tbuckley/cabot-search huggingface dataset:
Tau-focused therapy and tau transmission: Implications for Alzheimer’s Disease and related tauopathies
Authors: John Q Trojanowski
Journal: Molecular Neurodegeneration (2013)

Tau pathology is characteristic of Alzheimer’s disease (AD) and related tauopathies including Parkinson’s disease (PD) wherein a significant percentage of PD patients who develop dementia harbor AD-like tau pathology. Tau pathology is characterized by insoluble filamentous aggregates of hyperphosphorylated tau in CNS neurons known as neurofibrillary tangles (NFTs) and neuropil threads (NTs). NFTs and NTs are implicated in mechanisms of neurodegeneration through gains of toxic functions or losses of normal tau functions. Hyperphosphorylation and decreased solubility of tau leads to a loss of the ability of tau to bind to and stabilize microtubules (MTs) which impairs axonal transport and results in neuronal dysfunction and degeneration. This presentation describes the use of MT stabilizing drugs to counteract the loss of tau function and prevent/ameliorate tau mediated neurodegeneration in a transgenic (Tg) mouse model of an AD-like neurodegenerative tauopathy. Briefly, proof of concept prevention and intervention studies of the brain-penetrant MT-stabilizing agent epothilone D (EpoD) are described in young (prevention) and aged (intervention) P301S mutant tau Tg mice (PS 19 mice) with little (young PS 19 mice) or abundant tau pathology and behavioral impairments (aged PS19 mice). In the prevention and intervention studies, EpoD treatment reduced axonal dystrophy and increased axonal MT density which led to improved neuronal integrity and cognitive performance. EpoD treatment also improved fast axonal transport in the aged PS19 Tg mice. Unexpectedly, aged PS19 mice treated with EpoD showed a marked reduction in forebrain tau pathology and increased hippocampal neuronal integrity. There were no dose-limiting side effects in the EpoD treated young and aged PS19 mice. These studies support the view that EpoD and other brain-penetrant MT-stabilizing drugs offset the loss of tau function in neurodegenerative tauopathies and therefore are potential therapeutics for the treatment of AD and related tauopathies. Finally, a new seeded transmission model of tauopathy is presented using injections of preformed tau fibrils into the brains of PS19 mice which presents new opportunities to assess the efficacy of MT stabilizers and other potential passive immunization therapies for AD and related tauopathies.

Supported by grants from the NINDS/NIA.
British Diabetic Association: new criteria and classification for diabetes mellitus.
Authors: H Keen, P J Watkins, A Bloom
Journal: BMJ (1983)

were no deaths.I know, because I dealt with it and subsequently published details.' Hapton (not Huckton) Valley disaster in 1962 was an explosion, but the official report of HM Chief Inspector of Mines and Quarries records 32 and not 37 casualties.But "24 at Bethnal Mine, Lanarkshire in 1969" mystifies me.Neither in HM Chief Inspector's annual report for 1969-70, in the board's annual report for 1969-70, nor in the recollection of my mining colleagues was there ever a colliery of that name.So, I fear, nought out of three for historical accuracy.Finally, the industry was, as always, truly grateful for the care and dedication of our hospital colleagues to those unfortunately injured in this explosion.
Future Role of the General Practitioner in the Hospital Service
Authors: E. O. Evans, E. D. McEwan
Journal: BMJ (1969)

A special subcommittee of the General Practitioner Liaison Committee of the Birmingham Regional Hospital Board used five attitude surveys of groups of general practitioners and a comprehensive study of other publications to determine the future role of the general practitioner in the hospital service.From these and other studies they concluded that, although not all general practitioners wished to participate in hospital work, there was an urgent need to provide suitable facilities and a proper career structure early after qualification for those who did, and that there should be hospital inpatient accommodation in which general practitioners can treat their own patients, preferably in association with consultant beds rather than in separate general-practitioner units.
Abstract 133: A microRNA contribution to aberrant Ras activation in gastric cancer
Authors: Xian Wang, Emily Lam, Hongchuan Jin
Journal: Cancer Research (2011)

