tbuckley/cabot-search huggingface dataset:
Combination Treatment With Varenicline and Bupropion in an Adaptive Smoking Cessation Paradigm
Authors: Jed E. Rose, Frédérique M. Behm
Journal: American Journal of Psychiatry (2014)

The authors assessed the efficacy and safety of combination treatment with varenicline and sustained-release bupropion for smokers who, based on an assessment of initial smoking reduction prior to the quit date, were deemed unlikely to achieve abstinence using nicotine patch treatment.In a randomized, double-blind, parallel-group adaptive treatment trial, the authors identified 222 cigarette smokers who failed to show a reduction of more than 50% in smoking after 1 week of nicotine patch treatment. Smokers were randomly assigned to receive 12 weeks of varenicline plus bupropion or varenicline plus placebo. The primary outcome measure was continuous smoking abstinence at weeks 8-11 after the target quit date.Both treatments were well tolerated. Participants who received the combination treatment had a significantly higher abstinence rate than those who received varenicline plus placebo (39.8% compared with 25.9%; odds ratio=1.89; 95% CI=1.07, 3.35). Combination treatment had a significantly greater effect on abstinence rate in male smokers (odds ratio=4.26; 95% CI=1.73, 10.49) than in female smokers (odds ratio=0.94; 95% CI=0.43, 2.05). It also had a significantly greater effect in highly nicotine-dependent smokers (odds ratio=3.51, 95% CI=1.64, 7.51) than in smokers with lower levels of dependence (odds ratio=0.71, 95% CI=0.28, 1.80).Among smokers who did not show a sufficient initial response to prequit nicotine patch treatment, combination treatment with varenicline and bupropion proved more efficacious than varenicline alone for male smokers and for smokers with a high degree of nicotine dependence.
Are Randomized Controlled Trials Controlled? Patient Preferences and Unblind Trials
Authors: Klim Mcpherson, Annie R Britton, John E Wennberg
Journal: Journal of the Royal Society of Medicine (1997)

The most reliable information about treatment effects comes from randomized controlled trials (RCTs). However, the possibility of subtle interactions—for example, between treatment preferences and treatment effects—is generally subordinated in the quest for evidence about main treatment effects. If patient preferences can influence the effectiveness of treatments through poorly understood (psychological) pathways, then RCTs, particularly when unblinded, may wrongly attribute effects solely to a treatment's physiological/pharmacological properties. To interpret the RCT evidence base it is important to know whether any preference effects exist and, if so, by how much they affect outcome. Reliable measurement of these effects is difficult and will require new approaches to the conduct of trials. In view of the fanciful image with which such effects are portrayed and the uncertainties about their true nature and biological mechanisms, existing evidence is unlikely to provide sufficient justification for investment in trials. This is a Catch 22. Until an escape is found we might never know, even approximately, how much of modern medicine is attributable to psychological processes.
<i>In vivo</i> Cytotoxicity of Type I CD20 Antibodies Critically Depends on Fc Receptor ITAM Signaling
Authors: Simone de Haij, J.H. Marco Jansen, Peter Boross, Frank J. Beurskens, Jantine E. Bakema, Desiree L. Bos, Anton Martens, J. Sjef Verbeek, Paul W.H.I. Parren, Jan G.J. van de Winkel, Jeanette H.W. Leusen
Journal: Cancer Research (2010)

Antibody-Fc receptor (FcR) interactions play an important role in the mechanism of action of most therapeutic antibodies against cancer. Effector cell activation through FcR triggering may induce tumor cell killing via antibody-dependent cellular cytotoxicity (ADCC). Reciprocally, FcR cross-linking of antibody may lead to the induction of apoptotic signaling in tumor cells. The relative importance of these bisecting pathways to in vivo antibody activity is unknown. To unravel these roles, we developed a novel mouse model with normal FcR expression but in which FcR signaling was inactivated by mutation of the associated gamma-chain. Transgenic mice showed similar immune complex binding compared with wild-type mice. In contrast, ADCC of cells expressing frequently used cancer targets, such as CD20, epidermal growth factor receptor, Her2, and gp75, was abrogated. Using the therapeutic CD20 antibodies ofatumumab and rituximab, we show that FcR cross-linking of antibody-antigen immune complexes in the absence of gamma-chain signaling is insufficient for their therapeutic activity in vivo. ADCC therefore represents an essential mechanism of action for immunotherapy of lymphoid tumors.
Combinational FLt3 Ligand and Granulocyte Macrophage Colony-Stimulating Factor Treatment Promotes Enhanced Tumor Infiltration by Dendritic Cells and Antitumor CD8+ T-Cell Cross-priming but Is Ineffective as a Therapy
Authors: Aklile Berhanu, Jian Huang, Sean M. Alber, Simon C. Watkins, Walter J. Storkus
Journal: Cancer Research (2006)

