tbuckley/cabot-search huggingface dataset:
Abstract 674: Cooperative induction of apoptosis through p53 signaling and mTOR inhibition in neuroblastoma
Authors: Eveline Barbieri, Zaowen Chen, Andrew Ludwig, Eugene Kim, Danielle Patterson, Denae Sikorski, Jason Shohet
Journal: Cancer Research (2010)

Abstract The use of MDM2 inhibitors (e.g. Nutlin 3a) to stabilize p53 and induce apoptosis is an attractive therapeutic approach for neuroblastoma which is predominantly p53 wild-type at diagnosis and relapse. We sought to identify additional pathways to potentiate the p53 response. Mammalian target of rapamycin (mTOR) signaling pathway is active in neuroblastoma and mTOR inhibition has antiproliferative effects in vivo in neuroblastoma. It was recently demonstrated that two p53 target genes, Sestrin1 and Sestrin2, inhibit mTOR activity, linking genotoxic stress, p53 and the mTOR signaling pathway. We investigated the role of Sestrin1 and Sestrin2 in p53-mediated apoptosis in neuroblastoma and the interaction of mTOR and p53 pathways after their simultaneous blockade using the mTOR inhibitor, Temsirolimus and the MDM2 inhibitor, Nutlin 3a. We show here that stabilization and activation of wt-p53 through MDM2 inhibition result in significant and rapid p53-dependent apoptosis. Using microarray analysis in primary tumor line and RT-PCR in several neuroblastoma lines, we demonstrate that the global transcriptional response is p53-dependent and that Sestrin1 and Sestrin2 are significantly up-regulated in response to Nutlin. With MTT and Tunnel assays we demonstrate a p53-dependent synergistic effect of combined Nutlin 3a and Temsirolimus treatment on cell growth and apoptosis. Flow cytometric analysis of the phospho-S6 ribosomal protein demonstrates a profound dephosphorylation of S6 in vitro when low dose Nutlin 3a is combined with Temsirolimus. Additional in vivo studies suggest that mTOR inhibition reduces tumor burden and proliferation of neuroblastoma xenografts in nude mice. We conclude that MDM2 inhibition and p53 driven Sestrin1 and Sestrin2 activation enhance the apoptotic response to mTOR inhibition. Thus the therapeutic strategy of combined MDM2 and mTOR inhibition may represent a clinically potent approach to de novo and relapsed neuroblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 674.
Thrombin or platelets as major point of impact in vascular reocclusion and restenosis; a controversy?
Authors: M. Levi
Journal: Cardiovascular Research (1996)

Sometimes an apparent controversy is not that controversial on second thoughts. In the study of factors that lead to vascular reocclusion after initial successful reperfusion, both platelets and thrombin have shown to be of significant importance. Activated thrombi are major constituents of reoccluding thrombi and secreted platelet contents appear to significantly modulate thrombus dynamics [l-3]. Alternatively, thrombin which is generated at the surface of the injured vessel or bound to the clot, may be inaccessible for physiological inhibitors and may represent the ongoing propulsive force for further activation of coagulation and thrombus formation [4]. In line with this, potent treatment strategies aimed at either inhibition of platelet activation or blocking the generation and activity of thrombin have become available and have been employed in clinical studies [5,6]. In this “controversy” the basic research findings and results of clinical studies, which are the basis for the treatment of patients with either platelet inhibitors or antithrombin agents, are highlighted in the following two outstanding papers from highly respected investigators in this field. It appears that much can be stated in favour of both treatment modalities and that experimental and clinical evidence point to an agreeable effect of both approaches. Comparative clinical trials will ultimately yield important information on which approach (or combination [71) would be most useful in which situation and will hopefully provide more knowledge on the adverse effects of the different agents (i.e. bleeding in particular), which have to be offset against the benefits. In both papers, however, the fact that platelets and thrombin cannot be seen as two independent quantities is underscored. Trace amounts of thrombin are potent stimuli for platelet activation and, alternatively, activation of
ANGLED NEEDLE FOR SUTURING AURICULAR APPENDAGE IN COMMISSUROTOMY
Authors: Gerald H. Pratt
Journal: JAMA (1953)

