tbuckley/cabot-search huggingface dataset:
Serine-910 phosphorylation of focal adhesion kinase is critical for sarcomere reorganization in cardiomyocyte hypertrophy
Authors: Miensheng Chu, Rekha Iyengar, Yevgeniya E. Koshman, Taehoon Kim, Brenda Russell, Jody L. Martin, Alain L. Heroux, Seth L. Robia, Allen M. Samarel
Journal: Cardiovascular Research (2011)

Tyrosine-phosphorylated focal adhesion kinase (FAK) is required for the hypertrophic response of cardiomyocytes to growth factors and mechanical load, but the role of FAK serine phosphorylation in this process is unknown. The aims of the present study were to characterize FAK serine phosphorylation in cultured neonatal rat ventricular myocytes (NRVM), analyse its functional significance during hypertrophic signalling, and examine its potential role in the pathogenesis of human dilated cardiomyopathy (DCM). Endothelin-1 (ET-1) and other hypertrophic factors induced a time- and dose-dependent increase in FAK-S910 phosphorylation. ET-1-induced FAK-S910 phosphorylation required ETAR-dependent activation of PKCδ and Src via parallel Raf-1 → MEK1/2 → ERK1/2 and MEK5 → ERK5 signalling pathways. Replication-deficient adenoviruses expressing wild-type (WT) FAK and a non-phosphorylatable, S910A-FAK mutant were then used to examine the functional significance of FAK-S910 phosphorylation. Unlike WT-FAK, S910A-FAK increased the half-life of GFP-tagged paxillin within costameres (as determined by total internal reflection fluorescence microscopy and fluorescence recovery after photobleaching) and increased the steady-state FAK–paxillin interaction (as determined by co-immunoprecipitation and western blotting). These alterations resulted in reduced NRVM sarcomere reorganization and cell spreading. Finally, we found that FAK was serine-phosphorylated at multiple sites in non-failing, human left ventricular tissue. FAK-S910 phosphorylation and ERK5 expression were dramatically reduced in patients undergoing heart transplantation for end-stage DCM. FAK undergoes S910 phosphorylation via PKCδ and Src-dependent pathways that are important for cell spreading and sarcomere reorganization. Reduced FAK-S910 phosphorylation may contribute to sarcomere disorganization in DCM.
Reply: β<sub>2</sub>-Agonists and Acute Respiratory Distress Syndrome
Authors: G. R. Scott Budinger, Gökhan M. Mutlu
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

From the Editorialists*:

In their letter, Snyder and Johnson propose a mechanism to explain why the clinical trials evaluating β2-agonists as a treatment or preventive therapy for acute respiratory distress syndrome (ARDS) have failed. They suggest that extrapulmonary effects of β2-agonists on renal Na+ handling and the cardiovascular system might have caused an increase in total body water content, offsetting their beneficial effects on alveolar fluid clearance. Activation of β2-adrenergic receptors (β2ARs) may lead to increased total body water content by decreasing renal Na+ excretion (1). In addition, engagement of β2ARs on the vasculature may cause a drop in systemic vascular resistance, necessitating the increased administration of fluids and an increase in total body water content.

Several factors argue against this hypothesis. Although the systemic administration of β2-agonists in the BALTI 2 trial (2) may have affected renal Na+ handling and cardiovascular responses, the inhalation administration of β2-agonist is unlikely to have done so (3–5). Indeed, Perkins and colleagues found that β2-agonist therapy decreased extracellular lung water content in a subgroup of patients receiving inhaled β2-agonists in the BALTI prevention trial (4). Snyder and Johnson point out that patients receiving β2-agonist therapy received more cumulative fluids compared with those who did not in the ALTA trial (2,988 ± 6,614 ml in the albuterol group vs. 1,905 ± 6,388 ml in the control group; not significant) (5). Although this may be due to the effect of β2-agonists on renal Na+ excretion and caon the rdiovascular system, this disparity more likely reflects the inclusion of more patients with shock in the ALTA trial compared with the previous study (approximately one half vs. one third) (5, 6).

