tbuckley/cabot-search huggingface dataset:
Inhibition of Histone Deacetylase in Cancer Cells Slows Down Replication Forks, Activates Dormant Origins, and Induces DNA Damage
Authors: Chiara Conti, Elisabetta Leo, Gabriel S. Eichler, Olivier Sordet, Melvenia M. Martin, Angela Fan, Mirit I. Aladjem, Yves Pommier
Journal: Cancer Research (2010)

Abstract Protein acetylation is a reversible process regulated by histone deacetylases (HDAC) that is often altered in human cancers. Suberoylanilide hydroxamic acid (SAHA) is the first HDAC inhibitor to be approved for clinical use as an anticancer agent. Given that histone acetylation is a key determinant of chromatin structure, we investigated how SAHA may affect DNA replication and integrity to gain deeper insights into the basis for its anticancer activity. Nuclear replication factories were visualized with confocal immunofluorescence microscopy and single-replicon analyses were conducted by genome-wide molecular combing after pulse labeling with two thymidine analogues. We found that pharmacologic concentrations of SAHA induce replication-mediated DNA damage with activation of histone γH2AX. Single DNA molecule analyses indicated slowdown in replication speed along with activation of dormant replication origins in response to SAHA. Similar results were obtained using siRNA-mediated depletion of HDAC3 expression, implicating this HDAC member as a likely target in the SAHA response. Activation of dormant origins was confirmed by molecular analyses of the β-globin locus control region. Our findings demonstrate that SAHA produces profound alterations in DNA replication that cause DNA damage, establishing a critical link between robust chromatin acetylation and DNA replication in human cancer cells. Cancer Res; 70(11); 4470–80. ©2010 AACR.
Can medication packaging improve glycemic control and blood pressure in type 2 diabetes? Results from a randomized controlled trial.
Authors: D Simmons, M Upjohn, G D Gamble
Journal: Diabetes Care (2000)

To assess the impact of calendar blister pack (CBP) use on glycemic and blood pressure control.We conducted an 8-month randomized controlled double-blind study among diabetic patients with poor glucose control (HbA1c >9.0%) in an urban area of South Auckland, New Zealand, with a high proportion of Maori and Pacific Islands people. Subjects included 68 consecutive patients, of whom 50% were prescribed three or more medications per dayHbA1c was reduced by 0.95+/-0.22% in the CBP group and 0.15+/-0.25% in the control group (P = 0.026). Diastolic blood pressure decreased 5.8+/-1.5 mm Hg in the CBP group and increased 0.1+/-1.9 mm Hg in the control group (P = 0.0041). Systolic blood pressure did not change significantlyCBPs should be considered among diabetic patients with poor glycemic control receiving multiple medications.
Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms
Authors: Thorsten Klampfl, Heinz Gisslinger, Ashot S. Harutyunyan, Harini Nivarthi, Elisa Rumi, Jelena D. Milosevic, Nicole C.C. Them, Tiina Berg, Bettina Gisslinger, Daniela Pietra, Doris Chen, Gregory I. Vladimer, Klaudia Bagienski, Chiara Milanesi, Ilaria Carola Casetti, Emanuela Sant'Antonio, Virginia Ferretti, Chiara Elena, Fiorella Schischlik, Ciara Cleary, Melanie Six, Martin Schalling, Andreas Schönegger, Christoph Bock, Luca Malcovati, Cristiana Pascutto, Giulio Superti-Furga, Mario Cazzola, Robert Kralovics
Journal: New England Journal of Medicine (2013)

Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients.We performed whole-exome sequencing to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Resequencing of CALR, encoding calreticulin, was then performed in cohorts of patients with myeloid neoplasms.Somatic insertions or deletions in exon 9 of CALR were detected in all patients who underwent whole-exome sequencing. Resequencing in 1107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. In essential thrombocythemia and primary myelofibrosis, CALR mutations and JAK2 and MPL mutations were mutually exclusive. Among patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 or MPL, CALR mutations were detected in 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis. A total of 36 types of insertions or deletions were identified that all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2.Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F mutation. (Funded by the MPN Research Foundation and Associazione Italiana per la Ricerca sul Cancro.).
Cuba's international cooperative efforts in health
Authors: Pol De Vos, Patrick Van der Stuyft
Journal: BMJ (2006)

