tbuckley/cabot-search huggingface dataset:
Quercetin Induces Tumor-Selective Apoptosis through Downregulation of Mcl-1 and Activation of Bax
Authors: Senping Cheng, Ning Gao, Zhuo Zhang, Gang Chen, Amit Budhraja, Zunji Ke, Young-ok Son, Xin Wang, Jia Luo, Xianglin Shi
Journal: Clinical Cancer Research (2010)

Abstract Purpose: To investigate the in vivo antitumor efficacy of quercetin in U937 xenografts and the functional roles of Mcl-1 and Bax in quercetin-induced apoptosis in human leukemia. Experimental Design: Leukemia cells were treated with quercetin, after which apoptosis, Mcl-1 expression, and Bax activation and translocation were evaluated. The efficacy of quercetin as well as Mcl-1 expression and Bax activation were investigated in xenografts of U937 cells. Results: Administration of quercetin caused pronounced apoptosis in both transformed and primary leukemia cells but not in normal blood peripheral mononuclear cells. Quercetin-induced apoptosis was accompanied by Mcl-1 downregulation and Bax conformational change and mitochondrial translocation that triggered cytochrome c release. Knockdown of Bax by siRNA reversed quercetin-induced apoptosis and abrogated the activation of caspase and apoptosis. Ectopic expression of Mcl-1 attenuated quercetin-mediated Bax activation, translocation, and cell death. Conversely, interruption of Mcl-1 by siRNA enhanced Bax activation and translocation, as well as lethality induced by quercetin. However, the absence of Bax had no effect on quercetin-mediated Mcl-1 downregulation. Furthermore, in vivo administration of quercetin attenuated tumor growth in U937 xenografts. The TUNEL-positive apoptotic cells in tumor sections increased in quercetin-treated mice as compared with controls. Mcl-1 downregulation and Bax activation were also observed in xenografts. Conclusions: These data suggest that quercetin may be useful for the treatment of leukemia by preferentially inducing apoptosis in leukemia versus normal hematopoietic cells through a process involving Mcl-1 downregulation, which, in turn, potentiates Bax activation and mitochondrial translocation, culminating in apoptosis. Clin Cancer Res; 16(23); 5679–91. ©2010 AACR.
Excellent reliability for MRI grading and prognostic parameters in acute hamstring injuries
Authors: B Hamilton, R Whiteley, E Almusa, B Roger, C Geertsema, Johannes L Tol
Journal: British Journal of Sports Medicine (2013)

Background Categorical grading and other measurable MRI parameters are frequently utilised for predicting the outcome of hamstring injuries. However, the reliability and smallest detectable difference (SDD) have not been previously evaluated. It therefore remains unclear if the variability in previously reported results reflects reporting variation or actual injury status. Methods 25 hamstring injuries were scored by two experienced radiologists using the Peetrons grading and specific prognostic MRI parameters: distance from ischial tuberosity (cm), extent (cranio to caudal, anterior to posterior, medial to lateral; (cm)), maximum cross-sectional area (%), volume (cm 3 ) of the oedema. The interobserver and intraobserver reliability was calculated along with the SDDs for each scale variable. Results There were 3 Grade 0 (12%), 11 grade 1 (44%), 9 grade 2 (36%) and 2 grade 3 (8%) injuries. Cronbach's α values for grading were 1.00 (inter) and 0.96 (intra), respectively. The intraclass correlation coefficients for the prognostic MRI parameters were between 0.77 and 1.0. The SDDs varied between each parameter. Conclusions Excellent interobserver and intraobserver reliability was found for grading and prognostic MRI parameters in acute hamstring injuries. In daily practice and research, we can be confident that scoring hamstring injuries by experienced radiologists is reproducible. The documented SDDs allow meaningful clinical inferences to be made when assessing observed and reported changes in MRI status.
Waiting in the NHS: Part 1--a diagnosis
Authors: N. Devlin, A. Harrison, S. Derrett
Journal: Journal of the Royal Society of Medicine (2002)

The denial of potentially beneficial treatment is a characteristic of all health systems. In a tax-funded cash-limited health system providing services irrespective of ability to pay—such as the NHS—waiting lists are a key means of rationing access to treatment. Understanding this is critical to the design and implementation of policies concerning waiting lists. A commentary on UK waiting-list management in the 1980s and 1990s stated:


‘None of the policy initiatives have been based on an adequate account of the nature of the problem to be tackled. The simple view...that the waiting list is a backlog, which extra resources and better management could clear, was never fully dispelled’1.


