tbuckley/cabot-search huggingface dataset:
Joint space narrowing, cartilage and physical function: are we deceived by measurements and distributions?
Authors: R. Landewe, D. van der Heijde
Journal: Annals of the Rheumatic Diseases (2011)

Irreversible physical function loss—that part of physical function loss that remains in the absence of clinically perceptible disease activity—was elegantly conceptualised by Aletaha et al 1 a few years ago. They introduced the idea of the irreversible health assessment questionnaire (HAQ) score, which is the residual HAQ score if a patient is in clinical remission. While one may argue the construct validity of an irreversible HAQ score (eg, the absence of clinical disease activity does not necessarily imply the absence of joint inflammation), the model is valuable because it allows the investigator to disentangle the contribution of signs and symptoms and that of structural damage on physical function.

From many studies performed during the past 10 years we have learnt that structural joint damage independently of disease activity contributes to explaining physical function (eg, Welsing et al ).2 Therefore, in the absence of disease activity, it is structural joint damage that explains irreversible physical function loss.

Aletaha et al 1 have taken up his hypothesis as a starting point, and have tried to unravel the relationship between the two components of radiographic damage—erosions and joint space narrowing (JSN)—and irreversible physical function loss. The analysis they have done, which is presented in this issue of the journal, is in all aspects provocative and challenging, and we truly commend the authors for taking up this exercise (see page 733). Strong elements of their study are the access to databases of large clinical trials with inherently high-quality data and completeness, as well as a hypothesis-driven approach. It is a broadly endorsed idea among clinicians that JSN matters more than erosions. So, the main conclusion of the analysis by Aletaha et al ,1 namely that JSN more than erosions impacts irreversible physical function loss, will be easily accepted by the clinical readership. …
The Position and the Value of the Operation of Internal Urethrotomy
Authors: B. Browne
Journal: BMJ (1887)

tudes and phthisis.In the populous towns on the Bolivian plateau, and elsewhere in the Andes, phthisis is practically unknown, although the ordinary exciting causes, such as industrial occupation, sedentary habits, and the like, are the same as at lower levels.It is significant that Professor Hirsch, in treating of this matter (Geographical and Historical Pathology, iii, p. 211, English translation), seems to say that-the immunity is due to an almost universal or ubiquitous tend- ency being counteracted.Although Dr. Hirsch accepts Paul Bert's hnmoglobin theory for the mal des mnontagnes, and the acclimatisa- tion thereto (vol.ii, 505), he does not go beyond a mechanical ex- planation for the mountain-cure in phthisis.Living in a rarefied atmosphere, he thinks, will lead to a sort of pulmonary gymnastics; one must inspire deeper or oftener to cover the requirements.for oxygen; and that will lead to a more vigorous development of the breathing organs, and a greater power of resistance on their part to noxious influences from without (op.cit., iii, 212).But it may be questioned whether any such vigorous development of the organs, or more active exercise of their mechanism, does, as a matter of fact, show itself very decidedly in the residents at great altitudes in South America or elsewhere.The only evidence that I know of is the rather vague statement of Archibald Smith for Peru: "In the Indian of the plateaux, the lungs are capacious, bearing a due relation to the tenuity of the air which he inspires" (Edinburgh Medical and Surgical
John Joseph Smirke Herbert Ruston
Authors: R. M. M. Pegg
Journal: BMJ (2013)

John Joseph Smirke Herbert Ruston was educated at Tonbridge School in Kent and trained at the Royal Free Hospital Medical School. During his first house job in Hastings he developed an interest in anaesthesia and met his wife, Mandy. He moved to London to work at Barts and then became a senior registrar at the Royal Free, where he was appointed consultant in 1993.

John was …
Quality of care in managing hypertension by case finding in north west London.
Authors: G Michael
Journal: BMJ (1984)

