tbuckley/cabot-search huggingface dataset:
Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate.
Authors: C P Genain, M H Nguyen, N L Letvin, R Pearl, R L Davis, M Adelman, M B Lees, C Linington, S L Hauser
Journal: Journal of Clinical Investigation (1995)

In the human disease multiple sclerosis (MS), the immune mechanisms responsible for selective destruction of central nervous system myelin are unknown. In the common marmoset Callithrix jacchus, a unique demyelinating form of experimental allergic encephalomyelitis resembling MS can be induced by immunization with whole myelin. Here we show that the MS-like lesion can be reproduced by immunization against the extracellular domain of a single myelin protein, myelin/oligodendrocyte glycoprotein (MOG). By contrast, immunization against the quantitatively major myelin proteins myelin basic protein or proteolipid protein results in inflammation but little or no demyelination. Furthermore, in the presence of encephalitogenic (e.g., disease-inducing) T cells, the fully demyelinated lesion is reconstructed by systemic administration of IgG purified from whole myelin-, or MOG-immunized animals, and equally by a monoclonal antibody against MOG, but not by control IgG. Encephalitogenic T cells may contribute to the MS-like lesion through disruption of the blood-brain barrier that permits access of demyelinating antibody into the nervous system. The identification of MOG as a major target antigen for autoimmune demyelination in a nonhuman primate should facilitate development of specific immunotherapies for human MS.
Chief medical officer speaks out on antimicrobial resistance, drugs, and homeopathy
Authors: A. O'Dowd
Journal: BMJ (2013)

A cross government strategy to tackle antimicrobial resistance will be launched in the spring, aimed at targeting the problem of the growing ineffectiveness of antibiotics in the United Kingdom and beyond, England’s chief medical officer, Sally Davies, has told MPs.

Davies was giving evidence to parliament’s Science and Technology Committee on 23 January as part of a one-off evidence session on the work of the chief medical officer. Her forthcoming annual report, due in the spring, would have a strong focus on the issue of increasing antimicrobial resistance, she said.

“The apocalyptic scenario is that when I need a new hip in 20 years I’ll die of a routine infection because we’ve run out of antibiotics,” Davies said. “For gonorrhoea, for example, there is only one useful antibiotic now, but cases of gonorrhoea in younger …
RAS Synthetic Lethal Screens Revisited: Still Seeking the Elusive Prize?
Authors: Julian Downward
Journal: Clinical Cancer Research (2015)

Abstract The RAS genes are critical oncogenic drivers activated by point mutation in some 20% of human malignancies. However, no pharmacologic approaches to targeting RAS proteins directly have yet succeeded, leading to suggestions that these proteins may be “undruggable.” This has led to two alternative indirect approaches to targeting RAS function in cancer. One has been to target RAS signaling pathways downstream at tractable enzymes such as kinases, particularly in combination. The other, which is the focus of this review, has been to seek targets that are essential in cells bearing an activated RAS oncogene, but not those without. This synthetic lethal approach, while rooted in ideas from invertebrate genetics, has been inspired most strongly by the successful use of PARP inhibitors, such as olaparib, in the clinic to treat BRCA defective cancers. Several large-scale screens have been carried out using RNA interference-mediated expression silencing to find genes that are uniquely essential to RAS-mutant but not wild-type cells. These screens have been notable for the low degree of overlap between their results, with the possible exception of proteasome components, and have yet to lead to successful new clinical approaches to the treatment of RAS-mutant cancers. Possible reasons for these disappointing results are discussed here, along with a reevaluation of the approaches taken. On the basis of experience to date, RAS synthetic lethality has so far fallen some way short of its original promise and remains unproven as an approach to finding effective new ways of tackling RAS-mutant cancers. Clin Cancer Res; 21(8); 1802–9. ©2015 AACR. See all articles in this CCR Focus section, “Targeting RAS-Driven Cancers.”
Management of Persistent Pain in the Older Patient
Authors: Una E. Makris, Robert C. Abrams, Barry Gurland, M. Carrington Reid
Journal: JAMA (2014)

