the presence of beta 1H were significantly correlated to the number of molecules of heparin/particle. By linear regression analysis of the correlation (r = 0.99) the number of heparin molecules/particle required to promote total inactivation of bound C3b by purified control proteins was 13.8 X 10(6). This molecular analysis suggests that the action of heparin coupled to an activating particle of the alternative pathway is to promote the interaction between particle-bound C3b and the regulatory proteins, thereby preventing particle-associated amplified C3 cleavage. It is noteworthy that both surface constituents known to maintain a particle as a nonactivator of the alternative pathway, sialic acid and N-sulfated mucopolysaccharide, act by facilitating the inactivation by regulatory proteins of the function of particle-bound C3b.
Minister defends controversial NHS Health Checks programme
Authors: A. O'Dowd
Journal: BMJ (2014)

The Health Checks programme of the NHS in England is currently operating on a “reasonable” evidence base while still being evaluated, MPs have been told.

Jane Ellison, the public health minister for England, defended the programme when she appeared before MPs on the House of Commons Science and Technology Committee on 9 July for their inquiry into national health screening.

NHS Health Checks was introduced in England in 2009 and was designed to cut cardiovascular mortality and morbidity. Under the programme, everyone aged between 40 and 74 who has not already been given a diagnosis of certain conditions or has certain risk factors is invited once every five years to have a check to assess their risk …
Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity
Authors: Christian Vaisse, Karine Clement, Emmanuelle Durand, Serge Hercberg, Bernard Guy-Grand, Philippe Froguel
Journal: Journal of Clinical Investigation (2000)

By integrating an agonist satiety signal, provided by alpha–melanocyte-stimulating hormone (α-MSH), and an antagonist signal, provided by agouti-related protein (AGRP), the melanocortin-4 receptor (MC4-R) is a key element in the hypothalamic control of food intake. Inactivation of the gene encoding this G protein–coupled receptor causes obesity in mice. In humans, frameshift mutations in MC4-R cause an early-onset dominant form of obesity in two families. In this study we find a high frequency (4%) of rare heterozygous MC4-R mutations in a large population of morbidly obese patients. No such mutations were found in controls. By analyzing the phenotypes of the probands carrying these mutations, we demonstrate that these patients display a common, nonsyndromic form of obesity. Interestingly, functional analysis of the mutant receptors indicates that obesity-associated defects in MC4-R range from loss of function to constitutive activation. Transmission of these mutations in the families of the carriers indicates a variable expressivity that is not related to the functional severity of the mutations. This variable expressivity of MC4-R–associated obesity is not due to variations in genes for α-MSH or AGRP. Taken together, these results demonstrate that MC4-R mutations are a frequent but heterogeneous genetic cause of morbid obesity.
A new analytical system for quantification scratching behaviour in mice
Authors: K. Orito, Y. Chida, C. Fujisawa, P.D. Arkwright, H. Matsuda
Journal: British Journal of Dermatology (2004)

Scratching behaviour is an important component of human atopic dermatitis. The duration of scratching determines the extent of skin damage and thus the rash, but quantification of this is difficult. Establishment of a method for measuring the duration of scratching is important in order to make objective assessments of the factors that may cause the itch and also the efficacy of new antipruritic drugs.A novel method for assessing the duration of scratching in mice was evaluated, based on the time course changes in the distance between the animal's hind limbs and the back of the neck during scratching behaviour.Compound 48/80 was administered intradermally to the back of ICR mice and their scratching behaviour was recorded on digital videotape. The distance between the back and the hind limb was measured continuously using an image analysis system.Measurement of the frequency and duration when the mouse's hind limb came into contact with the back of the neck provided an accurate method of quantitating scratching behaviour.This system provides a new method of quantifying scratching behaviour in a mouse.
Poldip2, a Novel Regulator of Nox4 and Cytoskeletal Integrity in Vascular Smooth Muscle Cells
Authors: Alicia N. Lyle, Nita N. Deshpande, Yoshihiro Taniyama, Bonnie Seidel-Rogol, Lily Pounkova, Pingfeng Du, Christopher Papaharalambus, Bernard Lassègue, Kathy K. Griendling
Journal: Circulation Research (2009)

