tbuckley/cabot-search huggingface dataset:
Ethics and research governance in a multicentre study: add 150 days to your study protocol
Authors: Glyn Elwyn, Anne Seagrove, Kym Thorne, Wai Yee Cheung
Journal: BMJ (2005)

Synthetic immune response modifiers (IRM) such as imidazoquinolines can selectively activate human TLR7 or TLR8. Although these endosomal TLRs are close relatives, TLR7-deficient mice are unresponsive to TLR8 agonist IRMs. Similarly, natural ssRNA cannot activate murine TLR8, leading to the belief that murine TLR8 is nonfunctional. In this study, we transfected HEK293 cells with murine TLR8 and NF-κB reporter constructs and stimulated them with combinations of IRM and oligodeoxynucleotides (ODNs). When stimulated with TLR7 or TLR8 agonists alone, no NF-κB response was observed. However, a combination of polyT ODN plus the TLR8 agonist activated NF-κB, whereas polyT ODN plus the TLR7 agonist did not activate. Primary mouse cells responded to the IRM/polyT ODN by secreting TNF. Cells from TLR7<sup>−/−</sup> and TLR9<sup>−/−</sup> mice responded to the IRM/polyT ODN combination, whereas MyD88<sup>−/−</sup> cells did not respond. In conclusion, this study demonstrates for the first time that mouse TLR8 is functional.
Relationship of Pericardial to Pleural Pressure During Quiet Respiration and Cardiac Tamponade
Authors: BEVERLY C. MORGAN, WARREN G. GUNTHEROTH, DAVID H. DILLARD, Donald G. Breazeale, George A. McGough
Journal: Circulation Research (1965)

Pericardial pressure was studied in chronic experiments on dogs with relation to intrathoracic pressure in the normal state and in cardiac tamponade. In the normal resting animal, the two pressures were in good agreement throughout the respiratory cycle. The cardiac cycle produced superimposed pressure fluctuations amounting to 30% of the respiratory swings. Adding saline to the pericardial sac produced sigmoid pressure-volume curves; tamponade required 100 to 330 ml of fluid. Although during tamponade the pericardial pressure greatly exceeded the intrathoracic pressure, the pericardial pressure invariably fell with inspiration, generally by the same amount as the intrathoracic pressure. The cardiac cycle produced greater pressure fluctuations (50% of the respiratory pressure fluctuations). The superior vena caval pressure always fell with inspiration in the normal state and during tamponade. Hypovolemia did not change the resting pericardial pressure, but decreased the slope of the pressure-volume curve measured during cardiac tamponade. Hypervolemia increased the resting pericardial pressure considerably, and increased the slope of the pericardial pressure-volume curve. The results suggest that pleural pressure is a reasonable approximation of the pericardial pressure in normal dogs. There appears to be no substantial evidence that pulsus paradoxus is due to failure of the pericardial sac to transmit inspiratory reductions of pleural pressure.
The Activities of Current Antimalarial Drugs on the Life Cycle Stages of Plasmodium: A Comparative Study with Human and Rodent Parasites
Authors: Michael Delves, David Plouffe, Christian Scheurer, Stephan Meister, Sergio Wittlin, Elizabeth A. Winzeler, Robert E. Sinden, Didier Leroy
Journal: PLoS Medicine (2012)

Michael Delves and colleagues compare the activity of 50 current and experimental antimalarials against liver, sexual blood, and mosquito stages of selected human and nonhuman parasite species, including Plasmodium falciparum, Plasmodium berghei, and Plasmodium yoelii.
Statins Prevent Oxidized LDL-Induced Injury of Glomerular Podocytes by Activating the Phosphatidylinositol 3-Kinase/AKT-Signaling Pathway
Authors: Benedetta Bussolati, Maria Chiara Deregibus, Valentina Fonsato, Sophie Doublier, Tiziana Spatola, Simone Procida, Francesco Di Carlo, Giovanni Camussi
Journal: Journal of the American Society of Nephrology (2005)