Abstract Dendritic cells play significant roles in the development and maintenance of antitumor immune responses. Therapeutic recruitment of dendritic cells into the tumor microenvironment has the potential to result in enhanced antitumor T-cell cross-priming against a broad array of naturally processed and presented tumor-associated antigens. We have observed that the treatment of BALB/c mice bearing syngeneic CMS4 sarcomas with the combination of recombinant Flt3 ligand and recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) for five sequential days is sufficient to optimize the number of tumor-infiltrating dendritic cells (TIDC). However, despite the significant increase in the number of TIDCs, the therapeutic benefit of Flt3 ligand and GM-CSF treatment is minimal. Therapy-associated TIDCs do not exhibit a “suppressed” or “suppressor” phenotype in vitro, and their enhanced numbers in cytokine-treated mice were associated with increased levels of peripheral antitumor CD8+ T effector cells and with an augmented population of CD8+ tumor-infiltrating lymphocytes (TIL). These data suggest that Flt3 ligand + GM-CSF therapy of murine tumors fails at a mechanistic point that is downstream of specific T-cell priming by therapy-induced TIDCs and the recruitment of these T cells into the tumor microenvironment. Based on the enhanced infiltration of tumors by CD4+CD25+ TIL in Flt3 ligand + GM-CSF–treated mice, this could reflect the dominant influence of regulatory T cells in situ. (Cancer Res 2006; 66(9): 4895-903)
STUDIES ON THE SUPRARENAL CORTEX
Authors: George A. Harrop, Louis J. Soffer, Read Ellsworth, John H. Trescher
Journal: The Journal of Experimental Medicine (1933)

A characteristic alteration in the electrolyte structure of the blood plasma of the suprarenalectomized dog occurs when injections of cortical extract are stopped. This alteration progresses during the course of the suprarenal insufficiency, parallel with the hemoconcentration and the loss in weight. When injections of cortical extract are resumed, the electrolyte structure returns to its original form, the alterations paralleling the dilution of the blood and the return of the body weight to its original level. The hemoconcentration, with the resulting physiological changes which take place in the suprarenalectomized dog after the cessation of cortical extract injections, is associated with a loss of sodium and chloride, accompanied by their proper complement of body water, by way of the kidney. Since this effect is produced in the suprarenalectomized animal, well nourished and in excellent condition, solely by cessation of injections of the cortical hormone, and since the reverse process of repair of the electrolyte and water losses can be effected solely by resumption of extract injections, it follows that all of the observed phenomena are due to this cause, and to this alone. It can be concluded that one function of the cortical extract in the suprarenalectomized dog is that of participation in the regulation of the sodium and chloride metabolism, and consequently, of the balance and distribution of water. The loss of water, in the absence of the cortical hormone, is sustained partly by the blood plasma, but to a far greater extent by the interstitial body fluid. The available evidence points to the kidney as the locus of this regulatory function of the cortical hormone.
News Media Coverage of Screening Mammography for Women in Their 40s and Tamoxifen for Primary Prevention of Breast Cancer
Authors: Lisa M. Schwartz
Journal: JAMA (2002)

