tbuckley/cabot-search huggingface dataset:
Ethics, consent and blinding: lessons from a placebo/sham controlled CPAP crossover trial
Authors: Y. Djavadkhani, N. S. Marshall, A. L. D'Rozario, M. R. Crawford, B. J. Yee, R. R. Grunstein, C. L. Phillips
Journal: Thorax (2015)

<h3>Introduction</h3> Performing rigorously designed clinical trials in device-based treatments is challenging. Continuous positive airway pressure (CPAP) is the most effective device-based treatment for obstructive sleep apnoea. We performed a randomised crossover trial of CPAP versus placebo therapy and did not disclose the presence of placebo. We assessed rates of staff unblinding, the likelihood of patient unblinding and obtained patient perceptions on lack of full disclosure. <h3>Methods</h3> All patients (n=30) underwent a semi-structured exit interview. Prior to full disclosure patients were asked questions to ascertain whether they suspected one therapy was ineffective. The use of placebo was then disclosed and additional questions were administered to indicate the likelihood of unblinding had full disclosure occurred during consent. Staff unblinding was determined by means of a questionnaire that was completed after each patient encounter. <h3>Results</h3> While the lack of full disclosure prevented patient unblinding during the trial, patients revealed a clear preference for active CPAP. After disclosing the presence of placebo, 73% (n=22) felt they would have been unblinded had they known at the start of the trial. Only one patient described unease about the lack of full disclosure. Staff thought they were unblinded in 6% (n=16/282) of encounters. They correctly identified the treatment device in 69% of cases (n=11/16, p&lt;0.001). <h3>Conclusions</h3> Successful patient blinding was achieved, however this was probably reliant on the lack of full disclosure. Staff unblinding occurred and highlights the difficulty with investigator blinding in device-based trials. Ethical challenges in this type of study are likely to compromise research feasibility. <h3>Trial registration number</h3> This clinical trial is registered with the Australian and New Zealand Clinical Trials Registry at http://www.anzctr.org.au (ACTRN 12605000066684).
Microglia: a novel treatment target in gliomas
Authors: M. Weller
Journal: Neuro-Oncology (2012)

Microglial cells have not received much attention in neuro-oncology over the past decades, despite the fact that they may be the most abundant cell in glioma tissue. Accordingly, Neuro-Oncology has now devoted a major review article to the changing concepts of what microglial cells do or do not do, both in the normal and diseased brain, with a focus on the biology of gliomas (1).

Traditionally, microglial cells have been considered part of the immune system, but to what extent these cells are capable of antigen presentation and participation in immune responses has remained controversial. Their origin, local resident brain cell versus bone marrow derived, has been one focus of microglia research for years, and it now seems clear that the microglial cell population, especially in the disease state, is likely derived from both cellular sources.

Currently, microglial cells are seen not as an efficient arm of the immune system but rather as a misguided host cell population, abused by the growing glioma for its own advantage. Microglial cells are attracted to the site of tumor growth and expand locally through signaling molecules, such as monocyte chemoattractant protein 1, macrophage colony-stimulating factor, vascular endothelial growth factor, and placental growth factor. These factors are not only released by glioma cells but presumably also by the microenvironment that is constantly shaped by these tumors. Thus, microglial cells are now thought to support invasiveness by releasing matrix metalloproteases, angiogenesis by releasing proangiogenic factors, and immunosuppression. The latter is mediated by converting microglial cells or macrophages recruited from the periphery, into the M2 macrophage phenotype, which is characterized by the release of immunosuppressive (e.g., interleukin 10) rather than immunostimulatory cytokines, (e.g., tumor necrosis factor-α or interferon-γ), less nitric oxide production, and poor antigen presentation. These changes in the microglia/macrophage phenotype, in turn, are thought to be controlled by soluble factors such as transforming growth factor-β, which interact with their respective receptors expressed on microglial cells.

Together, these considerations may lead to new treatment approaches for glioblastoma that not only focus on glioma cells but also on trying to contain glioma growth by modulating its microenvironment, notably its permissiveness for immune responses against the tumor. Thus, any immunotherapy will work better if the M2 phenotype of microglial cells and macrophages can be (re)converted to a M1 phenotype.