The injury of podocytes is associated with alterations of the glomerular size-selective barrier to proteins. In this study, oxidized LDL (oxLDL) but not native LDL induced apoptosis in human cultured podocytes and reduced Akt activity and P-Akt/Akt ratio. Moreover, oxLDL-induced redistribution and loss of nephrin, an adhesion molecule specific for the glomerular slit diaphragm. Nephrin reduction was preceded by inhibition of nephrin tyrosine phosphorylation and of its association with p85 phosphatidylinositol 3-kinase (PI3K). Moreover, three different statins, mevastatin, pravastatin, and simvastatin, inhibited in a dose-dependent manner apoptosis and loss of nephrin induced by oxLDL by stimulating Akt activity. In addition, simvastatin significantly increased the expression of nephrin protein and mRNA by podocytes. The protective effects of statins were blocked by treatment of podocytes with two unrelated pharmacologic inhibitors of PI3K, LY294002 and wortmannin, suggesting a role for PI3K, and by mevalonate, indicating dependency on HMG-CoA reductase activity. Statins directly stimulated Akt phosphorylation ad activity. Finally, oxLDL induced a retraction of cultured podocytes and an increase in the albumin diffusion across their monolayer that was inhibited by treatment with statins. In conclusion, statins reduced the oxLDL-induced apoptosis and loss of nephrin in glomerular podocytes. The statin-induced Akt activation may protect from the loss of nephrin by an inhibition of its redistribution and shedding and by a stimulation of its synthesis. These data provide a rationale for the anti-proteinuric effect of statins.
Topically applied lactic acid increases spontaneous secretion of vascular endothelial growth factor by human reconstructed epidermis
Authors: M. Rendl, C. Mayer, W. Weninger, E. Tschachler
Journal: British Journal of Dermatology (2001)

Alpha-hydroxy acids (AHAs) are widely used for the treatment of hyperkeratotic skin disorders and photodamaged skin.To investigate the effect of lactic acid (LA) on the secretion of cytokines by keratinocytes (KCs) of human reconstructed epidermis.Creams containing 1.5%, 3% or 5% LA or vehicle controls were topically applied on to human epidermal equivalents (EEs). After 24 h, EEs were analysed for morphology and for the presence of apoptotic cells. Secretion of vascular endothelial growth factor (VEGF), angiogenin (ANG) and interleukin (IL)-8 was measured in the supernatants by enzyme-linked immunosorbent assay.LA led to a concentration-dependent increase in apoptotic cells as determined by cell morphology and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling. VEGF secretion was increased 2.5- and 2.8-fold (P < 0.05) over vehicle control after treatment with 1.5% and 3% LA, respectively. No significant increase in VEGF secretion was detected with 5% LA. In contrast to VEGF, secretion of ANG was decreased by LA in a concentration-dependent manner (0.5-fold for 5% LA; P < 0.01). No significant changes in IL-8 secretion were found with any of the concentrations tested.Our data demonstrate that the topical application of AHAs modulates the secretion of cytokines by KCs. Regulation of KC-derived growth factors and cytokines by AHAs might represent a mechanism contributing to their therapeutic effects in disorders such as photoageing.
Optimal asthma control, starting with high doses of inhaled budesonide
Authors: H.K. Reddel, C.R Jenkins, G.B Marks, S.I Ware, W Xuan, C.M Salome, C-A Badcock, A.J Woolcock
Journal: European Respiratory Journal (2000)

We recently reported that activation of the highly efficient phospholipase C (PLC) stimulatory m3 muscarinic acetylcholine receptor (mAChR) can induce a long-lasting G<sub>i</sub>-mediated heterologous potentiation of PLC stimulation in human embryonic kidney (HEK) 293 cells, which was accompanied by an increased cellular level of the PLC substrate phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P<sub>2</sub>]. Here, we examined whether such a potentiated PLC response is also induced by the rather poorly PLC stimulatory m2 mAChR and the endogenously expressed purinergic and lysophosphatidic acid receptors. Pretreatment of m2 mAChR-expressing HEK 293 cells for 2 min with carbachol, followed by agonist washout and measurement of PLC activity ≥40 min later, caused a long-lasting (up to ∼90 min) heterologous potentiation of receptor- and G protein-mediated PLC stimulation. A similar heterologous potentiation of receptor-mediated PLC stimulation was induced by short term activation of lysophosphatidic acid and purinergic receptors. Either of the three receptor agonists increased the cellular level of PtdIns(4,5)P<sub>2</sub> by ∼50%. The mAChR-induced PLC potentiation was fully prevented by either pertussis toxin or the protein kinase C (PKC) inhibitors staurosporine and Gö 6976, which did not affect acute PLC stimulation. On the other hand, the rise in PtdIns(4,5)P<sub>2</sub> was prevented only by combined treatment of HEK 293 cells with pertussis toxin and PKC inhibitors. In conclusion, we demonstrated that activation of poorly PLC stimulatory receptors can also induce a long-lasting G<sub>i</sub>-mediated heterologous potentiation of PLC signaling in HEK 293 cells and that this novel PLC regulatory process is under the control of PKC.
Mina53 as a Potential Prognostic Factor for Esophageal Squamous Cell Carcinoma
Authors: Makoto Tsuneoka, Hiromasa Fujita, Nobuyuki Arima, Kwesi Teye, Torahiko Okamura, Hiroki Inutsuka, Yoshiro Koda, Kazuo Shirouzu, Hiroshi Kimura
Journal: Clinical Cancer Research (2004)