In summary, we agree with Johnson and Snyder that many mechanisms likely play a role in the unexpected outcomes with the use of β2-agonists for the treatment or prevention of ARDS (7). However, we think the bulk of the evidence from these trials and others suggests that β2-agonist therapy reduces lung water content. Despite this improvement, these agents failed to improve or prevent ARDS. Perhaps this is because only a fraction of patients with ARDS die directly as a result of hypoxemia. The majority of deaths occur due to development of multiple organ dysfunction, and only patients with severe ARDS benefit from therapies improving oxygenation (8, 9). Alternatively, the activation of β2ARs in other cells in the lung may negate the beneficial effects of their activation in the alveolar epithelium. For example, we have recently shown that β2-agonist therapy worsens lung inflammation in a murine model of lung injury via engagement of β2ARs on macrophages (10). We agree with the authors that additional studies will be needed to distinguish the beneficial effects of β2ARs from their unwanted and harmful effects.
Endovascular Intervention for Peripheral Artery Disease
Authors: Arun K. Thukkani, Scott Kinlay
Journal: Circulation Research (2015)

Advances in endovascular therapies during the past decade have broadened the options for treating peripheral vascular disease percutaneously. Endovascular treatment offers a lower risk alternative to open surgery in many patients with multiple comorbidities. Noninvasive physiological tests and arterial imaging precede an endovascular intervention and help localize the disease and plan the procedure. The timing and need for revascularization are broadly related to the 3 main clinical presentations of claudication, critical limb ischemia, and acute limb ischemia. Many patients with claudication can be treated by exercise and medical therapy. Endovascular procedures are considered when these fail to improve quality of life and function. In contrast, critical limb ischemia and acute limb ischemia threaten the limb and require more urgent revascularization. In general, endovascular treatments have greater long-term durability for aortoiliac disease than femoral popliteal disease. Infrapopliteal revascularization is generally reserved for critical and acute limb ischemia. Balloon angioplasty and stenting are the mainstays of endovascular therapy. New well-tested innovations include drug-eluting stents and drug-coated balloons. Adjunctive devices for crossing chronic total occlusions or debulking plaque with atherectomy are less rigorously studied and have niche roles. Patients receiving endovascular procedures need a structured surveillance plan for follow-up care. This includes intensive treatment of cardiovascular risk factors to prevent myocardial infarction and stroke, which are the main causes of death. Limb surveillance aims to identify restenosis and new disease beyond the intervened segments, both of which may jeopardize patency and lead to recurrent symptoms, functional impairment, or a threatened limb.
The Burden of Illness of Cancer: Economic Cost and Quality of Life
Authors: Martin L Brown, Joseph Lipscomb, Claire Snyder
Journal: Annual Review of Public Health (2001)

▪ Abstract Cancer is a major public health issue and represents a significant burden of disease. In this chapter, we analyze the main measures of burden of disease as relate to cancer. Specifically, we review incidence and mortality, years of life lost from cancer, and cancer prevalence. We also discuss the economic burden of cancer, including cost of illness, phase-specific and long-term costs, and indirect costs. We then examine the impact of cancer on health-related quality of life as measured in global terms (disability-adjusted life years and quality-adjusted life years) and using evaluation-oriented applications of health-related quality of life scales. Throughout, we note the relative strengths and weaknesses of the various approaches to measuring the burden of cancer as well as the methodologic challenges that persist in burden-of-illness research. We conclude with a discussion of the research agenda to improve our understanding of the burden of cancer and of illness more generally.
Three-Dimensional Reconstruction of the Mouse Nephron
Authors: Xiao-Yue Zhai, Jesper S. Thomsen, Henrik Birn, Inger B. Kristoffersen, Arne Andreasen, Erik I. Christensen
Journal: Journal of the American Society of Nephrology (2005)

