tbuckley/cabot-search huggingface dataset:
Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials
Authors: Arthur Kavanaugh, Christopher Ritchlin, Proton Rahman, Lluis Puig, Alice B Gottlieb, Shu Li, Yuhua Wang, Lenore Noonan, Carrie Brodmerkel, Michael Song, Alan M Mendelsohn, Iain B McInnes
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> Evaluate ustekinumab, an anti-interleukin (IL)-12 and IL-23 antibody, effects on radiographic progression in psoriatic arthritis (PsA). <h3>Methods</h3> We conducted preplanned integrated analyses of combined radiographic data from PSUMMIT-1 and PSUMMIT-2 phase 3, randomised, controlled trials. Patients had active PsA despite prior conventional and/or biologic disease-modifying antirheumatic drugs (≥5/66 swollen, ≥5/68 tender joints, C-reactive protein ≥3.0 mg/L, documented plaque psoriasis). Patients (PSUMMIT-1, n=615; PSUMMIT-2, n=312) were randomised to ustekinumab 45 mg, 90 mg, or placebo, at weeks (wk) 0, 4 and every (q) 12 wks. At wk 16, patients with &lt;5% improvement in tender/swollen joint counts entered blinded early escape. All other placebo patients received ustekinumab 45 mg at wk 24 and wk 28, then q 12 wks. Radiographs of hands/feet at wks 0/24/52 were assessed using PsA-modified van der Heijde-Sharp (vdH-S) scores; combined PSUMMIT-1 and PSUMMIT-2 changes in total vdH-S scores from wk 0 to wk 24 comprised the prespecified primary radiographic analysis. Treatment effects were assessed using analysis of variance on van der Waerden normal scores (factors=treatment, baseline methotrexate usage, and study). <h3>Results</h3> Integrated data analysis results indicated that ustekinumab-treated patients (regardless of dose) demonstrated significantly less radiographic progression at wk 24 than did placebo recipients (wk 0–24 total vdH-S score mean changes: 0.4-combined/individual ustekinumab dose groups, 1.0-placebo; all p&lt;0.02). From wk 24 to wk 52, inhibition of radiographic progression was maintained for ustekinumab-treated patients, and progression was substantially reduced among initial placebo recipients who started ustekinumab at wk 16 or wk 24 (wk 24 – wk 52, total vdH-S score mean change: 0.08). <h3>Conclusions</h3> Ustekinumab 45 and 90 mg treatments significantly inhibited radiographic progression of joint damage in patients with active PsA.
A Nonsimultaneous, Extended, Altruistic-Donor Chain
Authors: Michael Kenneth Rees, Jonathan E. Kopke, Ronald P. Pelletier, Dorry L. Segev, Matthew E. Rutter, Alfredo J. Fabrega, Jeffrey David Rogers, Oleh G. Pankewycz, Janet Hiller, Alvin E. Roth, Tuomas Sandholm, M. Utku Ünver, Robert Armstrong Montgomery
Journal: New England Journal of Medicine (2009)

We report a chain of 10 kidney transplantations, initiated in July 2007 by a single altruistic donor (i.e., a donor without a designated recipient) and coordinated over a period of 8 months by two large paired-donation registries. These transplantations involved six transplantation centers in five states. In the case of five of the transplantations, the donors and their coregistered recipients underwent surgery simultaneously. In the other five cases, "bridge donors" continued the chain as many as 5 months after the coregistered recipients in their own pairs had received transplants. This report of a chain of paired kidney donations, in which the transplantations were not necessarily performed simultaneously, illustrates the potential of this strategy.
Regulation of the medical profession: fantasy, reality and legality
Authors: A. Samanta, J. Samanta
Journal: Journal of the Royal Society of Medicine (2004)

The past decade witnessed a series of high-profile inquiries that cast a noxious miasma over the medical profession and provoked demands for strict regulation. Somehow, a balance must be struck whereby the public can be confident that doctors practise competently, with due regard to ethical and technical standards, yet the regulations are not so overwhelming as to represent a sword of Damocles permanently hanging over doctors' heads. This article explores the current regulatory framework, exclusion from the workplace, serious professional misconduct and seriously deficient performance. The General Medical Council deals with a large number of regulatory cases each year, of which a small proportion are appealed. As well as providing valuable insight into judicial thought, case law in this area is helpful in understanding the balance between social policy and medical regulation.
THERAPEUTIC EFFECTIVENESS OF PENICILLIN IN EXPERIMENTAL MURINE TYPHUS INFECTION IN dba MICE
Authors: Vicente Moragues, Henry Pinkerton, Donald Greiff
Journal: The Journal of Experimental Medicine (1944)

