tbuckley/cabot-search huggingface dataset:
Discordant <i>In Vitro</i> and <i>In Vivo</i> Chemopotentiating Effects of the PARP Inhibitor Veliparib in Temozolomide-Sensitive versus -Resistant Glioblastoma Multiforme Xenografts
Authors: Shiv K. Gupta, Ann C. Mladek, Brett L. Carlson, Felix Boakye-Agyeman, Katrina K. Bakken, Sani H. Kizilbash, Mark A. Schroeder, Joel Reid, Jann N. Sarkaria
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Effective sensitizing strategies potentially can extend the benefit of temozolomide (TMZ) therapy in patients with glioblastoma (GBM). We previously demonstrated that robust TMZ-sensitizing effects of the [poly (ADP-ribose) polymerase] (PARP) inhibitor veliparib (ABT-888) are restricted to TMZ-sensitive GBM xenografts. The focus of this study is to provide an understanding for the differential sensitization in paired TMZ-sensitive and -resistant GBM models. Experimental Design: The impact of veliparib on TMZ-induced cytotoxicity and DNA damage was evaluated in vitro and in vivo in models of acquired TMZ resistance (GBM12TMZ-mgmtHigh, GBM12TMZ-mgmtLow, and U251TMZ), inherent TMZ resistance (T98G), and TMZ-sensitive (U251 and GBM12). In vivo drug efficacy, pharmacokinetics, and pharmacodynamics were analyzed using clinically relevant dosing regimens. Results: Veliparib enhanced TMZ cytotoxicity and DNA-damage signaling in all GBM models in vitro with more pronounced effects in TMZ-resistant lines at 3 to 10 μmol/L veliparib. In vivo, combined TMZ/veliparib, compared with TMZ alone, significantly delayed tumor growth and enhanced DNA-damage signaling and γH2AX levels in the sensitive GBM12 xenograft line but not in the resistant GBM12TMZ lines. The pharmacokinetic profile of veliparib was similar for GBM12 and GBM12TMZ tumors with Cmax (∼1.5 μmol/L) in tissue significantly lower than concentrations associated with optimal in vitro sensitizing effects for resistant tumors. In contrast, robust suppression of PARP-1 expression by shRNA significantly increased TMZ sensitivity of U251TMZ in vitro and in vivo. Conclusions: In vitro cytotoxicity assays do not adequately model the therapeutic index of PARP inhibitors, as concentrations of veliparib and TMZ required to sensitize TMZ-resistant cancer cells in vivo cannot be achieved using a tolerable dosing regimen. Clin Cancer Res; 20(14); 3730–41. ©2014 AACR.
Focus in Glaucoma May Change From Keeping Fluid Out to Letting Fluid Out
Authors: Paul Cotton
Journal: JAMA (1993)

CONVENTIONAL wisdom and treatment may have to give way as new evidence suggests that glaucoma treatments may be aimed the wrong way. Future therapy will likely be designed to clean out the trabecular meshwork encircling the cornea to allow fluid out, rather than to reduce the flow into the eye as most current treatments do. So suggest findings presented at a Research to Prevent Blindness science writers seminar in Universal City, Calif. If theory is confirmed in an ongoing phase III multicenter trial, one new treatment aimed at the trabecular meshwork may be needed as infrequently as once a year, predicts one researcher. "We know unequivocally that for all forms of glaucoma, it is not a disease of excess formation of fluid, it is a disease of impaired drainage," says David L. Epstein, MD, professor and chair of ophthalmology, Duke University Medical Center, Durham, NC. Ted S. Acott, PhD, another
Disciplinary procedures and secrecy.
Authors: W Savage
Journal: BMJ (1991)

<h3>Objective</h3> The Food and Drug Administration has the authority to set a minimum for cigar pack size, a product feature linked to price. This study examined the effects of cigarillo package size and price on young adults’ smoking and purchase intentions. <h3>Design</h3> Young adults (n=1032) 18–30 years old who smoked cigarillos in the past 12 months completed an online 3×2 within-subjects experiment testing the effects of cigarillo pack size (1, 2, 5) and price (actual price, standardised price per stick) on intentions to purchase and smoke cigarillos. We modelled the main effects and interactions of pack size and price on intentions to buy and smoke cigarillos overall and by cigarillo use frequency. <h3>Results</h3> Intentions to buy and smoke were strongest for lower priced singles and two packs compared with higher priced five packs. Under standardised price conditions, participants preferred larger packs, but under actual pricing conditions smaller packs, especially two packs, were preferred. Participants who smoked cigarillos less than monthly were more likely to buy and smoke the least expensive products (buy: singles actual price adjusted OR (aOR)=4.51, 95% CI 3.76 to 5.42; two packs actual price aOR=9.76, 95% CI 8.11 to 11.75; five packs standardised price aOR=3.17, 95% CI 2.89 to 3.48) with the strongest preference for two packs and singles. <h3>Conclusions</h3> Young adult cigarillo smokers prefer smaller packs in conditions where pricing incentivises smaller packs. Minimum pack size policies may reduce the appeal of cigarillos among young adults, especially less frequent cigarillo smokers. Pack size policy should take into consideration price, and ideally these two factors should be addressed together.
Oxford Textbook of Primary Medical Care, vols 1 &amp; 2
Authors: L. C. Karam-Danek
Journal: JAMA (2004)

