tbuckley/cabot-search huggingface dataset:
Involvement of Sphingosine Kinase 2 in p53-Independent Induction of p21 by the Chemotherapeutic Drug Doxorubicin
Authors: Heidi M. Sankala, Nitai C. Hait, Steven W. Paugh, Dai Shida, Sandrine Lépine, Lynne W. Elmore, Paul Dent, Sheldon Milstien, Sarah Spiegel
Journal: Cancer Research (2007)

Abstract Sphingosine-1-phosphate is a potent lipid mediator formed by phosphorylation of sphingosine, a metabolite of sphingolipids, catalyzed by two sphingosine kinase (SphK) isoenzymes, SphK1 and SphK2. Expression of SphK2, which is enriched in the nucleus of MCF7 human breast cancer cells, increased expression of the cyclin-dependent kinase inhibitor p21 but had no effect on p53 or its phosphorylation. The anticancer drug doxorubicin is known to increase p21 via p53-dependent and p53-independent mechanisms. Down-regulation of endogenous SphK2 with small interfering RNA targeted to unique mRNA sequences decreased basal and doxorubicin-induced expression of p21 without affecting increased expression of p53. Down-regulation of SphK2 also decreased G2-M arrest and markedly enhanced apoptosis induced by doxorubicin. Moreover, siSphK2 reduced doxorubicin-induced p21 expression in p53-inactivated MCF7 cells. Likewise, in human wild-type p53- and p21-expressing HCT116 colon carcinoma cells, as well as in p53-null counterparts, down-regulation of SphK2 markedly reduced p21 induction by doxorubicin. Knockdown of SphK2 sensitized HCT116 cells to apoptosis induced by doxorubicin with concomitant cleavage of poly(ADP-ribose) polymerase. Collectively, our results show that endogenous SphK2 is important for p53-independent induction of p21 expression by doxorubicin and suggest that SphK2 may influence the balance between cytostasis and apoptosis of human cancer cells. [Cancer Res 2007;67(21):10466–74]
Treatment and Prevention of Urinary Tract Infection with Orally Active FimH Inhibitors
Authors: Corinne K. Cusumano, Jerome S. Pinkner, Zhenfu Han, Sarah E. Greene, Bradley A. Ford, Jan R. Crowley, Jeffrey P. Henderson, James W. Janetka, Scott J. Hultgren
Journal: Science Translational Medicine (2011)

Optimized mannoside compounds that block uropathogenic E. coli entry into bladder epithelium were effective in the treatment and prevention of urinary tract infections in mice.
Training risk factors associated with wrestling injury
Authors: S Stanev, E Dimitrova
Journal: British Journal of Sports Medicine (2011)

Introduction Wrestling is strength sport that requires a large amount of muscle stamina superior flexibility, control and intensive training. The incidence of traumatic and overuse injury is high.1 2 The purpose of this study is to determine injury risk factors associated with wrestling training. Methods 120 (male and female) wrestling students aged 18–26.5 years were recruited from National Sports Academy. We retrieved through injury survey, information regarding chronic injuries, most recent wrestling related injuries as well as treatments, training history and awareness of injury prevention strategies. Risk factors were analysed by Pearson's correlation, ANOVA and t tests. Results The results indicate that 45.8% of wrestlers had sustained an injury within the past 6 months. The majority of wrestlers (52.5%) reported being affected by chronic injuries at the time of the survey. Age of onset for wrestling-related and chronic injuries averaged 15 and 17 years. The knee and ankle3 were the most common sites of injury (35%). Arms, shoulders, and hands injuries account for 20% of all injuries. The majority of participants (82%) who required treatment for their most recent wrestling-related injuries consulted a physiotherapist.4 Two of the significant risk factors for injuries were training over 8 h per week (p&lt;0.001) and the training methodology. Conclusions An individual training threshold may exist for wrestlers, which if exceeded, increases the risk of injuries. In freestyle wrestling these injuries most commonly affect the knee and ankle. A well-planned weekly training load may reduce injuries. As participation in sport activity does not increase injury risk, cross-training may improve these athletes’ fitness during competition period. Physiotherapists and coaches have a role in developing such a training program.
QUADAS-2: A Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies
Authors: Penny F. Whiting
Journal: Annals of Internal Medicine (2011)