The administration of penicillin in relatively large but non-toxic doses to dba mice after injection with murine typhus rickettsiae resulted in a marked reduction in mortality, particularly when the initial dosage of rickettsiae was relatively small, approaching the minimal lethal dose. No evidence of secondary bacterial infection was obtained by bacteriological and histological studies, and it seems justifiable to conclude that the greatly increased survival rate in the treated mice was caused by the action of penicillin on typhus rickettsiae. The theoretical and practical implications of the results are discussed.
P164 Enabling next day processing of blood samples with T-SPOT.TB
Authors: I. Durrant, J. Radcliffe
Journal: Thorax (2010)

<h3>Introduction</h3> The T-SPOT<sup>®</sup>.<i>TB</i> assay involves the collection of peripheral blood samples for analysis of the T cell response to TB-specific antigens. Traditionally the blood sample has been required to be processed on the same day as it is collected. This study was designed to investigate a new procedure, for use in combination with the T-SPOT.<i>TB</i> assay, which offers the potential to initiate the antigen stimulation the day following blood collection, thereby allowing overnight transportation of samples from the point of collection to a processing laboratory. <h3>Methodology</h3> Subjects were enrolled at two sites; one in the UK and one in South Africa. Patients all provided informed consent and a brief medical history; blood samples were taken into two lithium heparin tubes. One tube was selected for immediate testing by the T-SPOT.<i>TB</i> assay. The second tube was stored overnight at room temperature. Immediately prior to testing the stored blood sample, the T-Cell <i>Xtend</i> reagent (Oxford Immunotec Ltd, UK) was added to the sample and incubated for 20 min. <h3>Results</h3> A total of 208 participants were enrolled into the study and 3/208 (1.4%) subjects were excluded due to blood collection errors at enrolment. Of the 205 samples available for analysis, 10/205 (4.9%) failed to yield a valid T-SPOT.<i>TB</i> test result with either the fresh blood (3 samples) or the stored blood (7 samples) leaving 195 paired results with both fresh and stored blood samples for analysis (see Abstract P164 Table 1). The overall agreement for the study was 97.9% (191/195); 95% CI 94.8 to 99.4%, with a kappa value of 0.943 which indicates excellent agreement. <h3>Conclusions</h3> The T-SPOT.<i>TB</i> assay on overnight stored blood samples, when combined with a pre-incubation step utilising the T-Cell <i>Xtend</i> reagent, yields results that are equivalent to those obtained with fresh blood samples. This allows, when combined with overnight shipment to a central testing facility, greater flexibility in when and where blood samples can be collected.
Subnuclear cyclin D3 compartments and the coordinated regulation of proliferation and immunoglobulin variable gene repression
Authors: Sarah E. Powers, Malay Mandal, Satoshi Matsuda, Ana V. Miletic, Matthew H. Cato, Azusa Tanaka, Robert C. Rickert, Shigeo Koyasu, Marcus R. Clark
Journal: The Journal of Experimental Medicine (2012)

Ubiquitously expressed D-type cyclins are required for hematopoiesis but are dispensable in other cell lineages. Furthermore, within different hematopoietic progenitor populations the D-type cyclins play nonredundant roles. The basis of this lineage and developmental specificity is unknown. In pro–B cells we demonstrate four distinct nuclear D-type cyclin compartments, including one cyclin D3 fraction associated with CDK4 and another phosphoinositide 3-kinase–regulated fraction not required for proliferation. A third fraction of cyclin D3 was associated with the nuclear matrix and repression of &amp;gt;200 genes including the variable (V) gene segments Igkv1-117, Iglv1, and Igh-VJ558. Consistent with different subnuclear compartments and functions, distinct domains of cyclin D3 mediated proliferation and Igk V gene segment repression. None of the cyclin D3 nuclear compartments overlapped with cyclin D2, which was distributed, unbound to CDK4, throughout the nucleus. Furthermore, compartmentalization of the cyclins appeared to be lineage restricted because in fibroblasts, cyclin D2 and cyclin D3 occupied a single nuclear compartment and neither bound CDK4 efficiently. These data suggest that subnuclear compartmentalization enables cyclin D3 to drive cell cycle progression and repress V gene accessibility, thereby ensuring coordination of proliferation with immunoglobulin recombination.
VARIATION IN THE PLANE OF CELL CLEAVAGE DURING THE PROCESS OF STRATIFICATION IN THE MOUSE EPIDERMIS
Authors: I. H. M. SMART
Journal: British Journal of Dermatology (1970)