Finally, if microglial cells are indeed partly bone marrow derived and exhibit efficient homing to the brain, cellular therapy strategies may adopt some of the pathways mediating this specific cellular trafficking between the peripheral and central nervous systems to deliver therapeutic payloads to the intracranial tumor sites or even use engineered, reprogrammed microglial cells for such purposes.
Epstein-Barr Virus Nuclear Antigen 1
Authors: Christian Münz
Journal: The Journal of Experimental Medicine (2004)

Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)—the one EBV antigen that is expressed in all EBV-associated malignancies—has long been thought to go undetected by the cell-mediated immune system. However, recent studies show that EBNA1 can be presented to both CD4+ and CD8+ T cells, making it a potential new target for immunotherapy of EBV-related cancers.
A Regional Intervention to Improve the Hospital Mortality Associated With Coronary Artery Bypass Graft Surgery
Authors: Gerald T. O'Connor
Journal: JAMA (1996)

To determine whether an organized intervention including data feedback, training in continuous quality improvement techniques, and site visits to other medical centers could improve the hospital mortality rates associated with coronary artery bypass graft (CABG) surgery.Regional intervention study. Patient demographic and historical data, body surface area, cardiac catheterization results, priority of surgery, comorbidity, and status at hospital discharge were collected on CABG patients in Northern New England between July 1, 1987, and July 31, 1993.This study included all 23 cardiothoracic surgeons practicing in Maine, New Hampshire, and Vermont during the study period.Data were collected on 15,095 consecutive patients undergoing isolated CABG procedures in Maine, New Hampshire and Vermont during the study period.A three-component intervention aimed at reducing CABG mortality was fielded in 1990 and 1991. The interventions included feedback of outcome data, training in continuous quality improvement techniques, and site visits to other medical centers.A comparison of the observed and expected hospital mortality rates during the postintervention period.During the postintervention period, we observed the outcomes for 6488 consecutive cases of CABG surgery. There were 74 fewer deaths than would have been expected. This 24% reduction in the hospital mortality rate was statistically significant (P = .001). This reduction in mortality rate was relatively consistent across patient subgroups and was temporally associated with the interventions.We conclude that a multi-institutional, regional model for the continuous improvement of surgical care is feasible and effective. This model may have applications in other settings.
Clinic Attendance and Glycemic Control: Study of Contrasting Groups of Patients With IDDM
Authors: Alan M Jacobson, Andrew G Adler, Laura Derby, Barbara J Anderson, Joseph I Wolfsdorf
Journal: Diabetes Care (1991)

Objective To assess factors associated with attendance at a specialized clinic for diabetes care. Research Design and Methods Adults with insulin-dependent diabetes mellitus (IDDM) in poor (HbA1 ≥ to 12%) versus good (HbA1 ≤ 10%) control and with no known complications comprised the study group. Results Infrequent attenders were in worse glycemic control than regular attenders (χ 2 = 6.60, P ≤ 0.01) and held health beliefs that downplayed the importance of getting advice from physicians (P ≤ 0.002) or providing opinions to physicians about what might be done to improve their health (P ≤ 0.001). Conclusions Because infrequent attenders are more likely to be in poor glycemic control and thus at greater risk for diabetic complications, engaging them in regularly supervised treatment has important personal and public health implications. Additional studies are needed to understand why some diabetic patients limit their contact with medical providers and to develop more effective strategies for reversing this process. Initial findings from this study suggest that patient beliefs about the doctor-patient relationship may influence clinic attendance.
Hepatitis B virus seromarkers clearance and risk of hepatocellular carcinoma: serious risks of misinterpretation
Authors: Alexandre Pariente
Journal: Gut (2014)

Liu et al 1 have to be commended for their recent report concerning the predictive value of hepatitis B virus (HBV) seromarkers clearance for hepatocellular carcinoma (HCC) risk in the REVEAL study. There are, however, some limits and interrogations:
Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes
Authors: Hans-Henrik Parving, Barry M. Brenner, John J.V. McMurray, Dick de Zeeuw, Steven M. Haffner, Scott D. Solomon, Nish Chaturvedi, Frederik Persson, Akshay S. Desai, Maria Nicolaides, Alexia Richard, Zhihua Xiang, Patrick Brunel, Marc A. Pfeffer
Journal: New England Journal of Medicine (2012)