In 2003, the QUADAS tool for systematic reviews of diagnostic accuracy studies was developed. Experience, anecdotal reports, and feedback suggested areas for improvement; therefore, QUADAS-2 was developed. This tool comprises 4 domains: patient selection, index test, reference standard, and flow and timing. Each domain is assessed in terms of risk of bias, and the first 3 domains are also assessed in terms of concerns regarding applicability. Signalling questions are included to help judge risk of bias. The QUADAS-2 tool is applied in 4 phases: summarize the review question, tailor the tool and produce review-specific guidance, construct a flow diagram for the primary study, and judge bias and applicability. This tool will allow for more transparent rating of bias and applicability of primary diagnostic accuracy studies.
Duchenne muscular dystrophy
Authors: Y. ISHIKAWA, J. R BACH;, A K SIMONDS
Journal: Thorax (1999)

In their recently published paper Simonds et al 1 importantly emphasised the desirability of using non-invasive intermittent positive pressure ventilation (IPPV) rather than tracheostomy for optimising quality of life in patients with hypercapnic Duchenne muscular dystrophy, and suggested that the use of nocturnal nasal IPPV can help to prolong survival. They also noted that five of the 23 patients treated in this manner died from respiratory failure two years after beginning nocturnal nasal IPPV, and that most subsequent “admissions were for treatment of chest infections”. In reality, nocturnal nasal IPPV is only likely to prolong the lives of …
Mitochondria-Derived Reactive Oxygen Species Dilate Cerebral Arteries by Activating Ca <sup>2+</sup> Sparks
Authors: Qi Xi, Sergei Y. Cheranov, Jonathan H. Jaggar
Journal: Circulation Research (2005)

Mitochondria regulate intracellular calcium (Ca 2+ ) signals in smooth muscle cells, but mechanisms mediating these effects, and the functional relevance, are poorly understood. Similarly, antihypertensive ATP-sensitive potassium (K ATP ) channel openers (KCOs) activate plasma membrane K ATP channels and depolarize mitochondria in several cell types, but the contribution of each of these mechanisms to vasodilation is unclear. Here, we show that cerebral artery smooth muscle cell mitochondria are most effectively depolarized by diazoxide (−15%, tetramethylrhodamine [TMRM]), less so by levcromakalim, and not depolarized by pinacidil. KCO-induced mitochondrial depolarization increased the generation of mitochondria-derived reactive oxygen species (ROS) that stimulated Ca 2+ sparks and large-conductance Ca 2+ -activated potassium (K Ca ) channels, leading to transient K Ca current activation. KCO-induced mitochondrial depolarization and transient K Ca current activation were attenuated by 5-HD and glibenclamide, K ATP channel blockers. MnTMPyP, an antioxidant, and Ca 2+ spark and K Ca channel blockers reduced diazoxide-induced vasodilations by &gt;60%, but did not alter dilations induced by pinacidil, which did not elevate ROS. Data suggest diazoxide drives ROS generation by inducing a small mitochondrial depolarization, because nanomolar CCCP, a protonophore, similarly depolarized mitochondria, elevated ROS, and activated transient K Ca currents. In contrast, micromolar CCCP, or rotenone, an electron transport chain blocker, induced a large mitochondrial depolarization (−84%, TMRM), reduced ROS, and inhibited transient K Ca currents. In summary, data demonstrate that mitochondria-derived ROS dilate cerebral arteries by activating Ca 2+ sparks, that some antihypertensive KCOs dilate by stimulating this pathway, and that small and large mitochondrial depolarizations lead to differential regulation of ROS and Ca 2+ sparks.
Unfavorable histologies of non-Hodgkin's lymphoma treated with ProMACE-CytaBOM: a groupwide Southwest Oncology Group study.
Authors: T P Miller, S Dahlberg, J K Weick, J C Files, H J Eyre, K B Pendergrass, R I Fisher
Journal: Journal of Clinical Oncology (1990)