SUMMARY. The location and orientation of mitotic figures were recorded in the developing mouse epidermis from the initiation of stratification in the embryo to 32 days of post‐natal age. It was found that in the single‐layered stage mitotic figures were orientated to give a plane of cleavage at right angles to the epithelial surface to give daughter cells lying side by side, and that from the onset of stratification until the beginning of keratinization some 75–85% of mitotic figures in the basal layer were orientated to give horizontal cleavage, leaving one daughter cell on the basal layer and the other in the layer above. This contrasted with the orientation of the numerous mitotic figures in the supra‐basal layer, where 75–85% were partitioning vertically. In the later stages of stratification up to 32 days of post‐natal life, there was a progressive decline of mitotic figures outside the basal layer and a return of mitotic orientation in the basal layer to the vertical position. It was concluded that during the initiation of stratification superficial cells are recruited from the superficial daughter cells of horizontally cleaving basal cells whereas in the established keratinized epithelium these cells originate from upward migration of interphase basal cells.
Acid phosphatase activity in carcinoma of the bronchus
Authors: D. P. Nicholls, J. S. Davies
Journal: Thorax (1977)

<b>Nicholls, D. P. and Davies, J. S. (1977).</b><i>Thorax</i>, <b>32</b>, 472-477. <b>Acid phosphatase activity in carcinoma of the bronchus.</b> Two cases are presented in which an undifferentiated small-cell carcinoma of the bronchus was associated with a considerably raised serum tartrate-labile acid phosphatase concentration. In neither case was there any evidence of a carcinoma of the prostate which, with a few rare exceptions, is the only condition associated with such increased enzyme activity. A survey of acid phosphatase concentrations in 30 other male patients with carcinoma of the bronchus showed that five patients had a raised total acid phosphatase concentration, but only one patient had a raised tartrate-labile acid phosphatase concentration. When the histological type was taken into account, elevated total acid phosphatase concentrations were associated with squamous-cell and adenocarcinoma but not with undifferentiated, small-cell carcinoma. Raised tartrate-labile acid phosphatase concentrations were associated only with squamous-cell carcinoma, in contradistinction to the two individual cases reported. In no group was there any correlation between acid and alkaline phosphatase concentrations. Histological studies in one of our patients showed little tissue acid phosphatase staining in the primary tumours but intense staining in the cytoplasm of pancreatic cells surrounding a metastasis. Sections of pancreas from six normal subjects showed only slight tissue acid phosphatase activity. The possible sources of the increased serum acid phosphatase are discussed, and it is suggested that the pancreas could be the source of such increased activity in our second case.
Human Monocytes Undergo Functional Re-programming during Sepsis Mediated by Hypoxia-Inducible Factor-1α
Authors: Irina N. Shalova, Jyue Yuan Lim, Manesh Chittezhath, Annelies S. Zinkernagel, Federico Beasley, Enrique Hernández-Jiménez, Victor Toledano, Carolina Cubillos-Zapata, Annamaria Rapisarda, Jinmiao Chen, Kaibo Duan, Henry Yang, Michael Poidinger, Giovanni Melillo, Victor Nizet, Francisco Arnalich, Eduardo López-Collazo, Subhra K. Biswas
Journal: Immunity (2015)
Prognostic Value of Plasma von Willebrand Factor and Soluble P-Selectin as Indices of Endothelial Damage and Platelet Activation in 994 Patients With Nonvalvular Atrial Fibrillation
Authors: Dwayne S.G. Conway, Lesly A. Pearce, Bernard S.P. Chin, Robert G. Hart, Gregory Y.H. Lip
Journal: Circulation (2003)