Abstract Oncogenic Ras mutations are rare in gastric cancer, indicating that other mechanisms may be responsible for aberrant Ras activation in this type of cancer. Ezrin is critical to Ras activation by remodeling cortical actin cytoskeleton. In this study, we aimed to illustrate the relevance and regulation of ezrin in gastric cancer. Ezrin was upregulated in gastric cancer cells. Ezrin siRNA inhibited Ras activation, cell growth and cell migration. Ezrin overexpression was correlated with a poor outcome of gastric cancer patients (n=150, p&amp;lt;0.01). Cox regression analysis revealed a significant value of ezrin expression in prognosis prediction of gastric cancer (relative risk: 2.37, 95% confidence interval: 1.24-4.56, p&amp;lt;0.01). MiR-204, which was predicted to target ezrin, was downregulated in gastric cancer cells and gastric carcinomas (n=22, p&amp;lt;0.01). MiR-204 inhibited ezrin expression, Ras activation, cell growth and cell migration. Importantly, miR-204 suppressed the expression of luciferase controlled by wild-type but not mutated ezrin 3’-UTR. In conclusion, ezrin is important to Ras activation in gastric cancer. Its upregulation is an independent prognosis prediction factor for gastric cancer. By contributing to ezrin upregulation, miR-204 downregulation represents a novel mechanism for aberrant Ras activation in gastric carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 133. doi:10.1158/1538-7445.AM2011-133
Patency of infarct related artery influences in-hospital outcome of patients undergoing facilitated percutaneous coronary intervention for acute myocardial infarction
Authors: Dariusz Dudek, Jacek Legutko, Stanislaw Bartus, Artur Dziewierz, Krzysztof Zmudka, Mieczyslaw Pasowicz, Wieslawa Tracz, Jacek S. Dubiel
Journal: Journal of the American College of Cardiology (2003)
TCT-807 Self-expandable Transcatheter Aortic Valve Implantation for Aortic Stenosis after Mitral Valve Surgery
Authors: Giuseppe Bruschi, Federico De Marco, Alberto Barosi, Luca Botta, Paola Colombo, Jacopo Oreglia, Sandra Nonini, Luigi Martinelli, Silvio Klugmann
Journal: Journal of the American College of Cardiology (2012)
A4.5 Procollagen type 1 amino-terminal propeptide is negatively associated with bone stiffness in subpopulations of patients submitted to hip replacement surgery
Authors: MJ Gonçalves, A Sepriano, A Rodrigues, A Lopes, J Caetano-Lopes, JE Fonseca, H Canhão
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> Osteoporosis (OP) is a frequent disorder of bone metabolism. In OP, cortical bone changes lead to bone loss and deterioration of the microarchitecture increasing risk of fragility fractures of the hip. Bone turnover markers (BTM) reflect bone remodelling. Their role in daily clinical practice is still undefined. In a recent epidemiologic study, a relation between P1NP and hip fractures was found, suggesting both low and high levels of P1NP confer increased risk of osteoporotic fractures. We aim to analyse the relation between BTM and biomechanical features of the bone, in patients with stabilised osteoporosis and in patient with severe osteoarthritis. <h3>Materials and Methods</h3> We analysed patients submitted to hip replacement surgery in the context of severe OA or hip fragility fracture. The patients were asked for clinical data, blood samples and to perform dual x-ray absorptiometry. Blood biomechanical studies were performed and a bone cylinder was drilled from their femoral epiphyses. Stiffness, strength and toughness were assessed by young's modulus, yield stress and energy until yield point, respectively. <h3>Results</h3> We analysed 299 patients, 163 patients with OP and 136 with severe OA. OA patients were more frequently men (67%, p &lt; 0.001), significantly younger (67.5 ± 11.1y vs 78.9 ± 9.0y, p &lt; 0.001) and fatter (body mass index (Kg/m<sup>2</sup>) 28.1 ± 4.7 vs 23.92 ± 4.1, p &lt; 0.001). OA patients fell less (number of falls in the last year 0.44 ± 0.49 vs 0.12 ± 0.32, p &lt; 0.001). Only 15% of OP patients were being treated. Stiffness, strength and toughness were significantly increased in OA group (p = 0.005, 0.02 and 0.004, respectively), with adjustment to age and sex. Alkaline phosphatase was higher in OP patients (p = 0.05, with adjustment to age, sex and BMI), the other parameters didn't reach statistical difference. In OP patients, P1NP (coef = -1.42, p = 0.045) was associated with lower stiffness. In OA patients, P1NP (coef = -3.82, p = 0.006) and B-CTX (coef = -4.61, p = 0.035) were also associated with bone stiffness. P1NP was also associated with lower strength (coef = -0.058, p = 0.013). All analyses were adjusted to age, sex and BMI. <h3>Conclusions</h3> In both OA and OP patients, P1NP was associated with lower stiffness. This tendency was also found with strength in OA patients. This may reflect that extreme values P1NP associate with bone fragility. This study was performed on a post-surgery context and further studies in other populations should be done.
The natural history of childhood asthma to adult life.
Authors: A J Martin, L A McLennan, L I Landau, P D Phelan
Journal: BMJ (1980)