A prescription for better prescribing Medical education is a continuumEditor-The editorial by Aronson et al raises important concerns about the preparedness of newly qualified doctors to prescribe safely and effectively, but fails to provide evidence to support the claims that are made. 1 Importantly, the authors assume that the number of curricular hours equates to learning.The General Medical Council issues and regularly updates requirements for the content and outcomes of undergraduate medical education and the first foundation year.We deliberately do not tell medical schools how many hours must be spent on a particular subject: it is the acquisition of our learning objectives that is important.Medical education is a continuum.With respect to prescribing, as with so many other areas of medical education, we expect principles to be learnt and understood at medical school and then put into practice, under supervision, during the F1 year.Our requirements are laid out clearly in Tomorrow's Doctors and The New Doctor and include very clear expectations about the quality and extent of knowledge about the safe and effective use of drugs.Despite the strength of views expressed in the editorial, the authors have not presented robust and generally applicable evidence to show serious inadequacies in the learning of clinical pharmacology in the undergraduate medical curriculum.We look forward, however, to engaging with all interested parties to clarify the issues surrounding this very important subject.
Cost-benefit models as the next, best option for understanding subjective effort
Authors: Robert Kurzban, Angela Duckworth, Joseph W. Kable, Justus Myers
Journal: Behavioral and Brain Sciences (2013)

Abstract The commentaries on our target article are surprisingly sympathetic to our overall approach to explaining subjective effort, though disagreement with particulars inevitably emerged. Here, in our response, we first review the few disagreements concerning the basic structure of our proposal, highlighting areas in which little or no resistance was voiced. Opposition to the assumptions that underlie our opportunity cost model is noticeably limited. Areas of genuine disagreement, however, include: (1) the inputs to and outputs of the relevant decision-making systems; (2) how to interpret data regarding individual differences in performance; (3) how to explain persistence on tasks that give rise to the sensation of subjective effort; and (4) the details of the relevant neuropsychological systems. Throughout we point to empirical issues raised by the commentaries and suggest research that will be useful in arbitrating points of disagreement.
Acute patellofemoral pain: aggravating activities, clinical examination, MRI and ultrasound findings
Authors: C Brushøj, P Hölmich, M B Nielsen, E Albrecht-Beste
Journal: British Journal of Sports Medicine (2007)

To investigate acute anterior knee pain caused by overuse in terms of pain location, aggravating activities, findings on clinical examination and ultrasound/MRI examination. To determine if acute anterior knee pain caused by overuse should be classified as a subgroup of patellofemoral pain syndrome (PFPS).In a observational study design 30 army recruits with anterior knee pain (mean duration of pain 4 weeks) were examined using the PFPS pain severity scale (PSS), knee pain diagrams, standardised clinical examination, ultrasound and MRI examinations.On PSS typical knee loading activities were the most painful, while sitting with knee bend for prolonged time caused surprisingly little pain. Pain was most commonly perceived in the peripatellar area (25 patients (83%)). The most common site of pain on clinical examination was the peripatellar area (25 patients (83%)), but other synovial covered structures including the fat pad of Hoffa (12 patients (40%)), the medial plica and the joint line (12 patients (40%)) were also involved. Only eight patients (27%) experienced pain on the patellofemoral compression test. Only discrete changes was detected on MRI/ultrasound.Acute anterior knee pain should be regarded as a subgroup of PFPS as both symptoms and clinical examination suggests this. The clinical examination with disseminated pain in all synovial covered structures is consistent with ideas of the importance of synovium in the genesis of pain.
Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats
Authors: Shie-Chau Liu, Reem Alomran, Sophia B. Chernikova, Fred Lartey, Jason Stafford, Taichang Jang, Milton Merchant, Dirk Zboralski, Stefan Zöllner, Anna Kruschinski, Sven Klussmann, Lawrence Recht, J. Martin Brown
Journal: Neuro-Oncology (2013)