Rationale: NADPH oxidases (Noxes) regulate vascular physiology and contribute to the pathogenesis of vascular disease. In vascular smooth muscle cells (VSMCs), the interactions of individual Nox homologs with regulatory proteins are poorly defined. Objective: The objective of this study was to identify novel NADPH oxidase regulatory proteins. Methods and Results: Using a yeast 2-hybrid screen, we identified a novel p22phox binding partner, Poldip2, and demonstrated that it associates with p22phox, NADPH oxidase (Nox)1, and Nox4 and colocalizes with p22phox at sites of Nox4 localization. Poldip2 increases Nox4 enzymatic activity by 3-fold and positively regulates basal reactive oxygen species production in VSMCs (O 2 ·− : 86.3±15.6% increase; H 2 O 2 : 40.7±4.5% increase). Overexpression of Poldip2 activates Rho (180.2±24.8% increase), strengthens focal adhesions, and increases stress fiber formation. These phenotypic changes are blocked by dominant negative Rho. In contrast, depletion of either Poldip2 or Nox4 results in a loss of these structures, which is rescued by adding back active Rho. Cell migration, which requires dynamic cytoskeletal remodeling, is impaired by either excess (70.1±14.7% decrease) or insufficient Poldip2 (63.5±5.9% decrease). Conclusions: These results suggest that Poldip2 associates with p22phox to activate Nox4, leading to regulation of focal adhesion turnover and VSMC migration, thus linking reactive oxygen species production and cytoskeletal remodeling. Poldip2 may be a novel therapeutic target for vascular pathologies with a significant VSMC migratory component, such as restenosis and atherosclerosis.
The sympathetic nervous system stimulates anti-inflammatory B cells in collagen-type II-induced arthritis
Authors: Georg Pongratz, Madlen Melzer, Rainer H Straub
Journal: Annals of the Rheumatic Diseases (2011)

Background As previously shown, the sympathetic nervous system (SNS) shows proinflammatory activity during initiation of arthritis but is anti-inflammatory in established collagen-induced arthritis (CIA). Interleukin 10 (IL-10)-producing B cells suppress arthritis and are a potential target of the SNS because (1) B cells express functional β 2 -adrenoceptors (β 2 ARs) and (2) IL-10, at least in monocytes/macrophages, is regulated in a cAMP/PKA/CREB-dependent manner. Objective To test the hypothesis that anti-inflammatory effects of the SNS in CIA are mediated by stimulating IL-10-producing anti-inflammatory B cells. Methods Collagen-induced arthritis in DBA/1 mice, sympathectomy, adoptive B cell transfer, in vitro B cell culture, and assessment of B cell IL-10 production. Results and conclusion Mice treated with B cells from SNS-intact mice showed less severe arthritis than mice treated with B cells from sympathectomised mice. This anti-inflammatory action of B cells from SNS-intact mice correlated with increased IL-10 produced by B cells, which was mediated by norepinephrine (NE), in a β 2 AR, PKA-dependent manner. However, an NE-mediated increase in IL-10 was seen only in B cells from immunised but not naive mice, explaining in part the anti-inflammatory properties of the SNS in the late phase of arthritis. Finally, animals treated with B cells isolated from immunised mice and activated in vitro in the presence of a β 2 AR stimulus showed a decrease in arthritis severity in comparison with controls, an approach that might be used for future cellular treatment strategies.
Assessment of Systemic Right Ventricular Function in Patients With Transposition of the Great Arteries Using the Myocardial Performance Index
Authors: Omid Salehian, Markus Schwerzmann, Naeem Merchant, Gary D. Webb, Samuel C. Siu, Judith Therrien
Journal: Circulation (2004)

Background— Assessment of systemic right ventricular (RV) function is a key point in the follow-up of patients with transposition of the great arteries (TGA). Current echocardiographic assessment of RV function is at best an estimate, and cardiac magnetic resonance (CMR) is considered the gold standard. However, this technique is expensive, has limited availability, and requires significant expertise to acquire and interpret the images. The myocardial performance index (MPI) has recently been studied for assessment of pulmonary RV function and shows promise as a simple yet powerful tool for assessing patients with RV dysfunction of various origins. We set out to compare MPI and CMR assessment of systemic RV function in patients with TGA. Methods and Results— Data from patients with TGA (11 with congenitally corrected TGA, 18 with surgically corrected TGA) who had CMR within 6 months of their echocardiogram were reviewed. The average systemic RV ejection fraction (RVEF) by CMR was 39.4±11.4%, and the systemic RVMPI for this group was 0.56±0.21. There was a strong negative correlation between the systemic RVMPI and systemic RVEF by CMR ( r =−0.82, P &lt;0.01). The systemic RVEF can be estimated from this formula: RVEF=65%−(45.2×MPI). Conclusions— MPI can be used in patients with systemic RVs to assess global function and to estimate an EF with good accuracy.
J. McMASTER (Ed.) "The ABC's of Sports Medicine"
Authors: B. Helal
Journal: British Journal of Sports Medicine (1982)