Abstract Purpose: We previously identified mina53, a novel Myc target gene. Here we investigated whether mina53 is related to esophageal squamous cell carcinoma (ESCC), a disease with poor prognosis. Experimental Design: Mina53 expression was suppressed in ESCC cell lines by a RNA interference method to investigate whether Mina53 is involved in cell proliferation. Expression of Mina53 was investigated by Western blotting in tissue sections from patients with ESCC. Immunohistochemical analysis of Mina53 was carried out and compared with that using anti–Ki-67 antibody. Finally, the level of Mina53 expression was compared with the length of survival of patients with ESCC. Results: Reduction of mina53 expression by RNA interference suppressed cell proliferation in ESCC cell lines. Western blot analysis of surgically resected ESCC specimens indicated that the expression of Mina53 in tumors was increased compared with that in adjacent nonneoplastic tissues in all four specimens examined. When formalin-fixed specimens from 52 patients with ESCC were stained immunohistochemically, it was found that Mina53 was highly expressed in 83% of specimens. Anti-Mina53 antibody stained tumors more efficiently than antibody against Ki-67, a cell proliferation biomarker, in some cancer specimens. Patients with high expression of Mina53 had shorter survival periods, whereas the expression level of Ki-67 in ESCC showed no relationship to patient outcome. Conclusions: Taken together, our results indicate that expression of Mina53 is a characteristic feature of ESCC and suggest that immunostaining by anti-Mina53 antibody may be useful as a potential prognostic indicator.
The selective cyclooxygenase-2 inhibitor rofecoxib may improve the treatment of chronic idiopathic urticaria
Authors: W-H. Boehncke, R. J.Ludwig, T. M.Zollner, F. Ochsendorf, R. Kaufmann, B. F.Gibbs
Journal: British Journal of Dermatology (2003)

Sir, Chronic idiopathic urticaria (CIU) is one of the most common skin diseases, affecting about 3% of the Western population. Although the symptoms of CIU are primarily due to mast cell degranulation and subsequent histamine release, treatment with H1 antihistamines is often insufficient. One explanation for this is that the actions of other mast cell mediator types have been overlooked, such as prostaglandins and thromboxanes, which display inflammatory properties similar to those of histamine. Prostaglandins and thromboxanes are formed from arachidonic acid by the actions of the enzymes cyclooxygenases (COXs), of which there are two isoforms, with the inducible COX‐2 being responsible for pseudoallergic and other inflammatory responses. Reasoning that COX‐2 might therefore be a relevant target in the treatment of urticaria we investigated the clinical efficacy of a combination therapy comprising the H1 antihistamine desloratadine and the selective COX‐2 inhibitor rofecoxib. Ten caucasian patients with CIU, in whom conventional therapy with H1 antihistamines did not resolve the symptoms, chose to undergo this experimental treatment. The diagnosis was based on the patients' history and extensive laboratory investigations to exclude underlying causes. Disease severity was assessed using a scoring system based on weal formation and pruritus according to a recent consensus publication.1 A patient was considered ‘clinically improved’ if their score (on a 0–6 scale) declined by a value of at least 2. The patients were initially treated with the H1 antihistamine desloratadine 2 × 5 mg daily for 4 weeks, followed by a combination treatment with desloratadine 2 × 5 mg and rofecoxib 25 mg daily for another 4 weeks.
Some Current Problems in Industrial Dermatitis
Authors: F. R. Bettley
Journal: BMJ (1954)

