tbuckley/cabot-search huggingface dataset:
Periarticular bone changes in rheumatoid arthritis: pathophysiological implications and clinical utility
Authors: Steven R Goldring
Journal: Annals of the Rheumatic Diseases (2009)

Your key source of unbiased, independent advice For over 45 years DTB has been an independent, indispensable part of evidence-based clinical practice.DTB offers healthcare professionals detailed assessment of, and practical advice on, individual medicines and other treatments, groups of treatment and the overall management of disease.
Key role of poly-γ-dl-glutamic acid in immune evasion and virulence of Staphylococcus epidermidis
Authors: Stanislava Kocianova, Cuong Vuong, Yufeng Yao, Jovanka M. Voyich, Elizabeth R. Fischer, Frank R. DeLeo, Michael Otto
Journal: Journal of Clinical Investigation (2005)

Coagulase-negative staphylococci, with the leading species Staphylococcus epidermidis, are the predominant cause of hospital-acquired infections. Treatment is especially difficult owing to biofilm formation and frequent antibiotic resistance. However, virulence mechanisms of these important opportunistic pathogens have remained poorly characterized. Here we demonstrate that S. epidermidis secretes poly-γ-DL-glutamic acid (PGA) to facilitate growth and survival in the human host. Importantly, PGA efficiently sheltered S. epidermidis from key components of innate host defense, namely antimicrobial peptides and neutrophil phagocytosis, and was indispensable for persistence during device-related infection. Furthermore, PGA protected S. epidermidis from high salt concentration, a key feature of its natural environment, the human skin. Notably, PGA was synthesized by all tested strains of S. epidermidis and a series of closely related coagulase-negative staphylococci, most of which are opportunistic pathogens. Our study presents important novel biological functions for PGA and indicates that PGA represents an excellent target for therapeutic maneuvers aimed at treating disease caused by S. epidermidis and related staphylococci.
The G-protein-coupled receptor APJ is expressed in the second heart field and regulates Cerberus–Baf60c axis in embryonic stem cell cardiomyogenesis
Authors: Cristina D'Aniello, Alessandro Fiorenzano, Salvatore Iaconis, Giovanna L. Liguori, Gennaro Andolfi, Gilda Cobellis, Annalisa Fico, Gabriella Minchiotti
Journal: Cardiovascular Research (2013)

Mammalian cardiomyogenesis occurs through a multistep process that requires a complex network of tightly regulated extracellular signals, which integrate with the genetic and epigenetic machinery to maintain, expand, and regulate the differentiation of cardiac progenitor cells. Pluripotent embryonic stem cells (ESCs) recapitulate many aspects of development, and have provided an excellent opportunity to dissect the molecular mechanisms underlying cardiomyogenesis, which is still incompletely defined. We provide new in vivo evidence that the G-protein-coupled receptor angiotensin receptor-like 1 (Apj) is expressed in the mesodermal cells of the second heart field, a population of cardiac progenitors that give rise to a major part of the definitive heart. By combining loss-and-gain of function studies in mouse ESCs, we show that Apj (i) controls the balance between proliferation and cardiovascular differentiation, (ii) regulates the Nodal/Bone Morphogenetic Protein antagonist Cerberus and the Baf60c/Smarcd3 subunit of the Brg1/Brm-associated factors (BAF) chromatin-remodelling complex. We propose a model in which Apj controls a regulatory Cerberus–Baf60c pathway in pluripotent stem cell cardiomyogenesis, and speculate that this regulatory circuit may regulate cardiac progenitor cell behaviour.
Age-dependent Insulin Secretion of the Endocrine Pancreas In Vitro from Fetuses of Diabetic and Nondiabetic Patients
Authors: Horst Reiher, Kurt Fuhrmann, Silke Noack, Klaus-P Woltanski, Erich Jutzi, Herwig Hahn v Dorsche, Hans-J Hahn
Journal: Diabetes Care (1983)

Fetal hyperinsulinemia is assumed to play a key role in the pathogenesis of diabetic fetopathy. To investigate the role of enhanced fetal B-cell mass as one cause of fetal hyperinsulinemia during diabetic pregnancy, we studied human fetal pancreatic slices from diabetic women (FDW) with poor metabolic control and nondiabetic women (FNDW) between 11 and 26 wk of pregnancy, morphometrically and by in vitro incubation experiments. Abortions had been performed due to different medical indications. We found a good correlation between the calculated B-cell mass and the gestational age in both FDW and FNDW, but the increase in FDW was much more pronounced. Such a correlation was also found in vitro regarding the insulin response to glucose and IBMX. The FDW had significantly higher values than FNDW of the same age range. In contrast to this, we found in two diabetic patients with tight metabolic control during the whole pregnancy results similar to those in FNDW. Therefore, we assume that it could be possible to prevent fetal hyperinsulinemia and perhaps even diabetic fetopathy in diabetic women by tight metabolic control during the whole pregnancy, but further investigations are necessary.
Cisplatin Induces p53-Dependent FLICE-Like Inhibitory Protein Ubiquitination in Ovarian Cancer Cells
Authors: Mohammad R. Abedini, Emilie J. Muller, Jan Brun, Richard Bergeron, Douglas A. Gray, Benjamin K. Tsang
Journal: Cancer Research (2008)