Background— Abnormal plasma markers of a prothrombotic state have been described in atrial fibrillation (AF), but no such marker has yet been shown to reliably predict future stroke or cardiovascular outcome in AF. We hypothesized that raised plasma levels of von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and/or soluble P-selectin (sP-sel, an index of platelet activation) might predict vascular events in AF. Methods and Results— We measured vWf and sP-sel levels by ELISA in 994 participants receiving aspirin in the Stroke Prevention in Atrial Fibrillation III trial, at study entry or after 3 months, and related these indices to the subsequent incidence of stroke and vascular events. Plasma vWf levels were a significant predictor of both stroke ( P =0.03) and vascular events ( P &lt;0.001), with the greatest risk for those with the highest levels of vWf. After adjustment for other clinical predictors, the relationship between vWf and stroke became nonsignificant, but vWf remained an independent predictor of vascular events (relative risk, 1.2 [95% CI, 1.0–1.4] per 20 IU/dL increase in vWf; P =0.02). No significant relationships were found between sP-sel levels and outcome. Conclusion— Among patients with AF who received aspirin, raised levels of vWf (endothelial damage/dysfunction) were predictive of stroke and vascular events, but raised sP-sel levels (platelet activation) were not associated with increased cardiovascular risk. Endothelial damage/dysfunction (or vWf itself) may play an important role in the mechanisms behind stroke and cardiovascular outcome among aspirin-treated AF patients and might represent a target for novel therapies or an adjunctive aid to risk stratification in AF.
Virus isolation, genetic characterization and seroprevalence of Toscana virus in Algeria
Authors: C. Alkan, A.B. Allal-Ikhlef, S. Alwassouf, A. Baklouti, G. Piorkowski, X. de Lamballerie, A. Izri, R.N. Charrel
Journal: Clinical Microbiology and Infection (2015)
Phase I, Pharmacokinetic, and Pharmacodynamic Study of Intravenously Administered Ad5CMV-p53, an Adenoviral Vector Containing the Wild-Type <i>p53</i> Gene, in Patients With Advanced Cancer
Authors: Anthony W. Tolcher, Desiree Hao, Johann de Bono, Alex Miller, Amita Patnaik, Lisa A. Hammond, Leslie Smetzer, Jill Van Wart Hood, James Merritt, Eric K. Rowinsky, Chris Takimoto, Dan Von Hoff, S. Gail Eckhardt
Journal: Journal of Clinical Oncology (2006)

Purpose The purpose of this study was to assess the feasibility of administering Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene to patients with advanced malignancies, characterize the pertinent pharmacokinetic parameters, identify evidence of viral uptake in both normal and tumor tissue, and seek evidence of antitumor activity. Methods Patients were treated with escalating doses of Ad5CMV-p53 intravenously over 30 minutes on days 1, 2, and 3, every 28 days. The clearance of circulating Ad5CMV-p53 (INGN 201) DNA was characterized in the plasma and paired tumor and skin biopsies were performed in patients treated at the two highest dose levels to assess vector uptake into tissues. Results Seventeen patients received 36 courses of Ad5CMV-p53 at doses ranging from 3 × 10 10 to 3 × 10 12 virus particles (vp). Fatigue, nausea, vomiting, and fever were common, but rarely severe. Abnormalities of coagulation parameters, including decreases in fibrinogen and increases in fibrin degradation products at 3 × 10 12 vp, precluded additional dose escalation. Ad5CMV-p53 DNA could be detected in the plasma by polymerase chain reaction assay in the majority of patients at 14 days and 28 days at doses of 3 × 10 10 and higher. Six patients treated at 1 × 10 12 vp and 3 × 10 12 vp dose levels had Ad5CMV-p53 DNA detected within paired tumor tissue collected day 4. Conclusion Ad5CMV-p53 can be safely and repetitively administered up to 1 × 10 12 vp intravenously daily for 3 consecutive days. The absence of severe toxicities, the presence of circulating adenovirus 24 hours after administration, and detectable p53 transgene within tumor tissue distant from the site of administration demonstrates that systemic therapy with this adenoviral vector containing p53 is feasible.
Cardiac Troponin I Predicts Short-Term Mortality in Vascular Surgery Patients
Authors: Lauren J. Kim, Elizabeth A. Martinez, Nauder Faraday, Todd Dorman, Lee A. Fleisher, Bruce A. Perler, G. Melville Williams, Daniel Chan, Peter J. Pronovost
Journal: Circulation (2002)