Persistent pain is highly prevalent, costly, and frequently disabling in later life.To describe barriers to the management of persistent pain among older adults, summarize current management approaches, including pharmacologic and nonpharmacologic modalities; present rehabilitative approaches; and highlight aspects of the patient-physician relationship that can help to improve treatment outcomes. This review is relevant for physicians who seek an age-appropriate approach to delivering pain care for the older adult.Search of MEDLINE and the Cochrane database from January 1990 through May 2014, using the search terms older adults, senior, ages 65 and above, elderly, and aged along with non-cancer pain, chronic pain, persistent pain, pain management, intractable pain, and refractory pain to identify English-language peer-reviewed systematic reviews, meta-analyses, Cochrane reviews, consensus statements, and guidelines relevant to the management of persistent pain in older adults.Of the 92 identified studies, 35 evaluated pharmacologic interventions, whereas 57 examined nonpharmacologic modalities; the majority (n = 50) focused on older adults with osteoarthritis. This evidence base supports a stepwise approach with acetaminophen as first-line therapy. If treatment goals are not met, a trial of a topical nonsteroidal anti-inflammatory drug, tramadol, or both is recommended. Oral nonsteroidal anti-inflammatory drugs are not recommended for long-term use. Careful surveillance to monitor for toxicity and efficacy is critical, given that advancing age increases risk for adverse effects. A multimodal approach is strongly recommended-emphasizing a combination of both pharmacologic and nonpharmacologic treatments to include physical and occupational rehabilitation, as well as cognitive-behavioral and movement-based interventions. An integrated pain management approach is ideally achieved by cultivating a strong therapeutic alliance between the older patient and the physician.Treatment planning for persistent pain in later life requires a clear understanding of the patient's treatment goals and expectations, comorbidities, and cognitive and functional status, as well as coordinating community resources and family support when available. A combination of pharmacologic, nonpharmacologic, and rehabilitative approaches in addition to a strong therapeutic alliance between the patient and physician is essential in setting, adjusting, and achieving realistic goals of therapy.
Efficient Tumor Targeting with High-Affinity Designed Ankyrin Repeat Proteins: Effects of Affinity and Molecular Size
Authors: Christian Zahnd, Martin Kawe, Michael T. Stumpp, Christine de Pasquale, Rastislav Tamaskovic, Gabriela Nagy-Davidescu, Birgit Dreier, Roger Schibli, H. Kaspar Binz, Robert Waibel, Andreas Plückthun
Journal: Cancer Research (2010)

Slow-clearing, tumor-targeting proteins such as monoclonal antibodies typically exhibit high tumor accumulation but low tissue contrast, whereas intermediate-sized proteins such as scFvs show faster clearance but only moderate tumor accumulation. For both, tumor targeting does not seem to improve further above an optimal affinity. We show here that with very small high-affinity proteins such as designed ankyrin repeat proteins (DARPins), these limits can be overcome. We have systematically investigated the influence of molecular mass and affinity on tumor accumulation with DARPins with specificity for HER2 in SK-OV-3.ip nude mouse xenografts. DARPins with a mass of 14.5 kDa and affinities between 270 nmol/L and 90 pmol/L showed a strong correlation of tumor accumulation with affinity to HER2, with the highest affinity DARPin reaching 8% ID/g after 24 hours and 6.5% ID/g after 48 hours (tumor-to-blood ratio >60). Tumor autoradiographs showed good penetration throughout the tumor mass. Genetic fusion of two DARPins (30 kDa) resulted in significantly lower tumor accumulation, similar to values observed for scFvs, whereas valency had no influence on accumulation. PEGylation of the DARPins increased the circulation half-life, leading to higher tumor accumulation (13.4% ID/g after 24 hours) but lower tumor-to-blood ratios. Affinity was less important for tumor uptake of the PEGylated constructs. We conclude that two regimes exist for delivering high levels of drug to a tumor: small proteins with very high affinity, such as unmodified DARPins, and large proteins with extended half-life, such as PEGylated DARPins, in which the importance of affinity is less pronounced.
Randomised controlled trial of high concentration versus titrated oxygen therapy in severe exacerbations of asthma
Authors: K. Perrin, M. Wijesinghe, B. Healy, K. Wadsworth, R. Bowditch, S. Bibby, T. Baker, M. Weatherall, R. Beasley
Journal: Thorax (2011)