<h3>Background:</h3> International guidelines recommend routine computed tomography (CT) of the chest for gastric cancer staging. In Asian countries, where the incidence of pulmonary metastases is less than 1%, some guidelines recommend chest CT only for gastroesophageal junction cancers. If the incidence of pulmonary metastases is also low in Canada, routine chest CT may not be beneficial. <h3>Methods:</h3> We performed a retrospective review of patients in northern Alberta with newly diagnosed gastric cancer from January 2010 to July 2016. The primary aim of the study was to determine the incidence of pulmonary metastases at the time of diagnosis in this population. A secondary aim was to identify potential predictors of pulmonary metastases. We reviewed CT reports for pulmonary metastases. Imaging data also included liver metastases, abdominal lymphadenopathy (&gt; 1 cm), ascites and omental or peritoneal nodules. Other data recorded were age, sex, primary tumour location, histologic type and tumour grade. <h3>Results:</h3> Four hundred and sixty-two patients (311 men, 151 women) were included in the analysis. Pulmonary metastases were identified in 25 patients (5.4%) overall and in 11 of 299 patients (3.7%) whose primary cancer was not in the cardia. On univariate analysis the presence of liver metastases (odds ratio [OR] 7.72, 95% confidence interval [CI] 3.24–18.37, <i>p</i> &lt; 0.001) and abdominal lymphadenopathy (OR 3.30, 95% CI 1.29–8.48, <i>p</i> = 0.01) was associated with an increased risk of pulmonary metastases. Liver metastases retained statistical significance on multivariate analysis (OR 6.17, 95% CI 2.53–15.03, <i>p</i> &lt; 0.001). <h3>Conclusion:</h3> The incidence of pulmonary metastases at the time of gastric cancer diagnosis is higher in northern Alberta than previously reported in Asian studies. Abdominal lymphadenopathy and liver metastases confer an elevated risk of pulmonary metastases.
Molecular characterization and dynamics of hepatitis C virus replication in human fetal hepatocytes infectedin vitro
Authors: S Iacovacci, A Manzin, S Barca, M Sargiacomo, A Serafino, M B Valli, G Macioce, H J Hassan, A Ponzetto, M Clementi, C Peschle, G Carloni
Journal: Hepatology (1997)

The molecular features of hepatitis C virus (HCV) replication in human fetal hepatocytes (HFHs) were addressed in this study. Using a competitive reverse-transcription polymerase chain reaction (RT-PCR) assay for the quantitation of HCV-RNA molecules, the highest level of viral replication was detected 30 days' postinfection. At this time point, viral particles of 41 to 45 nm in diameter accumulated in the cell cytoplasm. Their density in cell extracts and culture medium was distributed between heavy (1.180-1.360 g/cm 3 ) and light fractions (1.105-1.050 g/cm 3 ) of a sucrose gradient, while, in the serum inoculum, they had a positive fraction at 1.180 g/cm 3 . In infected HFHs, minus-strand HCV RNA was observed in fractions displaying a sedimentation coefficient of 28 S to 18 S, while plus-strand HCV RNA showed a peak restricted to the 21 S fraction; the HCV RNA of serum inoculum had a sedimentation coefficient of 38 to 40 S, which revealed the presence of HCV RNA of unique positive polarity. The 21 S RNA fraction of cell extracts was resistant to 20 minutes of RNase I digestion, while the same incubation time totally inactivated a comparable amount of HCV RNA purified from the serum inoculum, revealing the presence of completely and/or partially double-stranded HCV-RNA molecules in the infected cells. Detection in HFHs of replicative forms and replicative intermediates suggests that the dynamic profile of HCV replication in these cells is similar to that described in other flaviviruses.
Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial
Authors: Jennifer G Wilson, Kathleen D Liu, Hanjing Zhuo, Lizette Caballero, Melanie McMillan, Xiaohui Fang, Katherine Cosgrove, Rosemary Vojnik, Carolyn S Calfee, Jae-Woo Lee, Angela J Rogers, Joseph Levitt, Jeanine Wiener-Kronish, Ednan K Bajwa, Andrew Leavitt, David McKenna, B Taylor Thompson, Michael A Matthay
Journal: The Lancet Respiratory Medicine (2014)
A Phylogenetic Model for Investigating Correlated Evolution of Substitution Rates and Continuous Phenotypic Characters
Authors: N. Lartillot, R. Poujol
Journal: Molecular Biology and Evolution (2010)