A randomly selected group of 331 children who had started to wheeze in childhood and a control group of 77 children were prospectively studied clinically and physiologically from 7 to 21 years of age. Most subjects improved during adolescence and about 55% of those whose wheezing had started before 7 years and stopped before adolescence remained wheeze free. Forty-five per cent of subjects who had apparently ceased to wheeze at 14 years had minor recurrences of wheezing between 14 and 21 years of age. Fewer than 20% of those with persistent symptoms in childhood had become totally wheeze free during adolescence, although there was amelioration in symptoms. Girls did less well during adolescence than boys, so that there was no longer an increased preponderance of boys with increasing severity of asthma. Normal growth was achieved in all grades despite the persistence of symptoms in many cases. At 21 years of age features of airways obstruction were often found during an interval phase, especially in those who had more persistent symptoms.
Air pollution and daily mortality in London: 1987-92
Authors: H R. Anderson, A. P. de Leon, J M. Bland, J. S Bower, D. P Strachan
Journal: BMJ (1996)

To investigate whether outdoor air pollution levels in London influence daily mortality.Poisson regression analysis of daily counts of deaths, with adjustment for effects of secular trend, seasonal and other cyclical factors, day of the week, holidays, influenza epidemic, temperature, humidity, and autocorrelation, from April 1987 to March 1992. Pollution variables were particles (black smoke), sulphur dioxide, ozone, and nitrogen dioxide, lagged 0-3 days.Greater London.Relative risk of death from all causes (excluding accidents), respiratory disease, and cardiovascular disease.Ozone levels (same day) were associated with a significant increase in all cause, cardiovascular, and respiratory mortality; the effects were greater in the warm seasons (April to September) and were independent of the effects of other pollutants. In the warm season an increase of the eight hour ozone concentration from the 10th to the 90th centile of the seasonal change (7-36 ppb) was associated with an increase of 3.5% (95% confidence interval 1.7 to 5.3), 3.6% (1.04 to 6.1), and 5.4% (0.4 to 10.7) in all cause, cardiovascular, and respiratory mortality respectively. Black smoke concentrations on the previous day were significantly associated with all cause mortality, and this effect was also greater in the warm season and was independent of the effects of other pollutants. For black smoke an increase from the 10th to 90th centile in the warm season (7-19 microg/m3) was associated with an increase of 2.5% (0.9 to 4.1) in all cause mortality. Significant but smaller and less consistent effects were also observed for nitrogen dioxide and sulphur dioxide.Daily variations in air pollution within the range currently occurring in London may have an adverse effect on daily mortality.
Viral neuroinvasion and encephalitis induced by lipopolysaccharide and its mediators.
Authors: S Lustig, H D Danenberg, Y Kafri, D Kobiler, D Ben-Nathan
Journal: The Journal of Experimental Medicine (1992)

The present study was designed to test the effect of bacterial endotoxin on penetration of viruses into the central nervous system (CNS). As a model we used two neurovirulent viruses that lack neuroinvasive capacity: West Nile virus-25 (WN-25) and neuroadapted Sindbis virus (SVN). Administration of lipopolysaccharide (LPS, 100 micrograms/mouse) to CD-1 mice, followed by WN-25 inoculation resulted in 83% encephalitis and death, compared with less than 5% in controls. The results in SVN-inoculated CD-1 mice were quite similar. LPS-treated mice suffered 62% mortality compared with 6% in the nontreated group. No changes in viral neuroinvasiveness were demonstrated in viruses isolated from brains of encephalitic mice, suggesting that neuroinvasion is not due to a selection process for an invasive variant, but to direct penetration of the viruses through the blood-brain barrier (BBB). LPS did not induce WN-25 encephalitis in LPS-insensitive C3H/HeJ mice, compared with 100% neuroinvasion in C3H/HeB mice. Induction of neuroinvasion could be transferred to C3H/HeJ mice by transfusion with serum obtained from LPS-treated, LPS-responsive mice. Passive immunization of CD-1 mice with anti-mTNF antibodies before LPS administration did not prevent LPS-induced WN-25 encephalitis. Furthermore, neutralization of tumor necrosis factor activity in the serum of LPS-treated mice did not abolish its activity, and transfusion-associated encephalitis was observed after the administration of the neutralized serum with WN-25. We suggest that LPS can contribute to virus penetration from the blood into the CNS, a process which turns a mild viral infection into a severe lethal encephalitis. This effect is mediated by soluble factors, and is probably achieved by injury to cerebral microvascular endothelium and modulation of BBB permeability.
WHO's ambitious new European health strategy
Authors: D. J. Hunter
Journal: BMJ (2012)