The development of instruments necessary to perform a new operative technique do not keep pace with the surgical advance. The tools are fashioned of necessity and at first are makeshift. The ingenious aortic clamp of Potts and the rib retractor of Sinochietto are examples. Operating in the thoracic cage requires variations from standard instruments and needles. In the operation of mitral commissurotomy, a now accepted surgical treatment, the purse-string suture and over-sewing of the auricular appendage are of primary importance. Accidents or technical errors at this point, such as the slipping of a clamp or the tearing of the suture, not only are hazardous but may be fatal. The standard needle and needle holder are constructed so that the needle is grasped at right angles to its direction of insertion. Such clasping is adequate if the surgeon is able to lower his hand to a level parallel to the needle.
All emergency departments should include GP staff, say experts
Authors: G. Iacobucci
Journal: BMJ (2014)

All hospital emergency departments in the United Kingdom should include a primary care out-of-hours facility to help ease the ongoing pressure on the system, experts have recommended.

The recommendation is one of 13 in a joint report from the College of Emergency Medicine, Royal College of Paediatrics and Child Health, Royal College of Physicians, and Royal College of Surgeons that outlines solutions for tackling major challenges, including rising activity levels, crowding, and patient flow in emergency departments and staffing levels.1

The report said that co-locating emergency departments with out-of-hours primary care would enable patients to be streamed more appropriately after triage and would foster more collaboration, such as sharing diagnostic facilities. Produced after a joint summit of the four organisations …
Lesion Dimensions During Temperature-Controlled Radiofrequency Catheter Ablation of Left Ventricular Porcine Myocardium
Authors: Helen Høgh Petersen, Xu Chen, Adrian Pietersen, Jesper Hastrup Svendsen, Stig Haunsø
Journal: Circulation (1999)

Background —It is important to increase lesion size to improve the success rate for radiofrequency ablation of ischemic ventricular tachycardia. This study of radiofrequency ablation, with adjustment of power to approach a preset target temperature, ie, temperature-controlled ablation, explores the effect of catheter-tip length, ablation site, and convective cooling on lesion dimensions. Methods and Results —In vitro strips of porcine left ventricular myocardium during different levels of convective cooling and in vivo pig hearts at 2 or 3 left ventricular sites were ablated with 2- to 12-mm-tip catheters. We found increased lesion volume for increased catheter-tip length ≤8 mm in vitro ( P &lt;0.05) and 6 mm in vivo ( P &lt;0.0001), but no further increase was found for longer tips. For the 4- to 10-mm catheter tips, we found smaller lesion volume in low-flow areas (apex) than in high-flow areas (free wall and septum) ( P &lt;0.05). Increasing convective cooling of the catheter tip in vitro increased lesion volume ( P &lt;0.0005) for the 4- and 8-mm tips but not for the 12-mm tip as the generator reached maximum output. In contrast to power-controlled ablation, we found a negative correlation between tip temperature reached and lesion volume for applications in which maximum generator output was not achieved ( P &lt;0.0001), whereas delivered power and lesion volume correlated positively ( P &lt;0.0001). Conclusions —Lesion size differs in different left ventricular target sites, which is probably related to convective cooling, as illustrated in vitro. Longer electrode tips increase lesion size for tip lengths ≤6 to 8 mm. For temperature-controlled ablation, the tip temperature achieved is a poor predictor of lesion size.
THE EFFECT OF INTERMEDIATE MECHANICAL INDEX ULTRASOUND ON THROMBOLYTIC EFFICACY OF DIAGNOSTIC ULTRASOUND AND MICROBUBBLES IN TREATING ACUTE ST SEGMENT ELEVATION MYOCARDIAL INFARCTION
Authors: Thomas Richard Porter, Shunji Gao, Evan Unger, Jenny Johnson, Jinjin Liu, William Shi, Francois Vignon, Jeffry Powers, John Lof, Shelby Kutty, Feng Xie
Journal: Journal of the American College of Cardiology (2011)
The Shear Stress of Busting Blood Clots
Authors: David M. Wootton, B. Rita Alevriadou
Journal: New England Journal of Medicine (2012)