ContextIn the late 1990s, 3 events pertaining to breast cancer prevention received considerable attention in the US news media: a National Institutes of Health (NIH) consensus panel recommended against routine screening mammography for women in their 40s (January 1997), the National Cancer Institute (NCI) subsequently reversed the recommendation (March 1997), and an NCI-sponsored study demonstrated the efficacy of tamoxifen in the primary prevention of breast cancer (April 1998).ObjectiveTo examine how the major US news media covered the potential benefits and harms of 2 breast cancer preventive strategies.Design and SettingContent analysis of US news stories reporting on the breast cancer prevention events. We used Lexis-Nexis to search for print news stories in the 10 highest-circulation US newspapers and requested transcripts from 3 major television networks to obtain all relevant news coverage in the 2 weeks following each event.Main Outcome MeasuresAttitude toward preventive strategy (encourage, neutral, discourage); level of uncertainty about benefit and how benefits and harms were presented.ResultsTwenty-seven stories about the NIH consensus panel, 24 about the NCI reversal, and 34 about tamoxifen appeared in high-profile news media within 2 weeks of each event. Sixty-seven percent of NIH consensus panel stories left the impression that there was a lot of uncertainty about whether women aged 40 to 49 years should undergo screening, but 59% suggested that women should probably or definitely be screened. Only 4 stories suggested that women faced a genuine decision about what to do. The level of uncertainty reported was substantially lower following the NCI reversal (21% suggested a lot of uncertainty), and most stories (96%) suggested that women should be screened. In contrast, tamoxifen stories highlighted uncertainty about what women at high risk should do (62% suggested there was a lot of uncertainty), and none left the impression that women should definitely take the drug (24% suggested they probably should). Sixty-five percent of these stories suggested that women faced a genuine choice and would have to weigh the risks and benefits themselves.ConclusionsMost news stories favored routine use of screening mammography and urged caution about using tamoxifen. Almost all noted the potential harms of each preventive strategy; however, the negative aspects of tamoxifen received greater emphasis. Whereas taking tamoxifen was presented as a difficult decision, having a mammogram was presented as something women ought to do.
Reproducibility of biochemical markers obtained during endoscopic ultrasound guided aspiration of pancreatic cystic lesions
Authors: J. S. Leeds, M. K. Nayar, K. E. Oppong
Journal: Gut (2011)

<h3>Introduction</h3> Imaging morphology alone does not currently have high enough accuracy to determine the nature of pancreatic cystic lesions and therefore sampling of cyst fluid for biochemical markers via endoscopic ultrasound (EUS) has value. There is little data showing whether these markers are stable over time in an individual cyst. The aim of this study was to determine the variability of these markers. <h3>Methods</h3> Patients are prospectively added to the EUS FNA database when attending for EUS and the period April 2003–April 2010 was examined with reference to patients undergoing repeat EUS and aspiration of cystic lesions. These individuals had either declined surgery or there was clinical doubt concerning the neoplastic potential of the cyst. <h3>Results</h3> During the study period 267 EUS and cyst aspiration were performed. 28 individuals had 61 repeat procedures (24 had 2 procedures, 3 had 3 procedures and 1 had 4 procedures). Complete data was available on 13 individuals. Mean CEA at first aspiration was 74.8 compared to 121.0 at second aspiration (p=0.32) with a mean difference of −46.2. Mean amylase at first aspiration was 7142.4 compared to 7344.1 at second aspiration (p=0.98) with a mean difference of −186.2. There were no changes in CEA from normal to abnormal between aspirations. In two individuals there was a significant change in amylase level from normal to abnormal, both of whom were subsequently found to have undergone malignant change at surgery. <h3>Conclusion</h3> In this small study, biochemical markers appear relatively constant. Major changes in amylase may be associated with malignant change. Further study on a larger cohort is required.
A multiparameter flow cytometric analysis of the effect of bexarotene on the epidermis of the psoriatic lesion
Authors: M.E.J. Franssen, J.V. Smit, P.E.J. Van Erp, P.C.M. Van de Kerkhof
Journal: British Journal of Dermatology (2003)