This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both.In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level.The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons).The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).
Molecular and immunological dissection of diffuse large B cell lymphoma: CD5+, and CD5− with CD10+ groups may constitute clinically relevant subtypes
Authors: S Harada, R Suzuki, K Uehira, Y Yatabe, Y Kagami, M Ogura, H Suzuki, A Oyama, Y Kodera, R Ueda, Y Morishima, S Nakamura, M Seto
Journal: Leukemia (1999)
Inhibition of the phosphoinositide 3-kinase pathway for the treatment of patients with metastatic metaplastic breast cancer
Authors: S. Moulder, T. Helgason, F. Janku, J. Wheler, J. Moroney, D. Booser, C. Albarracin, P.K. Morrow, J. Atkins, K. Koenig, M. Gilcrease, R. Kurzrock
Journal: Annals of Oncology (2015)
Diffuse hypertrophy of gastric mucosa (Menetrier's disease) and iron-deficiency anaemia
Authors: A. K. Singh, R. C. Cumaraswamy, B. Corrin
Journal: Gut (1969)

A 23-year-old woman presented with intractable iron-deficiency anaemia. A barium meal showed widespread mucosal abnormalities in the stomach and massive mucosal hypertrophy was found at laparotomy. Repeated tests for occult blood were negative but gastrointestinal haemorrhage was confirmed by isotopic blood labelling. In the face of persistent anaemia and radiological progression, total gastrectomy was performed, since when a normal blood picture has been maintained. The excised stomach showed hyperplasia of all the mucosal elements, minimal inflammation, and no obvious bleeding point. Blood loss was attributed to diapedesis from a greatly increased capillary network.
Primary ciliary dyskinesia syndrome associated with abnormal ciliary orientation in infants
Authors: E. Biggart, K. Pritchard, R. Wilson, A. Bush
Journal: European Respiratory Journal (2001)

Primary ciliary dyskinesia (PCD) syndrome associated with abnormal ciliary orientation but with normal ciliary ultrastructure has been described in adults, but there are no normal ranges for orientation in infants, despite the fact that half of all patients with PCD present in the new-born period. Nasal brush biopsies were obtained from eight infants (three males), mean age 13.1 months, range 7-23, in order to determine ciliary orientation. They had no upper or lower airway disease and normal organ arrangement and were undergoing general anaesthesia for other reasons. Two infants with typical PCD syndrome but normal ultrastructure of individual cilia also had orientation studies. In the eight normal subjects, a mean of 254 central pairs was examined, range 82-453. The mean ciliary orientation was 14.9 degrees, range 12.9-17.5. The two infants with PCD syndrome but normal ultrastructure of individual cilia had ciliary orientation of (Case 1) 44.5 degrees (range 10.6-64.5) in 218 central pairs; and on a second occasion, 28.9 degrees, (range 9.0-47.5) in 259 central pairs; for Case 2, 24.4 degrees, (range 13.1-38.4) in 196 central pairs. The normal range for ciliary orientation is similar in infants to that described in other work in adults. The two cases of phenotypic primary ciliary dyskinesia in the presence of normal ciliary ultrastructure but abnormal ciliary orientation in infants supports the contention that measurement of ciliary orientation should be part of the assessment of ciliary structure and function in cases of possible primary ciliary dyskinesia, in particular when the ultrastructure of individual cilia appear to be normal.
Central Role of IFNγ–Indoleamine 2,3-Dioxygenase Axis in Regulation of Interleukin-12–Mediated Antitumor Immunity
Authors: Tao Gu, Rachael B. Rowswell-Turner, Mehmet O. Kilinc, Nejat K. Egilmez
Journal: Cancer Research (2009)