Political will must be galvanised for Health 2020 to succeed

It may seem the wrong moment to launch an ambitious European health policy framework and strategy and invite governments to adopt it, as the World Health Organization’s Regional Office for Europe is asking its 53 member states to do. However, the architects of Health 2020 ,1 2 WHO’s flagship strategy that has been in preparation for almost two years and will be launched at the 62nd Regional Committee in Malta, 10-14 September 2012, regard the timing as propitious. They insist that, although the economic and fiscal crises facing Europe present major challenges, they also present opportunities to renew efforts to improve the health of European people. The argument that lies at the heart of Health 2020 is that “good health is essential for economic and social development.” It echoes Derek Wanless’s recommendation a decade ago to the UK government that it should emphasise public health more strongly to ensure the survival of the NHS.3

WHO issues its European health report every three years. The 2012 report provides the context that explains why the Health 2020 strategy needs to be taken seriously.4 Although people across Europe are generally living longer, often in better health, these improvements are not being shared equally. Substantial health inequalities persist between and within countries and are increasing in some cases, as set out in WHO’s European review of social determinants of health …
Possible Teratogenic Effect of Chlorambucil on a Human Fetus
Authors: Donald Shotton
Journal: JAMA (1963)

THE EFFECTS OF SODIUM AMINOPTERIN,<sup>1</sup>and more recently, of thalidomide,<sup>2</sup>on the human fetus, when administered to the mother during early pregnancy, have stressed the necessity of carefully checking all drugs for teratogenic properties. Since it is desirable that any suspicions of this nature should be reported, the following case is felt worthy of mention. It concerns the possible teratogenic effect of chlorambucil on a human fetus removed from a mother receiving this drug for the treatment of Hodgkin's diseae. <h3>Report of a Case</h3> A 27-year-old married white woman was diagnosed as suffering from Hodgkin's paragranuloma after a biopsy of a left supraclavicular lymph node in the Lynchburg General Hospital in February, 1958. Since then her illness has been characterized by fever, generalized adenopathy, pulmonary infiltration, hepatosplenomegaly, anemia, lymphopenia, and weight loss, although the degree of each of these symptoms has varied from time to time. She was
Researchers find discordance between standard human epidermal growth factor receptor 2 (HER2) testing and HER2 status reported on Onco<i>type</i> DX
Authors: Mary Kay Barton
Journal: CA A Cancer Journal for Clinicians (2012)

CA: A Cancer Journal for Clinicians publishes information about the prevention, early detection, and treatment of cancer, as well as nutrition, palliative care, survivorship, and additional topics of interest related to cancer care.
903 INTERACTION BETWEEN THE PNPLA3 I148M MUTATION, BODY WEIGHT, AND STEATOSIS, IN DETERMINING THE PROGRESSION TO CIRRHOSIS IN HEREDITARY HEMOCHROMATOSIS
Authors: L. Valenti, P. Maggioni, A. Piperno, E. Galmozzi, S. Pelucchi, R. Rametta, R. Mariani, P. Dongiovanni, A.L. Fracanzani, S. Fargion
Journal: Journal of Hepatology (2011)
Messages From Afar-Reply
Authors: Gary G. Kardos
Journal: JAMA (1988)

