tbuckley/cabot-search huggingface dataset:
THE KINETICS OF PROMONOCYTES AND MONOCYTES IN THE BONE MARROW
Authors: Ralph van Furth, Martina M. C. Diesselhoff-den Dulk
Journal: The Journal of Experimental Medicine (1970)

The mononuclear phagocytes of the bone marrow can be classified into two cell types, promonocytes and monocytes. The present study was performed to establish whether the promonocytes are the progenitors of the monocytes and to determine the kinetic characteristics of the promonocytes and monocytes in the bone marrow compartment. Both in vitro labeling studies with thymidine-(3)H and determination of the relative amount of DNA in the nuclei of individual cells showed that under normal steady-state conditions the promonocytes are proliferating cells and the monocytes, nondividing cells. In vivo labeling studies provided further evidence that the promonocytes are the progenitor cells of the monocytes. During the first 24 hr after labeling, the promonocytes showed a constant high level of labeling (about 70%). The mean grain count of these cells decreased with time. The labeling index of the monocytes of the bone marrow increased during the first 24 hr after in vivo labeling, but during the same period the mean grain counts remained almost constant, with values amounting to about half those of the promonocytes during the first 6 hr of the experiment. The data concerning the labeling indices and the percentage distribution ratio of the promonocytes and monocytes in the bone marrow, and the labeling indices of the peripheral blood monocytes are used to construct a model population. The results lead to the conclusions that the promonocytes are multiplicative cells and that both daughter cells arising from the division of a promonocyte are monocytes. The DNA-synthesis time found for the promonocytes is 13.6 hr. From this value, the average generation time was computed to be 19.5 hr.
National Hospice Survey Results
Authors: Melissa D. Aldridge, Mark Schlesinger, Colleen L. Barry, R. Sean Morrison, Ruth McCorkle, Rosemary Hürzeler, Elizabeth H. Bradley
Journal: JAMA Internal Medicine (2014)

IMPORTANCE The impact of the substantial growth in for-profit hospices in the United States on quality and hospice access has been intensely debated, yet little is known about how for-profit and nonprofit hospices differ in activities beyond service delivery. OBJECTIVE To determine the association between hospice ownership and (1) provision of community benefits, (2) setting and timing of the hospice population served, and (3) community outreach. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional survey (the National Hospice Survey), conducted from September 2008 through November 2009, of a national random sample of 591 Medicare-certified hospices operating throughout the United States. EXPOSURES For-profit or nonprofit hospice ownership. MAIN OUTCOMES AND MEASURES Provision of community benefits; setting and timing of the hospice population served; and community outreach. RESULTS A total of 591 hospices completed our survey (84% response rate). For-profit hospices were less likely than nonprofit hospices to provide community benefits including serving as training sites (55% vs 82%; adjusted relative risk [ARR], 0.67 [95% CI, 0.59-0.76]), conducting research (18% vs 23%; ARR, 0.67 [95% CI, 0.46-0.99]), and providing charity care (80% vs 82%; ARR, 0.88 [95% CI, 0.80-0.96]). For-profit compared with nonprofit hospices cared for a larger proportion of patients with longer expected hospice stays including those in nursing homes (30% vs 25%; P = .009). For-profit hospices were more likely to exceed Medicare's aggregate annual cap (22% vs 4%; ARR, 3.66 [95% CI, 2.02-6.63]) and had a higher patient disenrollment rate (10% vs 6%; P &lt; .001). For-profit were more likely than nonprofit hospices to engage in outreach to low-income communities (61% vs 46%; ARR, 1.23 [95% CI, 1.05-1.44]) and minority communities (59% vs 48%; ARR, 1.18 [95% CI, 1.02-1.38]) and less likely to partner with oncology centers (25% vs 33%; ARR, 0.59 [95% CI, 0.44-0.80]). CONCLUSIONS AND RELEVANCE Ownership-related differences are apparent among hospices in community benefits, population served, and community outreach. Although Medicare's aggregate annual cap may curb the incentive to focus on long-stay hospice patients, additional regulatory measures such as public reporting of hospice disenrollment rates should be considered as the share of for-profit hospices in the United States continues to increase.
Inhibitors of Ubiquitin-Activating Enzyme (E1), a New Class of Potential Cancer Therapeutics
Authors: Yili Yang, Jirouta Kitagaki, Ren-Ming Dai, Yien Che Tsai, Kevin L. Lorick, Robert L. Ludwig, Shervon A. Pierre, Jane P. Jensen, Ilia V. Davydov, Pankaj Oberoi, Chou-Chi H. Li, John H. Kenten, John A. Beutler, Karen H. Vousden, Allan M. Weissman
Journal: Cancer Research (2007)

