tbuckley/cabot-search huggingface dataset:
PML–RARA-RXR Oligomers Mediate Retinoid and Rexinoid/cAMP Cross-Talk in Acute Promyelocytic Leukemia Cell Differentiation
Authors: Dmitrii Kamashev, Dominique Vitoux, Hugues de Thé
Journal: The Journal of Experimental Medicine (2004)

PML–RARA was proposed to initiate acute promyelocytic leukemia (APL) through PML–RARA homodimer–triggered repression. Here, we examined the nature of the PML–RARA protein complex and of its DNA targets in APL cells. Using a selection/amplification approach, we demonstrate that PML–RARA targets consist of two AGGTCA elements in an astonishing variety of orientations and spacings, pointing to highly relaxed structural constrains for DNA binding and identifying a major gain of function of this oncogene. PML–RARA-specific response elements were identified, which all conveyed a major transcriptional response to RA only in APL cells. In these cells, we demonstrate that PML–RARA oligomers are complexed to RXR. Directly probing PML–RARA function in APL cells, we found that the differentiation enhancer cyclic AMP (cAMP) boosted transcriptional activation by RA. cAMP also reversed the normal silencing (subordination) of the transactivating function of RXR when bound to RARA or PML–RARA, demonstrating that the alternate rexinoid/cAMP-triggered APL differentiation pathway also activates PML–RARA targets. Finally, cAMP restored both RA-triggered differentiation and PML–RARA transcriptional activation in mutant RA-resistant APL cells. Collectively, our findings directly demonstrate that APL cell differentiation parallels transcriptional activation through PML–RARA-RXR oligomers and that those are functionally targeted by cAMP, identifying this agent as another oncogene-targeted therapy.
B70/B7-2 is identical to CD86 and is the major functional ligand for CD28 expressed on human dendritic cells.
Authors: C Caux, B Vanbervliet, C Massacrier, M Azuma, K Okumura, L L Lanier, J Banchereau
Journal: The Journal of Experimental Medicine (1994)

Dendritic cells comprise a system of highly efficient antigen-presenting cells involved in the initiation of T cell responses. Herein, we investigated the role of the CD28 pathway during alloreactive T cell proliferation induced by dendritic-Langerhans cells (D-Lc) generated by culturing human cord blood CD34+ progenitor cells with granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha. In addition to expressing CD80 (B7/BB1), a subset of D-Lc expressed B70/B7-2. Binding of the CTLA4-Ig fusion protein was completely inhibited by a combination of monoclonal antibodies (mAbs) against CD80 and B70/B7-2, indicating the absence of expression of a third ligand for CD28/CTLA-4. It is interesting to note that mAbs against CD86 completely prevented the binding of CTLA4-Ig in the presence of mAbs against CD80 and bound to a B70/B7-2-transfected fibroblast cell line, demonstrating that the B70/B7-2 antigen is identical to CD86. CD28 triggering was essential during D-Lc-induced alloreaction as it was inhibited by mAbs against CD28 (9 out of 11 tested). However, none of six anti-CD80 mAbs demonstrated any activity on the D-Lc-induced alloreaction, though some were previously described as inhibitory in assays using CD80-transfected cell lines. In contrast, a mAb against CD86 (IT-2) was found to suppress the D-Lc-dependent alloreaction by 70%. This inhibitory effect was enhanced to > or = 90% when a combination of anti-CD80 and anti-CD86 mAbs was used. The present results demonstrate that D-Lc express, in addition to CD80, the other ligand for CTLA-4, CD86 (B70/B7-2), which plays a primordial role during D-Lc-induced alloreaction.
A loss-of-function p.G191R variant in the anionic trypsinogen (PRSS2) gene in Japanese patients with pancreatic disorders
Authors: K Kume, A Masamune, Y Takagi, K Kikuta, T Watanabe, K Satoh, A Satoh, M Hirota, S Hamada, T Shimosegawa
Journal: Gut (2008)

