tbuckley/cabot-search huggingface dataset:
In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells
Authors: Bradley T. Messmer, Davorka Messmer, Steven L. Allen, Jonathan E. Kolitz, Prasad Kudalkar, Denise Cesar, Elizabeth J. Murphy, Prasad Koduru, Manlio Ferrarini, Simona Zupo, Giovanna Cutrona, Rajendra N. Damle, Tarun Wasil, Kanti R. Rai, Marc K. Hellerstein, Nicholas Chiorazzi
Journal: Journal of Clinical Investigation (2005)

Due to its relatively slow clinical progression, B cell chronic lymphocytic leukemia (B-CLL) is classically described as a disease of accumulation rather than proliferation. However, evidence for various forms of clonal evolution suggests that B-CLL clones may be more dynamic than previously assumed. We used a nonradioactive, stable isotopic labeling method to measure B-CLL cell kinetics in vivo. Nineteen patients drank an aliquot of deuterated water (2H2O) daily for 84 days, and 2H incorporation into the deoxyribose moiety of DNA of newly divided B-CLL cells was measured by gas chromatography/mass spectrometry, during and after the labeling period. Birth rates were calculated from the kinetic profiles. Death rates were defined as the difference between calculated birth and growth rates. These analyses demonstrated that the leukemic cells of each patient had definable and often substantial birth rates, varying from 0.1% to greater than 1.0% of the entire clone per day. Those patients with birth rates greater than 0.35% per day were much more likely to exhibit active or to develop progressive disease than those with lower birth rates Thus, B-CLL is not a static disease that results simply from accumulation of long-lived lymphocytes. Rather, it is a dynamic process composed also of cells that proliferate and die, often at appreciable levels. The extent to which this turnover occurs has not been previously appreciated. A correlation between birth rates and disease activity and progression appears to exist, which may help identify patients at risk for worsening disease in advance of clinical deterioration.
THE ROLE OF THE ALVEOLAR MACROPHAGE IN THE CLEARANCE OF BACTERIA FROM THE LUNG
Authors: Gareth M. Green, Edward H. Kass
Journal: The Journal of Experimental Medicine (1964)

Pulmonary clearance of bacteria was studied using histologic, bacteriologic, and radiotracer methods. When mice were exposed to an aerosol of P(32)-tagged Staphylococcus aureus or Proteus mirabilis, and the rate of disappearance of viable bacteria compared with the rate of their mechanical removal, it was found that bacterial viability declined 80 to 90 per cent in 4 hours, whereas radioactivity declined by only 14 to 20 per cent. The marked disparity in these rates indicated that mechanical removal comprised a relatively small fraction of the total clearing process. The in situ bactericidal action of the lung predominated over the mechanical removal process in achieving clearance of the inhaled bacteria. By immunofluorescent methods, the inhaled bacteria were found to be localized in the alveolar spaces and within alveolar macrophages. These observations suggest that the bactericidal action of the bronchopulmonary tree is due primarily to the phagocytic activity of the alveolar macrophages, and that the action of the mucociliary stream, in relation to bacterial particles, may be largely related to the transport from the lung of phagocytes containing material of bacterial origin.
Potential markers of heavy training in highly trained distance runners.
Authors: T Verde, S Thomas, R J Shephard
Journal: British Journal of Sports Medicine (1992)