Background A new retinoid, bexarotene (Targretin®), was recently investigated in a large multicentre trial for its efficacy and safety in psoriasis. Bexarotene is a novel retinoid X receptor (RXR)‐selective ligand. Objectives The aim was to study the effect of bexarotene in psoriasis by analysing markers for epidermal differentiation, proliferation and inflammation in epidermal single cell suspensions from lesions of patients with psoriasis treated with various doses of bexarotene. Methods Thirty‐four patients with moderate to severe plaque psoriasis participated in this study and were assigned in sequence to four different dose regimens: 0·5, 1, 2 and 3 mg kg−1 once daily. Before and after 12 weeks of bexarotene treatment, punch biopsies were taken from lesional skin from which epidermal single cell suspensions were prepared using an optimized thermolysin protocol. A sum of scores was determined for each biopsy site, based on a four‐point scale for erythema, induration and desquamation. An improved multiparameter flow cytometric assay was used that enabled simultaneous assessment of epidermal proliferation, various aspects of differentiation and epidermal inflammation. The following variables were measured simultaneously: relative DNA content, relative cell size, keratin (K) 10, K6 and vimentin expression. Results The psoriasis area and severity index (PASI) and sum of scores for the individual psoriatic lesion each showed a statistically significant decrease of 28% after 12 weeks of bexarotene treatment (P < 0·001). However, no significant dose–response effect was found. The total percentage of K10+ cells showed a significant increase of 43% (P < 0·01). The total population of K6 expressing cells did not show significant changes. Regarding the subpopulations of K6 single, K10 single and K6 and 10 co‐expressing cells, a significant increase of 77% was seen in the K10+ K6– cells (P < 0·05), a significant decrease of 33% in K10– K6+ cells (P < 0·01), and no significant changes in the remaining population of K10+ K6+ cells. After 12 weeks of treatment with bexarotene no significant changes in epidermal proliferation and inflammation were shown. Conclusions The present study indicates a direct effect of RXR activation by bexarotene on the transition of proliferation‐associated keratinization into normal keratinization. Although no direct effect of bexarotene on DNA content in the total K10– cells was shown, further studies on subpopulations within the germinative layer such as stem cells and transit amplifying cells might be worthwhile.
(26) Acne due to congenital adrenal hyperplasia
Authors: E.D.A. Mitchell, B.R. Allen, D.I. Johnston
Journal: British Journal of Dermatology (1978)

Journal Article (26) Acne due to congenital adrenal hyperplasia Get access E.D.A. Mitchell, E.D.A. Mitchell Children's Hospital, Nottingham Search for other works by this author on: Oxford Academic Google Scholar B.R. Allen, B.R. Allen Children's Hospital, Nottingham Search for other works by this author on: Oxford Academic Google Scholar D.I. Johnston D.I. Johnston Children's Hospital, Nottingham Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 99, Issue s16, 1 December 1978, Pages 56–58, https://doi.org/10.1111/j.1365-2133.1978.tb15248.x Published: 01 December 1978
Prostacyclin Formation Elicited by Endothelin-1 in Rat Aorta Is Mediated via Phospholipase D Activation and Not Phospholipase C or A <sub>2</sub>
Authors: Harold M. Wright, Kafait U. Malik
Journal: Circulation Research (1996)

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that also stimulates production of prostacyclin (PGI 2 ) from arachidonic acid. The purpose of this study was to determine the contribution of phospholipases (PLs) A 2 , C, and/or D in ET-1–induced PGI 2 formation in the rat aorta, measured as immunoreactive 6-ketoprostaglandin (PG) F 1α . ET-1 increased 6-keto-PGF 1α formation, which was not affected by a PLA 2 inhibitor, 7,7-dimethyl eicosadienoic acid (DEDA). Furthermore, ET-1 failed to stimulate PLA 2 activity measured in the cytosol (cPLA 2 ), using phosphatidylcholine, l -a-1-palmitoyl-2-arachidonyl[ 14 C] as a substrate. However, the adrenergic agonist norepinephrine increased 6-keto-PGF 1α formation, which was attenuated by DEDA, and enhanced PLA 2 activity. ET-1 enhanced PLC activity, as indicated by increased inositol phosphate production, which was prevented by a PLC inhibitor, U-73122. However, ET-1–induced 6-keto-PGF 1α production was not altered by U-73122. An inhibitor of PLD activation, C 2 -ceramide, attenuated ET-1–induced PLD activity, as indicated by the production of phosphatidylethanol. Furthermore, ET-1–induced 6-keto-PGF 1α formation was inhibited by C 2 -ceramide as well as by ethanol treatment. Moreover, inhibitors of phosphatidate phosphohydrolase (propranolol) and diacylglycerol lipase (RHC-80267), attenuated ET-1–induced 6-keto-PGF 1α formation. Finally, ET-1–induced activation of PLD was not attenuated by a selective PKC inhibitor, bisindolylmaleimide I. These data suggest a novel pathway for ET-1–induced PGI 2 formation in the rat aorta involving activation of PLD but not cPLA 2 and independent of PLC or PKC activation.
KLOSSIELLA INFECTION OF THE GUINEA PIG
Authors: Louise Pearce
Journal: The Journal of Experimental Medicine (1916)