Tumor irradiation blocks local angiogenesis, forcing any recurrent tumor to form new vessels from circulating cells. We have previously demonstrated that the post-irradiation recurrence of human glioblastomas in the brains of nude mice can be delayed or prevented by inhibiting circulating blood vessel–forming cells by blocking the interaction of CXCR4 with its ligand stromal cell-derived factor (SDF)–1 (CXCL12). In the present study we test this strategy by directly neutralizing SDF-1 in a clinically relevant model using autochthonous brain tumors in immune competent hosts. We used NOX-A12, an l-enantiomeric RNA oligonucleotide that binds and inhibits SDF-1 with high affinity. We tested the effect of this inhibitor on the response to irradiation of brain tumors in rat induced by n-ethyl-N-nitrosourea. Rats treated in utero with N-ethyl-N-nitrosourea began to die of brain tumors from approximately 120 days of age. We delivered a single dose of whole brain irradiation (20 Gy) on day 115 of age, began treatment with NOX-A12 immediately following irradiation, and continued with either 5 or 20 mg/kg for 4 or 8 weeks, doses and times equivalent to well-tolerated human exposures. We found a marked prolongation of rat life span that was dependent on both drug dose and duration of treatment. In addition we treated tumors only when they were visible by MRI and demonstrated complete regression of the tumors that was not achieved by irradiation alone or with the addition of temozolomide. Inhibition of SDF-1 following tumor irradiation is a powerful way of improving tumor response of glioblastoma multiforme.
TCT-697 Outcomes from MitraClip Therapy in Functional Compared to Degenerative Mitral Regurgitation: Multi-centre Experience from the MitraClip Asia-Pacific Registry (MARS)
Authors: Edgar L. Tay, Jonathan Yap, David W. Muller, Darren L. Walters, M Nasir Muda, Eric Yamen, James W. Yip, Robaayah Zambahari, Jurgen Passage, Paul Jansz, Tian Hai Koh, Khung Keong Yeo
Journal: Journal of the American College of Cardiology (2013)
GPs' out of hours arrangements are not to blame for pressure on emergency departments, MPs hear
Authors: A. O'Dowd
Journal: BMJ (2013)

Growing pressure on hospitals’ accident and emergency departments in England have not been directly caused by GPs’ arrangements for out of hours care, experts have told MPs.

Speaking at the parliamentary health select committee on 21 May, expert witnesses said that many factors had contributed to the worrying level of pressure on emergency departments.

The committee, holding the first evidence session of its inquiry into emergency services and emergency care, asked witnesses whether they agreed with the view of the health secretary for England, Jeremy Hunt, that the main reason for rising attendances at emergency departments was changes to the GP contract in 2004 concerning out of hours work.

Mike Farrar, chief executive of the NHS Confederation, which represents organisations that commission and provide NHS services, told the …
Mannose Receptor Is a Novel Ligand for L-Selectin and Mediates Lymphocyte Binding to Lymphatic Endothelium
Authors: Heikki Irjala, Eva-Liz Johansson, Reidar Grenman, Kalle Alanen, Marko Salmi, Sirpa Jalkanen
Journal: The Journal of Experimental Medicine (2001)

Continuous lymphocyte recirculation between blood and lymphoid tissues forms a basis for the function of the immune system. Lymphocyte entrance from the blood into the tissues has been thoroughly characterized, but mechanisms controlling lymphocyte exit from the lymphoid tissues via efferent lymphatics have remained virtually unknown. In this work we have identified mannose receptor (MR) on human lymphatic endothelium and demonstrate its involvement in binding of lymphocytes to lymphatic vessels. We also show that the binding requires L-selectin, and L-selectin and MR form a receptor-ligand pair. On the other hand, L-selectin binds to peripheral lymph node addressins (PNAds) on high endothelial venules (HEVs) that are sites where lymphocytes enter the lymphatic organs. Interestingly, MR is absent from HEVs and PNAds from lymphatic endothelium. Thus, lymphocyte L-selectin uses distinct ligand molecules to mediate binding at sites of lymphocyte entrance and exit within lymph nodes. Taken together, interaction between L-selectin and MR is the first molecularly defined mechanism mediating lymphocyte binding to lymphatic endothelium.
Abnormal Sequencing of Motor Actions in Patients With Schizophrenia: Evidence From Grip Force Adjustments During Object Manipulation
Authors: Yvonne Delevoye, Anne Giersch, Jean-Marie Danion
Journal: American Journal of Psychiatry (2002)