Markers of a heavy increase in training were examined in ten highly trained distance runners (mean(s.d.) age 29.8(1.7) years, maximal oxygen intake 65.3 ml kg-1 min-1, personal best 10-km time 31 min 4 s) who undertook a deliberate 38% increment of training over a 3-week period. Their running performance did not improve, and six of the ten subjects developed sustained fatigue, suggesting that training was excessive, although the full clinical picture of overtraining did not develop. The Profile of Mood States was the best single marker of disturbed function, indicating increased fatigue and decreased vigour. There were no useful changes of resting heart rate or perceived exertion during submaximal running, sleep was undisturbed, and there were no orthopaedic injuries. Two subjects developed rhinoviral infections following the heavy training, and a third complained of symptoms that were diagnosed 2 weeks later as exercise-induced asthma. The increase of serum cortisol normally induced by 30 min of submaximal exercise was no longer seen when the same acute exercise was performed after heavy training. Resting lymphocyte proliferation tended to increase in response to phytohaematoglutinin (PHA) and concanavalin A (Con A), the ratio of helper to suppressor cells (H/S) decreased, and pokeweed mitogen induced smaller increases in IgG and IgM synthesis. Whereas before heavy training, PHA-stimulated lymphocyte proliferation was unchanged by 30 min of acute submaximal exercise, after 3 weeks of heavy training the same bout of exercise caused an 18% suppression of proliferation. Likewise, heavy training brought about a decrease of T-lymphocytes in response to acute submaximal exercise, but an abolition of the acute exercise-induced decrease in the H/S ratio. The previously observed exercise-induced decrease of IgG synthesis did not occur when the same acute bout of exercise was performed after heavy training. We conclude that such minor and transient changes of immune function may possibly be a warning that training is becoming excessive, but they have only a limited significance for overall immune function.
Isolation of phenotypically and functionally distinct macrophage subpopulations from human bronchoalveolar lavage
Authors: MA Spiteri, SW Clarke, LW Poulter
Journal: European Respiratory Journal (1992)

Bronchoalveolar lavage was used to obtain alveolar macrophages (AM) from the lower respiratory tract of healthy normal volunteers. Monoclonal antibody (MoAb) probes specific against macrophage determinants were then applied, in conjunction with density separation techniques, to identify and isolate three relatively homogeneous subpopulations from the AM pool. The MoAbs used, RFD1 and RFD7, have previously been shown to differentiate between "dendritic" cells and mature macrophages, respectively, in normal tissue. In addition to these two phenotypically distinct AM subsets (RFD1+D7- and RFD1-D7+ AM), a third AM subpopulation was isolated, which appeared to express both markers (RFD1+D7+). All three separated macrophage subsets were morphologically similar but exhibited distinct differences in surface receptor expression, enzyme content and physiology. Isolated RFD1+D7- AM (the phenotype of "dendritic" cells) did not adhere to the glass, had weak expression of C3b and FcR1 receptors, low fibronectin content and lysosomal activity; only a small proportion of these cells exhibited phagocytosis. The other two isolated AM subsets adhered to glass, expressed C3b and FcR1 receptors, had high fibronectin and acid phosphatase content, and a large majority exhibited phagocytic capacity; qualitative and quantitative differences in these features existed between the two AM subtypes. Furthermore, a diverse spectrum of hexose monophosphate shunt activity was observed throughout all three AM subpopulations, with the highest activity being recorded in the non-adherent AM. These data support the concept of a dynamic heterogeneity within the AM population. The variation in surface antigen expression and physiological capabilities observed amongst the three isolated AM subsets implies the presence of functionally distinct AM within the human lung, which, during steady-state conditions, may be critically balanced under the influence of stimuli in their local microenvironment. In support, proportional and functional shifts have been witnessed amongst these three AM subpopulations with the advent of disease.
Quality control of spirometry: a lesson from the BRONCUS trial
Authors: R. Pellegrino
Journal: European Respiratory Journal (2005)

This report describes the quality control programme used within the Bronchitis Randomized on N-acetylcysteine (NAC) Cost-Utility Study, a trial designed to assess the decline in lung function, exacerbation rate, health status, and cost-effectiveness with NAC or a placebo in 523 patients with chronic obstructive pulmonary disease over a 3-yr period. Spirometry was scored from 0 (worst quality) to 6 (best quality). The mean score of 314 spirometries from 243 patients evaluated during the trial was 5.63±0.83. Linear regression analysis of the scores of 47 participating centres plotted against the time at which spirometries were performed yielded an intercept of 5.7±0.5 and a slope of -0.0001±0.001, which suggests that the initial high quality was maintained over time. Retrospective examination of a further 345 postbronchodilator spirometries from 208 patients with a forced expiratory volume at one second exceeding the mean individual value recorded over the study in excess of 20% revealed a slightly lower quality of the start-of-test manoeuvre compared with the 314 spirometries. In conclusion, these findings would suggest that the quality control programme is likely to have helped achieve and maintain long-term spirometry performance in the Bronchitis Randomized on N-acetylcysteine (NAC) Cost-Utility Study trial. Special care should be paid to the spirometries whose forced expiratory volume in one second values exceed the mean value.
Sympathetic innervation alters growth and intrinsic heart rate of fetal rat atria maturing in oculo.
Authors: D C Tucker, R Gist
Journal: Circulation Research (1986)