<h3>Background</h3> The effect on Paco<sub>2</sub> of high concentration oxygen therapy when administered to patients with severe exacerbations of asthma is uncertain. <h3>Methods</h3> 106 patients with severe exacerbations of asthma presenting to the Emergency Department were randomised to high concentration oxygen (8 l/min via medium concentration mask) or titrated oxygen (to achieve oxygen saturations between 93% and 95%) for 60 min. Patients with chronic obstructive pulmonary disease or disorders associated with hypercapnic respiratory failure were excluded. The transcutaneous partial pressure of carbon dioxide (Ptco<sub>2</sub>) was measured at 0, 20, 40 and 60 min. The primary outcome variable was the proportion of patients with a rise in Ptco<sub>2</sub> ≥4 mm Hg at 60 min. <h3>Results</h3> The proportion of patients with a rise in Ptco<sub>2</sub> ≥4 mm Hg at 60 min was significantly higher in the high concentration oxygen group, 22/50 (44%) vs 10/53 (19%), RR 2.3 (95% CI 1.2 to 4.4, p&lt;0.006). The high concentration group had a higher proportion of patients with a rise in Ptco<sub>2</sub> ≥8 mm Hg, 11/50 (22%) vs 3/53 (6%), RR 3.9 (95% CI 1.2 to 13.1, p=0.016). All 10 patients with a final Ptco<sub>2</sub> ≥45 mm Hg received high concentration oxygen therapy, and in five there was an increase in Ptco<sub>2</sub> ≥10 mm Hg. <h3>Conclusion</h3> High concentration oxygen therapy causes a clinically significant increase in Ptco<sub>2</sub> in patients presenting with severe exacerbations of asthma. A titrated oxygen regime is recommended in the treatment of severe asthma, in which oxygen is administered only to patients with hypoxaemia, in a dose that relieves hypoxaemia without causing hyperoxaemia. <h3>Clinical trial number</h3> ACTRN12607000131459.
Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease
Authors: C.A.D Smith, C.R Wolf, A.C Gough, N.K Spurr, P.N Leigh, B.A Summers, A.E Harding, D.M Maranganore, S.G Sturman, A.C Williams, A.H.V Schapira
Journal: The Lancet (1992)
HUMAN PANCREATIC GROWTH-HORMONE-RELEASING FACTOR SELECTIVELY STIMULATES GROWTH-HORMONE SECRETION IN MAN
Authors: MichaelO Thorner, Joachim Spiess, Mary Lee Vance, AlanD Rogol, DonaldL Kaiser, JoanD Webster, Jean Rivier, JoaoL Borges, StephenR Bloom, MichaelJ Cronin, WilliamS Evans, RobertM Macleod, Wylie Vale
Journal: The Lancet (1983)
Circulating precursors of human CD1c+ and CD141+ dendritic cells
Authors: Gaëlle Breton, Jaeyop Lee, Yu Jerry Zhou, Joseph J. Schreiber, Tibor Keler, Sarah Puhr, Niroshana Anandasabapathy, Sarah Schlesinger, Marina Caskey, Kang Liu, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2015)

Two subsets of conventional dendritic cells (cDCs) with distinct cell surface markers and functions exist in mouse and human. The two subsets of cDCs are specialized antigen-presenting cells that initiate T cell immunity and tolerance. In the mouse, a migratory cDC precursor (pre-CDC) originates from defined progenitors in the bone marrow (BM). Small numbers of short-lived pre-CDCs travel through the blood and replace cDCs in the peripheral organs, maintaining homeostasis of the highly dynamic cDC pool. However, the identity and distribution of the immediate precursor to human cDCs has not been defined. Using a tissue culture system that supports the development of human DCs, we identify a migratory precursor (hpre-CDC) that exists in human cord blood, BM, blood, and peripheral lymphoid organs. hpre-CDCs differ from premonocytes that are restricted to the BM. In contrast to earlier progenitors with greater developmental potential, the hpre-CDC is restricted to producing CD1c+ and CD141+ Clec9a+ cDCs. Studies in human volunteers demonstrate that hpre-CDCs are a dynamic population that increases in response to levels of circulating Flt3L.
Risk of Death With Nesiritide
Authors: J. Schuller Gortney
Journal: JAMA (2005)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Margaret McCartney: What use is mass flu vaccination?
Authors: M. McCartney
Journal: BMJ (2014)

It’s flu vaccination season again. People over 65 and those aged six months to 65 years who have a clinical risk factor (such as heart disease, asthma with regular inhaled steroid use, or chronic kidney disease) are eligible for the vaccine, along with people who live in residential care homes, pregnant women, and carers. Health and social care workers in direct contact with patients are also being encouraged to have the vaccine. But does it work?1 2 3 4