Cardiac troponin I (cTnI) is a highly sensitive and specific marker for myocardial injury that predicts outcomes in patients with acute coronary syndromes. Cardiovascular complications are the leading cause of morbidity and mortality in patients who have undergone vascular surgery. However, postoperative surveillance with cardiac enzymes is not routinely performed in these patients. We evaluated the association between postoperative cTnI levels and 6-month mortality and perioperative myocardial infarction (MI) after vascular surgery.Two hundred twenty-nine patients having aortic or infrainguinal vascular surgery or lower extremity amputation were included in this study. Blood samples were analyzed for cTnI immediately after surgery and the mornings of postoperative days 1, 2, and 3. An elevated cTnI was defined as serum concentrations >1.5 ng/mL in any of the 4 samples. Twenty-eight patients (12%) had postoperative cTnI >1.5 ng/mL, which was associated with a 6-fold increased risk of 6-month mortality (adjusted OR, 5.9; 95% CI, 1.6 to 22.4) and a 27-fold increased risk of MI (OR, 27.1; 95% CI, 5.2 to 142.7). Furthermore, we observed a dose-response relation between cTnI concentration and mortality. Patients with cTnI >3.0 ng/mL had a significantly greater risk of death compared with patients with levels < or =0.35 ng/mL (OR, 4.9; 95% CI, 1.3 to 19.0).Routine postoperative surveillance for cTnI is useful for identifying patients who have undergone vascular surgery who have an increased risk for short-term mortality and perioperative MI. Further research is needed to determine whether intervention in these patients can improve outcome.
Simultaneous alignment of short reads against multiple genomes
Authors: Korbinian Schneeberger, Jörg Hagmann, Stephan Ossowski, Norman Warthmann, Sandra Gesing, Oliver Kohlbacher, Detlef Weigel
Journal: Genome biology (2009)

Genome resequencing with short reads generally relies on alignments against a single reference. GenomeMapper supports simultaneous mapping of short reads against multiple genomes by integrating related genomes (e.g., individuals of the same species) into a single graph structure. It constitutes the first approach for handling multiple references and introduces representations for alignments against complex structures. Demonstrated benefits include access to polymorphisms that cannot be identified by alignments against the reference alone. Download GenomeMapper at http://1001genomes.org.
Nonpharmacologic Management of Behavioral Symptoms in Dementia
Authors: Laura N. Gitlin, Helen C. Kales, Constantine G. Lyketsos
Journal: JAMA (2012)

Behavioral symptoms such as repetitive speech, wandering, and sleep disturbances are a core clinical feature of Alzheimer disease and related dementias. If untreated, these behaviors can accelerate disease progression, worsen functional decline and quality of life, cause significant caregiver distress, and result in earlier nursing home placement. Systematic screening for behavioral symptoms in dementia is an important prevention strategy that facilitates early treatment of behavioral symptoms by identifying underlying causes and tailoring a treatment plan. First-line nonpharmacologic treatments are recommended because available pharmacologic treatments are only modestly effective, have notable risks, and do not effectively treat some of the behaviors that family members and caregivers find most distressing. Examples of nonpharmacologic treatments include provision of caregiver education and support, training in problem solving, and targeted therapy directed at the underlying causes for specific behaviors (eg, implementing nighttime routines to address sleep disturbances). Based on an actual case, we characterize common behavioral symptoms and describe a strategy for selecting evidence-based nonpharmacologic dementia treatments. Nonpharmacologic management of behavioral symptoms in dementia can significantly improve quality of life and patient-caregiver satisfaction.
A CONSIDERATION OF THE RELATIVE TOXICITY OF URANIUM NITRATE FOR ANIMALS OF DIFFERENT AGES. I
Authors: William deB. MacNider
Journal: The Journal of Experimental Medicine (1917)

1. The toxic effect of uranium when given in a constant quantity per kilo of body weight is variable. This variation has been constantly associated with differences in the age of the animals. Uranium is more toxic for an old animal than for a young animal. The establishment of this fact, namely, that the age of an animal may modify the toxicity of a substance, should be taken into account in establishing by animal experiment the degree of activity of substances which are to be used for therapeutic purposes. 2. The toxic effect of uranium nitrate is constantly associated with its ability to induce a tissue acidosis. A severer grade of acidosis is induced in an old animal from uranium than is induced in a young animal. It would appear that in the response of dogs of different ages to uranium the animals represent a reaction system to this substance which shows an increasing susceptibility as the animal advances from youth to senility. Insufficient experimental data are as yet available to allow a discussion of the mechanism by which such an acid intoxication is produced. 3. The toxic effect of uranium is manifested locally by certain degenerative changes in the kidney. These changes are more marked in the kidney of an old animal than they are in the kidney of a young animal. Associated with the severer kidney changes which are especially characterized by a beginning swelling of the renal epithelium and by an accumulation of stainable fat in these cells is the development of a severe grade of tissue acidosis. 4. The functional capacity of the kidney shows a parallel with the degree of acid intoxication and with the severity of the histological changes which have developed in the renal epithelium.