Systemic delivery of tissue-type plasminogen activator (t-PA) to dissolve a thrombus after a heart attack or stroke is accompanied by the risk of hemorrhage. A recent study shows the use of nanoaggregates to target t-PA to the thrombus in mouse models of mesenteric injury and pulmonary embolism.
Mumps virus isolated from a fetus.
Authors: J B Kurtz, A H Tomlinson, J Pearson
Journal: BMJ (1982)

Treatment was started with Benoral Suspension 10 ml twice daily, and steroid treatment was begun two days later at a dose of 30 mg of enteric- coated prednisolone daily.Good clinical control of the polyarthropathy enabled the steroid dosage to be reduced to 5 mg twice daily after 10 days, by which time erythrocyte sedimentation rate was 21 mm in the first hour and the rash had largely cleared.She was discharged taking enteric-coated prednisolone 5 mg twice daily and naproxen 500 mg in the morning with food.Steroids were reduced over the next three months and all medication then stopped; tests for rheumatoid factor remained negative and both the rash and joint symptoms resolved completely.
Potential Complications of High-Dose Epinephrine-Reply
Authors: Marcia Feingold
Journal: JAMA (1991)

<h3>In Reply.</h3> — Fleg suggests an interesting possibility. None of the animal studies that support the use of larger doses of epinephrine for the treatment of cardiac arrest has considered age.<sup>1</sup>We would also guess that most of the animals studied were not senescent. Our study compared the pressor response after standard- and high-dose epinephrine and found that in patients in prolonged cardiac arrest there was a significant difference in the change in coronary perfusion pressure after standard and high doses of epinephrine, with high-dose epinephrine causing a greater increase. To answer Fleg's question, we analyzed the difference in pressor response with respect to age. This showed no significant relationship (<i>r</i>=.23;<i>P</i>=.46). Although this does not indicate a relationship between age and response to high-dose epinephrine, the small sample size could easily hide a slight effect. Because the serum levels of epinephrine after administration of high-dose epinephrine
Tricuspid Valve Repair With an Annuloplasty Ring Results in Improved Long-Term Outcomes
Authors: Gilbert H. L. Tang, Tirone E. David, Steve K. Singh, Manjula D. Maganti, Susan Armstrong, Michael A. Borger
Journal: Circulation (2006)

Background— The purpose of this study was to compare the long-term results of tricuspid valve (TV) repair with or without an annuloplasty ring. Methods and Results— 702 patients underwent TV repair at our institution (1978 to 2003), of which 493 had, predominantly, a De Vega procedure (no ring) and 209 had an annuloplasty ring (ring). TV pathology was functional (secondary) in 74% of patients. Concomitant procedures consisted of mitral valve surgery in 80% of patients, aortic valve surgery in 33%, and coronary bypass in 14%. Clinical and echocardiographic follow-up data were obtained. Follow-up was 99% complete and was 5.9±4.9 (mean±SD) years long. Ring patients were younger (55±14 versus 59±14 years; P =0.001) and less likely to have coronary artery disease (10% versus 17%; P =0.02), more likely to be female (75% versus 65%; P =0.01) and having had previous cardiac surgery (56% versus 42%; P =0.001). Operative times were similar between the 2 groups. Long-term survival, event-free survival and freedom from recurrent TR were significantly better in the ring group, and there was a trend toward fewer TV reoperations. Multivariable analysis demonstrated that the use of an annuloplasty ring was an independent predictor of long-term survival (hazard ratio [HR], 0.7; 95% confidence interval [CI], 0.5 to 1.0; P =0.03) and event-free survival (HR, 0.8; CI, 0.6 to 1.0; P =0.04). Conclusions— Placement of an annuloplasty ring in patients undergoing tricuspid valve repair is associated with improved survival and event-free survival.
Estimation of the probability of exercise-induced ischemia by quantitative ECG analysis.
Authors: M L Simoons, P G Hugenholtz
Journal: Circulation (1977)