Abstract Sustained intratumoral delivery of interleukin-12 (IL-12) and granulocyte macrophage colony-stimulating factor induces tumor regression via restoration of tumor-resident CD8+ T-effector/memory cell cytotoxicity and subsequent repriming of a secondary CD8+ T-effector cell response in tumor-draining lymph nodes (TDLN). However, treatment-induced T-effector activity is transient and is accompanied with a CD4+ CD25+ Foxp3+ T-suppressor cell rebound. Molecular and cellular changes in posttherapy tumor microenvironment and TDLN were monitored to elucidate the mechanism of counterregulation. Real-time PCR analysis revealed a 5-fold enhancement of indoleamine 2,3-dioxygenase (IDO) expression in the tumor and the TDLN after treatment. IDO induction required IFNγ and persisted for up to 7 days. Administration of the IDO inhibitor d-1-methyl tryptophan concurrent with treatment resulted in a dramatic enhancement of tumor regression. Enhanced efficacy was associated with a diminished T-suppressor cell rebound, revealing a link between IDO activity and posttherapy regulation. Further analysis established that abrogation of the regulatory counterresponse resulted in a 10-fold increase in the intratumoral CD8+ T-cell to CD4+ Foxp3+ T-cell ratio. The ratio of proliferating CD8+ T-effector to CD4+ Foxp3+ T-suppressor cells was prognostic for efficacy of tumor suppression in individual mice. IFNγ-dependent IDO induction and T-suppressor cell expansion were primarily driven by IL-12. These findings show a critical role for IDO in the regulation of IL-12–mediated antitumor immune responses. Cancer Res; 70(1); 129–38.
Novel and Highly Recurrent Chromosomal Alterations in Sézary Syndrome
Authors: Maarten H. Vermeer, Remco van Doorn, Remco Dijkman, Xin Mao, Sean Whittaker, Pieter C. van Voorst Vader, Marie-Jeanne P. Gerritsen, Marie-Louise Geerts, Sylke Gellrich, Ola Söderberg, Karl-Johan Leuchowius, Ulf Landegren, Jacoba J. Out-Luiting, Jeroen Knijnenburg, Marije IJszenga, Karoly Szuhai, Rein Willemze, Cornelis P. Tensen
Journal: Cancer Research (2008)

Abstract This study was designed to identify highly recurrent genetic alterations typical of Sézary syndrome (Sz), an aggressive cutaneous T-cell lymphoma/leukemia, possibly revealing pathogenetic mechanisms and novel therapeutic targets. High-resolution array-based comparative genomic hybridization was done on malignant T cells from 20 patients. Expression levels of selected biologically relevant genes residing within loci with frequent copy number alteration were measured using quantitative PCR. Combined binary ratio labeling-fluorescence in situ hybridization karyotyping was done on malignant cells from five patients. Minimal common regions with copy number alteration occurring in at least 35% of patients harbored 15 bona fide oncogenes and 3 tumor suppressor genes. Based on the function of the identified oncogenes and tumor suppressor genes, at least three molecular mechanisms are relevant in the pathogenesis of Sz. First, gain of cMYC and loss of cMYC antagonists (MXI1 and MNT) were observed in 75% and 40% to 55% of patients, respectively, which were frequently associated with deregulated gene expression. The presence of cMYC/MAX protein heterodimers in Sézary cells was confirmed using a proximity ligation assay. Second, a region containing TP53 and genome maintenance genes (RPA1/HIC1) was lost in the majority of patients. Third, the interleukin 2 (IL-2) pathway was affected by gain of STAT3/STAT5 and IL-2 (receptor) genes in 75% and 30%, respectively, and loss of TCF8 and DUSP5 in at least 45% of patients. In sum, the Sz genome is characterized by gross chromosomal instability with highly recurrent gains and losses. Prominent among deregulated genes are those encoding cMYC, cMYC-regulating proteins, mediators of MYC-induced apoptosis, and IL-2 signaling pathway components. [Cancer Res 2008;68(8):2689–98]
Does Fluoxetine Augment the Inpatient Treatment of Anorexia Nervosa?
Authors: Evelyn Attia, Claire Haiman, B. Timothy Walsh, Susanne R. Flater
Journal: American Journal of Psychiatry (1998)

