tbuckley/cabot-search huggingface dataset:
Allergic sensitization is associated with inadequate antioxidant responses in mice and men
Authors: L. Utsch, C. Folisi, J. H. Akkerdaas, A. Logiantara, M. A. van de Pol, J. S. van der Zee, E. J. M. Krop, R. Lutter, R. van Ree, L. S. van Rijt
Journal: Allergy (2015)

Allergies arise from aberrant Th2 responses to allergens. The processes involved in the genesis of allergic sensitization remain elusive. Some allergens such as derived from house dust mites have proteolytic activity which can induce oxidative stress in vivo. A reduced capacity of the host to control oxidative stress might prime for allergic sensitization.Two different strains of mice were compared for their antioxidant and immune response to HDM. Protease activity of the HDM extract was reduced to investigate its role in oxidative stress induction in the airways and whether this induction could determine allergic sensitization and inflammation. The role of oxidative stress in allergic sensitization was also investigated in humans. An occupational cohort of animal workers was followed for the development of sensitization to rodent urinary proteins. Levels of oxidative stress in serum and antioxidant responses by PBMCs were determined.Susceptibility to allergic sensitization to mite allergens in mice was highly dependent on host genetic background and was associated with oxidative stress in the lungs before allergen exposure and poor antioxidant response after allergen exposure. Reduction in mite protease activity limited its capacity to induce oxidative stress and allergic inflammation in mice. We showed that also in human subjects, oxidative stress before allergen exposure and poor antioxidant responses were associated with predisposition to occupational allergy.Our study indicates that oxidative stress condition before allergen exposure due to an inadequate antioxidant response may prime for allergic Th2 responses.
Abstract 3479: The cellular thermal shift assay as a tool for setting indivual treatment schemes
Authors: Daniel M. Molina, Pär Nordlund
Journal: Cancer Research (2014)

Abstract Many cancers respond insufficiently to existing therapies and acquired drug resistance often develops. To address this challenge, a range of different therapeutic strategies is currently in development. Many of these are based on the concept of targeted therapies, where target proteins are drivers of cancer processes or synthetic vulnerabilities of cancer cells. In this project we have used the newly developed CETSA method to monitor levels of drug binding to specific target proteins in tumors and primary cells from breast cancer patients. CETSA is a generic method for evaluating drug binding to target proteins in cells and tissues. The technique is based on the physical phenomenon of ligand-induced thermal stabilization of target proteins. Using this technique, it is possible to look at interactions between a drug and protein of interest without having to label them. Previously, we have validated drug binding in mammalian cancer cell lines for a set of important clinical targets and shown that a range of critical factors that are important for drug development can be identified at the target engagement level, including drug transport and activation, off-target effects, drug resistance as well as drug distribution in animal tissues. By using different drugs and amounts we now have preliminary data suggesting that CETSA could be used as a tool for optimizing treatment schemes for individual care and for detecting resistance development at an early stage. Citation Format: Daniel M. Molina, Pär Nordlund. The cellular thermal shift assay as a tool for setting indivual treatment schemes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3479. doi:10.1158/1538-7445.AM2014-3479
A difficult case of dermatitis artefacta requiring surgical intervention
Authors: R.T. Woolf, A.P. Bewley, R.E. Taylor, A. D’Souza, S.R. Hoque
Journal: British Journal of Dermatology (2012)

Funding sources: none. Conflicts of interest: none declared. Madam, Dermatitis artefacta (DA, also called dermatitis factitia) refers to skin lesions produced in secret by the patient to satisfy an internal psychological need, usually a need to be taken care of.1 DA is often difficult to diagnose and treatment requires an empathic, multidisciplinary approach. A 44‐year‐old woman was referred to our care in 2010 with a 3‐year history of recurrent lesions affecting the face and neck, which had initially improved with oral antibiotics. At presentation she was tearful, describing a painful scalp wound. She did not recall how the lesions had developed, except that they started around the time of the death of her nephew. She admitted to feeling depressed and acknowledged that her condition was worsened by stress. She had no other comorbidities and was taking doxycycline, temazepam and ibuprofen (up to 4000 mg per 24 h) for pain. Examination revealed a deep midline ulcer on the forehead, exposing bone, and multiple atrophic irregular scars on the face and neck. Blood tests demonstrated marked iron‐deficiency anaemia (haemoglobin 7·6 g dL−1, mean corpuscular volume 71·2 fL, ferritin 3 μg L−1) attributed to chronic gastritis due to excessive self‐medication of ibuprofen. DA was considered. A skin biopsy from a right cheek ulcer, taken at another centre, was reviewed. This demonstrated well‐demarcated ulceration with dermal fibrosis, vascular proliferation and a chronic dermal inflammatory infiltrate with foreign body giant cells around birefringent material. This was felt to be consistent with DA.
The Encyclopedia of Stress
Authors: Judy Siegel-Itzkovich
Journal: BMJ (2001)

