tbuckley/cabot-search huggingface dataset:
Mutations with epigenetic effects in myeloproliferative neoplasms and recent progress in treatment: Proceedings from the 5th International Post-ASH Symposium
Authors: A Tefferi, O Abdel-Wahab, F Cervantes, J D Crispino, G Finazzi, F Girodon, H Gisslinger, J Gotlib, J-J Kiladjian, R L Levine, J D Licht, A Mullally, O Odenike, A Pardanani, R T Silver, E Solary, T Mughal
Journal: Blood Cancer Journal (2011)

Immediately following the 2010 annual American Society of Hematology (ASH) meeting, the 5th International Post-ASH Symposium on Chronic Myelogenous Leukemia and BCR-ABL1-Negative Myeloproliferative Neoplasms (MPNs) took place on 7-8 December 2010 in Orlando, Florida, USA. During this meeting, the most recent advances in laboratory research and clinical practice, including those that were presented at the 2010 ASH meeting, were discussed among recognized authorities in the field. The current paper summarizes the proceedings of this meeting in BCR-ABL1-negative MPN. We provide a detailed overview of new mutations with putative epigenetic effects (TET oncogene family member 2 (TET2), additional sex comb-like 1 (ASXL1), isocitrate dehydrogenase (IDH) and enhancer of zeste homolog 2 (EZH2)) and an update on treatment with Janus kinase (JAK) inhibitors, pomalidomide, everolimus, interferon-α, midostaurin and cladribine. In addition, the new 'Dynamic International Prognostic Scoring System (DIPSS)-plus' prognostic model for primary myelofibrosis (PMF) and the clinical relevance of distinguishing essential thrombocythemia from prefibrotic PMF are discussed.
Prospective 7 year follow up imaging study comparing radiography, ultrasonography, and magnetic resonance imaging in rheumatoid arthritis finger joints
Authors: A K Scheel, K-G A Hermann, S Ohrndorf, C Werner, C Schirmer, J Detert, M Bollow, B Hamm, G A Müller, G R Burmester, M Backhaus
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To perform a prospective long term follow up study comparing conventional radiography (CR), ultrasonography (US), and magnetic resonance imaging (MRI) in the detection of bone erosions and synovitis in rheumatoid arthritis (RA) finger joints. <b>Methods:</b> The metacarpophalangeal and proximal interphalangeal joints II–V (128 joints) of the clinically dominant hand of 16 patients with RA were included. Follow up joint by joint comparisons for erosions and synovitis were made. <b>Results:</b> At baseline, CR detected erosions in 5/128 (4%) of all joints, US in 12/128 (9%), and MRI in 34/128 (27%). Seven years later, an increase of joints with erosions was found with CR (26%), US (49%) (p&lt;0.001 each), and MRI (32%, NS). In contrast, joint swelling and tenderness assessed by clinical examination were decreased at follow up (p = 0.2, p&lt;0.001). A significant reduction in synovitis with US and MRI (p&lt;0.001 each) was seen. In CR, 12 patients did not have any erosions at baseline, while in 10/12 patients erosions were detected in 25/96 (26%) joints after 7 years. US initially detected erosions in 9 joints, of which two of these joints with erosions were seen by CR at follow up. MRI initially found 34 erosions, of which 14 (41%) were then detected by CR. <b>Conclusion:</b> After 7 years, an increase of bone erosions was detected by all imaging modalities. In contrast, clinical improvement and regression of synovitis were seen only with US and MRI. More than one third of erosions previously detected by MRI were seen by CR 7 years later.
Letter: Oncology centres.
Authors: E A Benson
Journal: BMJ (1974)

virtues of establish.edsimple treatment" (my italics).Bed rest is certainly effective,'0 but when carbenoxolone has been preposed as the "drug of choice" it would be prudent to mention that the drug actually confers no benefit on patients in bed."1As regards smoking, I agree that patients should be advised to stop."When this was done the reduction in ulcer crater size was 83 20/% in patients who stopped smoking and 71 8% in those who did not; it was only 56-6% in those not so advised.Interestingly, the reduotion was 61-3% in non-smokers.-Iam, etc.,
Structural heterogeneity of the C3b/C4b receptor (Cr 1) on human peripheral blood cells.
Authors: T R Dykman, J L Cole, K Iida, J P Atkinson
Journal: The Journal of Experimental Medicine (1983)

