tbuckley/cabot-search huggingface dataset:
Statin-induced inhibition of the Rho-signaling pathway activates PPARα and induces HDL apoA-I
Authors: Geneviève Martin, Hélène Duez, Christophe Blanquart, Vincent Berezowski, Philippe Poulain, Jean-Charles Fruchart, Jamila Najib-Fruchart, Corine Glineur, Bart Staels
Journal: Journal of Clinical Investigation (2001)

Statins are inhibitors of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In addition to reducing LDL cholesterol, statin treatment increases the levels of the antiatherogenic HDL and its major apolipoprotein apoA-I. Here, we investigated the molecular mechanisms of apoA-I regulation by statins. Treatment with statins increased apoA-I mRNA levels in human HepG2 hepatoma cells, and this effect was reversed by the addition of mevalonate, implicating HMG-CoA reductase as the relevant target of these drugs. Pretreatment with Actinomycin D abolished the increase of apoA-I mRNA, indicating that statins act at the transcriptional level. Indeed, statins increased the human apoA-I promoter activity in transfected cells, and we have identified a statin response element that coincides with a PPARα response element known to confer fibrate responsiveness to this gene. The statin effect could be abolished not only by mevalonate, but also by geranylgeranyl pyrophosphate, whereas inhibition of geranylgeranyl transferase activity or treatment with an inhibitor of the Rho GTP-binding protein family increased PPARα activity. Using dominant negative forms of these proteins, we found that Rho A itself mediates this response. Because cotreatment with statins and fibrates activated PPARα in a synergistic manner, these observations provide a molecular basis for combination treatment with statins and fibrates in coronary heart disease.
Omalizumab: NICE to USE you, to LOSE you NICE
Authors: Andy Bush, Ian D Pavord
Journal: Thorax (2012)

National Institute for Health and Clinical Excellence (NICE) has just published draft recommendations for the use of omalizumab. These are as follows:

1.  Omalizumab is not recommended within its marketing authorisation for treating severe persistent allergic asthma

2.  People currently taking omalizumab should be able to continue treatment until they and their clinician consider it appropriate to stop. For children and adolescents, this decision should be made jointly by the clinician, the child or adolescent, and their parents or carers.



Clearly this blanket recommendation does not merely touch the confines of lunacy, but goes well beyond. Those who try to plough through NICE's obfuscatory documents would empathise with God's question to Job: Who is this that darkens counsel by words without knowledge?

However, it is facile solely to blame NICE for these ridiculous proposals; guilt must also be shared by doctors and the industry. The purpose of this annotation is not just to indulge in mere vulgar abuse of NICE, agreeable though this pastime may be, but to try at the 59th minute of the 11th hour to propose a way of salvaging something from the impending wreck. We propose a way forward which, since it will not please everyone, will in the best traditions of family life, annoy everyone hopefully equally.

It is common ground that (a) most patients with asthma can have their disease controlled with properly administered low to moderate doses of inhaled corticosteroids, sometimes supplemented by an …
Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis
Authors: Evolve Trial Investigators, Chertow Gm, Block Ga, Correa-Rotter R, Drüeke Tb, Floege J, Goodman Wg, Herzog Ca, Kubo Y, London Gm, Mahaffey Kw, Mix Tc, Moe Sm, Trotman Ml, Wheeler Dc, Parfrey Ps
Journal: New England Journal of Medicine (2012)

Disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to extraskeletal (including vascular) calcification among patients with chronic kidney disease. It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients.In this clinical trial, we randomly assigned 3883 patients with moderate-to-severe secondary hyperparathyroidism (median level of intact parathyroid hormone, 693 pg per milliliter [10th to 90th percentile, 363 to 1694]) who were undergoing hemodialysis to receive either cinacalcet or placebo. All patients were eligible to receive conventional therapy, including phosphate binders, vitamin D sterols, or both. The patients were followed for up to 64 months. The primary composite end point was the time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event. The primary analysis was performed on the basis of the intention-to-treat principle.The median duration of study-drug exposure was 21.2 months in the cinacalcet group, versus 17.5 months in the placebo group. The primary composite end point was reached in 938 of 1948 patients (48.2%) in the cinacalcet group and 952 of 1935 patients (49.2%) in the placebo group (relative hazard in the cinacalcet group vs. the placebo group, 0.93; 95% confidence interval, 0.85 to 1.02; P=0.11). Hypocalcemia and gastrointestinal adverse events were significantly more frequent in patients receiving cinacalcet.In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis. (Funded by Amgen; EVOLVE ClinicalTrials.gov number, NCT00345839.).
Macrophage Depletion Combined with Anticoagulant Therapy Increases Therapeutic Window of Systemic Treatment with Oncolytic Adenovirus
Authors: Elena V. Shashkova, Konstantin Doronin, Julien S. Senac, Michael A. Barry
Journal: Cancer Research (2008)