VI. 18 chapters and contains a glossary, appendix and indexThe title of the book is only half correct.ABC is right since the D to Z of Sports Medicine is missing.There is a misconception that Sports Medicine is synonymous with sports injury when in fact it forms a relatively small but important section of the whole.Very little space is given to medical, psychological, physiological and other disciplines.The sense of incompleteness is further conveyed by the layout.Only half the page space is used and most pages contain only one column of print This is clearly not intended for filling in the deficiencies since it is not uniform.It is not at all dear for whom the book is intended -the extensive glossary of medical terms suggests a lay audience.The standard varies wildly.The Salter classification of epiphyseal injuries is detailed and could only interest the trainee orthopaedist, whilst, for example, the description of ligament injuries to the ankle is too simplistic.References are often skimpy for so large a subject and those that are included are often not the best for further reading, being neither the most comprehensive nor the most authoritative.
New Approaches to Molecular Diagnosis
Authors: Bruce R. Korf, Heidi L. Rehm
Journal: JAMA (2013)

Advances in understanding the molecular basis of rare and common disorders, as well as in the technology of DNA analysis, are rapidly changing the landscape of molecular genetic and genomic testing. High-resolution molecular cytogenetic analysis can now detect deletions or duplications of DNA of a few hundred thousand nucleotides, well below the resolution of the light microscope. Diagnostic testing for "single-gene" disorders can be done by targeted analysis for specific mutations, by sequencing a specific gene to scan for mutations, or by analyzing multiple genes in which mutation may lead to a similar phenotype. The advent of massively parallel next-generation sequencing facilitates the analysis of multiple genes and now is being used to sequence the coding regions of the genome (the exome) for clinical testing. Exome sequencing requires bioinformatic analysis of the thousands of variants that are identified to find one that is contributing to the pathology; there is also a possibility of incidental identification of other medically significant variants, which may complicate genetic counseling. DNA testing can also be used to identify variants that influence drug metabolism or interaction of a drug with its cellular target, allowing customization of choice of drug and dosage. Exome and genome sequencing are being applied to identify specific gene changes in cancer cells to guide therapy, to identify inherited cancer risk, and to estimate prognosis. Genomic testing may be used to identify risk factors for common disorders, although the clinical utility of such testing is unclear. Genetic and genomic tests may raise new ethical, legal, and social issues, some of which may be addressed by existing genetic nondiscrimination legislation, but which also must be addressed in the course of genetic counseling. The purpose of this article is to assist physicians in recognizing where new approaches to genetic and genomic testing may be applied clinically and in being aware of the principles of interpretation of test results.
Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study
Authors: Lennart Hansson, Thomas Hedner, Per Lund-Johansen, Sverre Erik Kjeldsen, Lars H Lindholm, Jan Otto Syvertsen, Jan Lanke, Ulf de Faire, Björn Dahlöf, Bengt E Karlberg
Journal: The Lancet (2000)
Reference intervals for serum creatine kinase in athletes
Authors: Vassilis Mougios
Journal: British Journal of Sports Medicine (2007)

Background: The serum concentration of creatine kinase (CK) is used widely as an index of skeletal muscle fibre damage in sport and exercise. Since athletes have higher CK values than non-athletes, comparing the values of athletes to the normal values established in non-athletes is pointless. The purpose of this study was to introduce reference intervals for CK in athletes. Method: CK was assayed in serum samples from 483 male athletes and 245 female athletes, aged 7–44. Samples had been obtained throughout the training and competition period. For comparison, CK was also assayed in a smaller number of non-athletes. Reference intervals (2.5th to 97.5th percentile) were calculated by the non-parametric method. Results: The reference intervals were 82–1083 U/L (37°C) in male and 47–513 U/L in female athletes. The upper reference limits were twice the limits reported for moderately active non-athletes in the literature or calculated in the non-athletes in this study. The upper limits were up to six times higher than the limits reported for inactive individuals in the literature. When reference intervals were calculated specifically in male football (soccer) players and swimmers, a threefold difference in the upper reference limit was found (1492 vs 523 U/L, respectively), probably resulting from the different training and competition demands of the two sports. Conclusion: Sport training and competition have profound effects on the reference intervals for serum CK. Introducing sport-specific reference intervals may help to avoid misinterpretation of high values and to optimise training.