In order to improve the value of exercise tests for the detection of coronary artery disease (CAD) a system for on-line computer processing of the Frank lead exercise ECG was developed. Data were analyzed from 95 patients with CAD and 129 ostensibly healthy men. All subjects had a normal ECG at rest. Visual ECG interpretation during exercise yielded a sensitivity of 50% and a specificity of 95%. A large number of QRS and ST measurements were compared by discriminant function analysis in a group of 86 normal subjects and 52 patients (designated training group). Best results were obtained with a combination of two ST amplitudes from lead X: sensitivity, 85%, specificity, 90%. This was confirmed in a test group of 43 patients and 43 normal subjects. The results of the discriminant function were expressed as the likelihood ratio for an abnormal or normal ST segment at a given heart rate, a figure which provides a quantitative assessment of the degree of exercise-induces ischemia. This is a more realistic approach than classification into normal or abnormal since persons with and without CAD fall along the same continuous spectrum.
Minimum unit price for alcohol is planned for England and Wales
Authors: Z. Kmietowicz
Journal: BMJ (2012)

The Government is to introduce a minimum price for a unit of alcohol as soon as it has consulted on what that price should be, it says in its new national alcohol strategy for England and Wales. The price is likely to be around 40p per unit.

The strategy has been billed as “a radical approach to turn the tide against irresponsible drinking, which costs the UK £21bn [€25.1bn; $33.3bn] a year,” and aims to end the scenario of beer for sale at prices cheaper than water. The strategy is also being promoted as a means of reducing the 1.2 million alcohol related hospital admissions in 2011.

Minimum price policies are already being considered in Scotland and Northern Ireland.

As part of the strategy, the government is also considering giving more powers to hospital accident and emergency departments and pubs to refuse to deal with people who are drunk; banning multibuy promotions such as buy one, get one free; and a late night levy to make pubs and clubs help pay for policing.

Prime Minister David Cameron said, “Binge drinking isn’t some fringe issue, it accounts for half of all alcohol consumed in this country. …
Interactions between insulin resistance and insulin secretion in the development of glucose intolerance
Authors: Melissa K. Cavaghan, David A. Ehrmann, Kenneth S. Polonsky
Journal: Journal of Clinical Investigation (2000)

Subjects who develop type 2 diabetes have a complex phenotype with defects in insulin secretion, increased hepatic glucose production, and resistance to the action of insulin, all of which contribute to the development of overt hyperglycemia. Although the precise mechanisms whereby these three factors interact to produce glucose intolerance and diabetes are uncertain, it has been suggested that the final common pathway responsible for the development of type 2 diabetes is the failure of the pancreatic β cell to compensate for insulin resistance (1). Here, we review evidence for this model from both human and animal studies, and we consider the effects of specific drug treatments and of heightened FFA levels on insulin sensitivity and insulin secretion in individuals at risk for type 2 diabetes.

Coleman and coworkers (2), drawing on their work with the ob/ob mouse, first proposed that a failure of β-cell compensation for insulin resistance is responsible for the development of type 2 diabetes. When insulin-resistant ob/ob mice, which provide a genetic model of obesity, were bred with mice of different strains, the phenotypes of the progeny differed depending on their genetic background. Mice carrying the ob mutation in the C57BL/6 background had relatively normal blood glucose levels, whereas in the C57Ks background the animals developed overt hyperglycemia. The major difference between these two mouse strains lay in their β-cell responses. The nondiabetic C57BL/6 mice underwent a marked expansion of β-cell mass, whereas C57Ks animals showed histologic evidence of islet degeneration, degranulation, and progressive atrophy. The C57Ks animals accordingly had insulin levels about one-tenth those of the C57BL/6 animals, and these levels declined progressively with age. These data indicated that the genetic background on which insulin resistance develops influences the adequacy of pancreatic β-cell compensation for insulin resistance, and hence the predisposition to diabetes.
The Crazy Iris: And Other Stories of the Atomic Aftermath
Authors: Tony Miksanek
Journal: JAMA (1986)

