tbuckley/cabot-search huggingface dataset:
P149 Characteristic And Prognosis Of Patients With Copd And Type 2 Respiratory Failure
Authors: T. Spruell, C. Dave, R. Mukherjee, A. Turner
Journal: Thorax (2014)

<h3>Introduction</h3> Factors associated with type 2 respiratory failure (T2RF) in COPD have been poorly described. Co-existent obstructive sleep apnoea is thought to play a part,<sup>1</sup> and episodes of worsening hypercapnia, associated with acidosis (AHRF), at the time of exacerbations is a well recognised feature.<sup>2</sup> We hypothesised that the development of hypercapnia or type 2 respiratory failure would associate with a higher risk of subsequent AHRF and higher mortality. <h3>Methods</h3> 292 patients who had been prescribed oxygen for their COPD during 2006–2010 were studied. Medical records were reviewed for lung function, blood gases in the stable state, episodes of AHRF and mortality up to the end of March 2014. Cross-sectional analyses seeking associations of hypercapnia and T2RF were carried out, together with comparisons of FEV1 decline, AHRF and mortality between those with and without T2RF. <h3>Results</h3> Mean follow up duration was 6.7 years. 164 patients died and 90 had one or more episodes of AHRF; AHRF was more common in T2RF (p = 0.046). Cox regression analysis, adjusting for age, demonstrated that death was more likely in those with T2RF compared to T1RF (Figure 1; p = 0.018). A rise in CO<sub>2</sub> after administration of oxygen during the test of LTOT eligibility showed a similar association, but it was less strong (p = 0.041). Lung function was strongly associated with T2RF and subsequent use of NIV for AHRF; 53% of those with FEV1 &lt;30% predicted eventually required it. This increased to 81% if FEV1 was less than 20% predicted. After adjusting for baseline FEV1 in the regression model, FEV1 decline did not differ between T2RF and T1RF. <h3>Conclusions</h3> LTOT patients with T2RF are at higher risk of AHRF and death, thus should be followed up more closely and more effort made to record advance wishes regarding NIV, if appropriate. <h3>References</h3> Obesity and respiratory diseases. Murugan AT, Sharma G. <i>Chron Respir Dis</i>. 2008; 5(4):233–42 Acidosis, non-invasive ventilation and mortality in hospitalised COPD exacerbation. Roberts CM, Stone RA, Buckingham RJ, Pursey NA, Lowe D. <i>Thorax</i> (2011) 66(1): 43–8
Cyclosporine Therapy for Inflammatory Bowel Disease
Authors: R. Balfour Sartor
Journal: New England Journal of Medicine (1994)

Currently, patients with ulcerative colitis or Crohn's disease are treated sequentially with 5-aminosalicylic acid preparations, corticosteroids, and mercaptopurine or azathioprine; metronidazole is beneficial in patients with colonic or perianal Crohn's disease. New systems to deliver 5-aminosalicylic acid are useful in patients with Crohn's disease of the small intestine and eliminate sulfapyridine-associated toxicity, but they are not more effective than sulfasalazine for colonic inflammation. Mercaptopurine and azathioprine are effective in patients with steroid-dependent or unresponsive Crohn's disease, but a three-month delay in response limits their use in acutely ill patients.The medical community and patients with inflammatory bowel disease have eagerly . . .
Overexpression of Hyperactive Integrin-Linked Kinase Leads to Increased Cellular Radiosensitivity
Authors: Nils Cordes
Journal: Cancer Research (2004)