The comparative approach is routinely used to test for possible correlations between phenotypic or life-history traits. To correct for phylogenetic inertia, the method of independent contrasts assumes that continuous characters evolve along the phylogeny according to a multivariate Brownian process. Brownian diffusion processes have also been used to describe time variations of the parameters of the substitution process, such as the rate of substitution or the ratio of synonymous to nonsynonymous substitutions. Here, we develop a probabilistic framework for testing the coupling between continuous characters and parameters of the molecular substitution process. Rates of substitution and continuous characters are jointly modeled as a multivariate Brownian diffusion process of unknown covariance matrix. The covariance matrix, the divergence times and the phylogenetic variations of substitution rates and continuous characters are all jointly estimated in a Bayesian Monte Carlo framework, imposing on the covariance matrix a prior conjugate to the Brownian process so as to achieve a greater computational efficiency. The coupling between rates and phenotypes is assessed by measuring the posterior probability of positive or negative covariances, whereas divergence dates and phenotypic variations are marginally reconstructed in the context of the joint analysis. As an illustration, we apply the model to a set of 410 mammalian cytochrome b sequences. We observe a negative correlation between the rate of substitution and mass and longevity, which was previously observed. We also find a positive correlation between ω = dN/dS and mass and longevity, which we interpret as an indirect effect of variations of effective population size, thus in partial agreement with the nearly neutral theory. The method can easily be extended to any parameter of the substitution process and to any continuous phenotypic or environmental character.
B-1 B lymphocytes require Blimp-1 for immunoglobulin secretion
Authors: David Savitsky, Kathryn Calame
Journal: The Journal of Experimental Medicine (2006)

B-1 B cells produce circulating natural antibodies that provide “innate-like” protection against bacterial and viral pathogens. They also provide adaptive responses to blood and air-borne pathogens. B lymphocyte–induced maturation protein 1 (Blimp-1) is a transcriptional repressor that is required for the formation of B-2–derived antibody-secreting plasma cells. In this study, we used mice lacking Blimp-1 in the B cell lineage to show that Blimp-1 is not necessary for the formation or self-renewal of B-1 B cells but that Blimp-1 is required for normal immunoglobulin (Ig) secretion by B-1 cells. B-1 cells lacking Blimp-1 do not repress Pax5 mRNA and do not induce X-box binding protein 1, and μ secreted mRNA normally, showing that B-1 and B-2 cells both use a common pathway for Ig secretion. Blimp-1–deficient B-1 B cells are also defective in providing early protection against influenza infection.
Effects of salbutamol and enantiomers on allergen-induced asthmatic reactions and airway hyperreactivity
Authors: F. J. Westerhof, A. B. Zuidhof, L. Kok, H. Meurs, J. Zaagsma
Journal: European Respiratory Journal (2005)

Salbutamol consists of a racemic mixture of R - and S -salbutamol. R -salbutamol (levalbuterol) is the active bronchodilating enantiomer, whereas S -salbutamol is thought to be pharmacologically inactive or to exert adverse effects. This study evaluated the bronchoprotective effects of inhalation of therapeutically relevant doses of the racemate and individual enantiomers in guinea pigs. It was found that basal airway reactivity to histamine was similarly reduced 30 min after inhalation of equivalent doses of RS - and R -salbutamol; this protective effect disappeared within 3 h. Inhalation of RS - and R -salbutamol 30 min before and 5.5 h after allergen challenge suppressed allergen-induced airway hyperreactivity to histamine after the early and late asthmatic reaction, completely inhibiting the early asthmatic reaction and tending to reduce the development of the late asthmatic reaction. At 5 h after allergen challenge, the inhibition of airway hyperreactivity was more pronounced in animals treated with R -salbutamol compared to racemate-treated animals. Both basal airway reactivity and allergen–induced hyperreactivity were not affected by S -salbutamol. Inflammatory cell infiltration was not affected by the racemate or the individual enantiomers. In conclusion, inhalation of therapeutically relevant doses of R - and RS -salbutamol effectively suppress allergen-induced airway reactivity after the early and late asthmatic reactions, the R -enantiomer being slightly more potent with respect to early airway reactivity than the racemate. No adverse effects were observed for the S -enantiomer.
Male-Driven Biased Gene Conversion Governs the Evolution of Base Composition in Human Alu Repeats
Authors: Matthew T. Webster, Nick G. C. Smith, Lina Hultin-Rosenberg, Peter F. Arndt, Hans Ellegren
Journal: Molecular Biology and Evolution (2005)