During object manipulation, grip force must be adjusted in anticipation of destabilizing load forces to prevent the object from slipping. This study used three gripping tasks to assess whether schizophrenia affects the predictive mechanisms required for the scaling, timing, and/or sequencing of motor actions.Sixteen patients with schizophrenia and 16 comparison subjects matched for age, sex, and educational level 1) lifted objects of various mass and texture (lift task) and 2) used a manipulandum to hit (hit task) or resist (resist task) impacts produced by a collision with a pendulum. For an optimized performance, all tasks demanded a predictive increase in grip force and the timing of external events. The fluid sequencing of finger and hand submovements was required for the lift and the hit tasks but not for the resist task.Patients were impaired in the smooth execution of both the lift and the hit tasks but not in the performance of the resist task. In all three tasks, the scaling of grip force was similar for patients and comparison subjects.Schizophrenia is associated with a specific deficit in the sequencing of motor actions rather than with an overall problem in the predictive control of movement.
Is the UK government right that seven day working in hospitals would save 6000 lives a year?
Authors: Martin McKee
Journal: BMJ (2015)

The claim turned out to come from a single study that shows nothing so simple

On 16 July 2015, Health Secretary Jeremy Hunt used BBC Radio 4’s Today programme to warn the British public that “we have about 6000 avoidable deaths every year in the NHS” and that “lack of senior consultant cover at weekends is one of the critical points.”1

But it subsequently emerged that only one of more than 4000 consultants has opted out of weekend working.2 And we do not know whether excess mortality is a consequence of lower quality of care or of some difference in case mix comparing weekend with weekday admissions. The evidence underpinning Hunt’s claim has received too little attention.

One reason for the lack of scrutiny was that the Department of Health did not disclose the evidence. The BBC reported, “The 6000 figure . . . that was used by the government was from research that has yet to be published.”3

Hunt did refer to a paper published in 2012,4 but only as background, perhaps reflecting how that study painted a much more complex picture than the one being portrayed. Consequently, it was a surprise when, on 13 August 2015, in response to freedom of information requests I made, the department …
277Study of the role of Scn5a in the occurrence of arrhythmic events during myocardial infarction and post-ischemic remodeling.
Authors: B Jagu, T Le Tourneau, F Charpentier, G Toumaniantz
Journal: Cardiovascular Research (2014)

The sodium channel Nav1.5, encoded by the Scn5a gene, is responsible for the excitability and the conduction velocity of electrical impulses through the heart. Nav1.5 mutations are involved in rhythmic or structural pathologies. During the acute phase of myocardial infarction (MI), arrhythmias were associated with an increased risk of mortality. Over time, progressive left ventricular remodeling will lead to heart failure. Objectives: The association of polymorphisms and mutations carried by genes encoding for channels with acquired forms of arrhythmias and post-MI remodeling, are not well characterized. In this context, we have investigated the role of Nav1.5 genetic alterations in the occurrence of ventricular arrhythmias, structural remodeling and cardiac contraction abnormalities during the acute phase of MI. Methods: The Nav1.5 contribution in this context was evaluated after permanent occlusion of coronary artery performed on mouse model invalidated at the heterozygous state for the Scn5a gene (Scn5a+/- mice; 10-12 weeks old). After validation of the infarction by echocardiography, these animals were studied in vivo by echocardiography and ECG and in vitro using molecular and biochemical investigations during the first 48 hours post-MI. These protocols were extended to a second transgenic model, animals carriers of a mutation in SCN5A identified in humans and leading to loss of function: the T220I mutation. This original model has never been studied in this pathophysiological context. Results: Series of animals placed in this pathophysiological context, revealed that Scn5a+/− animals have a higher mortality due to arrhythmic events. In addition, the ECG recorded by telemetry during 48 hours post-MI revealed that Scn5a+/− mice present an increased incidence of premature ventricular beats (5.6±2.7 & 33.1±11 PVB/hour respectively for WT-MI and Scn5a+/−MI mice) without any difference in structural and functional remodelling compared to WT-MI. However, mRNA expression revealed that Scn5a+/−MI mice have an increased up-regulation of pro-inflammatory factors IL-6 (3.7±0.9 & 17.4±9.3 Relative Expression respectively) and IL-1β mRNA (1,8±0.3 & 4.6±0.8 RE respectively) and downregulation of Cx43 mRNA (0.61±0.08 & 0.39±0.03 RE respectively) without interstitial fibrosis induction. Conclusions: These observations, 48 hours post-MI, suggest that Scn5a+/− mice present factors for the establishment of a more severe post-ischemic heart failure. In addition, preliminary results obtained on small series of animals revealed that Scn5a+/− mice seem to have a more pronounced LV remodelling at 4 weeks post-MI.
Cytokine responses to quantiferon peptides in pediatric tuberculosis: A pilot study
Authors: Marine Armand, Vibol Chhor, Agathe de Lauzanne, Valérie Guérin-El Khourouj, Béatrice Pédron, Mohamed Jeljeli, Pierre Gressens, Albert Faye, Ghislaine Sterkers
Journal: Journal of Infection (2013)
<sup>99m</sup>Tc-MDP bone SPECT in evaluation of the knee in asymptomatic soccer players
Authors: M Yildirim, R Gursoy, E Varoglu, Y Oztasyonar, S Cogalgil
Journal: British Journal of Sports Medicine (2004)