Abstract Integrin-linked kinase (ILK), bound to the cytoplasmic tails of integrin β1, β2, and β3, is thought to signal through AKT and glycogen synthase kinase-3β (GSK-3β) for survival and proliferation regulation. To determine the role of ILK in the cellular radiation response, stably transfected A549 lung cancer cells overexpressing either wild-type (ILK-wk) or hyperactive ILK (ILK-hk) were studied for survival, signaling, proliferation, and examined in immunofluorescence and adhesion assays. Strong radiosensitization was observed in ILK-hk in contrast to ILK-wk mutants and empty vector controls. ILK small interfering RNA transfections showed radioresistance similar to irradiation on fibronectin. AKT, GSK-3β-cyclin D1, mitogen-activated protein kinase kinase 1/2-mitogen-activated protein kinase, and c-Jun NH2-terminal kinase signaling was dysregulated in irradiated ILK-hk mutants. Immunofluorescence stainings of ILK-hk cells indicated disturbed ILK and paxillin membrane localization with concomitant decrease in focal adhesions. Profound ILK-hk-dependent changes in morphology were characterized by spindle-like cell shape, cell size reduction, increased cell protrusions, strong formation of membranous f-actin rings, and significantly reduced adhesion to matrix proteins. Additionally, ILK-wk and ILK-hk overexpression impaired β1-integrin clustering and protein Tyr-phosphorylation. Taken together, the data provide evidence that ILK signaling modulates the cellular radiation response involving diverse signaling pathways and through changes in f-actin-based processes such as focal adhesion formation, cell adhesion, and spreading. Identification of ILK and its signaling partners as potential targets for tumor radiosensitization might promote innovative anticancer strategies by providing insight into the mechanism of cell adhesion-mediated radioresistance, oncogenic transformation, and tumor growth and spread.
p53 Is a Direct Transcriptional Target of MYCN in Neuroblastoma
Authors: Lindi Chen, Nunzio Iraci, Samuele Gherardi, Laura D. Gamble, Katrina M. Wood, Giovanni Perini, John Lunec, Deborah A. Tweddle
Journal: Cancer Research (2010)

MYCN amplification occurs in approximately 25% of neuroblastomas, where it is associated with rapid tumor progression and poor prognosis. MYCN plays a paradoxical role in driving cellular proliferation and inducing apoptosis. Based on observations of nuclear p53 accumulation in neuroblastoma, we hypothesized that MYCN may regulate p53 in this setting. Immunohistochemical analysis of 82 neuroblastoma tumors showed an association of high p53 expression with MYCN expression and amplification. In a panel of 5 MYCN-amplified and 5 nonamplified neuroblastoma cell lines, and also in the Tet21N-regulatable MYCN expression system, we further documented a correlation between the expression of MYCN and p53. In MYCN-amplified neuroblastoma cell lines, MYCN knockdown decreased p53 expression. In Tet21N MYCN+ cells, higher levels of p53 transcription, mRNA, and protein were observed relative to Tet21N MYCN- cells. In chromatin immunoprecipitation and reporter gene assays, MYCN bound directly to a Myc E-Box DNA binding motif located close to the transcriptional start site within the p53 promoter, where it could initiate transcription. E-Box mutation decreased MYCN-driven transcriptional activation. Microarray analysis of Tet21N MYCN+/- cells identified several p53-regulated genes that were upregulated in the presence of MYCN, including MDM2 and PUMA, the levels of which were reduced by MYCN knockdown. We concluded that MYCN transcriptionally upregulates p53 in neuroblastoma and uses p53 to mediate a key mechanism of apoptosis.
Reintroduction of C/EBPα in leukemic CD34+ stem/progenitor cells impairs self-renewal and partially restores myelopoiesis
Authors: Hein Schepers, Albertus T. J. Wierenga, Djoke van Gosliga, Bart J. L. Eggen, Edo Vellenga, Jan Jacob Schuringa
Journal: Blood (2007)
Regional absence of mitochondria causing energy depletion in the myocardium of muscle LIM protein knockout mice
Authors: B VANDENBOSCH, C VANDENBURG, K SCHOONDERWOERD, P LINDSEY, H SCHOLTE, R DECOO, E VANROOIJ, H ROCKMAN, P DOEVENDANS, H SMEETS
Journal: Cardiovascular Research (2004)