<h3>Objective:</h3> There is a concept that pancreatitis results from an imbalance of proteases and their inhibitors within the pancreatic parenchyma. It has been recently shown that a loss-of-function variant, c.571G&gt;A (p.G191R), in the anionic trypsinogen (<i>PRSS2</i>) gene protects against chronic pancreatitis in European populations. Here we examined the association of the p.G191R variant with pancreatic disorders in Japan. <h3>Methods:</h3> Genomic DNA was prepared from 378 healthy controls and 604 patients with pancreatic disorders (241 patients with chronic pancreatitis, 174 with acute pancreatitis, and 189 with pancreatic neoplasm). Mutational analysis of the <i>PRSS2</i> gene was performed by polymerase chain reaction–restriction fragment length polymorphism and direct sequencing. <h3>Results:</h3> The heterozygous p.G191R variant was found in three of 241 (1.2%) patients with chronic pancreatitis, in seven of 174 (4.0%) patients with acute pancreatitis, and in 12 of 189 (6.3%) patients with pancreatic neoplasm. The p.G191R variant was found in 25 (two were homozygous and 23 were heterozygous) of 378 (6.6%) healthy controls. The p.G191R frequency in patients with chronic pancreatitis was lower than that in healthy controls (p<i> = </i>0.001; odds ratio (OR) 0.178; 95% confidence interval (CI) = 0.057 to 0.561). The p.G191R frequency was lower in patients with alcoholic (0.9%; p<i> = </i>0.015; OR, 0.132; 95% CI, 0.022 to 0.779) and idiopathic (1.0%; p<i> = </i>0.025; OR, 0.144; 95% CI, 0.025 to 0.851) chronic pancreatitis than that in healthy controls. There were no statistical differences in the p.G191R frequency between healthy controls and patients with acute pancreatitis or with pancreatic neoplasm. Patients with alcoholic acute pancreatitis (n = 59) had no variant carrier, and the p.G191R frequency was lower than that in healthy controls (p<i> = </i>0.035). <h3>Conclusion:</h3> The p.G191R variant protected against alcoholic and idiopathic chronic pancreatitis as well as alcoholic acute pancreatitis in Japan.
Angiotensin II Augments Reflex Activity of the Sympathetic Nervous System During Cardiopulmonary Resuscitation in Pigs
Authors: Karl H. Lindner, Andreas W. Prengel, Ernst G. Pfenninger, Ingrid M. Lindner
Journal: Circulation (1995)

Background During hypotensive states, angiotensin II augments reflex activity of the sympathetic nervous system. The purpose of the present study was to assess the effects of this vasoconstrictor on myocardial blood flow and plasma catecholamine concentrations during and after CPR. Methods and Results After 4 minutes of ventricular fibrillation and 3 minutes of open-chest CPR, 14 pigs (24 to 26 kg) were randomized into two groups receiving either saline (n=7) or 0.05 mg/kg angiotensin II (n=7). Arterial plasma catecholamine concentration was measured with high-pressure liquid chromatography. Organ blood flow was measured with radiolabeled microspheres. During CPR, after drug administration, left ventricular myocardial blood flow was significantly higher in the angiotensin II–treated group than in the control group. During CPR, median epinephrine concentrations before and 90 seconds and 5 minutes after drug administration were 63.0, 35.2, and 22.5 ng/mL, respectively, in the control group and 63.2, 139.8, and 154.2 ng/mL, respectively, in the angiotensin II group ( P &lt;.001 at 90 seconds and P &lt;.01 at 5 minutes). At the same times, median norepinephrine concentrations were 52.6, 59.8, and 33.9 ng/mL, respectively, in the control group and 42.5, 98.7, and 111.3 ng/mL, respectively, in the angiotensin II group ( P &lt;.01 at 5 minutes). Restoration of spontaneous circulation was possible in all of the angiotensin II–treated pigs, whereas only 3 of the 7 saline-treated pigs could be resuscitated. At 5 minutes after successful resuscitation, epinephrine was 6.8 ng/mL in the control group and 16.1 ng/mL in the angiotensin II group ( P &lt;.05). Conclusions During CPR, angiotensin II appears to increase coronary perfusion pressure and myocardial blood flow, not only by direct peripheral arteriolar vasoconstriction via angiotensin II receptors but also by inducing a massive catecholamine release with adrenergic peripheral vasoconstriction.
Flamingos? Nowt like that round here
Authors: Peter Davies
Journal: Journal of the Royal Society of Medicine (2008)