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Ed George Fink 

Academic Press, £370, pp 1900

ISBN 0 12 226735 4

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Only on some small desert island could man find himself liberated from stress. On second thoughts, perhaps 21st century man could not escape from it even there.

Stress has profound effects on people's physical and mental health and on society's medical care, workplace productivity, educational institutions, …

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Abstract 18342: Inducible Cardiomyocyte-Specific Deletion of Stromal Interaction Molecules Results in Cardiomyopathy in Mice
Authors: Saravanakumar Murugesan, Ryan D Sullivan, Salvatore Mancarella
Journal: Circulation (2014)

Background: Stromal interaction molecules (STIM1 and STIM2) are sarco/endoplasmic calcium sensors ubiquitously expressed in mammalian cells. Upon Ca2+ store discharge STIM proteins oligomerize in proximity of the plasma membrane to activate the Ca2+ selective channels (Orai) and trigger Ca2+ entry. While this mechanism is widely accepted to be the main source of calcium in non-excitable cells, in cardiomyocytes the calcium-induced calcium-release is the major controller of myocardial function, and the presence of STIM in these cells appears somewhat puzzling. Here we investigated the role of STIM in cardiomyocytes and its role in regulating cardiac contractility and intracellular Ca2+ dynamics. Methods: We have generated an inducible cardiac-specific STIM1 knockout (STIM KO) mouse model to elucidate the role of STIM in the myocardium. Echocardiography was used to evaluate structure and function of the left ventricle. Heart rate was monitored continuously in conscious mice by telemetry. Cell dimensions, shortening, and relaxation were determined by videomicroscopy and calcium transients by fura 2. Results: Echocardiographic analyses revealed development of dilated cardiomyopathy with a significant reduction of left ventricular fractional shortening (39.91±4.05% vs. 22.41±7.92%, p&lt;0.01). Histological and morphological analyses confirmed a dilated cardiomyopathy characterized by enlarged ventricular chambers. Electrocardiography showed higher heart rate in the STIM1 KO mice with no differences in P-wave duration and QRS interval while Q-T interval was reduced in the STIM1 KO mice as compared to the WT mice. Sarcomere length and cell shortening measurements in freshly isolated cardiomyocytes from STIM1 KO mice confirmed the reduced contractility associated with a reduction of time to 50% relaxation (283±13ms vs. 258±8ms, p&lt;0.05) . Intracellular calcium transient analysis in STIM1 KO cardiomyocytes showed a higher peak amplitude and a time to 50% decay of calcium significantly accelerated. Conclusions: Our data demonstrate that STIM proteins play an important role in the maintaining normal cardiac function in the adult heart and reveal that STIM plays an important role during cardiac repolarization.
Early intervention in psychosis: concepts, evidence and future directions
Authors: PATRICK D. MCGORRY, EÓIN KILLACKEY, ALISON YUNG
Journal: World Psychiatry (2008)

The rise of the early intervention paradigm in psychotic disorders represents a maturing of the therapeutic approach in psychiatry, as it embraces practical preventive strategies which are firmly established in mainstream health care. Early intervention means better access and systematic early delivery of existing and incremental improvements in knowledge rather than necessarily requiring dramatic and elusive breakthroughs. A clinical staging model has proven useful and may have wider utility in psychiatry. The earliest clinical stages of psychotic disorder are non-specific and multidimensional and overlap phenotypically with the initial stages of other disorders. This implies that treatment should proceed in a stepwise fashion depending upon safety, response and progression. Withholding treatment until severe and less reversible symptomatic and functional impairment have become entrenched represents a failure of care. While early intervention in psychosis has developed strongly in recent years, many countries have made no progress at all, and others have achieved only sparse coverage. The reform process has been substantially evidence-based, arguably more so than other system reforms in mental health. However, while evidence is necessary, it is insufficient. It is also a by-product as well as a catalyst of reform. In early psychosis, we have also seen the evidence-based paradigm misused to frustrate overdue reform. Mental disorders are the chronic diseases of the young, with their onset and maximum impact in late adolescence and early adult life. A broader focus for early intervention would solve many of the second order issues raised by the early psychosis reform process, such as diagnostic uncertainty despite a clear-cut need for care, stigma and engagement, and should be more effective in mobilizing community support. Early intervention represents a vital and challenging project for early adopters in global psychiatry to consider.
996. Application of a Novel Human Artificial Chromosome (HAC) Vector to Gene Therapy Aimed at Erythropoietin (EPO) Replacement
Authors: Minoru Kakeda, Masaharu Hiratsuka, Keiko Nagata, Masayo Takahashi, Fumiaki Ayabe, Motonobu Katoh, Mitsuo Oshimura, Kazuma Tomizuka
Journal: Molecular Therapy (2004)