Defects in myocardial mitochondrial structure and function have been associated with heart failure in humans and animal models. Mice lacking the muscle LIM protein (MLP) develop morphological and clinical signs resembling human dilated cardiomyopathy and heart failure. We tested the hypothesis that defects in the cytoskeleton lead to dilated cardiomyopathy through mitochondrial dysfunction in the MLP mouse model.Oxidative phosphorylation activity was determined in left ventricles of MLP knockout (KO) mice and control littermates by measuring complex activities of the electron transport chain (I-IV) and ATP synthase (complex V). All complexes and citrate synthase (CS) showed decreased activities in the KO mice, although activity per amount of CS, a measure for mitochondrial density, was normal. Light and electron microscopy revealed a disorganization of mitochondria and a dramatic decrease in mitochondrial density, even revealing regions completely lacking mitochondria in the KO hearts. Real-time PCR analysis showed decreased transcript levels of mtDNA and nuclear encoded mitochondrial genes and of peroxisome proliferator activated receptor gamma co-activator 1alpha (PGC-1alpha), a key regulator of mitochondrial biogenesis. MtDNA copy number (ratio mtDNA/nuclear DNA) was slightly increased in the MLP KO mice.Our results show that the absence of MLP causes a local loss of mitochondria. We hypothesize that this is caused by a disturbed interaction between cytoskeleton and mitochondria, which interferes with energy sensing and energy transfer. Recovery of energy depletion by stimulating mitochondrial biogenesis might be a useful therapeutic strategy for improving the energy imbalance in heart failure.
Do sensorial manipulations affect subjects differently depending on their postural abilities?
Authors: Frédéric Noé, Nicolas Bernard, Clement Hazard, Thierry Paillard, R. Bizid, Philippe Dupui
Journal: British Journal of Sports Medicine (2007)

To examine whether sensorial manipulation affects subjects differently according to their postural performance and the strategies used. The literature showed that the level of competition of soccer players influences their postural performance and strategy.Eight high-level (HL) professional soccer players and nine regional-level (RL) soccer players were tested (1) in a reference condition and (2) in a manipulated sensorial condition (MAN). The MAN condition consisted of perturbing the proprioceptive and exteroceptive information. For each postural condition, balance was assessed by measuring the centre of foot pressure using a force platform during a test of bipedal standing posture.The postural control was less perturbed in the HL than in the RL players in the two postural conditions. Moreover, the group-condition interaction showed that the postural control was less disturbed in the HL than in the RL players when the sensory information was manipulated.The HL soccer players probably possessed a better internal model of verticality than the RL players. Subjects who had a better postural control level were less disturbed by sensorial manipulation than the others in postural regulation.
Controlled prospective study on the mental health of women following pregnancy loss
Authors: H J Janssen, M C Cuisinier, K A Hoogduin, K P de Graauw
Journal: American Journal of Psychiatry (1996)

This study investigated the hypothesis that following a pregnancy loss, women have more mental health complaints than women who give birth to a living baby.Mental health was assessed for 2,140 women during their first trimester of pregnancy through use of the Dutch version of the SCL-90. A total of 227 women who had lost their babies and 213 women who gave birth to a living baby were followed over a period of 18 months, during which their mental health was reassessed four times.When mental health complaints at the beginning of pregnancy and reproductive loss history were taken into account, data analysis revealed that up to 6 months after their pregnancy loss, women showed greater depression, anxiety, and somatization than women who gave birth to living babies. Over time the mental health of women who had experienced a loss was found to improve and at 1 year was comparable to that of women who gave birth to living babies and to that of women in general.The majority of women are able to recover from pregnancy loss without psychiatric treatment in about 1 year. A pregnancy loss is nevertheless a stressful life event that can give rise to a marked deterioration in a woman's mental health, particularly in the first 6 months following loss.
Heatwaves and hospital staff: Taking the temperatures may be important
Authors: J C. Oliver
Journal: BMJ (2006)