Renal function is crucially dependent on renal microstructure which provides the basis for the regulatory mechanisms that control the transport of water and solutes between filtrate and plasma and the urinary concentration. This study provides new, detailed information on mouse renal architecture, including the spatial course of the tubules, lengths of different segments of nephrons, histotopography of tubules and vascular bundles, and epithelial ultrastructure at well-defined positions along Henle's loop and the distal convolution of nephrons. Three-dimensional reconstruction of 200 nephrons and collecting ducts was performed on aligned digital images, obtained from 2.5-mum-thick serial sections of mouse kidneys. Important new findings were highlighted: (1) A tortuous course of the descending thin limbs of long-looped nephrons and a winding course of the thick ascending limbs of short-looped nephrons contributed to a 27% average increase in the lengths of the corresponding segments, (2) the thick-walled tubules incorporated in the central part of the vascular bundles in the inner stripe of the outer medulla were identified as thick ascending limbs of long-looped nephrons, and (3) three types of short-looped nephron bends were identified to relate to the length and the position of the nephron and its corresponding glomerulus. The ultrastructure of the tubule segments was identified and suggests important implications for renal transport mechanisms that should be considered when evaluating the segmental distribution of water and solute transporters within the normal and diseased kidney.
Optimisation of indices of external pneumatic compression for prophylaxis against deep vein thrombosis: radionuclide gated imaging studies
Authors: R. KAMM, R. BUTCHER, J. FROELICH, M. JOHNSON, E. SALZMAN, A. SHAPIRO, H W. STRAUSS
Journal: Cardiovascular Research (1986)

The amount and rate of blood expelled with different modes of intermittent external pneumatic compression applied to the lower leg were studied on a regional basis in a series of experiments on healthy human volunteers. Radionuclide imaging of the labelled blood pool, with acquisition of counts synchronised to the pressurisation cycle, provided data on regional blood volumes in the leg in relation to time. To determine the changes in blood volume of the lower leg resulting from external pneumatic compression labelled red blood cell counts were determined during 10 different types of compression cycle. Since venous stasis is considered to be a major cause of venous thrombosis the red blood cell counts were used to calculate regional values of the fraction of blood ejected as well as comparative indices proportional to regional flow rate, regional velocity, and regional wall shear stress. All these indices should be maximised for optimal prophylaxis against deep vein thrombosis. The four compartment cuff in each compression mode applied a mean pressure of 45 mm Hg, but different combinations of values were used for intercompartmental pressure gradation (delta p) and for intercompartmental time sequencing to the onset of compression (delta t). Uniform compression (delta p = 0; delta t = 0) was substantially inferior to cycles with gradation and sequencing. The optimal values of delta p were in the range 5-10 mm Hg and of delta t in the range 0-0.5 seconds.
Instrumental variability of respiratory blood gases among different blood gas analysers in different laboratories
Authors: MJ Kampelmacher, RG van Kesteren, EK Winckers
Journal: European Respiratory Journal (1997)

The aim of this study was to test the hypothesis that differences in oxygen tension (PO2) and carbon dioxide tension (PCO2) values from measurements performed on different blood gas analysers in different laboratories are clinically insignificant. Samples of fresh whole human tonometered blood (PO2 8.1 kPa (60.8 mmHg); PCO2 5.3 kPa (39.9 mmHg)) were placed in airtight glass syringes and transported in ice-water slush. Blood gas analysis was performed within 3.5 h by 17 analysers (10 different models) in 10 hospitals on one day. The mean of the differences between the measured and target values was -0.01+/-0.19 and 0.21+/-0.13 kPa (-0.06+/-1.45 and 1.55+/-1.01 mmHg) for PO2 and PCO2, respectively. The mean of the differences between two samples on one analyser was 0.06+/-0.06 and 0.04+/-0.03 kPa (0.47+/-0.48 and 0.29+/-0.24 mmHg), respectively. For PO2 and PCO2 the interinstrument standard deviations (s(b)) were 0.18 and 0.13 kPa (1.38 and 0.99 mmHg), respectively, whereas the intra-instrument standard deviations (s) were 0.06 and 0.03 kPa (0.47 and 0.26 mmHg), respectively. Both for PO2 and PCO2 the ratios of s(b)2 and s2 were statistically significant (analysis of variance (ANOVA) p&lt;0.001). The standard deviations of a random measurement on a random analyser were 0.19 and 0.14 kPa (1.46 and 1.02 mmHg) for PO2 and PCO2, respectively. We conclude that the variability in measurement of blood gas values among different blood gas analysers, although negligible, depends much more on inter- than intra-instrument variation, both for oxygen tension and carbon dioxide tension. Technical improvements and adequate quality control programmes, including tonometry, may explain why the variability in blood gas values depends mainly on errors in the pre-analytical phase.
PSYCHOGENIC DISORDERS AND THE CIVILIZATION OF THE MIDDLE AGES
Authors: ALFRED GALLINEK
Journal: American Journal of Psychiatry (1942)