In these studies CR 1 polymorphism previously demonstrated on erythrocytes (E) was also found on CR 1-bearing peripheral blood leukocytes including polymorphonuclear (PMN), eosinophils, monocytes, and B lymphocytes. However several cell-specific differences in CR1 were found: (a) an approximately 5,000-dalton increase in CR 1 on PMN and eosinophils, (b) unequal band intensity among heterozygotes suggests that there is preferential expression of 220,000- or 225,000-dalton receptors on leukocytes compared to E, and (c) "minor" bands, approximately 15,000 daltons larger than the major receptor molecule, were found on E but not on leukocytes. These observations constitute a unique example of heterogeneity of an integral membrane receptor.
Autocrine inhibition of Na+/K(+)-ATPase by nitric oxide in mouse proximal tubule epithelial cells.
Authors: N J Guzman, M Z Fang, S S Tang, J R Ingelfinger, L C Garg
Journal: Journal of Clinical Investigation (1995)

An inducible nitric oxide synthase has recently been described in proximal tubule epithelium. To investigate the effects of proximal tubule NO on Na+/K(+)-ATPase, we induced NO production in mouse proximal tubule epithelial cells by treatment with lipopolysaccharide (LPS) and interferon-gamma (IFN gamma) followed by determinations of ouabain-sensitive ATPase activity. Na+/K(+)-ATPase activity decreased after 4 h of LPS/IFN gamma treatment, reaching maximal inhibition after 24 h (34% reduction in activity). The inhibition of Na+/K(+)-ATPase activity by LPS/IFN gamma was prevented by simultaneous incubation with N omega-nitro L-arginine and markedly blunted by removal of L-arginine from the medium. The NO donors sodium nitroprusside and SIN-1 also inhibited Na+/K(+)-ATPase activity to a similar extent than LPS/IFN gamma. However, treatment with 8-pCPT-cGMP only modestly reduced Na+/K(+)-ATPase activity. Interestingly, superoxide dismutase prevented the inhibitory effects of NO on Na+/K(+)-ATPase activity, suggesting a role for peroxynitrite in this inhibition. We conclude that NO generated by mouse proximal tubule epithelial cell iNOS inhibits Na/K ATPase activity in an autocrine fashion and that this inhibition is accompanied by a reduction in Na-dependent solute transport.
Brain imaging and functional gastrointestinal disorders: has it helped our understanding?
Authors: A R Hobson
Journal: Gut (2004)

he 1990s were heralded as the ''decade of the brain'' amid excitement that major advances in imaging technology coupled with huge financial investment would finally allow neuroscientists to unravel the mysteries of the human brain.Several gastrointestinal disease research groups, frustrated by the lack of objective methods to assess gastrointestinal sensory dysfunction in functional gastrointestinal disorders (FGD), recognised this period as an opportunity to utilise these new brain imaging techniques and gain a novel insight into brain-gut interactions.What followed was a period of intense activity and a flurry of publications describing the cortical representation of visceral sensation appeared (for review see Derbyshire 1 ).It seemed only a matter of time before central mechanisms for chronic gastrointestinal pain in FGD patients would be identified, and appropriate treatment strategies designed.Nearly a decade on from the initiation of these studies, we are still waiting.The apparent failure of brain imaging to have an impact on the diagnosis and treatment of FGD has, rather like the emperors new clothes, led an increasing number of sceptics to wonder whether this has been another false dawn in the search for a solution to the problem of chronic pain in FGD.Despite such scepticism, we believe that brain imaging has greatly increased our understanding of the neuroanatomy and functional relevance of the cortical and subcortical structures involved in processing gastrointestinal sensation.The aim of this article is to guide the reader through a summary of this information, paying particular attention to its relevance to FGD.
New Therapeutic Approaches for Multiple Sclerosis
Authors: Philip L. De Jager, David A. Hafler
Journal: Annual Review of Medicine (2007)