I just wanted to be a doctorWe need to be more than "just" doctors Editor-Hunt articulates the feelings of many doctors on discovering that the effective practice of modern medicine requires a range of skills beyond the provision of direct clinical care. 1 Her slightly delayed entry into medicine may explain why this issue is troubling her now, rather than later in her career: certainly these are sentiments I hear more commonly from consultant colleagues than juniors.However, to imagine that good medical practice is confined to the delivery of care to one patient at a time is to overlook the role of doctors in organising healthcare systems and delivery in the wider context.It is disappointing that Hunt's appraiser chose to frame the process in terms of her trust's participation in the clinical negligence scheme, since most junior doctors value well conducted appraisals.Nevertheless, cheaper insurance premiums for hospitals mean more money to spend on health care, and also indicate that organisations that carry out effective appraisal make fewer clinical errors: presumably these are both outcomes that Hunt would approve of.Furthermore, research and audit without the active participation of doctors will soon become clinically irrelevant or ineffective.We have a wider responsibility for patient care that is served by informed participation in these and many other activities, such as teaching and continuous quality improvement (which also seem to get irritatingly in the way of a narrowly focused approach to patient care).However, all is not lost.Hunt appears well placed to fall into the "Modernising Medical Careers" vacuum that currently threatens to swallow those junior doctors who are too old for a foundation programme yet too young to have secured a specialist registrar post.If this does indeed curtail all opportunities for career progression she may end up as "just" a doctor after all.
Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia
Authors: Dana M Cairns, Robert J Pignolo, Tomoya Uchimura, Tracy A Brennan, Carter M Lindborg, Meiqi Xu, Frederick S Kaplan, Eileen M Shore, Li Zeng
Journal: Journal of Clinical Investigation (2013)

Progressive osseous heteroplasia (POH) is a rare developmental disorder of heterotopic ossification (HO) caused by heterozygous inactivating germline mutations in the paternal allele of the GNAS gene. Interestingly, POH lesions have a bewildering mosaic distribution. Using clinical, radiographic, and photographic documentation, we found that most of the 12 individuals studied had a lesional bias toward one side or the other, even showing exclusive sidedness. Most strikingly, all had a dermomyotomal distribution of HO lesions. We hypothesized that somatic mutations in a progenitor cell of somitic origin may act on a background of germline haploinsufficiency to cause loss of heterozygosity at the GNAS locus and lead to the unilateral distribution of POH lesions. Taking advantage of the chick system, we examined our hypothesis by mimicking loss of heterozygosity of GNAS expression using dominant-negative GNAS that was introduced into a subset of chick somites, the progenitors that give rise to dermis and muscle. We observed rapid ectopic cartilage and bone induction at the axial and lateral positions in a unilateral distribution corresponding to the injected somites, which suggests that blocking GNAS activity in a targeted population of progenitor cells can lead to mosaic ectopic ossification reminiscent of that seen in POH.
Prognostic significance of miR-34a in Ewing sarcoma is associated with cyclin D1 and ki-67 expression
Authors: M.T. Marino, A. Grilli, C. Baricordi, M.C. Manara, S. Ventura, R.S. Pinca, M. Bellenghi, M. Calvaruso, G. Mattia, D. Donati, C. Tripodo, P. Picci, S. Ferrari, K. Scotlandi
Journal: Annals of Oncology (2014)
The effects of hypoproteinemia on blood-to-lymph fluid transport in sheep lung.
Authors: G C Kramer, B A Harms, R A Gunther, E M Renkin, R H Demling
Journal: Circulation Research (1981)

We studied the effects of reducing the plasma protein concentration on flow and composition of pulmonary lymph in 12 unanesthetized sheep. Whole blood was removed while red cells were returned and lactated Ringers was infused at a rate sufficient to maintain pulmonary vascular pressures at baseline values. A 44-54% reduction in plasma protein concentration resulted in a decrease in the plasma oncotic pressure from 18.6 +/- 1.1 to 7.8 +/- 0.9 mm Hg. Within an hour after plasmapheresis, lymph flows increased to a maximum of 4 times baseline. Subsequently, lymph flow gradually decreased and were close to baseline at 24 hours. The plasma-to-lymph oncotic gradient was reestablished in 5 hours due to decreased lymph protein. Maintained elevation of lymph flow with hydrostatic and oncotic gradients at baseline values suggest that the blood-to-lymph barrier offers less resistance to fluid transport. The calculated filtration coefficient increased 2- to 3-fold after plasmapheresis. Protein clearances remained normally coupled to lymph flows. Thus the enhanced fluid transport cannot be attributed to a permeability change in the large pore pathways. Hypoproteinemia may alter the interstitial gel so that there is less resistance to fluid movement. Such changes in fluid conductivity between blood capillaries and lymphatics may augment the lymphatic safety factor against pulmonary edema during hypoproteinemia.
Overexpression and Activation of the α9-Nicotinic Receptor During Tumorigenesis in Human Breast Epithelial Cells
Authors: Chia-Hwa Lee, Ching-Shui Huang, Ching-Shyang Chen, Shih-Hsin Tu, Ying-Jan Wang, Yu-Jia Chang, Ka-Wai Tam, Po-Li Wei, Tzu-Chun Cheng, Jan-Show Chu, Li-Ching Chen, Chih-Hsiung Wu, Yuan-Soon Ho
Journal: JNCI Journal of the National Cancer Institute (2010)