For each healthy adult, a Cochrane review found that vaccination saved an average of just 0.04 days off work and concluded that no evidence supported it as a routine public health measure.5 And among over 65s, Cochrane reviews found only poor quality data and were unable to draw conclusions of …
Androgen Deprivation With or Without Radiation Therapy for Clinically Node-Positive Prostate Cancer
Authors: Chun Chieh Lin, Phillip J. Gray, Ahmedin Jemal, Jason A. Efstathiou
Journal: JNCI Journal of the National Cancer Institute (2015)

Clinically lymph node–positive (cN+) prostate cancer (PCa) is an often-fatal disease. Its optimal management remains largely undefined given a lack of prospective, randomized data to inform practice. We sought to describe modern practice patterns in the management of cN+ PCa and assess the effect of adding radiation therapy (RT) to androgen deprivation therapy (ADT) on survival using the National Cancer Data Base. Patients with cN+ PCa and without distant metastases diagnosed between 2004 and 2011 were included. Five-year overall survival for patients diagnosed between 2004 and 2006 and treated with ADT alone or ADT+RT were compared. Propensity score (PS) matching was used to balance baseline characteristics, and Cox multivariate regression analysis was used to estimate hazard ratios (HRs) for all-cause mortality. Of 3540 total patients, 32.2% were treated with ADT alone and 51.4% received ADT+RT. Compared with ADT alone, patients treated with ADT+RT were younger and more likely to have private insurance, lower comorbidity scores, higher Gleason scores, and lower PSA values. After PS matching, 318 patients remained in each group. Compared with ADT alone, ADT+RT was associated with a 50% decreased risk of five-year all-cause mortality (HR = 0.50, 95% CI = 0.37 to 0.67, two-sided P < .001; crude OS rate: 71.5% vs 53.2%). Using a large national database, we have identified a statistically significant survival benefit for patients with cN+ PCa treated with ADT+RT. These data, if appropriately validated by randomized trials, suggest that a substantial proportion of such patients at high risk for prostate cancer death may be undertreated, warranting a reevaluation of current practice guidelines.
Report calls for better UK coordination to solve devolution problems
Authors: A. O'Dowd
Journal: BMJ (2008)

The four national governments in the United Kingdom need to work far more closely and to coordinate formally over health issues or face growing conflict, a major report says.

Since 1999, devolution has meant ever widening differences in health policy between the four countries, and lack of coordination will damage all four healthcare systems, warns the report by the health policy think tank the Nuffield Trust.

Its report says that extensive overlaps and complexities have arisen since devolution was agreed, leading to “messy intergovernmental relations.” Its findings are drawn from research and extensive interviews carried out over the past seven years.

A basic problem, says the report, is that the current …
Candesartan restored cardiac Hsp72 expression and tolerance against reperfusion injury in hereditary insulin-resistant rats
Authors: Y. Taniguchi, N. Takahashi, A. Fukui, Y. Nagano-Torigoe, L. C. Thuc, Y. Teshima, T. Shinohara, O. Wakisaka, T. Ooie, Y. Murozono, K. Yufu, M. Nakagawa, M. Hara, H. Yoshimatsu, T. Saikawa
Journal: Cardiovascular Research (2011)

We tested the hypothesis that candesartan, an angiotensin II (AII) type 1 receptor antagonist, would restore the depressed phosphatidylinositol 3 (PI3) kinase-dependent Akt phosphorylation, an essential signal to induce heat-shock protein 72 (Hsp72) in response to hyperthermia, in Otsuka Long-Evans Tokushima fatty (OLETF) rats.At 14 weeks of age, male OLETF rats and Long-Evans Tokushima Otsuka (LETO) rats were treated with candesartan (0.25 mg/kg/day) for 2 weeks. Thereafter, hyperthermia (43°C for 20 min) was applied. We observed the following: (i) Candesartan did not improve insulin sensitivity in OLETF rats. (ii) Candesartan restored depressed PI3 kinase-dependent Akt phosphorylation and Hsp72 expression in OLETF rat hearts. (iii) Cardiac ventricular tissue contents of AII were greater in OLETF rats, which were suppressed by candesartan. (iv) Cardiac levels of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphorylation were greater in OLETF rats, which were suppressed by candesartan. In cultured cardiomyocytes, application of AII induced PTEN phosphorylation, which was suppressed by candesartan. (v) In high-fat diet insulin-resistant rats, similar results were observed with respect to Hsp72 expression, Akt phosphorylation and PTEN phosphorylation. (vi) In isolated, perfused heart experiments, reperfusion-induced cardiac functional recovery was suppressed in OLETF rat hearts, which was improved by candesartan.Our results suggest that the depression of PI3 kinase-dependent Akt activation in response to hyperthermia in OLETF rats can be restored by candesartan. Substantial activation of the renin-angiotensin system, represented by increased myocardial AII content and subsequent PTEN phosphorylation, may underlie the pathogenesis which is ameliorated by candesartan.
Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials
Authors: E. Litton, J. Xiao, K. M. Ho
Journal: BMJ (2013)