<h3>In Reply—</h3> Drs Alexander and Wyatt make appropriate points. My essay was not a treatise on therapy. Let me assure them that the patient underwent a comprehensive medical evaluation and that there was no organic basis for his paranoid schizophrenia. Pharmacotherapy was considered and rejected by my attending psychiatrist and by the patient on many occasions during and after discharge from the hospital. Such discussions, however, did not lend themselves to the short essay form. As a nonpsychiatrist it is not for me to argue about whether such patients should in fact receive pharmacotherapy, but I will note that I have received telephone calls and letters from other psychiatrists applauding the way this patient was treated. There was no intent in this essay to "turn one's back on the last 30 years of progress." I personally believe that this patient's treatment was appropriate and the outcome unfortunate. It serves to
Biologic and genetic characterization of the novel amyloidogenic lambda light chain–secreting human cell lines, ALMC-1 and ALMC-2
Authors: Bonnie K. Arendt, Marina Ramirez-Alvarado, Laura A. Sikkink, Jonathan J. Keats, Gregory J. Ahmann, Angela Dispenzieri, Rafael Fonseca, Rhett P. Ketterling, Ryan A. Knudson, Erin M. Mulvihill, Renee C. Tschumper, Xiaosheng Wu, Steven R. Zeldenrust, Diane F. Jelinek
Journal: Blood (2008)
US judge fines Johnson &amp; Johnson $1.1bn for misleading marketing of risperidone
Authors: J. H. Tanne
Journal: BMJ (2012)

Judge Tim Fox of the Arkansas Circuit Court fined the Johnson & Johnson subsidiary Janssen Pharmaceuticals $1.1bn (£0.7bn; €0.84bn) for promotional information about the antipsychotic drug risperidone that misled the state into spending Medicaid funds for the drug. He also fined the company $11m for violating the state’s law on deceptive practices. Medicaid is a joint federal and state health insurance scheme for people on low incomes.

The Arkansas attorney general, Dustin McDaniel, charged that Johnson & Johnson and Janssen had not clearly described the risks of risperidone (which is marketed as Risperdal), had marketed the drug for unapproved uses, …
Role of Potassium in the Pathogenesis of the "Electrolyte-Steroid-Cardiopathy with Necrosis"
Authors: P. Prioreschi
Journal: Circulation Research (1962)

During the development of the "electrolytesteroid-cardiopathy with necroses" (ESCN) in rats, there is a decrease of myocardial potassium in the group bound to develop the cardiac necroses. A similar variation was observed in the control animals treated with a noncardiotoxic association of steroid and electrolytes. Only after the necrosis had been established was an important increase of sodium and decrease of potassium observed. On the basis of these and other previously deseribed facts, the author concludes that, although it is conceivable that the diminution of potassium in the heart could favor the development of the necroses, the hypothesis of the ESCN as a result of a simple potassium depletion cannot be accepted.
Prevalence of Eosinophilic Esophagitis in an Adult Population Undergoing Upper Endoscopy: A Prospective Study
Authors: Ganesh R. Veerappan, Joseph L. Perry, Timothy J. Duncan, Thomas P. Baker, Corinne Maydonovitch, Jason M. Lake, Roy K.H. Wong, Eric M. Osgard
Journal: Clinical Gastroenterology and Hepatology (2008)

Eosinophilic esophagitis (EoE) is characterized by eosinophilic infiltration of the esophagus. The purpose of this prospective study was to determine the prevalence and clinical predictors of EoE in patients undergoing elective upper endoscopy.We enrolled 400 consecutive adults (median age, 50 years; range, 19-92 years) who underwent routine upper endoscopy from March to September 2007 at a tertiary care military hospital. All patients completed a symptom questionnaire. All endoscopic findings were noted. Eight biopsies were obtained from proximal and distal esophagus and were reviewed by a blinded gastrointestinal pathologist. Patients had EoE if > or =20 eosinophils/high-power field were present.The prevalence of EoE in this cohort was 6.5% (25/385; 95% confidence interval, 4.3%-9.4%). Compared with EoE negative patients, EoE positive patients were more likely to be male (80.0% vs 48.1%, P = .003), younger than 50 years (72.0% vs 48.9%, P = .037), and have asthma (32.0% vs 10.8%, P = .006), a food impaction (32.0% vs 8.9%, P = .002), dysphagia (64.0% vs 38.1%, P = .018), and classic endoscopic findings (rings, furrows, plaques, or strictures) of EoE (all P < .01). Logistic regression identified asthma (odds ratio [OR], 4.48), male gender (OR, 4.23), and esophageal rings (OR, 13.1) as independent predictors of EoE. The presence of classic endoscopic findings of EoE had a sensitivity of 72% (54%-88%), specificity of 89% (87%-90%), and negative predictive value of 98% (95.6%-99.1%).The prevalence of EoE in an outpatient population undergoing upper endoscopy was 6.5%. The characteristic findings of EoE patients included male gender, history of asthma, and the presence of classic findings of EoE on endoscopy, which is the strongest predictor of this disease process.