Regional biases in substitution pattern are likely to be responsible for the large-scale variation in base composition observed in vertebrate genomes. However, the evolutionary forces responsible for these biases are still not clearly defined. In order to study the processes of mutation and fixation across the entire human genome, we analyzed patterns of substitution in Alu repeats since their insertion. We also studied patterns of human polymorphism within the repeats. There is a highly significant effect of recombination rate on the pattern of substitution, whereas no such effect is seen on the pattern of polymorphism. These results suggest that regional biases in substitution are caused by biased gene conversion, a process that increases the probability of fixation of mutations that increase GC content. Furthermore, the strongest correlate of substitution patterns is found to be male recombination rates rather than female or sex-averaged recombination rates. This indicates that in addition to sexual dimorphism in recombination rates, the sexes also differ in the relative rates of crossover and gene conversion.
Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on biophysical and biochemical surfactant properties
Authors: A. Gunther, R. Schmidt, J. Harodt, T. Schmehl, D. Walmrath, C. Ruppert, F. Grimminger, W. Seeger
Journal: European Respiratory Journal (2002)

The purpose of the present study was to investigate the impact of bronchoscopic surfactant administration, on the biochemical and biophysical surfactant properties, in patients with severe and early acute respiratory distress syndrome (ARDS) and septic shock. A total number of 27 ARDS patients received 300–500 mg·kg·body·weight<sup>−1</sup> of a natural bovine surfactant extract (Alveofact®) <i>via</i> a flexible bronchoscope. Bronchoalveolar lavages were performed 3 h prior to, and 15–18 h and 72 h after surfactant administration. A comparison to healthy volunteers, undergoing an identical lavage procedure, was made (control, n=12). Severe biophysical and biochemical surfactant abnormalities were encountered throughout in the ARDS patients. These included a massive alveolar protein load, a reduced percentage of large surfactant aggregates (LA), a loss of palmitoylated phosphatidylcholine species and a significant reduction of surfactant apoprotein (SP)-A, SP-B and SP-C in the LA fraction. Both minimum (γmin) and adsorption (γads) surface tension values (pulsating bubble surfactometer) were dramatically increased. Surfactant treatment resulted in a marked increase in the lavagable phospholipid (PL) pool, but predominance of the alveolar surfactant-inhibitory protein load was still encountered. Far-reaching or even complete normalization of the PL profile, the LA fraction and its SP-B and SP-C (but not SP-A) content as well as the fatty acid composition of the phosphatidylcholine class was noted. Surface tension lowering properties (γmin and γads) significantly improved, but were still not fully normalized. Bronchoscopic administration of large quantities of natural bovine surfactant in severe acute respiratory distress syndrome causes far-reaching restoration of biochemical surfactant properties and significant improvement, however not full normalization, of biophysical surfactant function.
Randomised comparison of three methods of administering a screening questionnaire to elderly people: findings from the MRC trial of the assessment and management of older people in the community
Authors: L. Smeeth, A. E Fletcher, S. Stirling, M. Nunes, E. Breeze, E. Ng, C. J Bulpitt, D. Jones
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objective:</b> To compare three different methods of administering a brief screening questionnaire to elderly people: post, interview by lay interviewer, and interview by nurse. <b>Design:</b> Randomised comparison of methods within a cluster randomised trial. <b>Setting:</b> 106 general practices in the United Kingdom. <b>Participants:</b> 32 990 people aged 75 years or over registered with participating practices. <b>Main outcome measures:</b> Response rates, proportion of missing values, prevalence of self reported morbidity, and sensitivity and specificity of self reported measures by method of administration of questionnaire for four domains. <b>Results:</b> The response rate was higher for the postal questionnaire than for the two interview methods combined (83.5% <i>v</i> 74.9%; difference 8.5%, 95% confidence interval 4.4% to 12.7%, P&lt;0.001). The proportion of missing or invalid responses was low overall (mean 2.1%) but was greater for the postal method than for the interview methods combined (4.1% <i>v</i> 0.9%; difference 3.2%, 2.7% to 3.6%, P&lt;0.001). With a few exceptions, levels of self reported morbidity were lower in the interview groups, particularly for interviews by nurses. The sensitivity of the self reported measures was lower in the nurse interview group for three out of four domains, but 95% confidence intervals for the estimates overlapped. Specificity of the self reported measures varied little by method of administration. <b>Conclusions:</b> Postal questionnaires were associated with higher response rates but also higher proportions of missing values than were interview methods. Lower estimates of self reported morbidity were obtained with the nurse interview method and to a lesser extent with the lay interview method than with postal questionnaires. <h3>What is already known on this topic</h3> The optimum method of administering a brief multidimensional screening assessment to elderly people is not known <h3>What this study adds</h3> Postal questionnaires produce a higher response rate than interviews by nurses or lay interviewers but also higher proportions of missing data Interview by nurses and to a lesser degree by lay interviewers is associated with lower levels of self reported morbidity than are postal questionnaires
Accelerated Tumor Growth Mediated by Sublytic Levels of Antibody-Induced Complement Activation Is Associated with Activation of the PI3K/AKT Survival Pathway
Authors: Xiaohong Wu, Govind Ragupathi, Katherine Panageas, Feng Hong, Philip O. Livingston
Journal: Clinical Cancer Research (2013)