Rarely does a family physician come across a textbook that serves not only as a useful educational tool but also as an enjoyable source of leisure reading. The Oxford Textbook of Primary Medical Care is such a book. It addresses the full scope of primary care and includes a valuable CD-ROM.
Differences in stratum corneum pH gradient when comparing white caucasian and black African‐American skin
Authors: None Berardesca, None Pirot, None Singh, None Maibach
Journal: British Journal of Dermatology (1998)

This study assessed pH gradient changes in relation to stratum corneum (SC) depth and possible differences between white caucasian and black African-American skin. Ten white and eight black people entered the study. SC was progressively removed by cellophane tape stripping on the volar forearm and weighed with a microbalance. Transepidermal water loss (TEWL) and SC pH were measured every three tape strippings. Significantly increased TEWL and decreased pH values were found with increasing SC depth in both races. Significantly increased TEWL in black people was found after three and six tape strippings (P < 0.05 and 0.03, respectively); pH was significantly decreased in black people after three tape strippings (P < 0.005). No differences were found between the races after nine, 12 and 15 strippings, i.e. in the deeper SC layers. The data confirm that pH in the superficial SC layers decreases with SC depth; only total SC removal results in increased pH values. In the superficial layers, there are significant differences in both water evaporation and skin pH, possibly explaining the contradictory literature.
Borrelia infection and risk of non-Hodgkin lymphoma
Authors: Claudia Schöllkopf, Mads Melbye, Lars Munksgaard, Karin Ekström Smedby, Klaus Rostgaard, Bengt Glimelius, Ellen T. Chang, Göran Roos, Mads Hansen, Hans-Olov Adami, Henrik Hjalgrim
Journal: Blood (2008)
Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice.
Authors: S Ishibashi, J L Goldstein, M S Brown, J Herz, D K Burns
Journal: Journal of Clinical Investigation (1994)

Mice that are homozygous for a targeted disruption of the LDL receptor gene (LDLR-/- mice) were fed a diet that contained 1.25% cholesterol, 7.5% cocoa butter, 7.5% casein, and 0.5% cholic acid. The total plasma cholesterol rose from 246 to > 1,500 mg/dl, associated with a marked increase in VLDL, intermediate density lipoproteins (IDL), and LDL cholesterol, and a decrease in HDL cholesterol. In wild type littermates fed the same diet, the total plasma cholesterol remained < 160 mg/dl. After 7 mo, the LDLR-/- mice developed massive xanthomatous infiltration of the skin and subcutaneous tissue. The aorta and coronary ostia exhibited gross atheromata, and the aortic valve leaflets were thickened by cholesterol-laden macrophages. No such changes were seen in the LDLR-/- mice on a normal chow diet, nor in wild type mice that were fed either a chow diet or the high-fat diet. We conclude that LDL receptors are largely responsible for the resistance of wild type mice to atherosclerosis. The cholesterol-fed LDLR-/- mice offer a new model for the study of environmental and genetic factors that modify the processes of atherosclerosis and xanthomatosis.
Reduction of Malaria Transmission to Anopheles Mosquitoes with a Six-Dose Regimen of Co-Artemether
Authors: Colin J Sutherland, Rosalynn Ord, Sam Dunyo, Musa Jawara, Christopher J Drakeley, Neal Alexander, Rosalind Coleman, Margaret Pinder, Gijs Walraven, Geoffrey A. T Targett
Journal: PLoS Medicine (2005)

Resistance of malaria parasites to chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) is increasing in prevalence in Africa. Combination therapy can both improve treatment and provide important public health benefits if it curbs the spread of parasites harbouring resistance genes. Thus, drug combinations must be identified which minimise gametocyte emergence in treated cases, and so prevent selective transmission of parasites resistant to any of the partner drugs.
Profound spatial clustering of simultaneous peptic ulcers.
Authors: M S Cappell
Journal: Gut (1989)