Abstract The conjugation of proteins with ubiquitin plays numerous regulatory roles through both proteasomal-dependent and nonproteasomal-dependent functions. Alterations in ubiquitylation are observed in a wide range of pathologic conditions, including numerous malignancies. For this reason, there is great interest in targeting the ubiquitin-proteasome system in cancer. Several classes of proteasome inhibitors, which block degradation of ubiquitylated proteins, are widely used in research, and one, Bortezomib, is now in clinical use. Despite the well-defined and central role of the ubiquitin-activating enzyme (E1), no cell permeable inhibitors of E1 have been identified. Such inhibitors should, in principle, block all functions of ubiquitylation. We now report 4[4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR-41) as the first such inhibitor. Unexpectedly, in addition to blocking ubiquitylation, PYR-41 increased total sumoylation in cells. The molecular basis for this is unknown; however, increased sumoylation was also observed in cells harboring temperature-sensitive E1. Functionally, PYR-41 attenuates cytokine-mediated nuclear factor-κB activation. This correlates with inhibition of nonproteasomal (Lys-63) ubiquitylation of TRAF6, which is essential to IκB kinase activation. PYR-41 also prevents the downstream ubiquitylation and proteasomal degradation of IκBα. Furthermore, PYR-41 inhibits degradation of p53 and activates the transcriptional activity of this tumor suppressor. Consistent with this, it differentially kills transformed p53-expressing cells. Thus, PYR-41 and related pyrazones provide proof of principle for the capacity to differentially kill transformed cells, suggesting the potential for E1 inhibitors as therapeutics in cancer. These inhibitors can also be valuable tools for studying ubiquitylation. [Cancer Res 2007;67(19):9472–81]
Safety and efficacy of routine postoperative ibuprofen for pain and disability related to ectopic bone formation after hip replacement surgery (HIPAID): randomised controlled trial
Authors: Marlene Fransen, Craig Anderson, Jan Douglas, Stephen MacMahon, Bruce Neal, Robyn Norton, Mark Woodward, Ian D Cameron, Ross Crawford, Sing Kai Lo, Garnet Tregonning, Margaret Windolf
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objectives</b> To determine the benefits and risks of a non-steroidal anti-inflammatory drug (NSAID) as prophylaxis for ectopic bone formation in patients undergoing total hip replacement (or revision) surgery. <b>Design</b> Double blind randomised placebo controlled clinical trial, stratified by treatment site and surgery (primary or revision). <b>Setting</b> 20 orthopaedic surgery centres in Australia and New Zealand. <b>Participants</b> 902 patients undergoing elective primary or revision total hip replacement surgery. <b>Intervention</b> 14 days9 treatment with ibuprofen (1200 mg daily) or matching placebo started within 24 hours of surgery. <b>Main outcome measures</b> Changes in self reported hip pain and physical function 6 to 12 months after surgery (Western Ontario and McMaster University Arthritis index). <b>Results</b> There were no significant differences between the groups for improvements in hip pain (mean difference −0.1, 95% confidence interval −0.4 to 0.2, P = 0.6) or physical function (−0.1, −0.4 to 0.2, P = 0.5), despite a decreased risk of ectopic bone formation (relative risk 0.69, 0.56 to 0.83) associated with ibuprofen. There was a significantly increased risk of major bleeding complications in the ibuprofen group during the admission period (2.09, 1.00 to 4.39). <b>Conclusions</b> These data do not support the use of routine prophylaxis with NSAIDs in patients undergoing total hip replacement surgery. <b>Trial registration</b>NCT00145730[ClinicalTrials.gov].
Stress and Cardiovascular Disease: An Update on Current Knowledge
Authors: Andrew Steptoe, Mika Kivimäki
Journal: Annual Review of Public Health (2013)