MAXIMUM URINE CONCENTRATIONJoT= 905If the cells at the most distal site of tubular reabsorption of water were partially permeable to urea, then the " effective" osmolarity of the urea in the urine would be less than that measured by freezing-point depression, the differ- ence varying with the urea concentration.-Thus,urines with different urea concentrations might have the same " effective " osmolarity (as regards the tubule cells) but different total osmolarity as measured by freezing-point depression.Selective distal permeability to urea might also permit in- creased water economy without an increase in osmotic work.If this hypothesis is correct it may mean that specific gravity is fortuitously a better indication of "effective" osmolarity than we have shown it to be of total osmolarity, for when the urea concentration is high the specific gravity is relatively low. SummaryThe specific gravities of normal urines have been compared with their osmolarities.Considerable varia- tion of specific gravity may occur in urines of like osmolarity.Dehydration for less than 22 hours gives an unre- liable indication of maximum osmolarity.In some subjects with good renal function 5 units of pitressin tannate in oil produce a urine concentration significantly less than that obtained after dehydration for more than 24 hours.In patients with impaired renal function no difference in concentration is apparent.Unexplained fluctuations in urine osmolarity occur during progressive dehydration.Possible causes are discussed.
Child-Pugh versus MELD score in predicting survival in patients undergoing transjugular intrahepatic portosystemic shunt
Authors: B Angermayr
Journal: Gut (2003)

<b>Background:</b> In patients undergoing transjugular intrahepatic portosystemic shunt (TIPS), prognostic scores may identify those with a poor prognosis or even those with a clear survival benefit. The Child-Pugh score (CPS) is well established but several drawbacks have led to development of the model of end stage liver disease (MELD). <b>Aim:</b> The aim of the study was to compare the predictive power of CPS and MELD, to validate the original MELD formula, and to assess the predictive value of the determinants used in the two prognostic scores outside of a study setting. <b>Patients:</b> A total of 501 patients underwent elective TIPS placement and 475 patients fulfilled the inclusion criteria. <b>Methods:</b> Data of all patients undergoing elective TIPS in one university hospital and four community hospitals in Vienna, Austria, between 1991 and 2001, were analysed retrospectively. The main statistical tests were Cox proportional hazards regression model, the log rank test, Kaplan-Meier analysis, and concordance c statistics. <b>Results:</b> Median follow up was 5.2 years and median survival was 4.6 years. During follow up, 230 patients died, 75 within three months after TIPS placement. In stepwise proportional hazards analyses, independent predictors of death were creatinine level, bilirubin level, age, and refractory ascites. MELD was better in predicting survival in a stepwise Cox model but both scores were equally predictive in c statistics for one month, three month, and one year survival. Renal function was the strongest independent predictor of survival. <b>Conclusions:</b> Although MELD was the primary predictor of overall survival in multivariate analysis, c statistics showed that both scores can be used for patients undergoing TIPS with equal accuracy. For assessing prognosis in patients undergoing TIPS implantation, there seems little reason to replace the well established Child-Pugh score.
Deficient Emotional Self-Regulation and Adult Attention Deficit Hyperactivity Disorder: A Family Risk Analysis
Authors: Craig B.H. Surman, Joseph Biederman, Thomas Spencer, Dayna Yorks, Carolyn A. Miller, Carter R. Petty, Stephen V. Faraone
Journal: American Journal of Psychiatry (2011)