Chemotherapy using cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, methotrexate with leucovorin, and prednisone (ProMACE-CytoBOM) for patients with intermediate- and high-grade non-Hodgkin's lymphomas was tested by the Southwest Oncology Group (SWOG) to confirm the activity of the regimen and to test the feasibility and safety of administering third-generation drug regimens in a cooperative group setting. On day 1, cyclophosphamide, doxorubicin, and etoposide were administered, followed by cytarabine, bleomycin, vincristine and methotrexate with leucovorin given on day 8. There were 51 complete remissions (CRs) among 78 previously untreated patients (65%) having clinical stage II-IV disease. The median length of follow-up is 37.9 months with 57% of patients alive at 3 years and 50% of CR patients free of disease at 3 years. Patients with diffuse large-cell lymphoma have the best survival (63% at 3 years) and relapse-free survival (RFS; 68% at 3 years with no relapses seen after 14 months). Administration of ProMACE-CytoBOM is feasible and safe in a cooperative group setting with 84% of 537 courses of treatment given exactly according to schedule and fatal toxicities seen in five patients (6%). ProMACE-CytaBOM may represent improved treatment for diffuse large-cell lymphoma, but the modest differences compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) indicate the need for a prospective randomized comparative trial.
Pocked erythrocyte counts in patients with hereditary spherocytosis before and after splenectomy
Authors: George R. Buchanan, Christine A. Holtkamp
Journal: American Journal of Hematology (1987)

Abstract The pocked (pitted or vacuolated) erythrocyte count has become increasingly utilized as a simple inexpensive test of splenic reticuloendothelial function. Values are less than 2.0% in normal subjects and 20 to 70% following splenectomy. Because scant and conflicting data are available about pocked erythrocyte measurements in hemolytic anemias other than the hemoglobinopathies, we performed pocked erythrocyte counts in 27 patients with hereditary spherocytosis. Prior to splenectomy patients often had elevated values (mean 4.9%). This unexpected observation suggests that hemolytic anemia may result in congestion of the red pulp and/or induce mild splenic reticuloendothelial blockade. As expected, but contrary to a previous report, pocked erythrocyte values following splenectomy were markedly increased (mean 54.9%).
Implantable Cardioverter-Defibrillators in Tetralogy of Fallot
Authors: Paul Khairy, Louise Harris, Michael J. Landzberg, Sangeetha Viswanathan, Amanda Barlow, Michael A. Gatzoulis, Susan M. Fernandes, Luc Beauchesne, Judith Therrien, Philippe Chetaille, Elaine Gordon, Isabelle Vonder Muhll, Frank Cecchin
Journal: Circulation (2008)

Background— Tetralogy of Fallot is the most common form of congenital heart disease in implantable cardioverter-defibrillator (ICD) recipients, yet little is known about the value of ICDs in this patient population. Methods and Results— We conducted a multicenter cohort study in high-risk patients with Tetralogy of Fallot to determine actuarial rates of ICD discharges, identify risk factors, and characterize ICD-related complications. A total of 121 patients (median age 33.3 years; 59.5% male) were enrolled from 11 sites and followed up for a median of 3.7 years. ICDs were implanted for primary prevention in 68 patients (56.2%) and for secondary prevention in 53 (43.8%), defined by clinical sustained ventricular tachyarrhythmia or resuscitated sudden death. Overall, 37 patients (30.6%) received at least 1 appropriate and effective ICD discharge, with a median ventricular tachyarrhythmia rate of 213 bpm. Annual actuarial rates of appropriate ICD shocks were 7.7% and 9.8% in primary and secondary prevention, respectively ( P =0.11). A higher left ventricular end-diastolic pressure (hazard ratio 1.3 per mm Hg, P =0.004) and nonsustained ventricular tachycardia (hazard ratio 3.7, P =0.023) independently predicted appropriate ICD shocks in primary prevention. Inappropriate shocks occurred in 5.8% of patients yearly. Additionally, 36 patients (29.8%) experienced complications, of which 6 (5.0%) were acute, 25 (20.7%) were late lead-related, and 7 (5.8%) were late generator-related complications. Nine patients died during follow-up, which corresponds to an actuarial annual mortality rate of 2.2%, which did not differ between the primary and secondary prevention groups. Conclusions— Patients with tetralogy of Fallot and ICDs for primary and secondary prevention experience high rates of appropriate and effective shocks; however, inappropriate shocks and late lead-related complications are common.
Comprehensive analysis of inflammatory markers in chronic thromboembolic pulmonary hypertension patients
Authors: Diana Zabini, Akos Heinemann, Vasile Foris, Chandran Nagaraj, Patrick Nierlich, Zoltán Bálint, Grazyna Kwapiszewska, Irene M. Lang, Walter Klepetko, Horst Olschewski, Andrea Olschewski
Journal: European Respiratory Journal (2014)

Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with chronic inflammation but the pathological mechanisms are largely unknown. Our study aimed to simultaneously profile a broad range of cytokines in the supernatant of pulmonary endarterectomy (PEA) surgical material, as well as prospectively in patients with CTEPH to investigate whether circulating cytokines are associated with haemodynamic and physical characteristics of CTEPH patients. Herein, we show that PEA specimens revealed a significant upregulation of interleukin (IL)-6, monocyte chemoattractant protein-1, interferon-γ-induced protein-10 (IP)-10, macrophage inflammatory protein (MIP)1α and RANTES compared to lung tissue from healthy controls. In prospectively collected serum, levels of IL-6, IL-8, IP-10, monokine induced by interferon-γ (MIG) and MIP1α were significantly elevated in CTEPH patients compared to age- and sex-matched healthy controls. In serum of idiopathic pulmonary arterial hypertension (IPAH) patients, only IP-10 and MIG were significantly increased. In CTEPH but not in IPAH, IP-10 was negatively correlated with cardiac index, 6-min walking distance and carbon monoxide diffusion capacity. In vitro , IP-10 significantly increased migration of freshly isolated adventitial fibroblasts. Our study is the first to show that IP-10 secretion is associated with poor pulmonary haemodynamics and physical capacity in CTEPH and might be involved in the pathological mechanism of PEA tissue formation.
Serum cytokines and steroidal hormones in polymyalgia rheumatica and elderly-onset rheumatoid arthritis
Authors: M Cutolo, C M Montecucco, L Cavagna, R Caporali, S Capellino, P Montagna, L Fazzuoli, B Villaggio, B Seriolo, A Sulli
Journal: Annals of the Rheumatic Diseases (2006)

Polymyalgia rheumatica (PMR) may create some difficulties in the differential diagnosis of elderly-onset rheumatoid arthritis (EORA) and of EORA with PMR-like onset (EORA/PMR).To investigate possible differences between three groups of patients, with regard to serum levels of inflammatory cytokines and steroidal hormones at baseline and after 1 month of treatment with glucocorticoids (prednisone 7.5-12.5 mg/day).14 patients with PMR, 15 with EORA and 14 with EORA/PMR, as well as 15 healthy, matched controls were analysed. Tumour necrosis factor alpha (TNFalpha), interleukin (IL)6, IL1 receptor antagonist (IL1Ra), cortisol, dehydroepiandrosterone sulphate (DHEAS) and 17-hydroxy-progesterone (PRG) were evaluated.Serum levels of both TNFalpha and IL6 were significantly higher in all three groups of patients than in controls (p<0.01). Serum IL6 levels were significantly higher in patients with both PMR and EORA/PMR than in patients with EORA (p<0.05). IL1Ra serum levels were significantly higher in patients with EORA than in controls (p<0.001) and in patients with PMR and EORA/PMR (p<0.05). DHEAS was significantly lower in patients with EORA/PMR than in those with EORA (p<0.05). PRG was significantly higher in all patient groups (p<0.05). After glucocorticoid treatment, serum TNFalpha and IL6 levels significantly decreased in all patient groups; IL1Ra significantly increased in patients with PMR and in those with EORA/PMR; cortisol, DHEAS, and PRG significantly decreased in patients with PMR and in those with EORA/PMR (p<0.05).Different cytokine and steroidal hormone patterns suggest that patients with PMR and those with EORA/PMR seem to be have a more intensive inflammatory reaction and are more efficient responders to glucocorticoid treatment than patients with EORA.
166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials
Authors: Sergio Giralt, William Bensinger, Mark Goodman, Donald Podoloff, Janet Eary, Richard Wendt, Raymond Alexanian, Donna Weber, David Maloney, Leona Holmberg, Joseph Rajandran, Hazel Breitz, Richard Ghalie, Richard Champlin
Journal: Blood (2003)
Vasculature and Kidney Complications in Sickle Cell Disease
Authors: Karl A. Nath, Zvonimir S. Katusic
Journal: Journal of the American Society of Nephrology (2012)