The notion of infinite demand for elective surgery is questionable2. Nevertheless, the view that demand for surgery is both static and completely unresponsive to changes in waiting time is an inadequate basis for policy, for two reasons. First, the wait faced by patients is a determinant of their demand for taxpayer-funded treatment3. Second, potential patients can substitute privately funded treatment for publicly funded treatment at high waits (and vice versa). Demand for publicly funded elective surgery is more usefully characterized as being neither infinite nor fixed but responsive, to some degree, to waiting times and other factors.

Despite a range of new initiatives since publication of the NHS Plan4, including a massive injection of funding to increase capacity, strategies for better waiting-list information and management5 and new waiting-time targets, the Government is unlikely to ‘solve’ the waiting-list problem. We go on to argue, in part 2, that a more explicit and comprehensive strategy is required to prioritize patients for treatment in a manner consistent with NHS aims.
Loss of Plasma Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) After Lipoprotein Apheresis
Authors: Hagai Tavori, Ilaria Giunzioni, MacRae F. Linton, Sergio Fazio
Journal: Circulation Research (2013)

Lipoprotein apheresis (LA) reduces low-density lipoprotein (LDL) levels in patients with severe familial hypercholesterolemia (FH). We have recently reported that >30% of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) is bound to LDL, thus we predicted that LA would also reduce plasma PCSK9 levels by removing LDL.Pre- and post-apheresis plasma from 6 patients with familial hypercholesterolemia on 3 consecutive treatment cycles was used to determine changes in PCSK9 levels.LA drastically reduced plasma LDL (by 77 ± 4%). Concomitantly, PCSK9 levels fell by 52 ± 5%, strongly correlating with the LDL drop (P=0.0322; r(2)=0.26), but not with decreases in triglyceride (49 ± 13%) or high-density lipoprotein levels (18 ± 2%). Levels of albumin, creatinine, and CK-MB did not show significant changes after LA. Similar to LDL, PCSK9 levels returned to pretreatment values between cycles (2-week intervals). Fractionation of pre- and post-apheresis plasma showed that 81 ± 11% of LDL-bound PCSK9 and 48 ± 14% of apolipoprotein B-free PCSK9 were removed. Separation of whole plasma, purified LDL, or the apolipoprotein B-free fraction through a scaled-down, experimental dextran sulfate cellulose beads column produced similar results.Our results show, for the first time, that modulation of LDL levels by LA directly affects plasma PCSK9 levels, and suggest that PCSK9 reduction is an additional benefit of LA. Because the loss of PCSK9 could contribute to the LDL-lowering effect of LA, then (1) anti-PCSK9 therapies may reduce frequency of LA in patients currently approved for therapy, and (2) LA and anti-PCSK9 therapies may be used synergistically to reduce treatment burden.
Analysis of the cell infiltrate and expression of proinflammatory cytokines and matrix metalloproteinases in arthroscopic synovial biopsies: comparison with synovial samples from patients with end stage, destructive rheumatoid arthritis
Authors: T J M Smeets
Journal: Annals of the Rheumatic Diseases (2003)