Abstract Liver tropism of systemically delivered adenoviruses (Ad) represents a considerable challenge for their use as anticancer therapeutics. More than 90% of i.v. injected Ad is rapidly taken up by the liver leading to hepatotoxicity, reduced virus uptake by target tumor tissue, and diminished therapeutic efficacy. The lack of clinical activity of systemically given oncolytic Ad demands for better understanding and improvement of virus pharmacokinetics. We studied the effects of Ad “detargeting” from liver macrophages (Kupffer cells) and hepatocytes on toxicity and anticancer efficacy using a nonattenuated oncolytic Ad expressing enhanced green fluorescent protein-firefly luciferase fusion protein (Ad-EGFPLuc). Kupffer cell depletion before i.v. injection of Ad-EGFPLuc increased transgene expression in the liver 40.7-fold on day 3 after the injection indicating compensatory enhancement of hepatocyte transduction due to increased bioavailability of the virus. Pretreatment of mice with the anticoagulant drug warfarin to block blood factor–dependent binding of the virus to hepatocytes markedly reduced luciferase expression in the liver and mediated the corresponding decrease of hepatotoxicity in mice with intact and depleted liver macrophages. Combined depletion of Kupffer cells and pretreatment with warfarin before a single i.v. injection of Ad-EGFPLuc significantly reduced tumor growth and prolonged survival of nude mice bearing subcutaneous xenografts of aggressive human hepatocellular carcinoma. The improved antitumor activity correlated with enhanced transgene expression and virus spread in the tumors. These data suggest that detargeting oncolytic Ad from liver macrophages and hepatocytes is an effective strategy to increase the therapeutic window for therapy against disseminated tumor sites. [Cancer Res 2008;68(14):5896–904]
Prevalence of Anti–RNA Polymerase III Antibodies in Systemic Sclerosis: New Data From a French Cohort and a Systematic Review and Meta‐Analysis
Authors: Vincent Sobanski, Luc Dauchet, Guillaume Lefèvre, Marc Lambert, Sandrine Morell‐Dubois, Thierno Sy, Eric Hachulla, Pierre‐Yves Hatron, David Launay, Sylvain Dubucquoi
Journal: Arthritis & Rheumatology (2013)

Objective Studies assessing the prevalence of anti–RNA polymerase III (anti–RNAP III) antibodies in systemic sclerosis (SSc) have yielded a wide range of results. The aim of the present study was to describe a new SSc cohort tested for presence of anti–RNAP III and perform a systematic review and meta‐analysis to assess the prevalence of anti–RNAP III in patients worldwide and the potential factors of variability. Methods Seropositivity for anti–RNAP III was evaluated in a French cohort of SSc patients. A systematic review of the literature was carried out in PubMed and EMBase. Meta‐analysis was performed using available data on prevalence, clinical characteristics of SSc patients, and the types of assays used for anti–RNAP III testing. Results One hundred thirty‐three French SSc patients were tested for anti–RNAP III, and a prevalence of 6–9% was found in these patients. Thirty studies representing a total population of 8,437 SSc patients were included in the meta‐analysis. Prevalence of anti–RNAP III in this population was highly variable (range 0–41%). The overall pooled prevalence of anti–RNAP III was 11% (95% confidence interval 8–14), but heterogeneity was high among studies (I 2 = 93%, P &lt; 0.0001). Geographic factors such as continent or country of study origin partially explained this heterogeneity and correlated with the prevalence. No other baseline SSc characteristics were significantly correlated with the prevalence of anti–RNAP III. Conclusion Data on our new cohort and our meta‐analysis of the literature confirmed that anti–RNAP III prevalence in SSc varies among centers. Geographic factors were significantly associated with prevalence, which underscores the probable implication that genetic background and environmental factors play a role. Heterogeneity among studies remained largely unexplained.
Childhood smoking is an independent risk factor for obstructive airways disease in women
Authors: B D Patel
Journal: Thorax (2004)