In the conventional virus and non-viral vectors for gene therapy, it comes up with crucial issues to be solved; 1) The introduced vector might develop lesions on the host chromosome and the fears for safety such as the malignant transformation are mentioned, 2) The copy number of the introduced gene is not regulated, 3) Sufficient expression in the host cell is not sustained for long term, 4) The introduced gene is inactivated or suffers the effects of controlled sequence on the host chromosome.
Abstract 964: Inhibiting glycolysis with an LDHA inhibitor: A new solution to an old problem
Authors: Thomas O'Brien, Hans Purkey, Anna Hitz, Dave Peterson, Aaron Boudreau, Christopher Delnagro, Mandy Kwong, Rebecca Hong, Min Gao, Jodi Pang, Alex Vanderbilt, Simon Williams, Laurent Salphati, Deepak Sampath, Georgia Hatzivassiliou, Marie Evangelista
Journal: Cancer Research (2014)

Abstract Tumors exhibit altered metabolic profiles compared to normal, non-transformed tissues. In the presence of oxygen, most differentiated cells convert glucose to ATP by oxidative phosphorylation (OX-PHOS), whereas tumor cells consume glucose and convert it to lactate, a phenomenon known as “aerobic glycolysis” or the “Warburg effect”. There is increased interest in targeting glycolysis as a therapeutic strategy in oncology, and one of the key enzymes in this pathway is lactate dehydrogenase (LDH), which catalyzes the conversion of pyruvate to lactate in the last step of glycolysis. A small molecule LDHA inhibitor that was identified by high throughput screening was optimized to generate GNE-140, which has a biochemical EC50 of 0.005 μM and inhibits MiaPaCa-2 pancreatic cell proliferation with an EC50 of 0.25 μM. We show that inhibition of LDHA reduces carbon flux from pyruvate to lactate, impairs glycolysis, and leads to global effects in cell metabolism. Cells cease proliferation within 24 hours of LDHA inhibition, yet only undergo cell death following sustained pathway inhibition. Finally, we show that pancreatic cell lines that are resistant to LDHA inhibition can be re-sensitized to LDHA inhibition by inhibiting OX-PHOS. In conclusion, we describe a potent cell active LDHA inhibitor that modulates glycolysis, induces cell death, and that can be used to help evaluate the importance of LDHA in tumor growth. Citation Format: Thomas O'Brien, Hans Purkey, Anna Hitz, Dave Peterson, Aaron Boudreau, Christopher Delnagro, Mandy Kwong, Rebecca Hong, Min Gao, Jodi Pang, Alex Vanderbilt, Simon Williams, Laurent Salphati, Deepak Sampath, Georgia Hatzivassiliou, Marie Evangelista. Inhibiting glycolysis with an LDHA inhibitor: A new solution to an old problem. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 964. doi:10.1158/1538-7445.AM2014-964
Comparison of standard and accelerated initiation of renal replacement therapy in acute kidney injury
Authors: Ron Wald, Neill K.J. Adhikari, Orla M. Smith, Matthew A. Weir, Karen Pope, Ashley Cohen, Kevin Thorpe, Lauralyn McIntyre, Francois Lamontagne, Mark Soth, Margaret Herridge, Stephen Lapinsky, Edward Clark, Amit X. Garg, Swapnil Hiremath, David Klein, C. David Mazer, Robert M.A. Richardson, M. Elizabeth Wilcox, Jan O. Friedrich, Karen E.A. Burns, Sean M. Bagshaw
Journal: Kidney International (2015)
Prognostic Significance of Silent Myocardial Infarction in Newly Diagnosed Type 2 Diabetes Mellitus
Authors: Timothy M.E. Davis, Ruth L. Coleman, Rury R. Holman
Journal: Circulation (2013)