Considerable progress has been made during the past decade in research on cardiovascular effects of stress. Early-life stressors, such as childhood abuse and early socioeconomic adversity, are linked to increased cardiovascular morbidity in adulthood. Our updated meta-analyses of prospective studies published until 2011 show a 1.5-fold (95% confidence interval 1.2-1.9) increased risk of coronary heart disease among adults experiencing social isolation and a 1.3-fold (1.2-1.5) excess risk for workplace stress; adverse metabolic changes are one of the underlying plausible mechanisms. Stress, anger, and depressed mood can act as acute triggers of major cardiac events; the pooled relative risk of acute coronary syndrome onset being preceded by stress is 2.5 (1.8-3.5) in case-crossover studies. Stress is also implicated in the prognosis of cardiovascular disease and in the development of stress (takotsubo) cardiomyopathy. A major challenge over the next decade is to incorporate stress processes into the mainstream of cardiovascular pathophysiological research and understanding.
Cancer Immunotherapy and Breaking Immune Tolerance: New Approaches to an Old Challenge
Authors: Amani Makkouk, George J. Weiner
Journal: Cancer Research (2014)

Abstract Cancer immunotherapy has proven to be challenging as it depends on overcoming multiple mechanisms that mediate immune tolerance to self-antigens. A growing understanding of immune tolerance has been the foundation for new approaches to cancer immunotherapy. Adoptive transfer of immune effectors such as antitumor mAb and chimeric antigen receptor T cells bypasses many of the mechanisms involved in immune tolerance by allowing for expansion of tumor-specific effectors ex vivo. Vaccination with whole tumor cells, protein, peptide, or dendritic cells has proven challenging, yet may be more useful when combined with other cancer immunotherapeutic strategies. Immunomodulatory approaches to cancer immunotherapy include treatment with agents that enhance and maintain T-cell activation. Recent advances in the use of checkpoint blockade to block negative signals and to maintain the antitumor response are particularly exciting. With our growing knowledge of immune tolerance and ways to overcome it, combination treatments are being developed, tested, and have particular promise. One example is in situ immunization that is designed to break tolerance within the tumor microenvironment. Progress in all these areas is continuing based on clear evidence that cancer immunotherapy designed to overcome immune tolerance can be useful for a growing number of patients with cancer. Cancer Res; 75(1); 5–10. ©2014 AACR.
Palliative medicine must accept responsibility for end of life care
Authors: A. N. Davies
Journal: BMJ (2013)

Stephenson highlights the vacuum of care that has developed in many parts of the country since publication of the independent review of the Liverpool care pathway.1 2 3 He states that the “buck stops” with doctors, but many would contend that end of life care should be the responsibility of all healthcare professionals.

If anything, …
Effects of Oral Folic Acid Supplementation on Endothelial Function in Familial Hypercholesterolemia
Authors: Marianne C. Verhaar, Robert M. F. Wever, John J. P. Kastelein, Douwe van Loon, Sheldon Milstien, Hein A. Koomans, Ton J. Rabelink
Journal: Circulation (1999)