To assess whether starting to smoke in childhood increases the risk of obstructive airways disease (OAD) in adult life.A retrospective cohort analysis was undertaken of 12 504 current and ex-smokers in the EPIC-Norfolk cohort. The main exposure was starting to smoke during childhood (age <16 years). Three definitions of OAD were used: doctor diagnosed asthma, doctor diagnosed bronchitis/emphysema, and "any OAD" (doctor diagnosed asthma or bronchitis/emphysema, or taking medication used in the treatment of OAD).Childhood smokers had significantly more pack years of exposure and poorer lung function than subjects who started to smoke in adulthood (>/=16 years). Compared with starting in adulthood, starting to smoke in childhood was associated with a greater risk of bronchitis/emphysema in female smokers (OR 1.79, 95% CI 1.25 to 2.56) and ex-smokers of both sexes (OR 1.29, 95% CI 1.07 to 1.55 in men and OR 1.40, 95% CI 1.05 to 1.85 in women), and of "any OAD" in female smokers (OR 1.72, 95% CI 1.24 to 2.38) and male and female ex-smokers (OR 1.20, 95% CI 1.03 to 1.40 in men and 1.34, 95% CI 1.07 to 1.57 in women). After adjustment for pack years, childhood smoking was associated with poorer lung function (FEV(1) 92.3% predicted in adult smokers and 89.5% in childhood smokers, p = 0.03) and a greater risk of bronchitis/emphysema (adjusted OR 1.55, 95% CI 1.08 to 2.24) and for "any OAD" (OR 1.54, 95% CI 1.10 to 2.13) in female smokers but not in male and female ex-smokers.Starting to smoke in childhood is associated with an increased risk of airways disease because of the extra pack years smoked. In women, childhood smoking is itself an independent risk factor for the development of airways disease.
Low HLA-C expression at cell surfaces correlates with increased turnover of heavy chain mRNA.
Authors: J A McCutcheon, J Gumperz, K D Smith, C T Lutz, P Parham
Journal: The Journal of Experimental Medicine (1995)

In comparison with HLA-A and -B, the protein products of the HLA-C locus are poorly characterized, in part because of their low level of expression at the cell surface. Here, we examine how protein-protein interactions during assembly and regulation of the mRNA level affect cell surface expression of HLA-C. We find that intrinsic properties of the HLA-C heavy chain proteins do not correlate with low cell surface expression: HLA-C heavy chains associate and dissociate with beta 2-microglobulin (beta 2m) at rates comparable to those found for HLA-A and -B, and increased competition for beta 2m does not alter the surface expression of HLA-C. From studies of chimeric genes spliced from the HLA-B7 and -Cw3 genes, we find that chimeric proteins containing the B7 peptide-binding groove can have low cell surface expression, suggesting that inefficiency in binding peptides is not the cause of low cell surface expression for HLA-C. The surface levels of HLA-A, -B, or -C in cells transfected with cDNA can be similar, implicating noncoding regions of HLA-C heavy chain genes in the regulation of surface expression. We find that HLA-C mRNA is expressed at lower levels than HLA-B mRNA and that this difference results from faster degradation of the HLA-C message. Experiments examining chimeric B7/Cw3 and B7/Cw6 genes suggest that a region determining low expression of HLA-C is to be found between the 3' end of exon 3 and a site in the 3' untranslated region, approximately 600 bases downstream of the translation stop codon.
The Rhizome of the Multidrug-Resistant Enterobacter aerogenes Genome Reveals How New “Killer Bugs” Are Created because of a Sympatric Lifestyle
Authors: Seydina M. Diene, Vicky Merhej, Mireille Henry, Adil El Filali, Véronique Roux, Catherine Robert, Saïd Azza, Frederick Gavory, Valérie Barbe, Bernard La Scola, Didier Raoult, Jean-Marc Rolain
Journal: Molecular Biology and Evolution (2012)