Abstract Understanding the mechanism of cisplatin (CDDP) action may improve therapeutic strategy for ovarian cancer. Although p53 and FLICE-like inhibitory protein (FLIP) are determinants of CDDP sensitivity in ovarian cancer, the interaction between p53 and FLIP remains poorly understood. Here, using two chemosensitive ovarian cancer cell lines and various molecular and cellular approaches, we show that CDDP induces p53-dependent FLIP ubiquitination and degradation, and apoptosis in vitro. Moreover, we showed that Itch (an E3 ligase) forms a complex with FLIP and p53 upon CDDP treatment. These results suggest that p53 facilitates FLIP down-regulation by CDDP-induced FLIP ubiquitination and proteasomal degradation. [Cancer Res 2008;68(12):4511–7]
Serotonin Increases Interleukin-6 Synthesis in Human Vascular Smooth Muscle Cells
Authors: Takayuki Ito, Uichi Ikeda, Masahisa Shimpo, Keiji Yamamoto, Kazuyuki Shimada
Journal: Circulation (2000)

Background —Interleukin-6 (IL-6) is a key molecule in chronic inflammation and has been implicated in the progression of atherosclerosis. Serotonin (5-hydroxytryptamine; 5-HT) causes vascular contraction and proliferation, but its role in atherogenesis has not been clarified. We investigated the effects of 5-HT on IL-6 synthesis in human vascular smooth muscle cells (VSMCs). Methods and Results —IL-6 levels in the culture medium of VSMCs were determined by ELISA. IL-6 mRNA accumulation was determined by use of a Quantikine mRNA colorimetric quantification kit. NF-κB activation was tested by gel retardation assay. 5-HT induced IL-6 production by VSMCs in a time- and dose-dependent manner, with increased IL-6 mRNA accumulation and nuclear factor-κB activation. The effect of 5-HT on IL-6 production was significantly inhibited by the 5-HT 2 receptor antagonist ketanserin and the selective 5-HT 2A receptor antagonist sarpogrelate. Conversely, the 5-HT 2 receptor agonist α-methyl-5-HT increased IL-6 production. The protein kinase C (PKC) inhibitor calphostin C, but not the protein kinase A inhibitor KT5720, suppressed 5-HT–induced IL-6 production. The effect of 5-HT was also abolished in PKC-depleted VSMCs after pretreatment with phorbol 12-myristate 13-acetate for 24 hours. Conclusions —5-HT acts on 5-HT 2A receptors and increases IL-6 synthesis in human VSMCs at least partially through a PKC-dependent pathway. These results suggested that 5-HT may contribute to inflammatory activation of the vessels during atherogenesis.
Kidney Function as a Predictor of Noncardiovascular Mortality
Authors: Linda F. Fried, Ronit Katz, Mark J. Sarnak, Michael G. Shlipak, Paulo H.M. Chaves, Nancy Swords Jenny, Catherine Stehman-Breen, Dan Gillen, Anthony J. Bleyer, Calvin Hirsch, David Siscovick, Anne B. Newman
Journal: Journal of the American Society of Nephrology (2005)

Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.
On a wing and a prayer: surgeons learning from the aviation industry
Authors: Neil Singh
Journal: Journal of the Royal Society of Medicine (2009)

Surgery and aviation have many similarities. Both disciplines have made the extraordinary ordinary – involving teams of specialists using expensive equipment to perform previously unimaginable tasks in life-threatening situations. But perhaps what is most miraculous about these two astonishing human endeavours is not what they entail, but rather how frequently they occur. On any one day, an estimated 85,000 flights and 550,000 operations are completed worldwide. What are the implications of scaling up life-or-death events to such astronomical levels?