<b>Objectives</b> To evaluate the efficacy and safety of intravenous iron, focusing primarily on its effects on haemoglobin, requirement for transfusion, and risk of infection. <b>Design </b>Systematic review and meta-analysis of randomised controlled trials investigating the safety and efficacy of intravenous iron therapy. <b>Data sources </b>Randomised controlled trials from Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1966 to June 2013, with no language restrictions. <b>Eligibility criteria for selecting studies</b> Eligible trials were randomised controlled trials of intravenous iron compared with either no iron or oral iron. Crossover and observational studies were excluded. <b>Main outcome measures</b> Change in haemoglobin concentration and risk of allogeneic red blood cell transfusion (efficacy) and risk of infection (safety). <b>Results </b>Of the 75 trials meeting the inclusion criteria, 72 studies including 10 605 patients provided quantitative outcome data for meta-analysis. Intravenous iron was associated with an increase in haemoglobin concentration (standardised mean difference 6.5 g/L, 95% confidence interval 5.1 g/L to 7.9 g/L) and a reduced risk of requirement for red blood cell transfusion (risk ratio 0.74, 95% confidence interval 0.62 to 0.88), especially when intravenous iron was used with erythroid stimulating agents (ESAs) or in patients with a lower baseline plasma ferritin concentration. There were no significant interactions between the efficacy of intravenous iron and type or dose administered. Intravenous iron was, however, associated with a significant increase in risk of infection (relative risk 1.33, 95% confidence interval 1.10 to 1.64) compared with oral or no iron supplementation. The results remained similar when only high quality trials were analysed. <b>Conclusions </b>Intravenous iron therapy is effective in increasing haemoglobin concentration and reducing the risk of allogeneic red blood cell transfusion and could have broad applicability to a range of acute care settings. This potential benefit is counterbalanced by a potential increased risk of infection.
Can amiodarone induce hyperglycaemia and hypertriglyceridaemia?
Authors: A Politi, G Poggio, A Margiotta
Journal: BMJ (1984)

Volume of dead space and equivalent units of insulin in five syringes Volume ofEquivalent Type of syringe dead space (ml) units of insulin Old BS 1619 2 ml glass insulin syringe (U20 insulin) + 26 gauge, 0-5 inch needle 1-26 (U20), (Everett) 0-063 2-52 (U40) New BS 1619 1 ml glass insulin syringe (UIOO insulin) + 26 gauge, 0-5 inch needle (Rand Rocket) 0-051 5 1 (UIOO) New BS 1619 0 5 ml glass insulin syringe (UI00 insulin) + 26 gauge, 0-5 inch needle (Rand Rocket) 0-05 5 (U100) BD Plastipak 1 ml plastic disposable syringe (U100 insulin) with integral 27 gauge, 0-5 inch needle 0 0111 1 (U100) *Glycosuria developed during treatment.
CDC25A Phosphatase: a Rate-Limiting Oncogene That Determines Genomic Stability
Authors: Dipankar Ray, Hiroaki Kiyokawa
Journal: Cancer Research (2008)

Abstract CDC25A is a critical regulator of cell cycle progression and checkpoint response. Overexpression of this cyclin-dependent kinase phosphatase occurs often in human cancers. Our recent genetic studies in the mouse indicate that restricting CDC25A can limit tumorigenesis induced by the HER2/neu-RAS oncogenic pathway without compromising normal cell division or viability. These findings offer a sound foundation to justify development of CDC25A inhibitors for antitumor therapy. [Cancer Res 2008;68(5):1251–3]