Here, we sequenced the 5,419,609 bp circular genome of an Enterobacter aerogenes clinical isolate that killed a patient and was resistant to almost all current antibiotics (except gentamicin) commonly used to treat Enterobacterial infections, including colistin. Genomic and phylogenetic analyses explain the discrepancies of this bacterium and show that its core genome originates from another genus, Klebsiella. Atypical characteristics of this bacterium (i.e., motility, presence of ornithine decarboxylase, and lack of urease activity) are attributed to genomic mosaicism, by acquisition of additional genes, such as the complete 60,582 bp flagellar assembly operon acquired "en bloc" from the genus Serratia. The genealogic tree of the 162,202 bp multidrug-resistant conjugative plasmid shows that it is a chimera of transposons and integrative conjugative elements from various bacterial origins, resembling a rhizome. Moreover, we demonstrate biologically that a G53S mutation in the pmrA gene results in colistin resistance. E. aerogenes has a large RNA population comprising 8 rRNA operons and 87 cognate tRNAs that have the ability to translate transferred genes that use different codons, as exemplified by the significantly different codon usage between genes from the core genome and the "mobilome." On the basis of our findings, the evolution of this bacterium to become a "killer bug" with new genomic repertoires was from three criteria that are "opportunity, power, and usage" to indicate a sympatric lifestyle: "opportunity" to meet other bacteria and exchange foreign sequences since this bacteria was similar to sympatric bacteria; "power" to integrate these foreign sequences such as the acquisition of several mobile genetic elements (plasmids, integrative conjugative element, prophages, transposons, flagellar assembly system, etc.) found in his genome; and "usage" to have the ability to translate these sequences including those from rare codons to serve as a translator of foreign languages.
The Phosphorus Pills of the British Pharmacop ia
Authors: G. O. Rees
Journal: BMJ (1876)

tion of the life of the Jew is forty-nine years; of the Christian it is only thirty-seven years.Hence it appears that the life prospects of the Jew are nearly twenty-five per cent.more favourable than those of his Christian fellow-townsman.The vitality so characteristic of the de- scendants of Abraham can Fe traced to very simple causes.In their
Effect of Acute Cardiac Tamponade on Red Cell Volume, Total Plasma Protein and Plasma Volume
Authors: REX J. UNDERWOOD, HERBERT E. GRISWOLD, WILLIAM A. HURST
Journal: Circulation Research (1957)

Acute heart failure was produced by cardiac tamponade in unsplenectomized and splencetomized dogs. The results indicate that splenic contraction was entirely responsible for the rise in hematocrit observed following tamponade in the unsplenectomized dogs. A fall in the hematocrit values of the splenectomized dogs and a reduction in total plasma proteins of both groups indicates an increase in plasma volume following tamponade. There was no evidence of sequestration of red cells.
Current Therapy for IgA Nephropathy
Authors: Jürgen Floege, Frank Eitner
Journal: Journal of the American Society of Nephrology (2011)

IgA nephropathy (IgAN) is a very common glomerulonephritis worldwide. In this review, we discuss therapeutic options in four clinical scenarios encountered in patients with IgAN: first is the patient with minor urinary abnormalities where the mainstay of treatment is long-term, regular follow-up to detect renal progression and hypertension. Second is the typical patient presenting with microhematuria, significant but non-nephrotic proteinuria, hypertension, and variable degrees of renal failure. Here the mainstay of treatment is optimized supportive care. If this does not lower proteinuria below 1 g/d, corticosteroid monotherapy may be effective, as long as the GFR is above 50 ml/min. There is insufficient data to advocate the use of other immunosuppressive drugs or even combination therapy in such patients. Third is the atypical patient with overt nephrotic syndrome, or acute or rapidly progressive kidney injury where a possible vasculitic form of IgAN should be sought and, if present, treated with immunosuppression. In other atypical patients with secondary IgAN, treatment should target the underlying primary disease. And fourth is the transplanted patient with recurrent IgAN where the mainstay of treatment is optimized supportive care.
Modulation of Angiogenic Phenotype Alters Tumorigenicity in Rat Ovarian Epithelial Cells
Authors: Jennifer J. Schumacher, Ruud P.M. Dings, Jonathan Cosin, Indira V. Subramanian, Nelly Auersperg, Sundaram Ramakrishnan
Journal: Cancer Research (2007)