Recent developments in sickle cell disease include the concept of a vasculopathic state and the classification of sickle cell disease into a hemolysis-endothelial dysfunction phenotype or a viscosity-vasoocclusion phenotype. The hemolysis-endothelial dysfunction phenotype largely reflects deficiency of or resistance to nitric oxide. In addition to discussing these areas, we suggest that the hemolysis-endothelial dysfunction phenotype also reflects the instability of sickle hemoglobin, the release of heme, and the induction of heme oxygenase-1. From these perspectives the renal complications of sickle cell disease are discussed and classified.
Complement Regulatory Genes and Hemolytic Uremic Syndromes
Authors: David Kavanagh, Anna Richards, John Atkinson
Journal: Annual Review of Medicine (2007)

Hemolytic uremic syndrome is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It is one of a group of conditions termed the thrombotic microangiopathies, which are characterized by prominent endothelial cell injury. It may be diarrheal-associated or atypical (aHUS). Evidence for a pathogenic role of the alternative pathway of complement was first suggested in 1974. Mutations in the complement regulatory proteins factor H, membrane cofactor protein (CD46), and factor I predispose to aHUS development. Mutations of the activating components factor B and complement C3 have also been reported. Penetrance is ∼50%, suggesting other genetic and environmental modifiers are needed for disease expression. Identification of mutations is important owing to differences in mortality, renal survival, and outcome of renal transplantation. Current treatment is plasma infusion/exchange, but complement inhibitor therapy provides hope for the future.
The wear and tear of 26.2: dermatological injuries reported on marathon day
Authors: E A Mailler, B B Adams
Journal: British Journal of Sports Medicine (2004)

Whether it is to take on the challenge, to get in shape and lose weight, to relieve stress, or to enjoy the outdoors, people have increasingly turned to the marathon as their sporting event of choice. Although there are many health benefits, beginners should be aware that injuries are quite common in marathon runners. Among these are the wear and tear injuries to the skin. This is a review of the most commonly reported dermatological injuries on marathon day.
Interventions for Alleviating Cancer-Related Dyspnea: A Systematic Review
Authors: Irit Ben-Aharon, Anat Gafter-Gvili, Mical Paul, Leonard Leibovici, Salomon M. Stemmer
Journal: Journal of Clinical Oncology (2008)

Dyspnea is one of the most distressing symptoms experienced by terminally ill cancer patients. This study aimed to evaluate the role of interventions for the palliation of dyspnea.We conducted a systematic review of randomized controlled trials assessing all pharmacologic and nonpharmacologic interventions for dyspnea palliation in cancer patients, and searched the Cochrane Library, MEDLINE, conference proceedings, and references. Two reviewers independently appraised the quality of trials and extracted data.Our search yielded 18 trials. Fourteen evaluated pharmacologic interventions: seven assessing opioids (a total of 256 patients), five assessing oxygen (137 patients), one assessing helium-enriched air, and one assessing furosemide. Four trials evaluated nonpharmacologic interventions (403 patients). The administration of subcutaneous morphine resulted in a significant reduction in dyspnea Visual Analog Scale (VAS) compared with placebo. No difference was observed in dyspnea VAS score when nebulized morphine was compared with subcutaneous morphine, although patients preferred the nebulized route. The addition of benzodiazepines to morphine was significantly more effective than morphine alone, without additional adverse effects. Oxygen was not superior to air for alleviating dyspnea, except for patients with hypoxemia. Nursing-led interventions improved breathlessness. Acupuncture was not beneficial.Our review supports the use of opioids for dyspnea relief in cancer patients. The use of supplemental oxygen to alleviate dyspnea can be recommended only in patients with hypoxemia. Nursing-led nonpharmacologic interventions seem valuable. Only a few studies addressing this question were performed. Thus, further studies evaluating interventions for alleviating dyspnea are warranted.