<b>Background:</b> Synovial tissue (ST) from end stage destructive rheumatoid arthritis (RA) and arthroscopic biopsies obtained during active inflammation might exhibit different characteristics. <b>Objective:</b> To define the cell infiltrate and the expression of proinflammatory cytokines, angiogenic factors, and matrix metalloproteinases (MMPs) in ST selected at arthroscopy compared with that from end stage RA. <b>Methods:</b> Synovial biopsy specimens were obtained from the actively inflamed knee joints of 13 patients with chronic RA by arthroscopy and compared with ST from 10 patients with end stage, destructive RA. Immunohistological analysis was performed to detect T cells, plasma cells, macrophages, fibroblast-like synoviocytes (FLS), and the expression of interleukin (IL)1β, IL6, tumour necrosis factor α (TNFα), MMP-1, MMP-3, MMP-13, TIMP-1, and VEGF. <b>Results:</b> The expression of CD68+ macrophages was significantly higher in ST selected at arthroscopy than in samples obtained at surgery, both in the intimal lining layer and in the synovial sublining. The expression of CD3+ T cells also tended to be higher in arthroscopic samples. The expression of TNFα, IL6, MMP-1, MMP-3, MMP-13, TIMP-1, and VEGF was on average higher in ST obtained at arthroscopy. In contrast, the expression of IL1β was on average higher in surgical samples. <b>Conclusion:</b> Active arthritis activity is associated with increased cell infiltration, expression of proinflammatory cytokines, MMPs, and angiogenic growth factors in synovial biopsy samples selected at arthroscopy. Increased expression of IL1β in the synovium of patients with destructive RA requiring joint replacement may well reflect the important role of IL1β in cartilage and bone destruction.
Colonoscopy vs Sigmoidoscopy: New Studies Fuel Ongoing Debate
Authors: C. Schmidt
Journal: JNCI Journal of the National Cancer Institute (2012)

Mounting evidence shows that colorectal screening reduces cancer incidence and mortality, but scientists still disagree about the best way to look for risky polyps. Clinicians in the US favor colonoscopy, while European health systems rely far more on flexible sigmoidoscopy–a cheaper, less invasive method that can be performed without sedation, but that also reaches only into the distal or “left” side of the colon, while leaving the proximal or “right” side nearer to the large intestine un-monitored. According to Martin Brown, M.D., chief of the health services and economics branch at the National Cancer Institute (NCI), colonoscopy rates among those eligible for the procedure in the US (generally individuals aged 50 and over) climbed dramatically after Medicare began covering the procedure–from 19% in 2000 to 54.6% in 2010. Rates of flexible sigmoidoscopy (in combination with fecal occult blood testing, or FOBT) declined from 9.4% to 1.3% over the same time period.
The role of interleukin 1 in acute neurodegeneration and stroke: pathophysiological and therapeutic implications.
Authors: N Rothwell, S Allan, S Toulmond
Journal: Journal of Clinical Investigation (1997)

The last 5 yr have witnessed significant changes in research direction and new discoveries about the mechanisms of neurodegeneration.Earlier studies on neuronal death focused on neurons, neuronal pathways, and neurotransmitters.Now similar interest is directed toward glia and vascular cells, peptides, and inflammatory processes in the brain.This research has already revealed several potential therapeutic targets for the treatment of acute brain damage such as stroke and brain injury.The brain fails to exhibit a classical "inflammatory response," generally characterized by early invasion of macrophages and leukocytes.Nevertheless, the brain can exhibit many of the hallmarks of inflammation when subjected to ischemia, injury, or infection.Such responses include edema, activation of resident phagocytic cells (microglia), invasion of circulating immune cells, and activation or induction of numerous inflammatory molecules including cyclooxygenase products, kinins, complement, acute phase proteins, and proinflammatory cytokines.Of the cytokines, we have identified IL-1 as a mediator of diverse forms of acute neurodegeneration.IL-1 has also been implicated in chronic neurological conditions.
Prospective Longitudinal Evaluation of the Effect of Deployment-Acquired Traumatic Brain Injury on Posttraumatic Stress and Related Disorders: Results From the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS)
Authors: Murray B. Stein, Ronald C. Kessler, Steven G. Heeringa, Sonia Jain, Laura Campbell-Sills, Lisa J. Colpe, Carol S. Fullerton, Matthew K. Nock, Nancy A. Sampson, Michael Schoenbaum, Xiaoying Sun, Michael L. Thomas, Robert J. Ursano
Journal: American Journal of Psychiatry (2015)