Abstract Vascular endothelial growth factor (VEGF) expression correlates with microvessel density, stage, malignant ascites, metastasis, and survival in ovarian cancer. By transducing VEGF165 into a nontumorigenic rat ovarian surface epithelial cell line (ROSE199), we investigated the direct effect of an angiogenic phenotype on tumor development. The neu oncogene, which is overexpressed in &amp;gt;30% of ovarian cancers, was used in comparison. Neu-transfected ROSE199 cells showed phenotypic characteristics of transformation in vitro with an abundance of focus-forming units in monolayer cultures and anchorage-independent growth in soft agar. In contrast, VEGF-secreting ROSE199 cells (VR) retained normal morphology and in vitro growth characteristics (e.g., proliferation rate) compared with parental ROSE199 cells. Interestingly, injection of VR cells into athymic mice formed malignant ascites in 100% of the animals when injected into the peritoneum and developed vascularized tumors in 85% of the mice when injected s.c. Furthermore, blocking VEGF-mediated signaling by the Flk-1/KDR receptor kinase inhibitor SU5416 significantly inhibited the growth of VR tumors. To validate that the proangiogenic switch is responsible for tumor development, the angiogenic phenotype was balanced by the inducible coexpression of endostatin under the control of Tet-activated promoter. Coexpression of endostatin along with VEGF reversed the tumorigenic phenotype of VR cells. These studies show that alterations in the angiogenic characteristics of ovarian surface epithelium may play an important role in the etiology of ovarian cancer, and that inhibition of angiogenesis can be effective in the treatment of epithelial ovarian cancer. [Cancer Res 2007;67(8):3683–90]
Evolutionary diversification of class II P loci in the Mhc of the mole-rat Spalax ehrenbergi.
Authors: R Schöpfer, F Figueroa, D Nizetić, E Nevo, J Klein
Journal: Molecular Biology and Evolution (1987)

The class II region of the major histocompatibility complex (Smh) in the mole rat, Spalax ehrenbergi, consists of only two gene families, P and Q, instead of the four families (P, O, Q, and R) found in all other mammals studied to date. The Spalax P family consists of at least four beta and three alpha genes or gene fragments. In DNA-hybridization experiments, two of the beta genes behave as bona fide P-family members in that they hybridize strongly with human DP beta probes and hybridize weakly with probes specific for other class II gene families. The other two beta genes, on the other hand, hybridize weakly with human DP beta probes and nearly as well with human DQ beta probes. To determine the evolutionary relationships among these P-like genes, we have sequenced one of them. The sequence reveals, on the basis of its organization, that the gene clearly belongs to the P family, yet, on the basis of its nucleotide sequence, it is only slightly more similar to human DP than to human DQ genes. These results indicate that in the Spalax the P family of genes split into two subfamilies, PA and PB. For unknown reasons, one of these subfamilies (PB) retained more similarity to the Q gene family than did the other (PA).
Free immunoglobulin light chains in connective tissue diseases.
Authors: A Cooper, R Bluestone
Journal: Annals of the Rheumatic Diseases (1968)

The basic immunoglobulin subunit consists of two heavy and two light chains held together by covalent disulphide bonds.In most cases of myeloma and Waldenstrom's disease there is an excess synthesis of light over heavy chains, resulting in Bence Jones proteinaemia and proteinuria.Furthermore, in some cases ("light chain disease"), there is absence test.The quantitation was performed by the radial immunodiffusion technique (Mancini, Carbonara, and Heremans, 1965), incorporating the antisera into agar 537 copyright.
Coronary Disease in Type 1 Diabetes
Authors: Burton E. Sobel
Journal: Diabetes Care (2003)

Orchard et al. (1), in this issue of Diabetes Care , have provided valuable insights and illuminated pathophysiologic mechanisms underlying coronary artery disease associated with type 1 diabetes. All 603 patients studied were initially free from clinically overt coronary artery disease. Somewhat surprisingly, however, elevations of concentrations of HbA1c in blood were not descriptors of subsequent coronary events. The authors concluded that “greater glycemia does not seem to predict future coronary events.” Thus, although glycemic control may not be the key to reduction of coronary risk, favorable modification of a key factor that was identified, i.e., insulin resistance, may.

Hyperglycemia is, of course, not only the hallmark of type 1 and type 2 diabetes but also its defining feature. Glycemic control is imperative to prevent or retard microvascular complications associated with both types of diabetes. Subjects with either type 1 or type 2 diabetes exhibit increased concentrations of fibrinopeptide A in blood and urine, reflecting thrombin activity in vivo, indicative of activation of the coagulation system, compared with concentrations in nondiabetic subjects. Their platelets exhibit increased reactivity. Decreased platelet membrane fluidity, potentially reflecting increased glycation of platelet membrane proteins, may contribute (2). Endothelial cell function in vitro and in vivo is affected adversely. Advanced glycation end products (AGEs) in vessel walls may impair vasodilatory capacity. Such factors may contribute to the increased cardiovascular risk incurred by those with type 1 diabetes. Yet, as Paul Harvey would say, we must …