In medicine we are taught that common things are common, as exemplified by the example that canaries are not common in the UK. I enjoyed Hadridge and Pow's article in January (JRSM 2008;101:7–11)1 but I think flamingos will remain rare birds in the UK NHS. The centre at the Department of Health both fears and underestimates doctors. It has no confidence or trust in either doctors' abilities or motivations. Hence it seeks to regulate and control them, thereby stifling medical curiosity. This destroys medical connectedness, and ultimately it is only a residual medical professionalism that keeps compassion to patients in place, and this gets steadily reduced over time. Meanwhile a senior Department of Health adviser asks if doctors and other caregivers are knights or knaves.

Hadridge and Pow talk about tuning into the deep culture of an organization. In the NHS there are three alternative discourses. One is the orthodox management line emphasising ‘clinical engagement’. It is exemplified by glossy newsletters and mission statements that the workers know do not reflect reality, but only the management's distorted version of reality. Another is the formal medical discourse which hardly trusts management and its motives, but expresses itself carefully. The frank expression of the medical view is given on the medical blogs by Dr Crippen (http://nhsblogdoc.blogspot.com/) and Dr Rant (www.drrant.net/) and in the discussion fora at www.doctors.net.uk. The stories that doctors tell of the NHS speak of despair and disconnection. Doctors struggle to make sense of what is happening in their organization, and the suspicion is of hidden government agendas.

The deep diagnosis of the NHS is of an organization divided. There are clear disconnections between good medicine and what the NHS provides, and between what the leadership say and what is actually happening.

I see no flamingos taking flight around here. That large, ungainly, flightless Mauritian bird, the dodo, comes more easily to mind. And for Dutch explorers read United Health Europe, aided and abetted by former journal editors and government advisers.
A microarray screen for novel candidate genes in coeliac disease pathogenesis
Authors: B Diosdado
Journal: Gut (2004)

<b>Background and aims:</b> The causative molecular pathways underlying the pathogenesis of coeliac disease are poorly understood. To unravel novel aspects of disease pathogenesis, we used microarrays to determine changes in gene expression of duodenal biopsies. <b>Methods:</b> cDNA microarrays representing 19 200 genes were used to compare gene expression profiles of duodenal biopsies from 15 coeliac disease patients with villous atrophy (Marsh III) and seven control individuals with normal biopsies (Marsh 0). In addition, the specific effect of gluten was studied by comparing the expression profiles of Marsh III lesions of seven patients exposed to gluten with four patients on a gluten free diet. <b>Results:</b> Comparing Marsh III with Marsh 0 lesions identified 109 genes that differed significantly (p&lt;0.001) in expression levels between patients and controls. A large number of these genes have functions in proliferation and differentiation pathways and might be important for correct development of crypt-villous units. Alterations in these pathways may lead to the characteristic hyperplasia and villous atrophy seen in coeliac disease. The analyses also revealed 120 differentially expressed genes (p&lt;0.005) when comparing patients on a gluten free diet with those exposed to gluten. These genes further strengthen our observation of increased cell proliferation in the presence of gluten. <b>Conclusions:</b> Our study provides new candidate genes in the pathogenesis of coeliac disease. Based on our results, we hypothesise that villous atrophy in coeliac disease patients is due to failure in cell differentiation. These genes are involved in pathways not previously implicated in coeliac disease pathogenesis and they may provide new targets for therapy.
Neuropathy of the Hand
Authors: E. Wayne Massey
Journal: JAMA (1979)