Although several therapies exist for multiple sclerosis (MS), the most common inflammatory demyelinating disease of the central nervous system (CNS), there remains a large unmet clinical need for more effective immunomodulatory treatments in this category of diseases and for interventions that address their neurodegenerative component, which is currently untreated. Progress in our understanding of the immunology of MS over the past 30 years has recently synergized with novel computational methods and emerging high-throughput technologies that characterize variations in DNA, RNA, proteins, and metabolites to usher in a period of intense pathophysiologic investigation. These efforts are beginning to define subsets of patients with different forms of demyelinating disease. This partitioning of patients will prove valuable as we begin to tailor immunotherapy to the underlying pathophysiologic processes of individual patients using current therapies, emerging treatments, and rational combinations of all of these treatments. Preventing the entry of lymphocytes into the CNS and modifying the nature of the immune response are treatment approaches that work in the inflammatory component of MS but have little or no effect on neurodegeneration. Two challenges confront us: to develop cocktails of therapies that shift the immune homeostasis of patients with MS toward a healthy profile, and to identify and modulate the activity of targets within the neurodegenerative component of MS.
Developmental Regulation of VDJ Recombination By the Core Fragment of the T Cell Receptor α Enhancer
Authors: Joseph L. Roberts, Pilar Lauzurica, Michael S. Krangel
Journal: The Journal of Experimental Medicine (1997)

The role of T cell receptor α enhancer (Eα) cis-acting elements in the developmental regulation of VDJ recombination at the TCR α/δ locus was examined in transgenic mice containing variants of a minilocus VDJ recombination substrate. We demonstrate that the 116-bp Tα1,2 core enhancer fragment of the 1.4-kb Eα is sufficient to activate the enhancer-dependent step of minilocus rearrangement, and that within Tα1,2, intact binding sites for TCF/LEF and Ets family transcription factors are essential. Although minilocus rearrangement under the control of the 1.4-kb Eα initiates at fetal day 16.5 and is strictly limited to αβ T cells, we find that rearrangement under the control of Tα1,2 initiates slightly earlier during ontogeny and occurs in both γδ and αβ T cells. We conclude that the core fragment of Eα can establish accessibility to the recombinase in developing thymocytes in vivo in a fashion that is dependent on the binding of TCF/LEF and Ets family transcription factors, but that these and other factors that bind to the Eα core cannot account for the precise developmental onset of accessibility that is provided by the intact Eα. Rather, our data suggests a critical role for factors that bind Eα outside of the core Tα1,2 region in establishing the precise developmental onset of TCR α rearrangement in vivo.
Management of achalasia: surgery or pneumatic dilation
Authors: J. E. Richter, G. E. Boeckxstaens
Journal: Gut (2011)

Achalasia is an esophageal motility disorder of unknown cause, characterised by aperistalsis of the esophageal body and impaired lower esophageal sphincter relaxation. Patients present at all ages, primarily with dysphagia for solids/liquids and bland regurgitation. The diagnosis is suggested by barium esophagram or endoscopy and confirmed by esophageal manometry. Achalasia cannot be cured. Instead, our goal is to relieve symptoms, improve esophageal emptying and prevent the development of megaesophagus. The most successful therapies are pneumatic dilation and surgical myotomy. The advantages of pneumatic dilation include an outpatient procedure, minimal pain, return to work the next day, mild if any GERD, and can be performed in any age group and even during pregnancy. Pneumatic dilation does not hinder future myotomy, and all cost analyses find it less expensive than Heller myotomy. Laparoscopic myotomy with a partial fundoplication has the advantage of being a single procedure, dysphagia relief is longer at the cost of more troubling heartburn, and a myotomy may be more effective treatment in adolescents and younger adults, especially men. Over a two year horizon, the clinical success of pneumatic dilation and laparoscopic myotomy are comparable in a recent large European randomised trial. The prognosis for achalasia patients to return to near-normal swallowing and good quality of life are excellent, but few are "cured" with a single treatment and intermittent "touch up" procedures may be required.
Menopausal Hormone Therapy and Risks of Melanoma and Nonmelanoma Skin Cancers: Women’s Health Initiative Randomized Trials
Authors: Jean Y. Tang, Katrina M. Spaunhurst, Rowan T. Chlebowski, Jean Wactawski-Wende, Elizabeth Keiser, Fridtjof Thomas, Matthew L. Anderson, Nathalie C. Zeitouni, Joseph C. Larson, Marcia L. Stefanick
Journal: JNCI Journal of the National Cancer Institute (2011)