A growing body of research suggests that deficient emotional self-regulation (DESR) is prevalent and morbid among patients with attention deficit hyperactivity disorder (ADHD). Family studies provide a method of clarifying the co-occurrence of clinical features, but no family studies have yet addressed ADHD and DESR.Participants were 83 probands with and without ADHD and 128 siblings. All were assessed for axis I DSM-IV conditions with structured diagnostic interviews. The authors defined DESR in adult probands and siblings using items from the Barkley Current Behavior Scale. Analyses tested hypotheses about the familial relationship between ADHD and DESR.Siblings of ADHD probands were at elevated risk of having ADHD, irrespective of the presence or absence of DESR in the proband. The risk for DESR was elevated in siblings of ADHD plus DESR probands but not in siblings of ADHD probands. ADHD and DESR cosegregated in siblings. The risk for other psychiatric disorders was similar in siblings of the ADHD proband groups.The pattern of inheritance of ADHD with DESR preliminarily suggests that DESR may be a familial subtype of ADHD. Our data suggest that DESR is not an expression of other axis I DSM-IV disorders or of nonfamilial environmental factors. The authors cannot exclude contribution of non-axis-I DSM-IV disorders to risk for DESR and cannot determine whether the cosegregation of ADHD in DESR within families is a result of genes or familial environmental risk factors. Further investigation of DESR and its correlates and treatment both in and outside the context of ADHD is warranted.
Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome
Authors: Alexandra Y. Kreins, Michael J. Ciancanelli, Satoshi Okada, Xiao-Fei Kong, Noé Ramírez-Alejo, Sara Sebnem Kilic, Jamila El Baghdadi, Shigeaki Nonoyama, Seyed Alireza Mahdaviani, Fatima Ailal, Aziz Bousfiha, Davood Mansouri, Elma Nievas, Cindy S. Ma, Geetha Rao, Andrea Bernasconi, Hye Sun Kuehn, Julie Niemela, Jennifer Stoddard, Paul Deveau, Aurelie Cobat, Safa El Azbaoui, Ayoub Sabri, Che Kang Lim, Mikael Sundin, Danielle T. Avery, Rabih Halwani, Audrey V. Grant, Bertrand Boisson, Dusan Bogunovic, Yuval Itan, Marcela Moncada-Velez, Ruben Martinez-Barricarte, Melanie Migaud, Caroline Deswarte, Laia Alsina, Daniel Kotlarz, Christoph Klein, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Valerie Cormier-Daire, Stefan Rose-John, Capucine Picard, Lennart Hammarstrom, Anne Puel, Saleh Al-Muhsen, Laurent Abel, Damien Chaussabel, Sergio D. Rosenzweig, Yoshiyuki Minegishi, Stuart G. Tangye, Jacinta Bustamante, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis
Journal: The Journal of Experimental Medicine (2015)

Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17+ T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
Incidence and risk of hospitalisation due to shingles and chickenpox in patients with rheumatic diseases treated with TNF antagonists
Authors: I. Garcia-Doval, B. Perez-Zafrilla, M. A. Descalzo, R. Rosello, M. V. Hernandez, J. J. Gomez-Reino, L. Carmona
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objective</h3> To estimate the incidence of hospitalisation due to varicella zoster virus (VZV) infection in patients treated with tumour necrosis factor (TNF) antagonists for inflammatory rheumatic conditions and to compare it with the expected rate in the general population. <h3>Methods</h3> Secondary data analysis was performed of two large databases: (1) the national registry of rheumatic diseases patients treated with biological agents (BIOBADASER); and (2) the national hospital discharge database Conjunto Mínimo Básico de Datos al Alta Hospitalaria. Hospitalisations due to shingles or chickenpox were analysed. For each condition the incidence rate (IR) and the age and gender standardised IR per 100 000 person-years plus the standardised incidence ratio (SIR) and the standardised incidence difference (SID) were estimated. <h3>Results</h3> In patients exposed to TNF antagonists, the estimated IR of hospitalisation due to shingles was 32 cases per 100 000 patient-years (95% CI 14 to 78), the expected rate in the general population was 3.4 (95% CI 3.2 to 3.5), the SIR was 9 (95% CI 3 to 20) and the SID was 26 (95% CI 14 to 37). The estimated IR of hospitalisation due to chickenpox was 26 cases per 100 000 (95% CI 10 to 69), the expected rate was 1.9 (95% CI 1.8 to 2.0), the SIR was 19 (95% CI 5 to 47) and the SID 33 (95% CI 21 to 45). <h3>Conclusions</h3> Patients suffering rheumatic diseases exposed to TNF antagonists are hospitalised due to VZV infections significantly more frequently than expected in the general population. Since the absolute IR of hospitalisations due to chickenpox and shingles is low in these patients, the implementation of risky preventive measures may not be justified at present.