Authors have gone to great lengths to protect the saints from the accusation of hysteria. The complete identification of modern with medieval hysteria, the stigma attached to modern hysteria and other psychogenic disturbances, caused this vigorous defense. The study of medieval personality, environment and hysteria reveals this hysteria and related psychogenic disturbances as a means to achieve ecstatic maturity and great visionary religious experiences. At the same time hysteria was not only a means to an end, a tool, but also the result of the enormous tension, polarity and repression. If we disregard its late off-shoot of witch hunt, dance epidemics and inquisition, this hysteria was productive and of cultural significance in contrast to modern hysteria. It was different and it affected other personalities, ties, personalities who nowadays hardly would have a tendency toward hysteria and psychogenic disturbances. It affected those personalities who needed a stimulus and a tool in order to embody and express completely the essence of their era. We have given numerous examples of hysteria in great medieval personalities. They were great ones, but not the very great ones, not those of the very first order. The men of the second order needed the stimulus and tool of the hysterical mechanism. Not so the genius. Thus Beda Venerabilis, Hrabanus Maurus, Scotus Eriguena, Gerbert, Abelard, Thomas Aquinas and Albertus Magnus have few, or unimportant traces of hysteria. Others, those of second quality, needed the hysterical experience. The profoundness of mystical and ecstatic experience is not minimized or explained if we say that hysterical mechanisms were set in motion to make the experience possible. Between the poles of an overpowering tension stood medieval man. This tension and his desire to reach the eternal and transcendental created his hysteria which, at the same time, helped him to fulfill his yearning. Thus his suffering bore fruit: Passiflora.
Factors Contributing to Underuse of Radiation Among Younger Women With Breast Cancer
Authors: I.-W. Pan, B. D. Smith, Y.-C. T. Shih
Journal: JNCI Journal of the National Cancer Institute (2013)

BackgroundEvidence-based literature has confirmed the effectiveness of radiation therapy (RT) after breast-conserving surgery (BCS), especially for young women. However, women with young children may be less likely to be compliant. This study explores factors associated with noncompliance of RT among insured young patients.
Ultrasound imaging for lumbar punctures and epidural catheterisations: systematic review and meta-analysis
Authors: F. Shaikh, J. Brzezinski, S. Alexander, C. Arzola, J. C. A. Carvalho, J. Beyene, L. Sung
Journal: BMJ (2013)

To determine whether ultrasound imaging can reduce the risk of failed lumbar punctures or epidural catheterisations, when compared with standard palpation methods, and whether ultrasound imaging can reduce traumatic procedures, insertion attempts, and needle redirections.Systematic review and meta-analysis of randomised controlled trials.Ovid Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2012, without restriction by language or publication status.Randomised trials that compared ultrasound imaging with standard methods (no imaging) in the performance of a lumbar puncture or epidural catheterisation were identified.14 studies with a total of 1334 patients were included (674 patients assigned to the ultrasound group, 660 to the control group). Five studies evaluated lumbar punctures and nine evaluated epidural catheterisations. Six of 624 procedures conducted in the ultrasound group failed; 44 of 610 procedures in the control group failed. Ultrasound imaging reduced the risk of failed procedures (risk ratio 0.21 (95% confidence interval 0.10 to 0.43), P<0.001). Risk reduction was similar when subgroup analysis was performed for lumbar punctures (risk ratio 0.19 (0.07 to 0.56), P=0.002) or epidural catheterisations (0.23 (0.09 to 0.60), P=0.003). Ultrasound imaging also significantly reduced the risk of traumatic procedures (risk ratio 0.27 (0.11 to 0.67), P=0.005), the number of insertion attempts (mean difference -0.44 (-0.64 to -0.24), P<0.001), and the number of needle redirections (mean difference -1.00 (-1.24 to -0.75), P<0.001).Ultrasound imaging can reduce the risk of failed or traumatic lumbar punctures and epidural catheterisations, as well as the number of needle insertions and redirections. Ultrasound may be a useful adjunct for these procedures.
Urea Restrains Aldosterone-Induced Development of Peanut Agglutinin–Binding on Embryonic Renal Collecting Duct Epithelia
Authors: Karl Schumacher, Raimund Strehl, Will W. Minuth
Journal: Journal of the American Society of Nephrology (2003)