One consequence of such large throughputs is that even tiny risks are magnified. If even a small percentage of patients and passengers die, this amounts to a significant number of families affected by preventable deaths. Every year around 500 people die in aviation accidents, and the World Health Organization (WHO) estimates that a staggering 1 million people die in the perioperative period,1 many due to avoidable mistakes. So, what is being done to minimize these risks?
Enterohepatic circulation rates of cholic acid and chenodeoxycholic acid in man.
Authors: K A Einarsson, S M Gundy, W G Hardison
Journal: Gut (1979)

The rate of enterohepatic cycling of cholic acid and chenodeoxycholic acid was determined in five male subjects. Pool sizes were measured by isotope dilution technique after intraduodenal administration of 14C-labelled cholic and chenodeoxycholic acid. The hourly hepatic secretion rate of bile acids was determined by an intestinal perfusion technique. From these data the cycling frequency was calculated. Chenodeoxycholic acid circulated on an average 1.34 (range, 1.13--1.57) times faster than cholic acid, probably because chenodeoxycholic acid to a larger extent than cholic acid is absorbed from the proximal small intestine and thus partly bypasses the hepaticoileal circuit. This difference in cycling rate may have methodological as well as physiological implications.
Reply to A. Avan et al
Authors: José Baselga, Emma Clark, Astrid Kiermaier, Sandra M. Swain
Journal: Journal of Clinical Oncology (2015)

We thank Avan et al 1 for their interest in and valuable comments on our recently published article on biomarkers in the CLEOPATRA study (Clinical Evaluation of Pertuzumab and Trastuzumab; ClinicalTrials.govnumber NCT00567190). 2 First, we would like to clarify a few methodologic points that were not included in our original article.Tissue samples were macrodissected according to prespecified rules to enrich for tumor cells for analyses of tumor-specific signals.We agree that, from a scientific point of view, obtaining multiple samples from a tumor lesion, as well as serial samples both on treatment and after treatment, so as to assess changes over time, is warranted, and that this should indeed be the aim of appropriate studies.However, such analyses in a phase III trial with 808 patients across 204 clinical centers in 25 countries 3 is not logistically possible due to significant differences in infrastructure, local clinical practice, and access to state-of-the-art technologies.Tissue blocks were also required to be returned after 3 months which makes confirmatory assessments impossible.We did plan to obtain matched paired tissue samples from primary lesions corresponding to metastatic lesions; however, such samples were only received for 24 patients.We share Avan et al's concerns 1 on variability in scoring which is why all markers in CLEOPATRA were scored by several pathologists.Early in the study, all pathologists underwent specific training defined by a qualification test plan to ensure inter-reader concordance and harmonized reading of immunohistochemistry and in situ hybridization.Pathologists also had to pass a yearly internal ring assessment.Regarding prognostic markers and potential bias with single factor analyses, we would like to point out that multivariate analyses which included clinical covariates confirmed PIK3CA as an independent prognostic marker.The observation of human epidermal growth factor receptor 2 (HER2) as a marker of good prognosis in CLEOPATRA might initially seem to contradict HER2 as an established marker of poor prognosis (ie identifying a high-risk population).But this is explained by the fact that treatment with HER2-targeted therapies overcomes the poor prognosis associated with HER2-positive disease. 4All patients in CLEOPATRA received anti-HER2 therapies 3 and as such it could not be expected that we would find HER2 to be a poor prognostic marker: this could only have been observed in HER2 treatment-naive patients.In summary, we reiterate our conclusion that HER2 is the only marker suited for patient selection for the trastuzumab plus pertuzumab-based regimen in HER2-positive metastatic breast cancer, and that PIK3CA mutation status was the most relevant prognostic factor in CLEOPATRA.
Quantitative Imaging of Musculoskeletal Tissue
Authors: Peter Augat, Felix Eckstein
Journal: Annual Review of Biomedical Engineering (2008)

Quantitative imaging of musculoskeletal tissue, including radiography, computed tomography (CT), and magnetic resonance imaging (MRI), has become the essential methodology in clinical practice for diagnosis and monitoring of various musculoskeletal conditions. Furthermore, quantitative imaging technologies have become indispensable for research and development in diseases of the human skeleton. Standardized methods of image analysis have been developed through the years to quantify measurements on bone and cartilage with high precision and accuracy. Key areas of musculoskeletal disease where quantitative imaging is currently employed are osteoporosis and arthritis.
The interaction in vitro of Pneumocystis carinii with macrophages and L-cells.
Authors: H Masur, T C Jones
Journal: The Journal of Experimental Medicine (1978)

A model was developed for studying the interaction between Pneumocystis, rat-derived cells, and humoral factors. Pneumocystis were obtained in large quantity by bronchial lavage of steroid-treated rats. The trophozoite was the predominant form obtained, and it could readily be recognized by phase contrast microscopy. Organisms maintained a typical morphology for at least 3 days in culture, and 10-20% took up radiolabeled nucleotides. Pneumocystis readily adhered to cell surfaces in a similar manner in alveolar macrophages from steroid-treated or normal rats, mouse peritoneal macrophages, and L-cells. Adherent organisms were not interiorized to a significant degree in the absence of antipneumocystis serum. After addition of rabbit antipneumocystis serum, rapid interiorization of organisms occurred from the surface of macrophages but not L-cells. Organisms appeared to be promptly destroyed within macrophages after interiorization. Persisting or multiplying intracellular forms were not seen. Antipneumocystis serum did not morphologically alter Pneumocystis. These observations suggest a role for antibody and mononuclear phagocytes during the immune response to Pneumocystis.
Adverse Effects of Chronic Endogenous Sympathetic Drive Induced by Cardiac G <sub>sα</sub> Overexpression
Authors: Mitsunori Iwase, Sanford P. Bishop, Masami Uechi, Dorothy E. Vatner, Richard P. Shannon, Raymond K. Kudej, David C. Wight, Thomas E. Wagner, Yoshihiro Ishikawa, Charles J. Homcy, Stephen F. Vatner
Journal: Circulation Research (1996)