Objective: Traumatic brain injury (TBI) is increasingly recognized as a risk factor for deleterious mental health and functional outcomes. The purpose of this study was to examine the strength and specificity of the association between deployment-acquired TBI and subsequent posttraumatic stress and related disorders among U.S. Army personnel. Method: A prospective, longitudinal survey of soldiers in three Brigade Combat Teams was conducted 1–2 months prior to an average 10-month deployment to Afghanistan (T0), upon redeployment to the United States (T1), approximately 3 months later (T2), and approximately 9 months later (T3). Outcomes of interest were 30-day prevalence postdeployment of posttraumatic stress disorder (PTSD), major depressive episode, generalized anxiety disorder, and suicidality, as well as presence and severity of postdeployment PTSD symptoms. Results: Complete information was available for 4,645 soldiers. Approximately one in five soldiers reported exposure to mild (18.0%) or more-than-mild (1.2%) TBI(s) during the index deployment. Even after adjusting for other risk factors (e.g., predeployment mental health status, severity of deployment stress, prior TBI history), deployment-acquired TBI was associated with elevated adjusted odds of PTSD and generalized anxiety disorder at T2 and T3 and of major depressive episode at T2. Suicidality risk at T2 appeared similarly elevated, but this association did not reach statistical significance. Conclusions: The findings highlight the importance of surveillance efforts to identify soldiers who have sustained TBIs and are therefore at risk for an array of postdeployment adverse mental health outcomes, including but not limited to PTSD. The mechanism(s) accounting for these associations need to be elucidated to inform development of effective preventive and early intervention programs.
GMC guidance on neonatal palliative care
Authors: L. de Rooy
Journal: BMJ (2012)

The Personal view “How it feels to withdraw feeding from newborn babies” was poignant but does not represent current practice in the UK and is not aligned with current UK guidance.1 2 3 4

The article references the American guidance, which suggests that it may be ethically appropriate to withdraw feed and fluids under certain carefully …
Randomized Trial of Long-Term Follow-Up for Early-Stage Breast Cancer: A Comparison of Family Physician Versus Specialist Care
Authors: Eva Grunfeld, Mark N. Levine, Jim A. Julian, Doug Coyle, Barbara Szechtman, Doug Mirsky, Shailendara Verma, Susan Dent, Carol Sawka, Kathleen I. Pritchard, David Ginsburg, Marjorie Wood, Tim Whelan
Journal: Journal of Clinical Oncology (2006)

Most women with breast cancer are diagnosed at an early stage and more than 80% will be long-term survivors. Routine follow-up marks the transition from intensive treatment to survivorship. It is usual practice for routine follow-up to take place in specialist clinics. This study tested the hypothesis that follow-up by the patient's family physician is a safe and acceptable alternative to specialist follow-up.A multicenter, randomized, controlled trial was conducted involving 968 patients with early-stage breast cancer who had completed adjuvant treatment, were disease free, and were between 9 and 15 months after diagnosis. Patients may have continued receiving adjuvant hormonal therapy. Patients were randomly allocated to follow-up in the cancer center according to usual practice (CC group) or follow-up from their own family physician (FP group). The primary outcome was the rate of recurrence-related serious clinical events (SCEs). The secondary outcome was health-related quality of life (HRQL).In the FP group, there were 54 recurrences (11.2%) and 29 deaths (6.0%). In the CC group, there were 64 recurrences (13.2%) and 30 deaths (6.2%). In the FP group, 17 patients (3.5%) compared with 18 patients (3.7%) in the CC group experienced an SCE (0.19% difference; 95% CI, -2.26% to 2.65%). No statistically significant differences (P < .05) were detected between groups on any of the HRQL questionnaires.Breast cancer patients can be offered follow-up by their family physician without concern that important recurrence-related SCEs will occur more frequently or that HRQL will be negatively affected.
Primary Gastrointestinal Non-Hodgkin’s Lymphoma: I. Anatomic and Histologic Distribution, Clinical Features, and Survival Data of 371 Patients Registered in the German Multicenter Study GIT NHL 01/92
Authors: Peter Koch, Francisco del Valle, Wolfgang E. Berdel, Normann A. Willich, Berthold Reers, Wolfgang Hiddemann, Bernward Grothaus-Pinke, Gabriele Reinartz, Jens Brockmann, Altfried Temmesfeld, Rudolf Schmitz, Christian Rübe, Andreas Probst, Gert Jaenke, Heinrich Bodenstein, Arved Junker, Christiane Pott, Jürgen Schultze, Achim Heinecke, Reza Parwaresch, Markus Tiemann
Journal: Journal of Clinical Oncology (2001)