Background —Folates have been suggested to be of benefit in reducing cardiovascular risk. The present study was designed to examine whether oral folic acid supplementation could improve endothelial function as an intermediate end point for cardiovascular risk in patients with increased risk of atherosclerosis due to familial hypercholesterolemia (FH). Methods and Results —In a prospective, randomized, double-blind, placebo-controlled study with crossover design, we evaluated the effects of 4 weeks of treatment with oral folic acid (5 mg PO) on endothelial function in FH. In 20 FH patients, forearm vascular function was assessed at baseline, after 4 weeks of folic acid treatment, and after 4 weeks of placebo treatment by venous occlusion plethysmography, with serotonin and sodium nitroprusside used as endothelium-dependent and -independent vasodilators. In addition, we examined the vasoconstrictor response to the NO synthase inhibitor N G -monomethyl- l- arginine to assess basal NO activity. In FH patients, folic acid supplementation restored the impaired endothelium-dependent vasodilation, whereas it did not significantly influence endothelium-independent vasodilation or basal forearm vasomotion. There was a trend toward improvement in basal NO activity. Conclusions —These data demonstrate that oral supplementation of folic acid can improve endothelial function in patients with increased risk of atherosclerotic disease due to hypercholesterolemia, without changes in plasma lipids.
Systemic and Upper and Lower Airway Inflammation at Exacerbation of Chronic Obstructive Pulmonary Disease
Authors: John R. Hurst, Wayomi R. Perera, Tom M. A. Wilkinson, Gavin C. Donaldson, Jadwiga A. Wedzicha
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: In addition to pulmonary involvement, stable chronic obstructive pulmonary disease (COPD) is associated with nasal and systemic inflammation. Although exacerbations of COPD are associated with increased pulmonary and systemic inflammation, determinants of the systemic response remain obscure, and nor is it known whether there is nasal involvement.Objectives: To investigate upper airway, lower airway, and systemic inflammation at exacerbation of COPD.Methods: We sampled sputum, nasal wash, and serum from 41 exacerbations (East London cohort) for analysis of pathogenic microorganisms and inflammatory indices (sputum/nasal wash leukocytes, interleukin [IL]-6, IL-8, and myeloperoxidase; serum IL-6 and C-reactive protein). Values were compared with stable COPD.Measurements and Main Results: Exacerbation of COPD is associated with greater nasal, sputum, and serum inflammation than the stable state. At exacerbation, inflammatory markers were highly correlated within nasal wash and serum (all r ⩾ 0.62, p < 0.001), but not sputum. The degree of upper airway inflammation correlated with the degree of lower airway inflammation (e.g., nasal wash/sputum myeloperoxidase; r = 0.50, p = 0.001). The degree of systemic inflammation correlated with the degree of lower airway inflammation (e.g., serum IL-6/sputum IL-8; r = 0.35, p = 0.026), and was greater in the presence of a sputum bacterial pathogen (29.0 g/dl C-reactive protein difference, p = 0.002). We did not find relationships between the upper airway and systemic compartments.Conclusions: Exacerbation of COPD is associated with pan-airway inflammation; the systemic inflammatory response is proportional to that occurring in the lower airway and greater in the presence of a bacterial pathogen.
Intracellular β-Tubulin/Chaperonin Containing TCP1-β Complex Serves as a Novel Chemotherapeutic Target against Drug-Resistant Tumors
Authors: Yuan-Feng Lin, Wen-Ping Tsai, Hon-Ge Liu, Po-Huang Liang
Journal: Cancer Research (2009)

Abstract In the present study, treatment of HEK-293 cells with the synthetic small molecule N-iodoacetyl-tryptophan (I-Trp) at submicromolar concentrations efficiently induced cell apoptosis as judged from the accumulation of sub-G0 cells and intracellular DNA fragmentation. Activation of all intracellular caspases, except caspase-1, was detected in I-Trp–treated cells. Proteomic analysis revealed that β-tubulin acted as a specific intracellular target of I-Trp. Protein fingerprinting analysis indicated that the Cys354 residue in the peptide fragment TAVCDIPPR of β-tubulin, which is located at the binding interface with chaperonin containing TCP1-β (CCT-β), was alkylated by I-Trp. Moreover, site-directed mutagenesis of Cys354 (Cys-Ala) abolished the incorporation of I-Trp into β-tubulin, suggesting Cys354 is indeed the targeting site of I-Trp. Immunoprecipitation showed that the β-tubulin/CCT-β complex was constitutively formed but disrupted after treatment with I-Trp. Overexpression of the truncated β-tubulin (T351-S364) or treatment with I-Trp or the synthetic peptide Myr-TAVCDIPPRG caused more severe cell apoptosis in multidrug-resistant MES-SA/Dx5 cancer cells due to higher levels of CCT-β relative to wild-type MES-SA cancer cells. Silencing the expression of CCT-β rendered MES-SA/Dx5 cells less sensitive to I-Trp–induced apoptotic cell death. These findings suggest that the β-tubulin/CCT-β complex may serve as an effective chemotherapeutic target for treating clinical tubulin-binding agent-resistant or CCT-β–overexpressing tumors. [Cancer Res 2009;69(17):6879–88]
Intestinal metaplasia at the gastro-oesophageal junction:<i>Helicobacter pylori</i> gastritis or gastro-oesophageal reflux disease?
Authors: A Hackelsberger, T Günther, V Schultze, G Manes, J-E Dominguez-Muñoz, A Roessner, P Malfertheiner
Journal: Gut (1998)