Peanut agglutinin (PNA) represents a commonly used marker for beta-type intercalated (IC) cells and their distribution in the corticomedullary course of the collecting duct (CD) in the mature rabbit kidney. It has been shown that aldosterone is able to generate >90% of PNA-binding cells in an embryonic CD epithelium in vitro. In adult kidney, a maximum of only 25% PNA-positive cells is found in the cortical segment of the CD, and PNA-binding completely disappears in the inner-medullary CD. Molecules that regulate the gradual development of CD-specific cells during organ growth are unknown. In the present experiments, it was found that addition of physiologic concentrations of urea to the culture medium is able to restrain the action of aldosterone in embryonic CD epithelia. Urea antagonizes in a concentration-dependent manner the action of aldosterone finally leading to only 10% of PNA-binding cells. The data point to a urea-specific effect, because osmolytes such as NaCl and mannitol did not affect PNA binding. In addition, urea did not influence expression of principal-cell typical markers such as AQP2 and 3. The findings may explain that a higher number of PNA-positive cells is found in the cortical region of the kidney correlated with a low concentration of urea as compared with only few PNA-binding cells in the medullary CD, where a high concentration of urea occurs. Thus, an increasing concentration of urea may trigger the number of PNA-positive cells in the cortical-medullary course of the CD during organ development.
Synergistic Inhibition of ErbB Signaling by Combined Treatment with Seliciclib and ErbB-Targeting Agents
Authors: Ian N. Fleming, Morag Hogben, Sheelagh Frame, Steven J. McClue, Simon R. Green
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The aims of this study were to investigate whether the cyclin-dependent kinase inhibitor seliciclib could synergize with agents that target ErbB receptors and to elucidate the molecular mechanism of the observed synergy. Experimental Design: Synergy between seliciclib and ErbB receptor targeted agents was investigated in various cell lines using the Calcusyn median effect model. The molecular mechanism of the observed synergy was studied in cultured cells, and the combination of seliciclib and the epidermal growth factor receptor (EGFR) inhibitor erlotinib was evaluated in an H358 xenograft model. Results: Seliciclib synergized with the anti-HER2 antibody trastuzumab in a breast cancer cell line, which overexpresses the HER2 receptor, and with the erlotinib analogue AG1478 in non–small cell lung cancer cell lines. In the H358 non–small cell lung cancer cell line, synergy involved decreased signaling from the EGFR, with AG1478 directly inhibiting kinase activity while seliciclib decreased the levels of key components of the receptor signaling pathway, resulting in enhanced loss of phosphorylated extracellular signal-regulated kinase and cyclin D1. The combination of seliciclib and erlotinib was evaluated further in an H358 xenograft and shown to be significantly more active than either agent alone. An enhanced loss of cyclin D1 was also seen in vivo. Conclusions: This is the first report that investigates combining seliciclib with an EGFR inhibitor. The combination decreased signaling from the EGFR in vitro and in vivo and was effective in cell lines containing either wild-type or mutant EGFR, suggesting that it may expand the range of tumors that respond to erlotinib, and therefore, such combinations are worth exploring in the clinic.
Has the Incidence of Radiation-Induced Bowel Damage following Treatment of Uterine Carcinoma Changed in the Last 20 Years?
Authors: T G Allen-Mersh, E J Wilson, H F Hope-Stone, C V Mann
Journal: Journal of the Royal Society of Medicine (1986)

Radiation-induced bowel damage occurred in 4.3% of patients treated primarily by irradiation for uterine carcinoma during the period 1962–1982. There has been a progressive rise in the incidence of radiation damage and radiation-induced rectovaginal fistula during this 20-year period. Radiation from intracavitary sources was a contributory factor in 92% of injured cases. The rising incidence of bowel damage in our patients may be due to an increase in the number of patients receiving a high rectal dose from the intracavitary source. There was a significantly ( P&gt;0.01) higher incidence of radiation injury in cases of cervical carcinoma compared to endometrial carcinoma. This was because cervical carcinoma tended to present at a more advanced stage than endometrial carcinoma and was more frequently treated with combined external and intracavitary irradiation. There was no significant increase in the incidence of complications among patients undergoing hysterectomy.