<i>The Crazy Iris</i>is the English translation of an anthology of nine short stories chronicling the experiences of survivors of the bombings of Hiroshima and Nagasaki. Most of the authors represented were born in these cities and actually exposed to the atomic blasts. The stories are gorged with stark imagery of the destruction unleashed by nuclear weapons. Even the titles of some works, such as "Human Ashes" and "The Colorless Paintings," readily suggest the devastation, both physical and psychological, associated with nuclear warfare. " 'I myself have long cherished a vision of an age when harmony would come to the earth...' " Some stories, such as "Summer Flower" by Tamiki Hara, an author who is so profoundly affected by his exposure to the atomic bomb that he later commits suicide, are filled with gruesome and nightmarish images of hell The wounded did not recover satisfactorily, and even those who at first had
Renal Ischemia and Hypertension From a Constrictive Perirenal Hematoma
Authors: Arthur A. Hellebusch
Journal: JAMA (1970)

A unilateral perirenal subfascial hematoma caused cessation of renal function and development of arterial hypertension. The ischemic functional pattern occurred during the phase of nonfunction; following surgical removal of the constricting hematoma, function returned towards normal, and the hypertension subsided. This would seem to support the validity of Page's original concept, that hemodynamic change within the kidney is the basic mechanism of hypertension and nonfunction, in cases of extrinsic compression of one kidney.
The role of psychosocial factors in gastrointestinal disorders
Authors: I Wilhelmsen
Journal: Gut (2000)

Psychosocial factors play a part in how symptoms are experienced and interpreted, they modify illness behaviour, and can influence treatment. However, they do not have any diagnostic value in functional gastrointestinal disorders; if you have anxiety you can still have an organic disease.

It has been shown that there are no greater psychological disturbances in subjects with irritable bowel syndrome (IBS) than in the general population. Even in the 1980s, Sandler et al found that focusing on symptoms was one of the major factors causing patients with bowel dysfunction to seek medical advice.1 Further studies confirmed the finding that psychological factors are associated with patient status more than the bowel disorder itself.2 These findings were not confirmed in an Australian population based study3which was, however, a postal survey using self-administered questionnaires. In a British study, abdominal pain and diarrhoea differentiated consulters from non-consulters with symptoms of IBS.4 

Psychological stress or emotional responses to stress can affect gastrointestinal function, and the effects of different emotions on the gastrointestinal tract are well established5 (table1).

View this table:

Table 1 
Effects of different emotions on the gastrointerstinal tract



What about functional gastrointestinal disorders—do psychological factors contribute substantially? IBS is the most prevalent of these gastrointestinal disorders. There are many studies from the 1980s and 1990s indicating that patients with functional dyspepsia (FD) or IBS have more anxiety, depression, and “psychosomatic triad” (hysteria, hypochondriasis, and depression) than normal controls. Our own data support these findings in patients with FD; for example, we found a high score for neuroticism and somatisation.6-8 However, no study has found a unique psychological profile or mechanism for symptom …
Sarcoidosis presenting as massive splenomegaly and bicytopenia
Authors: Michal Z. Haran, Edith Feldberg, Galit Miller, Alain Berrebi
Journal: American Journal of Hematology (2000)

With the C282Y Mutation in the HFE GeneTo the Editor: The association between hereditary hemochromatosis and thalassemia syndrome might lead to a severe iron overload [1,2], but the results are still controversial.By PCR and restriction enzyme digestion [3], we analyzed the C282Y and H63D mutations in the HFE gene in one family whose propositus carried the ␤-thalassemia trait.The patient was a female, 38 years old, presenting weakness and arthralgia.She had 4 children and received transfusion (1 unit of red cell) during her last gestation.She did not present diabetes or cardiac disease and her hepatic enzymes were normal.Her mother and 2 sons also carried the ␤-thalassemia trait.