Background— We aimed to determine the prevalence of silent myocardial infarction (SMI) in people with newly diagnosed type 2 diabetes mellitus and its relationships to future myocardial infarction (MI) and all-cause mortality. Methods and Results— We examined data from the 5102 patients in the 30-year UK Prospective Diabetes Study (UKPDS) and used Cox proportional hazards regression to examine outcomes by SMI status. Of 1967 patients with complete baseline data, 326 (16.6%) had ECG evidence of SMI (Minnesota codes 1.1 or 1.2) at enrollment. Those with SMI were more likely to be older, female, sedentary, and nonsmokers compared with those without SMI. Their mean blood pressure was greater despite more intensive antihypertensive treatment; they were more likely to be taking aspirin and lipid-lowering therapy; and they had a greater prevalence of microangiopathy. Fully adjusted hazard ratios for those with versus those without SMI in multivariate models that included UKPDS Risk Engine variables were 1.58 (95% confidence interval, 1.22–2.05) for fatal MI and 1.31 (95% confidence interval, 1.10–1.56) for all-cause mortality. Hazard ratios for first fatal or nonfatal MI and for first nonfatal MI were nonsignificant. The net reclassification index showed no improvement when SMI was added to these models, and the integrated discrimination index showed that SMI marginally improved the prediction of fatal MI and all-cause mortality. Conclusions— About 1 in 6 UKPDS patients with newly diagnosed type 2 diabetes mellitus had evidence of SMI, which was independently associated with an increased risk of fatal MI and all-cause mortality. However, identification of SMI does not add substantively to current UKPDS Risk Engine predictive variables. Clinical Trial Registration— URL: http://www.controlled-trials.com . Identifier: ISRCTN number 75451837.
Abstract 9738: Endothelial Microparticles Reduce Icam-1 Expression in a Microrna-222-Dependent Mechanism
Authors: Feilx Jansen, Katharina Baumann, Georg Nickenig, Nikos Werner
Journal: Circulation (2014)

Introduction: Endothelial microparticles (EMP) are released from activated or apoptotic endothelial cells (ECs) and can be taken up by adjacent endothelial cells, but their effect on vascular inflammation after engulfment is largely unknown.

Hypothesis: EMP influence endothelial target cell inflammation.

Methods and Results: In vitro, EMP treatment significantly reduced TNF-α-induced endothelial ICAM-1 expression on mRNA and protein level, whereas there was no effect on VCAM-1 expression. Reduced ICAM-1 expression after EMP treatment resulted in diminished monocyte adhesion in vitro. In vivo, systemic treatment of ApoE-/- mice with EMP significantly reduced murine endothelial ICAM-1 expression and infiltration of macrophages into atherosclerotic plaques. In order to explore the underlying mechanisms, Taqman microRNA-array was performed and microRNA (miR)-222 was identified as the strongest regulated miR between EMP and endothelial cells. Following experiments demonstrated that miR-222 was transported into recipient endothelial cells by EMP and functionally regulated expression of its target protein ICAM-1. Interestingly, after simulating diabetic conditions, EMP derived from glucose-treated ECs contained significantly lower amounts of miR-222 and showed reduced anti-inflammatory capacity in vitro and in vivo.

Conclusions: Endothelial microparticles promote anti-inflammatory effects in vitro and in vivo by reducing endothelial ICAM-1 expression via the transfer of functional microRNA-222 into recipient cells. In pathological hyperglycaemic conditions, EMP-mediated miR-222-dependent anti-inflammatory effects are reduced.

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Effects of desipramine on clinical liver function tests
Authors: L H Price, J C Nelson, P I Jatlow
Journal: American Journal of Psychiatry (1984)

Results of liver function tests in 46 depressed patients changed little during treatment with desipramine and were uncorrelated with drug plasma levels. The findings suggest that tricyclic-associated hepatitis, rather than being dose dependent, is an uncommon, idiosyncratic phenomenon.
Abstract 11909: Changes in Brain Caudate Nuclei Functional Connectivity in Heart Failure
Authors: Mary A Woo, Bumhee Park, Paul M Macey, Gregg C Fonarow, Ronald M Harper, Rajesh Kumar
Journal: Circulation (2014)