Abstract To study the physiological effect of the overexpression of myocardial G sα (protein levels increased by approximately threefold in transgenic mice), we examined the responsiveness to sympathomimetic amines by echocardiography (9 MHz) in five transgenic mice and five control mice (both 10.3±0.2 months old). Myocardial contractility in transgenic mice, as assessed by left ventricular (LV) fractional shortening (LVFS) and LV ejection fraction (LVEF), was not different from that of control mice at baseline (LVFS, 40±3% versus 36±2%; LVEF, 78±3% versus 74±3%). LVFS and LVEF values in transgenic mice during isoproterenol (ISO, 0.02 μg/kg per minute) infusion were higher than the values in control mice (LVFS, 68±4% versus 48±3%; LVEF, 96±1% versus 86±3%; P &lt;.05). Norepinephrine (NE, 0.2 μg/kg per minute) infusion also increased LVFS and LVEF in transgenic mice more than in control mice (LVFS, 59±4% versus 47±3%; LVEF, 93±2% versus 85±3%; P &lt;.05). Heart rates of transgenic mice were higher than those of control mice during ISO and NE infusion. In three transgenic mice with heart rates held constant, LV dP/dt rose by 33±2% with ISO (0.02 μg/kg per minute) and by only 13±2% in three wild-type control mice ( P &lt;.01). NE (0.1 μg/kg per minute) also induced a greater effect on LV dP/dt in the three transgenic mice with heart rates held constant compared with three wild-type control mice (65±8% versus 28±4%, P &lt;.05). Pathological and histological analyses of older transgenic mouse hearts (16.0±0.8 months old) revealed hypertrophy, degeneration, atrophy of cells, and replacement fibrosis reflected by significant increases in collagen volume in the subendocardium (5.2±1.4% versus 1.2±0.3%, P &lt;.05) and in the cross-sectional area of myocytes (298±29 versus 187±12 μm 2 , P &lt;.05) compared with control mouse hearts. These results suggest that G sα overexpression enhances the efficacy of the β-adrenergic receptor–G s –adenylyl cyclase signaling pathway. This in turn leads to augmented inotropic and chronotropic responses to endogenous sympathetic stimulation. This action over the life of the animal results in myocardial damage characterized by cellular degeneration, necrosis, and replacement fibrosis, with the remaining cells undergoing compensatory hypertrophy. As a model, this transgenic mouse offers new insights into the mechanisms of cardiomyopathy and heart failure and provides a new tool for their study.
Genomewide characterization of non-polyadenylated RNAs
Authors: Li Yang, Michael O Duff, Brenton R Graveley, Gordon G Carmichael, Ling-Ling Chen
Journal: Genome biology (2011)

Abstract Background RNAs can be physically classified into poly(A)+ or poly(A)- transcripts according to the presence or absence of a poly(A) tail at their 3' ends. Current deep sequencing approaches largely depend on the enrichment of transcripts with a poly(A) tail, and therefore offer little insight into the nature and expression of transcripts that lack poly(A) tails. Results We have used deep sequencing to explore the repertoire of both poly(A)+ and poly(A)- RNAs from HeLa cells and H9 human embryonic stem cells (hESCs). Using stringent criteria, we found that while the majority of transcripts are poly(A)+, a significant portion of transcripts are either poly(A)- or bimorphic, being found in both the poly(A)+ and poly(A)- populations. Further analyses revealed that many mRNAs may not contain classical long poly(A) tails and such messages are overrepresented in specific functional categories. In addition, we surprisingly found that a few excised introns accumulate in cells and thus constitute a new class of non-polyadenylated long non-coding RNAs. Finally, we have identified a specific subset of poly(A)- histone mRNAs, including two histone H1 variants, that are expressed in undifferentiated hESCs and are rapidly diminished upon differentiation; further, these same histone genes are induced upon reprogramming of fibroblasts to induced pluripotent stem cells. Conclusions We offer a rich source of data that allows a deeper exploration of the poly(A)- landscape of the eukaryotic transcriptome. The approach we present here also applies to the analysis of the poly(A)- transcriptomes of other organisms.