Case–control studies have reported that exogenous estrogen use is associated with increased risk of skin cancer. The effects of menopausal hormone therapy on incidence of nonmelanoma skin cancer and melanoma were evaluated in post hoc analyses of the Women's Health Initiative randomized placebo-controlled hormone therapy trials of combined estrogen plus progestin (E + P) and estrogen only (E-alone). Postmenopausal women aged 50–79 years were randomly assigned to conjugated equine estrogen (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo in the E + P trial if they had an intact uterus (N = 16 608) or to conjugated equine estrogen alone or placebo in the E-alone trial if they had a hysterectomy (N =10 739); the mean follow-up was 5.6 and 7.1 years, respectively. Incident nonmelanoma skin cancers (n = 980 [E + P trial]; n = 820 [E-alone trial]) and melanomas (n = 57 [E + P trial]; n =38 [E-alone trial]) were ascertained by self-report. Incident cases of cutaneous malignant melanoma were confirmed by physician review of medical records. Incidences of nonmelanoma skin cancer and melanoma were compared between the two randomization groups within each trial using hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) and Wald statistic P values from Cox proportional hazards models. All statistical tests were two-sided. Rates of incident nonmelanoma skin cancer and melanoma were similar between the active hormone (combined analysis of E + P and E-alone) and placebo groups (nonmelanoma skin cancer: HR = 0.98, 95% CI = 0.89 to 1.07; melanoma: HR = 0.92, 95% CI = 0.61 to 1.37). Results were similar for the E + P and E-alone trials when analyzed individually. Menopausal hormone therapy did not affect overall incidence of nonmelanoma skin cancer or melanoma. These findings do not support a role of menopausal estrogen, with or without progestin, in the development of skin cancer in postmenopausal women.
Lack of association between adult asthma and the tumour necrosis factor α-308 polymorphism gene
Authors: R. Louis, E. Leyder, M Malaise, P. Bartsch, E Louis
Journal: European Respiratory Journal (2000)

Tumour necrosis factor (TNF)alpha is a cytokine endowed with potent inflammatory properties that may contribute to airway inflammation in asthma. It has previously been shown that the single base pair polymorphism-308 (G to A substitution) in the promoter of TNFalpha gene results in enhanced cytokine secretion. Whether this polymorphism is associated with the presence of phenotypic expression of asthma is questioned. In this study the relative frequency of TNF1 and TNF2 alleles in a population of adult healthy subjects (n=98) and adult Caucasian asthmatics (n=95) was compared taking into account their disease severity, atopic status and their smoking habit. For the whole group of asthma the genotype frequency for 1/1, 1/2, 2/2 were 67%, 33% and 0%, respectively, and not significantly different from those found in the control group that reached 70%, 28% and 2% respectively (p&gt;0.05). The allele frequencies in asthma were 86% and 14% for TNF1 and TNF2 respectively while the corresponding figures were 85% and 15% in the control group (p&gt;0.05). Furthermore, subdividing asthmatics into severe forced expiratory volume in one second &lt;60% pred), atopic or smoking patients did not show any significant association with this TNFalpha polymorphism. To conclude the polymorphism -308 in the promoter of the TNFalpha gene does not confer a susceptibility to develop asthma nor to grade its severity.
Colonoscopic Withdrawal Times and Adenoma Detection during Screening Colonoscopy
Authors: Robert L. Barclay, Joseph J. Vicari, Andrea S. Doughty, John F. Johanson, Roger L. Greenlaw
Journal: New England Journal of Medicine (2006)