The influence of sympathetic innervation on the growth and intrinsic rate of beating established by fetal rat heart was studied by culturing fetal atrial tissue in sympathetically innervated and denervated anterior eye chambers of adult Sprague-Dawley rats. One anterior eye chamber in each host rat was sympathetically denervated by removing the ipsilateral superior cervical ganglion. In oculo, atrial grafts were vascularized by blood vessels sprouting from the iris and innervated by sympathetic and parasympathetic fibers from the ground plexus of the iris. Innervation was assessed by light-activated efferent nerve stimulation to the grafts that changed their rates of beating. The norepinephrine contents of 16 atria cultured for 2.5 months in sympathetically innervated and denervated eye chambers were 5.7 +/- 1.1 ng/implant vs. 0.2 +/- 0.07 ng/implant (mean +/- SEM), indicating permanent sympathetic denervation of the anterior eye chamber and the implanted atria. By 8 weeks in oculo, atria maturing in sympathetically innervated anterior eye chambers were 86% larger than those in denervated eye chambers (2.22 +/- 0.29 vs. 1.19 +/- 0.13 mm2); the weight of innervated transplants was over 3 times that of noninnervated grafts (2.35 +/- 0.75 vs. 0.76 +/- 0.21 mg). After implanted atria had ceased growing rapidly (2.5 months in oculo), bipolar electrodes were implanted adjacent to the cornea to record impulses from atrial grafts while host rats were unanesthetized. The dark-adapted baseline heart rates of sympathetically innervated and noninnervated atria were virtually identical (289 vs. 290 bpm). Graft intrinsic heart rate was estimated by combined beta-adrenergic and muscarinic receptor blockade with atenolol (1.0 mg/kg) and methylatropine (10 micrograms/kg). Sympathetically innervated transplants had lower intrinsic heart rates than noninnervated atria (134 +/- 25 vs. 213 +/- 12 bpm). These data suggest that sympathetic innervation of the developing heart influences both growth and intrinsic rate of beating.
Top-up fees will lead to two tier NHS, doctors tell MPs
Authors: A. O'Dowd
Journal: BMJ (2009)

Expert clinicians believe that allowing NHS patients to pay top-up fees for expensive drugs as part of their treatment will create a complicated, two tier service.

The principles of the NHS are being undermined, clinicians told MPs on the parliamentary health select committee on Thursday 28 January during the first evidence session of the committee’s new inquiry into top-up fees, also known as copayments.

In November last year Mike Richards, England’s national clinical director for cancer, published a report, Improving Access to Medicines for NHS Patients , after reviewing the longstanding rule on copayments that meant that people deciding to buy their own drugs to top up treatment had to pay for the whole of their care …
B7-H4 Is Highly Expressed in Ductal and Lobular Breast Cancer
Authors: Barbara Tringler, Shaoqiu Zhuo, Glenn Pilkington, Kathleen C. Torkko, Meenakshi Singh, M. Scott Lucia, David E. Heinz, Jackie Papkoff, Kenneth R. Shroyer
Journal: Clinical Cancer Research (2005)

Abstract Purpose: This study was designed to investigate the expression of B7-H4 protein, a member of the B7 family that is involved in the regulation of antigen-specific immune responses, in normal breast and in primary and metastatic breast carcinomas. Experimental Design: Archival formalin-fixed tissue blocks from breast cancers and normal somatic tissues were evaluated for B7-H4 expression by immunohistochemistry with manual and automated image analysis. The proportion of B7-H4-positive cells and the intensity of B7-H4 staining were compared with histologic type, grade, stage, hormone receptor status, and HER-2/neu status. Results: B7-H4 was detected in 165 of 173 (95.4%) primary breast cancers and in 240 of 246 (97.6%) metastatic breast cancers. B7-H4 staining intensity was greater in invasive ductal carcinomas [24.61 relative units (RU)] and in invasive lobular carcinomas (15.23 RU) than in normal breast epithelium (4.30 RU, P = 0.0003). Increased staining intensity was associated with negative progesterone receptor status (P = 0.014) and history of neoadjuvant chemotherapy (P = 0.004), and the proportion of B7-H4-positive cells was associated with negative progesterone receptor (P = 0.001) and negative HER-2/neu (P = 0.024) status. However, there was no statistically significant relationship between the proportion of B7-H4-positive cells or staining intensity and grade, stage, or other clinicopathologic variables. Low levels of B7-H4 expression were also detected in epithelial cells of the female genital tract, lung, pancreas, and kidney, but B7-H4 was generally absent in most other normal somatic tissues. Conclusions: The nearly ubiquitous expression of B7-H4 in breast cancer, independent of tumor grade or stage, suggests a critical role for this protein in breast cancer biology.
Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for Metastatic Colorectal Cancer: Updated Analysis of Overall Survival According to Tumor <i>KRAS</i> and <i>BRAF</i> Mutation Status
Authors: Eric Van Cutsem, Claus-Henning Köhne, István Láng, Gunnar Folprecht, Marek P. Nowacki, Stefano Cascinu, Igor Shchepotin, Joan Maurel, David Cunningham, Sabine Tejpar, Michael Schlichting, Angela Zubel, Ilhan Celik, Philippe Rougier, Fortunato Ciardiello
Journal: Journal of Clinical Oncology (2011)