While pharmacological interventions are of established utility in bulimia nervosa, medications have no clear role in the treatment of anorexia nervosa. Because patients with anorexia nervosa frequently exhibit mood disturbances and symptoms of obsessive-compulsive disorder, the authors tested the utility of fluoxetine in the treatment of women participating in an inpatient program for anorexia nervosa.The authors conducted a randomized, placebo-controlled, double-blind, 7-week study of fluoxetine at a target daily dose of 60 mg in 31 women with anorexia nervosa receiving treatment for their eating disorder on a clinical research unit. Body weight and measures of eating behavior and psychological state were obtained at baseline and at termination.There were no significant differences in clinical outcome on any measure between patients receiving fluoxetine and patients receiving placebo.Fluoxetine does not appear to add significant benefit to the inpatient treatment of anorexia nervosa.
Role of defective monocyte interleukin-10 release in tumor necrosis factor-alpha overproduction in alcoholic cirrhosis
Authors: Olivier le Moine, Arnaud Marchant, Donat de Groote, Camille Azar, Michel Goldman, Jacques Devière
Journal: Hepatology (1995)

Monocytes of patients with alcoholic cirrhosis produce higher amounts of tumor necrosis factor-alpha (TNF-alpha) after lipopolysaccharide (LPS) stimulation. The mechanisms of the overproduction remain undefined. IL-10 (IL-10) is an antiinflammatory cytokine known to downregulate TNF-alpha secretion by monocytes. The present study analyzes IL-10 production by monocytes and its control on TNF-alpha secretion in alcoholic cirrhosis. LPS-stimulated monocytes from alcoholic cirrhotics (n = 13) showed decreased IL-10 (median, 240 pg/mL [40 to 500] upsilon 513 pg/mL [152 to 1,335]; P = .01) compared with controls (n = 13). Cells from cirrhotic patients were normally responsive to recombinant IL-10, which induced a dose dependent decrease of TNF-alpha secretion. On the other hand, preincubation with anti-IL-10 monoclonal antibodies led to significant increase in TNF-alpha secretion in controls (median, 7,325 to 16,800 pg/mL; P = .002) but not in cells from cirrhotic patients (16,535 to 20,450 pg/mL; P = .14), abolishing the difference in TNF-alpha production between cirrhotic patients and controls. It is concluded that defective IL-10 secretion by monocytes from alcoholic cirrhotic patients could be involved in the characteristics TNF-alpha overproduction observed in this disease.
Stent Placement to Prevent Restenosis After Angioplasty in Small Coronary Arteries
Authors: Serge Doucet, Martin J. Schalij, Mathy C.M. Vrolix, David Hilton, Patrick Chenu, Bernard de Bruyne, Wasan Udayachalerm, Ashok Seth, Luc Bilodeau, Johan H.C. Reiber, François Harel, Jacques Lespérance
Journal: Circulation (2001)

Lesions in small-diameter vessels (<3 mm) define a group with distinct clinical and morphological characteristics. There is an inverse relationship between vessel size and angiographic restenosis rate. This study assessed whether stents reduce angiographic restenosis in small coronary arteries compared with standard balloon angioplasty.We randomly assigned 351 symptomatic patients needing dilatation of 1 native coronary vessel between 2.3 and 2.9 mm in size to angioplasty alone (n=182) or stent implantation (n=169). The primary end point was angiographic restenosis at 6 months. Secondary end points included death, myocardial infarction, bypass surgery, and target vessel revascularization in hospital and at 6 months. There were no significant differences between groups in terms of major in-hospital complications. There was a trend toward fewer in-hospital events in the stent group (3% versus 7.1% in angioplasty group, P=0.076). Crossovers to stent occurred in 37 patients (20.3%). Repeat angiography at 6-month follow-up was performed in 85.3% of patients. Angiographic restenosis occurred in 28% of the stent group and 32.9% of the angioplasty group (P=0.36). Target vessel revascularization was required in 17.8% versus 20.3% of patients (P=0.54), respectively.Stenting and standard coronary angioplasty are associated with equal restenosis rate in small coronary arteries. With a lower in-hospital complication rate, stenting may be a superior strategy in small vessels.