<h3>To the Editor.—</h3> Michael R. Rask, MD, in his article, "Watchband Superficial Radial Neurapraxia" (241:2702, 1979), reminded us of local trauma from a watch to the superficial radial nerve. Stopford<sup>1</sup>reported neuropathy of the dorsal cutaneous branch of the ulnar nerve from a "wristlet watch," and a similar case involving the superficial branch of the radial nerve was reported by Matzdorff<sup>2</sup>in 1926. In 1932, Wartenberg<sup>3</sup>described other cases and called it cheiralgia paresthetica (hand pain), owing to its similarity to meralgia paresthetica (thigh pain), but many have referred to this isolated neuropathy as Wartenberg's syndrome.<sup>4</sup> Paresthesia, annoying numbness, and a Tinel's sign, such as in Rask's case, are usual and in most cases resolve spontaneously. Other wrist trauma resulting in cheiralgia paresthetica includes that caused by handcuffs, which we have seen several times.
False-positive results with a commercially available West Nile virus immunoglobulin M assay - United States, 2008.
Authors: D. F. Neitzel, M. M. Kemperman, S. Semple, S. Wong, J. Hallisey, M. A. Feist, T. K. Miller, W. M. Chung, S. Hojvat, P. Summers, R. S. Lanciotti, A. J. Panella, J. Laven, O. Kosoy, J. A. Lehman, R. S. Nasci, M. Fischer, J. E. Staples, E. Zielinski-Gutierrez, K. B. Janusz
Journal: MMWR Morbidity and Mortality Weekly Report (2009)
Bichat guidelines for the clinical management of Q fever and bioterrorism-related Q fever
Authors: P Bossi, A Tegnell, A Baka, F van Loock, A Werner, J Hendriks, H Maidhof, G Gouvras
Journal: Eurosurveillance (2004)

Q fever is a zoonotic disease caused by Coxiella burnetii. Its interest as a potential biological weapon stems from the fact that an aerosol of very few organisms could infect humans. Another route of transmission of C. burnetii could be through adding it to the food supply. Nevertheless, C. burnetii is considered to be one of the less suitable candidate agents for use in a bioterrorist attack; the incubation is long, many infections are inapparent and the mortality is low. In the case of an intentional release of C. burnetii by a terrorist, clinical presentation would be similar to naturally occurring disease. It may be asymptomatic, acute, normally accompanied by pneumonia or hepatitis, or chronic, usually manifested as endocarditis. Most cases of acute Q fever are asymptomatic and resolve spontaneously without specific treatment. Nevertheless, treatment can shorten the duration of illness and decrease the risk of complications such as endocarditis. Post-exposure prophylaxis is recommended after the exposure in the case of a bioterrorist attack.
Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome
Authors: John A. Belperio, Michael P. Keane, Marie D. Burdick, Joseph P. Lynch, Ying Ying Xue, Aaron Berlin, David J. Ross, Steven L. Kunkel, Israel F. Charo, Robert M. Strieter
Journal: Journal of Clinical Investigation (2001)