We addressed the possibility that low levels of tumor cell-bound antibodies targeting gangliosides might accelerate tumor growth.To test this hypothesis, we treated mice with a range of monoclonal antibody (mAb) doses against GM2, GD2, GD3, and CD20 after challenge with tumors expressing these antigens and tested the activity of the same mAbs in vitro. We also explored the mechanisms behind the complement-mediated tumor growth acceleration that we observed and an approach to overcome it.Serologically detectable levels of IgM-mAb against GM2 are able to delay or prevent tumor growth of high GM2 expressing cell lines both in vitro and in a SCID mouse model, whereas very low levels of this mAb resulted in slight but consistent acceleration of tumor growth in both settings. Surprisingly, this is not restricted to IgM mAb targeting GM2 but consistent against an IgG mAb targeting GD3 as well. These findings were mirrored by in vitro studies with antibodies against these antigens as well as GD2 and CD20 (with Rituxan), and shown to be complement-dependent in all cases. Complement-mediated accelerated growth of cultured tumor cell lines initiated by low mAb levels was associated with activation of the phosphoinositide 3-kinase (PI3K)/AKT survival pathway and significantly elevated levels of both p-AKT and p-PRAS40. This complement-mediated PI3K activation and accelerated tumor growth in vitro and in vivo are eliminated by PI3K inhibitors NVP-BEZ235 and Wortmannin. These PI3K inhibitors also significantly increased efficacy of high doses of these four mAbs.Our findings suggest that manipulation of the PI3K/AKT pathway and its signaling network can significantly increase the potency of passively administered mAbs and vaccine-induced antibodies targeting a variety of tumor cell surface antigens.
US Intergroup Anal Carcinoma Trial: Tumor Diameter Predicts for Colostomy
Authors: Jaffer A. Ajani, Kathryn A. Winter, Leonard L. Gunderson, John Pedersen, Al B. Benson, Charles R. Thomas, Robert J. Mayer, Michael G. Haddock, Tyvin A. Rich, Christopher G. Willett
Journal: Journal of Clinical Oncology (2009)

The US Gastrointestinal Intergroup Radiation Therapy Oncology Group 98-11 anal carcinoma trial showed that cisplatin-based concurrent chemoradiotherapy resulted in a significantly higher rate of colostomy compared with mitomycin-based therapy. Established prognostic variables for patients with anal carcinoma include tumor diameter, clinical nodal status, and sex, but pretreatment variables that would predict the likelihood of colostomy are unknown.A secondary analysis was performed by combining patients in the two treatment arms to evaluate whether new predictive and prognostic variables would emerge. Univariate and multivariate analyses were carried out to correlate overall survival (OS), disease-free survival, and time to colostomy (TTC) with pretreatment and treatment variables.Of 682 patients enrolled, 644 patients were assessable and analyzed. In the multivariate analysis, tumor-related prognosticators for poorer OS included node-positive cancer (P < or = .0001), large (> 5 cm) tumor diameter (P = .01), and male sex (P = .016). In the treatment-related categories, cisplatin-based therapy was statistically significantly associated with a higher rate of colostomy (P = .03) than was mitomycin-based therapy. In the pretreatment variables category, only large tumor diameter independently predicted for TTC (P = .008). Similarly, the cumulative 5-year colostomy rate was statistically significantly higher for large tumor diameter than for small tumor diameter (Gray's test; P = .0074). Clinical nodal status and sex were not predictive of TTC.The combined analysis of the two arms of RTOG 98-11, representing the largest prospective database, reveals that tumor diameter (irrespective of the nodal status) is the only independent pretreatment variable that predicts TTC and 5-year colostomy rate in patients with anal carcinoma.