Large epidemiological cohort studies in the United States have indicated that active and passive smoking are associated with increased breast cancer risk. However, there was no direct evidence of an effect of tobacco carcinogens on the cellular molecules involved in breast tumorigenesis.Reverse transcription-polymerase chain reaction was used to determine the expression of all of the nicotinic acetylcholine receptor (nAChR) subunits in 50 human breast cancer samples and to determine the expression of the alpha9-nAChR subunit in 276 surgical and laser capture microdissected breast tumor vs normal tissue pairs. Stable MDA-MB-231 breast cancer cell lines were established in which expression of the alpha9-nAChR subunit was inhibited using short interfering RNA. MCF-10A normal human breast epithelial cells were established in which the alpha9-nAChR subunit could be conditionally overexpressed by removal of doxycycline from the culture fluid. Cell proliferation and soft agar assays and tumor growth in nude mice were used as measures of cell transformation. All statistical tests were two-sided.In 186 (67.3%) of the 276 paired samples, alpha9-nAChR mRNA was expressed at (mean 7.84-fold) higher levels in breast cancers than in surrounding normal tissue. Stable expression of alpha9-nAChR short interfering RNA in MDA-MB-231 cells attenuated nicotine-stimulated proliferation and growth in soft agar and reduced tumor volume when the cells were introduced as xenografts in SCID mice (n = 5 mice per group; mean tumor volume at 6 weeks treatment in mice injected with Si alpha9 cells = 995.6 mm(3), in mice injected with parental cells = 2993.2 mm(3), difference = 1997.6 mm(3), 95% confidence interval [CI] = 1705 to 2290.2 mm(3), P = .009). Long-term treatment of MCF-10A normal breast epithelial cells with either nicotine or its active metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, triggered precancerous transformation as defined by soft agar assay. Inducible overexpression of alpha9-nAChR in MCF-10A cell xenografts in nude mice substantially increased tumor growth (n = 5 mice per group; DOX+, mean tumor volume without nicotine vs with nicotine = 266.2 vs 501.6 mm(3), difference = 235.4 mm(3), 95% CI = 112.7 to 358 mm(3), P = .009; DOX-, mean tumor volume without nicotine vs with nicotine = 621.2 vs 898.6 mm(3), difference = 277.4 mm(3), 95% CI = 98.1 to 456.7 mm(3), P = .016; mean tumor volume in the presence of nicotine, DOX+ vs DOX- = 501.6 vs 898.6 mm(3), difference = 397 mm(3), 95% CI = 241.3 to 552.6 mm(3), P = .009).The alpha9-nAChR is important for nicotine-induced transformation of normal human breast epithelial cells.
Stimulating effect of MDP and its adjuvant-active analogues on guinea pig fibroblasts for the production of thymocyte-activating factor.
Authors: H Iribe, T Koga, S Kotani, S Kusumoto, T Shiba
Journal: The Journal of Experimental Medicine (1983)

Synthetic muramyl dipeptide (MDP) could stimulate skin fibroblasts of the guinea pig to produce thymocyte-activating factor, which augments the proliferative response of thymocytes to phytohemagglutinin (PHA). Adjuvant-active analogues of MDP also stimulated fibroblasts to produce the factor, whereas adjuvant-inactive analogues failed to do so. Thus a marked parallelism was found between adjuvant activity of these compounds and the stimulating effect on fibroblasts. Thymocyte-activating factor derived from MDP-stimulated fibroblasts was found in the fraction of mol wt 30,000-60,000 by gel filtration on a Sephacryl S-200 column. Furthermore, this factor did not exhibit T cell growth factor activity.