We have found in the kidneys of twelve supposedly normal guinea pigs, coming from Pennsylvania and New Jersey, a parasite that closely resembles in some of its phases Klossiella muris, described by Smith and Johnson, and the renal parasite of two West African guinea pigs, described by Seidelin. The forms most commonly found by us and described as the sporoblast cycle, are evidently similar to those described by Smith and Johnson and by Seidelin. There are certain discrepancies of measurement between the parasite described by Seidelin and the one here described, but the most important difference between the two is the different number of sporozoites resulting from a final division of the daughter sporoblasts. Seidelin has found thirty sporozoites; we have found from eight to twelve, while the usual number is eight. Further, we have found a ring form which is unlike any of the stages in either the sporoblast or schizogonic cycle, and which we interpret tentatively as the male element or microgamete. In addition, we have found a tubular form which resembles the glomerular body of Klossiella muris and which we think is the schizogonic phase of this parasite.
Expression of ferritin, transferrin receptor, and non-specific resistance associated macrophage proteins 1 and 2 (Nramp1 and Nramp2) in the human rheumatoid synovium
Authors: J F Telfer
Journal: Annals of the Rheumatic Diseases (2002)

<b>Objective:</b> To gain a better understanding of how iron accumulates in human rheumatoid synovium. <b>Methods:</b> The distribution of ferritin, transferrin receptor, and non-specific resistance associated macrophage proteins 1 and 2 (Nramp1 and Nramp2) in the human rheumatoid synovium was investigated by immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). <b>Results:</b> Both heavy and light ferritin subunit types were detected in the lining layer and the subinitimal zone of rheumatoid synovium, heavy ferritin generally being more abundant than light. Both heavy and light ferritin were detected in isolated synovial macrophages and fibroblasts. Transferrin receptor expression was largely confined to fibroblasts of the synovial lining layer. Nramp2 was detected by PCR in both isolated synovial macrophages and fibroblasts, whereas Nramp1 was detected by PCR and immunocytochemistry in macrophages and neutrophils in the lining and subinitimal zone, and in inflammatory infiltrates, but was absent from fibroblasts. <b>Conclusion:</b> A complex chain of events, perhaps initiated by proinflammatory cytokines, may culminate in a toxic build up of iron in the rheumatoid joint.
Pharmacoeconomics: friend or foe?
Authors: M Drummond
Journal: Annals of the Rheumatic Diseases (2006)

The financial constraints faced by most health systems today make it necessary for manufacturers of new, expensive drugs to demonstrate value for money. This paper describes the different types of economic evaluation; the increasing use of these analysis in decision making; their application to new drugs in the field of in rheumatoid arthritis; and the pros and cons of pharmacoeconomics studies from the perspective of the patients, the physicians, and the general population.
Acute Febrile Cerebrovasculitis: A Syndrome of Unknown, Perhaps Rickettsial, Cause
Authors: R. P. Wenzel, F. G. Hayden, D. H M Groschel, R. A. Salata, W. S. Young, J. E. Greenlee, S. Newman, P. J. Miller, K. E. Hechemy, W. Burgdorfer
Journal: Annals of Internal Medicine (1986)

In late 1983, five patients living near Charlottesville, Virginia, were treated for an unusual syndrome of fever, headache, altered mentation, multifocal neurologic signs, and cerebrospinal fluid pleocytosis. Clinical signs of brainstem disease developed in four patients. All five had had recent exposure to forests or wood and contact with flea-infested dogs. Two patients died; one survivor has had recurrent seizures. Brain biopsy samples in two patients and autopsy findings in another showed cerebral vasculitis and perivasculitis involving mostly venules and capillaries. In the autopsy, the severest vascular lesions involved the brainstem and thalami, where they were accompanied by acute fibrinoid necrosis, but discrete vascular lesions of lesser intensity were randomly distributed in the white matter and cortex. Serologic studies on paired specimens in four patients showed significant cross-reacting antibody responses to rickettsial (typhus-group) antigens in the indirect hemagglutination, latex agglutination, and IgM microimmunofluorescence tests, but no agent was visualized or isolated. The cause of this serious inflammatory disorder is unknown.