Bronchiolitis obliterans syndrome (BOS) is the major limitation to survival after lung transplantation. Acute rejection, its main risk factor, is characterized by perivascular/bronchiolar leukocyte infiltration. BOS is characterized by persistent peribronchiolar leukocyte recruitment leading to airway fibrosis and obliteration. The specific mechanism(s) by which these leukocytes are recruited are unknown. Because MCP-1, acting through its receptor CCR2, is a potent mononuclear cell chemoattractant, we hypothesized that expression of this chemokine during an allogeneic-response promotes persistent recruitment of leukocytes and, ultimately, rejection. We found that elevated levels of biologically active MCP-1 in human bronchial lavage fluid (BALF) were associated with the continuum from acute to chronic allograft rejection. Translational studies in a murine model of BOS demonstrated increased MCP-1 expression paralleling mononuclear cell recruitment and CCR2 expression. Loss of MCP-1/CCR2 signaling, as seen in CCR2–/– mice or in WT mice treated with neutralizing antibodies to MCP-1, significantly reduced recruitment of mononuclear phagocytes following tracheal transplantation and led to attenuation of BOS. Lymphocyte infiltration was not reduced under these conditions. We suggest that MCP-1/CCR2 signaling plays an important role in recruitment of mononuclear phagocytes, a pivotal event in the pathogenesis of BOS.
Safety and immunogenicity of Ebola virus and Marburg virus glycoprotein DNA vaccines assessed separately and concomitantly in healthy Ugandan adults: a phase 1b, randomised, double-blind, placebo-controlled clinical trial
Authors: Hannah Kibuuka, Nina M Berkowitz, Monica Millard, Mary E Enama, Allan Tindikahwa, Arthur B Sekiziyivu, Pamela Costner, Sandra Sitar, Deline Glover, Zonghui Hu, Gyan Joshi, Daphne Stanley, Meghan Kunchai, Leigh Anne Eller, Robert T Bailer, Richard A Koup, Gary J Nabel, John R Mascola, Nancy J Sullivan, Barney S Graham, Mario Roederer, Nelson L Michael, Merlin L Robb, Julie E Ledgerwood
Journal: The Lancet (2014)
Prevalence of primary fibromyalgia in the Finnish population.
Authors: M Makela, M Heliovaara
Journal: BMJ (1991)

To obtain descriptive epidemiological data on fibromyalgia and its components in a representative sample of the Finnish population.Cross sectional study of 8000 Finns aged 30 or more invited for screening and a main examination for musculoskeletal disorders and other major disorders.A mobile clinic.7217 subjects who attended the screening phase; 3434 subjects positive on screening who attended the main examination for musculoskeletal disorders.Musculoskeletal, mental, and other symptoms detected by interview and questionnaire; results of standardised clinical examination of the musculoskeletal system; operational definition of fibromyalgia; mortality at 10 years.The prevalence of fibromyalgia was low (54 cases; 0.75%) and related to age (peak prevalence at 55-64 years), female sex (twice as prevalent in women), occupation (no cases among 1596 white collar professionals), level of education (strong inverse gradient), and high levels of physical stress at work. No significant associations were found with body mass index, smoking, or mental stress at work. The prevalence of fibromyalgia was sensitive to even minor modifications of the definition. Fibromyalgia was strongly coincident with many other disorders, especially musculoskeletal conditions. Fibromyalgia did not predict mortality.Descriptive epidemiological data offer little support for the concept of fibromyalgia.
Hypertriglyceridemic Waist Phenotype Predicts Increased Visceral Fat in Subjects With Type 2 Diabetes
Authors: Susan Sam, Steven Haffner, Michael H. Davidson, Ralph B. D'Agostino, Steven Feinstein, George Kondos, Alfonso Perez, Theodore Mazzone
Journal: Diabetes Care (2009)