Colonoscopy is commonly used to screen for neoplasia. To assess the performance of screening colonoscopy in everyday practice, we conducted a study of the rates of detection of adenomas and the amount of time taken to withdraw the colonoscope among endoscopists in a large community-based practice.During a 15-month period, 12 experienced gastroenterologists performed 7882 colonoscopies, of which 2053 were screening examinations in subjects who had not previously undergone colonoscopy. We recorded the numbers, sizes, and histologic features of the neoplastic lesions detected during screening, as well as the duration of insertion and of withdrawal of the colonoscope during the procedure. We compared rates of detection of neoplastic lesions among gastroenterologists who had mean colonoscopic withdrawal times of less than 6 minutes with the rates of those who had mean withdrawal times of 6 minutes or more. According to experts, 6 minutes is the minimum length of time to allow adequate inspection during instrument withdrawal.Neoplastic lesions (mostly adenomatous polyps) were detected in 23.5% of screened subjects. There were large differences among gastroenterologists in the rates of detection of adenomas (range of the mean number of lesions per subject screened, 0.10 to 1.05; range of the percentage of subjects with adenomas, 9.4 to 32.7%) and in their times of withdrawal of the colonoscope from the cecum to the anus (range, 3.1 to 16.8 minutes for procedures during which no polyps were removed). As compared with colonoscopists with mean withdrawal times of less than 6 minutes, those with mean withdrawal times of 6 minutes or more had higher rates of detection of any neoplasia (28.3% vs. 11.8%, P<0.001) and of advanced neoplasia (6.4% vs. 2.6%, P=0.005).In this large community-based gastroenterology practice, we observed greater rates of detection of adenomas among endoscopists who had longer mean times for withdrawal of the colonoscope. The effect of variation in withdrawal times on lesion detection and the prevention of colorectal cancer in the context of widespread colonoscopic screening is not known. Ours was a preliminary study, so the generalizability and implications for clinical practice need to be determined by future studies.
The 1997 American Diabetes Association Criteria Versus the 1985 World Health Organization Criteria for the Diagnosis of Abnormal Glucose Tolerance: Poor agreement in the Hoorn Study
Authors: Femmie De Vegt, Jacqueline M Dekker, Coen D A Stehouwer, Giel Nijpels, Lex M Bouter, Robert J Heine
Journal: Diabetes Care (1998)

OBJECTIVE Recently, the American Diabetes Association (ADA) introduced new diagnostic criteria. These new criteria are based on fasting plasma glucose levels, avoiding the burdensome oral glucose tolerance test (OGTT). We compared the 1997 ADA criteria with the 1985 World Health Organization (WHO) criteria with respect to the prevalence of diabetes and the cardiovascular risk profile in the population of the Hoorn Study. RESEARCH DESIGN AND METHODS The Hoorn Study is a population-based survey of 2,484 men and women, aged 50–75 years. An OGTT was performed and cardiovascular risk factors were determined in 2,378 subjects without known diabetes. Subjects were categorized according to both sets of diagnostic criteria. RESULTS Although the prevalence of diabetes was similar for both sets of criteria, 47 of 120 (39.2%) subjects who were diagnosed with diabetes according to the 1997 ADA criteria were not classified as having diabetes when using the 1985 WHO criteria. Similarly, of 285 subjects diagnosed with impaired fasting glucose by the 1997 ADA criteria, 195 (68.4%) were classified as having normal glucose tolerance by the 1985 WHO criteria. The overall agreement was poor (K 0.33; 95% CI 0.28−0.38). Subjects who were diagnosed as having diabetes by either set of criteria had an adverse cardiovascular risk profile, which was between the cardiovascular risk profiles of concordant normal and concordant diabetic subjects. CONCLUSIONS In this study, both sets of criteria diagnosed a similar number of diabetic subjects, but many of the subjects shifted between glucose intolerance categories. With either set of criteria, a considerable number of subjects at risk of developing diabetes and subjects carrying an increased risk of cardiovascular disease, as reflected by an adverse cardiovascular risk profile, will be missed.
From Unseen to Seen: Tackling the Global Burden of Uncorrected Refractive Errors
Authors: Nicholas J. Durr, Shivang R. Dave, Eduardo Lage, Susana Marcos, Frank Thorn, Daryl Lim
Journal: Annual Review of Biomedical Engineering (2014)

Worldwide, more than one billion people suffer from poor vision because they do not have the eyeglasses they need. Their uncorrected refractive errors are a major cause of global disability and drastically reduce productivity, educational opportunities, and overall quality of life. The problem persists most prevalently in low-resource settings, even though prescription eyeglasses serve as a simple, effective, and largely affordable solution. In this review, we discuss barriers to obtaining, and approaches for providing, refractive eye care. We also highlight emerging technologies that are being developed to increase the accessibility of eye care. Finally, we describe opportunities that exist for engineers to develop new solutions to positively impact the diagnosis and treatment of correctable refractive errors in low-resource settings.