The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken.Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series.The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis.The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.
Adenosine: a physiological modulator of superoxide anion generation by human neutrophils.
Authors: B N Cronstein, S B Kramer, G Weissmann, R Hirschhorn
Journal: The Journal of Experimental Medicine (1983)

The effects of adenosine were studied on human neutrophils with respect to their generation of superoxide anion, degranulation, and aggregation in response to soluble stimuli. Adenosine markedly inhibited superoxide anion generation by neutrophils stimulated with N-formyl methionyl leucyl phenylalanine (FMLP), concanavalin A (Con A), calcium ionophore A23187, and zymosan-treated serum; it inhibited this response to PMA to a far lesser extent. The effects of adenosine were evident at concentrations ranging from 1 to 1,000 microM with maximal inhibition at 100 microM. Cellular uptake of adenosine was not required for adenosine-induced inhibition since inhibition was maintained despite the addition of dipyridamole, which blocks nucleoside uptake. Nor was metabolism of adenosine required, since both deoxycoformycin (DCF) and erythro-9-(2-hydroxy-3-nonyl) adenine did not interfere with adenosine inhibition of superoxide anion generation. The finding that 2-chloroadenosine, which is not metabolized, resembled adenosine in its ability to inhibit superoxide anion generation added further evidence that adenosine metabolism was not required for inhibition of superoxide anion generation by neutrophils. Unexpectedly, endogenously generated adenosine was present in supernatants of neutrophil suspensions at 0.14-0.28 microM. Removal of endogenous adenosine by incubation of neutrophils with exogenous adenosine deaminase (ADA) led to marked enhancement of superoxide anion generation in response to FMLP. Inactivation of ADA with DCF abrogated the enhancement of superoxide anion generation. Thus, the enhancement was not due to a nonspecific effect of added protein. Nor was the enhancement due to the generation of hypoxanthine or inosine by deamination of adenosine, since addition of these compounds did not affect neutrophil function. Adenosine did not significantly affect either aggregation or lysozyme release and only modestly affected beta-glucuronidase release by neutrophils stimulated with FMLP. These data indicate that adenosine (at concentrations that are present in plasma) acting via cell surface receptors is a specific modulator of superoxide anion generation by neutrophils.
Contributions of IL-1β and IL-1α to Crescentic Glomerulonephritis in Mice
Authors: Jennifer R. Timoshanko, A. Richard Kitching, Yichiro Iwakura, Stephen R. Holdsworth, Peter G. Tipping
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Interleukin-1 (IL-1) is a pleiotropic proinflammatory cytokine with two distinct isoforms (IL-1α and IL-1β) that signal through the same IL-1 type I receptor (IL-1RI). Contributions of IL-1β have been demonstrated in human and experimental proliferative glomerulonephritis (GN), but the involvement of IL-1α has received little attention. To determine the combined contribution of IL-1α and IL-1β and to dissect the specific contribution of IL-1β, the development of anti-glomerular basement membrane globulin–induced crescentic GN was studied in mice genetically deficient in either the IL-1 receptor type I (IL-1RI−/−), which are unresponsive to both IL-1α and IL-1β, or IL-1β alone (IL-1β−/−). IL-1β−/− mice showed significant reductions in crescent formation and glomerular T cell and macrophage recruitment compared with strain matched controls (WT). No additional reductions of these indices of injury were observed in IL-1RI−/− mice. However, IL-1RI−/− mice showed greater functional renal protection with significantly less proteinuria and reduced serum creatinine compared with IL-1β−/− mice, suggesting a significant contribution of IL-1α to these parameters of injury. IL-1RI−/− mice had lower serum titers of antibody to the nephritogenic antigen (sheep globulin) and reduced glomerular deposition of complement compared with either IL-1β−/− or WT mice. This suggests that in the absence of responses to both IL-1α and IL-1β, attenuation of humoral mediators provides additional functional protection from renal injury that is not seen in the absence of IL-1β alone. These studies indicate that IL-1β but not IL-1α contributes to crescent formation and inflammatory cell recruitment, whereas IL-1α but not IL-1β contributes to humoral mechanisms of glomerular injury.
Decade of Histological Follow-Up for a Fully Biodegradable Poly- <i>l</i> -lactic Acid Coronary Stent (Igaki-Tamai Stent) in Humans
Authors: Soji Nishio, Shinsaku Takeda, Kunihiko Kosuga, Masaharu Okada, Eisho Kyo, Takafumi Tsuji, Eiji Takeuchi, Tsuyoshi Terashima, Yasutaka Inuzuka, Tatsuhiko Hata, Yuzo Takeuchi, Takeshi Harita, Junya Seki, Shigeru Ikeguchi
Journal: Circulation (2014)
Early response to chemotherapy: a surrogate for final outcome of Hodgkin's disease patients that should influence initial treatment length and intensity?
Authors: P. Carde, S. Koscielny, J. Franklin, U. Axdorph, J. Raemaekers, V. Diehl, B. Aleman, O. Brosteanu, D. Hasenclever, O. Oberlin, N. Bonvin, M. Björkholm
Journal: Annals of Oncology (2002)
DERIVATION OF VELOCITY/DISTANCE CURVES FROM A WIRELESS INERTIAL MEASUREMENT UNIT INSTRUMENTED BOB-SKELETON SLED AND COMPARISON TO LIGHT GATE AND VIDEO DERIVED VALUES
Authors: M Gaffney, M Walsh, B O'Flynn, C O'Mathuna
Journal: British Journal of Sports Medicine (2013)