INTRODUCTION:  Heart failure (HF) subjects show caudate nuclei injury. The caudate nuclei serve cognitive, learning, memory, and motor functions, which are dependent upon connections to prefrontal, frontal, and limbic sites in order to impact these activities. Whether specific functional connections (FC, interaction ability via white matter connections between brain areas) from the caudate to these brain sites are affected in HF is unknown.   METHODS:  We collected resting-state functional MRI data from 17 HF (age 54.4±8.1 years; Females 5; BMI 29.4±5.7 kg/m2; LVEF 0.28±0.07) and 45 controls (age 50.9±7.6; Females 15; BMI 25.1±3.8 kg/m2), using a 3.0 Tesla MRI scanner, and analyzed with SPM8 and MATLAB-based software. Individual correlation maps between left and right caudate seed areas and whole-brain were calculated, converted to z-scored maps and compared with ANCOVA (covariates, age and gender; P   RESULTS:  The right caudate (Fig. 1) showed decreased FC in HF with the medial paracentral lobule (b), precuneus (a), and left cerebellum (e), and increased FC with the right precuneus (c), left precentral gyrus (d), and right postcentral gyrus (g). The left caudate (Figure) showed increased FC in HF with the left insula (h), left precentral gyrus, and left and right postcentral gyrus (f), but no sites with decreased FC, over control subjects.   CONCLUSIONS:  Despite injury, both left and right caudate nuclei show increased FC to primary motor and sensory cortices, and the left shows enhanced insular FC in HF. The enhanced FC to motor and parasympathetic regions may reflect compensatory efforts to overcome injured gray matter regions (caudate, insular, and frontal) processes of impaired motor and autonomic regulation, with the diminished cerebellar FC reflecting the motor dis-coordination.
Stroke scoring systems
Authors: Maria Grazia Celani, Enrico Righetti, Rino Migliacci, Mauro Zampolini, Lucia Antoniutti, Fabio Chiodo Grandi, Stefano Ricci, C.J Weir, K.R Lees, K.W Muir, D.G Grosset, G.D Murray, E.J Dunstan, Richard Butterworth, Philip Bath
Journal: The Lancet (1994)
Abstract 17802: Ips Cells -derived Cardiac Progenitors Induce Dramatic Cardiac Regeneration and Improve Function by Cxcr4 Signaling Pathway in Infarcted Myocardium
Authors: Zeshan Pasha, Romana Saeed, Muhammad Ashraf
Journal: Circulation (2014)

Background: The participation of endogenous cardiac stem/progenitor cells is limited in restoring cardiac structure and function in the ischemic myocardium which is further aggravated by poor survival and propagation of transplanted stem cells of different origin in the infarcted heart. The goal of this study was to explore the survival and engraftability of newly discovered induced pluripotent stem cells (IPS) in the myocardium following infarction (MI). Methods and Results: Integration free iPS were generated from myoblasts and characterized. Cardiac progenitors (CPs) were created by treatment with a small molecule. CPs proliferation was assessed by BrdU labeling; Differentiation by both RT-PCR and immunofluorescent staining for cardiac markers Nkx2.5, actinin, and -MHC. Gene expression profiling was performed using Affymetrix array. In vivo studies were carried out by injecting CPs or nontreated IPS (3x105), into mouse model of permanent LAD. Echocardiography, histological parameters, TUNEL assay and capillary vessel density were measured 6 weeks post transplantation. Treatment of IPS with a small molecule upregulated Nkx2.5 and maintained up to 4 weeks (p&lt;0.01 vs nontreated IPS). Expression of actinin and -MHC was also detectable at 3 weeks. Increased proliferative activity (p&lt;0.01) evaluated by cell proliferation and Brdu assay was observed. Significant CPs survival and reduced apoptosis were noticed in the small molecule treated iPSC compared to nontreated and/or saline group. Enhanced ejection fraction and fractional shortening (p&lt; 0.05) was observed 6 weeks post transplantation. Interestingly there was 2-3 fold upregulation of chemokines including CCL7, CXCR2, CXCR5. miR Microarray analysis showed upregulation of cardiac specific mir-133,762. Western blot analysis showed increased phospho-Akt levels as compared to nontreated IPSC (p&lt;0.01). Survival and differentiation properties of CPs were abolished by concomitant treatment of IPS with CXR4 blocker (p&lt;0.05). Conclusion: This study provides a novel strategy for generating CPs and their enhanced survival, engraftment and differentiation with the treatment of cardiogenic small molecule post transplantation in the infarcted myocardium through CXCR4 signaling pathway.