The study was initiated to obtain epidemiologic data and information on anatomic and histologic distribution, clinical features, and treatment results in patients with primary gastrointestinal non-Hodgkin's lymphomas (PGI NHL).Between October 1992 and November 1996, 371 PGI NHL patients were eligible to evaluate clinical features. Radiotherapy and chemotherapy were stratified according to histologic grading, stage, and whether surgery had been carried out or not.A total of 74.8% patients had gastric NHL (PGL). Within the intestine, the small bowel and the ileocecal region were involved in 8.6% and 7.0% of the cases, respectively. Multiple GI involvement (MGI) was 6.5%. Approximately 90% of the GI NHL were in stages IE/IIE. Aggressive NHL accounted for the majority, with a distinguishable pattern in several sites. Forty percent of PGL were of low-grade mucosa-associated lymphatic tissue type. One third of large-cell lymphomas had low-grade components. Most intestinal NHL were germinal-center lymphomas. The site of origin was prognostic. In gastric and ileocecal lymphoma, event-free (EFS) and overall survival (OS) were significantly higher as compared with the small intestine or MGI (median time of observation, 51 months). In PGL, localized disease was prognostic for EFS and OS. Histologic grade influenced only EFS significantly. Numbers in intestinal lymphomas were too small for subanalyses.PGI NHL are heterogeneous diseases. The number of localized PGL allowed for detailed analyses. Larger studies are needed for stages III and IV and for intestinal NHL. A uniform reporting system for PGI NHL, in terms of definitions and histologic and staging classifications, is needed to facilitate comparison of treatment results.
Maximal mutual information, not minimal entropy, for escaping the “Dark Room”
Authors: Daniel Ying-Jeh Little, Friedrich Tobias Sommer
Journal: Behavioral and Brain Sciences (2013)

Abstract A behavioral drive directed solely at minimizing prediction error would cause an agent to seek out states of unchanging, and thus easily predictable, sensory inputs (such as a dark room). The default to an evolutionarily encoded prior to avoid such untenable behaviors is unsatisfying. We suggest an alternate information theoretic interpretation to address this dilemma.
Emerging techniques and technologies in brain tumor imaging
Authors: B. M. Ellingson, M. Bendszus, A. G. Sorensen, W. B. Pope
Journal: Neuro-Oncology (2014)

The purpose of this report is to describe the state of imaging techniques and technologies for detecting response of brain tumors to treatment in the setting of multicenter clinical trials. Within currently used technologies, implementation of standardized image acquisition and the use of volumetric estimates and subtraction maps are likely to help to improve tumor visualization, delineation, and quantification. Upon further development, refinement, and standardization, imaging technologies such as diffusion and perfusion MRI and amino acid PET may contribute to the detection of tumor response to treatment, particularly in specific treatment settings. Over the next few years, new technologies such as 2(3)Na MRI and CEST imaging technologies will be explored for their use in expanding the ability to quantitatively image tumor response to therapies in a clinical trial setting.
Clinical Trial Registries
Authors: Jais Oliver Berg
Journal: JAMA (2007)

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Homosexuality in the International Classification of Diseases: A Clarification
Authors: Jenny J. van Drimmelen-Krabbe
Journal: JAMA (1994)

<h3>To the Editor.</h3> —We have read with interest the essay "The Experience of Gay and Lesbian Students in Medical School" by Tinmouth and Hamwi<sup>1</sup>in your journal. We would like to comment on a phrase in the second paragraph, where the author states that the<i>International Classification of Diseases</i><sup>2</sup>of the World Health Organization "still maintains homosexuality as a medical diagnosis." <i>The International Statistical Classification of Diseases and Related Health Problems (ICD-10)</i><sup>2</sup>is a statistical tool that can be used by member states for reporting about people who contact health care facilities. In the ninth revision of the<i>ICD</i>(1977), homosexuality was classified under code 302.0, with an instruction to "code homosexuality here whether or not it is considered as a mental disorder." Although the<i>ICD</i>never stated that homosexuality should be regarded as a disease, this formulation carried a risk of misinterpretation. The 10th revision of