Intestinal metaplasia, whether in the cardia or the distal oesophagus, has been uniformly defined as specialised columnar epithelium, suggesting a relation with Barrett's oesophagus. It is, however, not clear whether the risk factors associated with intestinal metaplasia are identical at both sites.To investigate biopsy specimens obtained below the squamocolumnar junction (SCJ) in relation to endoscopic aspect, gastric histology, and clinical presentation.In 423 patients investigated the endoscopic aspect of the SCJ was classified as unremarkable (group I, n = 315) or suggestive of Barrett's oesophagus (group II, n = 108). Standardised biopsy specimens from the antrum, corpus, and directly below the SCJ were investigated.Intestinal metaplasia was detected at the SCJ in 13.4% of group I patients, where it was significantly associated with gastric intestinal metaplasia (odds ratio (OR) 6.96; confidence interval (CI) 2.48 to 19.54) and H pylori (OR 7.85; CI 2.82 to 21.85), and in 34.3% of group II patients where it was significantly associated with reflux symptoms (OR 19.98; CI 6.12 to 65.19), erosive oesophagitis (OR 12.16; CI 3.86 to 38.24), and male sex (OR 6.25, CI 2.16 to 18.14), but not with H pylori or gastric intestinal metaplasia.This study suggests that the pathogenesis of intestinal metaplasia at the SCJ is not uniform: at an endoscopically unremarkable SCJ it is a sequela of H pylori gastritis, but coexisting with endoscopic features of Barrett's oesophagus it is associated with male sex and gastro-oesophageal reflux disease.
PTH-022 Rectal Irrigation in Functional Bowel Symptoms: Prospective Audit of Patients Attending a Novel Tertiary Service (The Healthy Bowel Clinic)
Authors: S Blythin, C Molyneux, K Bodger, P Skaife
Journal: Gut (2013)

<h3>Introduction</h3> Rectal irrigation was developed to treat patients with neurogenic bowel dysfunction. More recently its application in the management of functional bowel disorders has increased but published outcome data are scarce. Our pelvic floor unit offers a novel tertiary referral service (the Healthy Bowel Clinic) and has employed rectal irrigation within a Bowel Care Pathway for the last 6 years to treat a variety of functional bowel symptoms, including constipation, faecal incontinence and obstructive defecation syndromes (ODS). As part of our service evaluation we aimed to audit patient-reported outcome using a postal questionnaire survey. <h3>Methods</h3> We identified a cohort of 101 consecutive patients (85 female; 16 male) who had commenced rectal irrigation and attended the service for at least 12 weeks (mean: 55 weeks; range 12–70). The cohort included 45 with predominant constipation, 27 with faecal incontinence and 29 with ODS. A cross-sectional postal survey was undertaken using a questionnaire which first asked whether irrigation was continuing at this time or not. Patients reporting continued use were asked to record it’s frequency, water volume and a pre- and post-treatment symptom score (VAS Scale:0–10). Those reporting cessation of treatment were asked to indicate their reasons for stopping. Reasons for discontinuation of irrigation were recorded. <h3>Results</h3> 68 of 101 patients (67.3%) reported continuing use of rectal irrigation. Of the patients still irrigating, 24 were in the constipated group, 18 were in the faecal incontinence group and 26 were in the ODS group. Their mean (sd) pre-treatment symptom score was 9.1 (1.5), confirming a high symptom burden among patients selected for treatment, and the post-treatment rating of current symptoms was significantly improved at 4.2 (2.3) (p &lt; 0.001). The mean irrigation volume was ~800 mls (range: 150–2000) and 41 patients (60%) reported daily use. Of 33 patients who stopped using irrigation, 11 (33.3%) cited a failure to address symptoms as the reason for cessation (Constipation: 21; Faecal Incontinence: 9; ODS: 3). <h3>Conclusion</h3> The results show that rectal irrigation is a viable treatment option for patients presenting with a range of functional bowel symptoms. Efficacy was achieved across a variety of sub-groups. It was acceptable and well-tolerated as indicated by frequent and prolonged use in many patients. Further research is needed to identify clinical criteria to guide patient selection and predictors of success. <h3>Disclosure of Interest</h3> None Declared.