In an endoscopic study of 90 consecutive patients with more than one peptic ulcer, the ulcers in an individual were profoundly spatially clustered. Clustering of ulcer locations was shown using a non-parametric test of clustering (Kruskal-Wallis statistic with 89 degrees of freedom = 151.31, probability of observing this extreme statistic with no clustering less than 0.0005) and a parametric test of clustering (F test statistic with 89 and 124 degrees of freedom = 5.41, probability of observing this extreme statistic with no clustering less than 0.0005). Patients having their largest ulcer in any given region had a much greater likelihood than other patients of having other ulcers in that same site. For example, the 26 patients with their largest ulcer in the proximal duodenal bulb had 20 of 33, or 61% (9) (standard error), of their other ulcers in the proximal duodenal bulb. In contrast, the 18 patients with their largest ulcer in the proximal stomach had four of 23, or 17% (8), of their other ulcers in the proximal duodenal bulb. Of the 59 patients who had two simultaneous ulcers, 28 patients had adjacent ulcers (distance between ulcers less than 4% of the distance from the gastric cardia to the apex of the duodenal bulb). These findings suggest that local factors may be important in the pathogenesis of simultaneous peptic ulcers, including infection caused by Campylobacter pylori or other microorganisms, ischaemia and mucosal barrier disruption.
Alpha<sub>1</sub>-Antitrypsin Deficiency and Autophagy
Authors: Stefan J. Marciniak, David A. Lomas
Journal: New England Journal of Medicine (2010)

The Z deficiency allele (PI*Z) of SERPINA1, which encodes the serine protease inhibitor (PI) alpha1-antitrypsin, results in the formation of intrahepatic inclusions that cause cirrhosis. The only curative therapy for patients with severe liver disease is transplantation. Hidvegi and colleagues recently described a new approach to clear the pathologic inclusions in cell and animal models of liver disease consequent to the Z mutation. The authors used the antiepileptic drug carbamazepine to stimulate "self-eating," or autophagy.1 The questions now are whether this approach will be useful for treating the liver disease associated with alpha1-antitrypsin . . .
The Cytoplasmic Expression of MUC1 in Papillary Thyroid Carcinoma of Different Histological Variants and its Correlation with Cyclin D1 Overexpression
Authors: Alexander Abrosimov, Vladimir Saenko, Serik Meirmanov, Masahiro Nakashima, Tatiana Rogounovitch, Olesya Shkurko, Eugeny Lushnikov, Norisato Mitsutake, Hiroyuki Namba, Shunichi Yamashita
Journal: Endocrine Pathology (2007)
Freeze-drying of hemoglobin solutions without adjuvant and in presence of glucose, tris, and β-alanine: A study by electron spin resonance of the oxidized compounds produced
Authors: B. Chaillot, P. Labrude, C. Vigneron, D. Simatos
Journal: American Journal of Hematology (1981)

Hemoglobin cannot be freeze-dried without the presence of protective compounds. Carbohydrates are a well-known example of such compounds, but we have shown that some amine buffer and amino acids are also very effective. The mechanism of action of all these molecules is unknown. We report here experimental data showing that the protective effect is not the result of a direct bond between iron and the protective compound added.
FACTORS INVOLVED IN THE INFECTION OF MICE AFTER VACCINATION WITH TYPE II PNEUMOCOCCI
Authors: James M. Neill, Emidio L. Gaspari
Journal: The Journal of Experimental Medicine (1927)

A group of mice was vaccinated against Type II pneumoccci and subsequently tested for immunity against different numbers of the live bacteria. The immunity tests were conducted within two zones of dosage. In the first zone where the doses were kept within reasonable limits (10(-6) to 10(-3) cc. of culture), the number of invading bacteria was without influence and the occurrence of infections was determined by the previous immunity response of the individual. In the second zone of dosage (where passive protection also fails), these relations were reversed, and invasion by overwhelming numbers of the bacteria invariably produced infection regardless of the previous immunity response of the individual. These results present an extreme example of the importance of the immunity response of the individual as a factor always concerned in the effectiveness of vaccination.
A novel dendritic cell subset involved in tumor immunosurveillance
Authors: Julien Taieb, Nathalie Chaput, Cédric Ménard, Lionel Apetoh, Evelyn Ullrich, Mathieu Bonmort, Marie Péquignot, Noelia Casares, Magali Terme, Caroline Flament, Paule Opolon, Yann Lecluse, Didier Métivier, Elena Tomasello, Eric Vivier, François Ghiringhelli, François Martin, David Klatzmann, Thierry Poynard, Thomas Tursz, Graça Raposo, Hideo Yagita, Bernard Ryffel, Guido Kroemer, Laurence Zitvogel
Journal: Nature Medicine (2006)
Rapid development and progression of proliferative retinopathy after strict diabetic control.
Authors: P Dandona, J P Bolger, F Boag, V Fonesca, J D Abrams
Journal: BMJ (1985)