The sprinting push-start in the Winter Olympic sport of Bob-Skeleton, constitutes 2% and 8% of the 1500 m distance and 70 s duration of each run (Official Results &amp; Track Data, www.fibt.com, Apr 2013). This phase is critical to performance (Zanoletti et al . JSCR 2006;20(3):579–583), but the sport's small size, seasonal nature and other issues i.e. access to tracks, the challenging environment, or even restrictions by the governing body (Bob-Skeleton Rules: 10.11, 14.1 &amp; 16.9, www.fibt.com, Apr 2013), mean no studies-with or sources-of fine-grained real-world data are available. A Wireless Inertial Measurement Unit (WIMU) system was used to instrument a Bob- Skeleton training sled to gather such data. A WIMU streamed 256Hz Accelerometer data; light-gate, video and track-shape data were also gathered. A 65 kg female athlete in her 20 s performed 11 runs with varying step count, push side and handedness. An adaptive integration method using track-shape compensation and filtered raw data, converted Acceleration to velocity/distance curves and compared it to values interpolated from combined timing data from 6.5–20.5 m after push-off. WIMU data from 7 runs was used (average of data points 486±96). The adaptive integration method results tracked timing data velocity/distance curves well. The average velocity error was 0.462±0.248 m/s (7.57±4.12%), best &amp; worst runs were 0.176±0.143 m/s (2.97±2.63%) &amp; 0.800±0.251 m/s (13.2±3.55%) respectively. WIMUs show promise for recording fine-grained Bob-Skeleton velocity/distance data, but results so far are not good enough for high-end users (&lt;0.1 m/s accuracy). Improved systems with higher sampling, better sensors, in-the-field re-calibration, integrated timing, and synchronisation capabilities could likely achieve this. Acknowledgements Supported by Science Foundation Ireland via CLARITY: Centre for Sensor Web Technologies under grant 07/CE/I1147 with the assistance of University of Bath &amp; UK Sports.