OBJECTIVE Greater accumulation of visceral fat is strongly linked to risk of cardiovascular disease. However, elevated waist circumference by itself does not always identify individuals with increased visceral fat. RESEARCH DESIGN AND METHODS We examined 375 subjects with type 2 diabetes from the CHICAGO cohort for presence of hypertriglyceridemic waist phenotype (waist circumference &amp;gt;90 cm in men or &amp;gt;85 cm in women, in conjunction with a plasma triglyceride concentration of ≥177 mg/dl) to determine its usefulness for identifying subjects with increased amounts of visceral fat. We divided subjects into three groups: group 1 (low waist circumference and low triglycerides; waist circumference ≤90 cm in men or ≤85 cm in women and triglyceride &amp;lt;177 mg/dl, n = 18), group 2 (high waist circumference and low triglycerides; waist circumference &amp;gt;90 cm in men or &amp;gt;85 cm in women and triglycerides &amp;lt;177 mg/dl, n = 230), and group 3 (high waist circumference and high triglycerides; waist circumference &amp;gt;90 cm in men or &amp;gt;85 cm in women and triglycerides ≥177 mg/dl, n = 127). RESULTS Subjects in group 3 had significantly higher visceral fat (P &amp;lt; 0.0001), A1C (P &amp;lt; 0.01), and coronary artery calcium (P &amp;lt; 0.05) compared with group 2, despite similar age, BMI, and waist circumference. The relationship of the phenotype to atherosclerosis, however, was attenuated by adjustment for HDL cholesterol, triglyceride-rich lipoprotein cholesterol, apolipoprotein B, or LDL particle number. CONCLUSIONS The presence of hypertriglyceridemic waist phenotype in subjects with type 2 diabetes identifies a subset with greater degree of visceral adiposity. This subset also has greater degree of subclinical atherosclerosis that may be related to the proatherogenic lipoprotein changes.
Excision of Multiple Metastases: Better Designed Studies Are Needed
Authors: Martin Adson
Journal: Hepatology (1990)

Metastatic carcinoma to the liver is generally considered to be associated with a poor prognosis, with five year survival of only 20% to 30% after resection of solitary lesions. Ninety–eight consecutive patients underwent the surgical removal of one to 13 metastatic lesions from the liver. A rising carcinoembryonic antigen level was considered an indication for reexploration. All gross tumor was removed in every patient; 66 had more than one metastasis. Survival was unexpectedly high: 91 of 98 were alive at 12 months, 50 (70%) of 71 at 13 to 24 months, 23 (66%) of 36 at 25 to 36 months, 14 (74%) of 19 at 37 to 48 months, six (60%) of ten at 49 to 60 months, four (80%) of five at 61 to 72 months, and two (50%) of four 73 to 84 months after resection of multiple liver metastases. The procedure appears to be a safe and, in some patients, beneficial surgical technique for the removal of multiple hepatic metastases.
HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages
Authors: James Dressman, Jeanie Kincer, Sergey V. Matveev, Ling Guo, Richard N. Greenberg, Theresa Guerin, David Meade, Xiang-An Li, Weifei Zhu, Annette Uittenbogaard, Melinda E. Wilson, Eric J. Smart
Journal: Journal of Clinical Investigation (2003)

Protease inhibitors decrease the viral load in HIV patients, however the patients develop hypertriglyceridemia, hypercholesterolemia, and atherosclerosis. It has been assumed that protease inhibitor-dependent increases in atherosclerosis are secondary to the dyslipidemia. Incubation of THP-1 cells or human PBMCs with protease inhibitors caused upregulation of CD36 and the accumulation of cholesteryl esters. The use of CD36-blocking antibodies, a CD36 morpholino, and monocytes isolated from CD36 null mice demonstrated that protease inhibitor-induced increases in cholesteryl esters were dependent on CD36 upregulation. These data led to the hypothesis that protease inhibitors induce foam cell formation and consequently atherosclerosis by upregulating CD36 and cholesteryl ester accumulation independent of dyslipidemia. Studies with LDL receptor null mice demonstrated that low doses of protease inhibitors induce an increase in the level of CD36 and cholesteryl ester in peritoneal macrophages and the development of atherosclerosis without altering plasma lipids. Furthermore, the lack of CD36 protected the animals from protease inhibitor-induced atherosclerosis. Finally, ritonavir increased PPAR-gamma and CD36 mRNA levels in a PKC- and PPAR-gamma-dependent manner. We conclude that protease inhibitors contribute to the formation of atherosclerosis by promoting the upregulation of CD36 and the subsequent accumulation of sterol in macrophages.