Objective: To evaluate stress fractures in leg (particularly around the knee, tibia, and femur) and knee pathology in active asymptomatic (no symptoms in the preceding month) soccer players. Method: The study included 42 asymptomatic soccer players (21 women, 21 men; age range 19–31 years). Players from seven teams in the major female professional and amateur male soccer leagues were examined by technetium-99m-methylene diphosphonate ( 99m Tc-MDP) bone scintigraphy during the soccer season. Four hours after intravenous injection of 20 mCi 99m Tc-MDP, standard imaging included anterior planar spot images of the legs, lateral images of the knee, and single photon emission computed tomography (SPECT). Results: Although the players were asymptomatic, increased tracer uptake, indicating stress fracture, was found in 28 (66%). Most of the stress fractures were in the tibia (62%) and femur (5%). In the 42 subjects (84 legs), 35 sites (42%) showed rupture of the posterior horn of the lateral meniscus and bone bruising of the tibial plateau, 16 sites (19%) showed rupture of the anterior horn of the medial meniscus, 11 sites (13%) showed bone bruising of the lateral femoral condyle, eight sites (10%) showed bone bruising of the medial femoral condyle, and there was avulsion injury to the infrapatellar tendon insertion in the anterior tibia in 34 sites (40%). There were 11 anterior cruciate ligament injuries. Conclusion: Bone SPECT is very accurate, easy to perform, cost effective, may give valuable information before magnetic resonance imaging studies in the detection of meniscal tears, and may be used successfully when magnetic resonance imaging is unavailable.
Normalization of hypercalcemia associated with a decrease in renal calcium reabsorption in Leydig cell tumor-bearing rats treated with WR-2721.
Authors: S Hirschel-Scholz, J Caverzasio, R Rizzoli, J P Bonjour
Journal: Journal of Clinical Investigation (1986)

The Rice-500 Leydig cell tumor (LCT) in Fischer rats is a model of humoral hypercalcemia of malignancy (HHM). In this model, the elevation of plasma calcium (Ca) does not result merely from an increased bone resorption, but also from an enhanced tubular Ca reabsorption (TRCa). We investigated the hypocalcemic response to WR-2721 [S-2,2-(3-aminopropylamino)-, ethylphosphorothioic acid] in LCT-bearing Fischer rats. WR-2721 is a potent inhibitor of normal and aberrant parathyroid hormone (PTH) secretion. Moreover, it exerts a PTH-independent inhibitory effect on TRCa. In hypercalcemic LCT-bearing rats WR-2721 induced a fall in plasma Ca from 3.24 +/- 0.12 to 2.66 +/- 0.23 mmol/liter within 2 h after one single injection of 0.7 mmol/kg body wt. The decrement in plasma Ca was associated with a marked increase in urinary Ca excretion, indicating an inhibition of TRCa. The elevated urine cyclic AMP of LCT-bearing rats, however, was not altered by WR-2721 treatment. These results suggest that in this HHM model, WR-2721 can normalize calcemia through its PTH-independent inhibitory effect on TRCa. WR-2721 could therefore be an effective drug to treat human hypercalcemia of malignancy, particularly in those tumors wherein a markedly enhanced renal Ca reabsorption contributes to the elevation of the plasma Ca level.