Une observation rare: malade de 31 ans, diabetique connue depuis 9 ans, traitee de facon irreguliere avec insuline, regime, glibenclamide, presentant une cetoacidose necessitant l'hospitalisation. Aucune retinopathie a ce moment. Apres institution d'un traitement presque parfait du diabete, developpement de novo d'une retinopathie rapidement progressive
Effect of Long-Term Monitoring of Glycosylated Hemoglobin Levels in Insulin-Dependent Diabetes Mellitus
Authors: Mogens Lytken Larsen, Mogens Hørder, Erik F. Mogensen
Journal: New England Journal of Medicine (1990)

The value of routine measurements of glycosylated hemoglobin (hemoglobin A1c) in the care of patients with diabetes mellitus is uncertain. We undertook this study to determine whether knowledge of hemoglobin A1c values would result in improved metabolic control in a group of patients with insulin-dependent diabetes mellitus (IDDM).
A randomised trial of a pre‐synaptic stimulator of DA<sub>2</sub>‐dopaminergic and α<sub>2</sub>‐adrenergic receptors on morbidity and mortality in patients with heart failure
Authors: Christian Torp‐Pedersen, Lars Køber, Jan E. Carlsen, Dilek Akkan, Niels E. Bruun, Dimitri Dacoronias, Kenneth Dickstein, Torben Haghfelt, Hans Öhlin, John JV McMurray
Journal: European Journal of Heart Failure (2008)
Hospital Utilization-Review Mechanisms
Authors: Sidney Shindell
Journal: JAMA (1966)

Utilization review is required as a prerequisite to participation in medicare (PL 89-97). Experience with such mechanisms has been restricted to a few areas in this country. The Hospital Utilization Project of Western Pennsylvania has developed an extensive mechanism for identifying areas of hospital practice which would warrant attention by a medical-staff utilization committee. Its approach, a technique of pattern review rather than the case-by-case approach, uses comparative statistics on length of stay for specific diagnostic categories to indicate the utilization patterns of the hospitals participating in the project. The provision in the medicare law which requires recertification of extended-care cases might divert effort from the more comprehensive utilization-review activities.
Are myocardial eNOS and nNOS involved in the β-adrenergic and muscarinic regulation of inotropy? A systematic investigation
Authors: S MARTIN, K EMANUEL, C SEARS, Y ZHANG, B CASADEI
Journal: Cardiovascular Research (2006)

The role of constitutive nitric oxide (NO) production in the regulation of beta-adrenergic and muscarinic responses remains controversial. Conflicting data in left ventricular (LV) myocytes from eNOS knockout mice (eNOS-/-) have been ascribed to inconsistent experimental conditions (i.e., differences in the choice of controls, age of the mice, myocytes' stimulation frequency, and in the level of beta-adrenergic stimulation); however, the recent identification of a neuronal-like NO synthase (nNOS) in the LV myocardium has raised the possibility that this isoform may be involved in the modulation of beta-adrenergic and muscarinic responses.To address these issues we recorded sarcomere shortening at 35 degrees C under basal conditions, in the presence of isoproterenol (ISO, 10-100 nmol/L) and of ISO plus carbamylcholine (CCh, 1 micromol/L) in LV myocytes isolated from eNOS-/- and nNOS-/- mice, their wild type littermates (eNOS+/+ and nNOS+/+) or C57BL/6J mice. eNOS-/- and control myocytes were studied at 1 and 3 Hz, in the presence of 10 and 100 nmol/L ISO, and responses were compared between young (3 months) and old (> or =12 months) mice.Contraction did not differ between young eNOS-/- and eNOS+/+ mice at all stages of the experimental protocol, either at 1 or 3 Hz or in response to 10 or 100 nmol/L ISO. However, myocytes from old eNOS-/- mice showed a reduced inotropic response to ISO compared with age-matched eNOS+/+ mice (P = 0.02). Similarly, there was a significant difference in the ISO response between eNOS+/+ and C57BL/6J myocytes (P < 0.01), suggesting that experimental variables such as age and the choice of control animals may have contributed to the inconsistency in the results reported in the literature. In contrast, nNOS-/- myocytes showed greater contraction and slower relaxation at all stages of the experimental protocol (P = 0.0003 and P = 0.01 vs. nNOS+/+ myocytes).Constitutive eNOS expression in murine LV myocytes is not essential for the muscarinic-mediated inhibition of beta-adrenergic signalling and does not appear to play a significant role in the regulation of basal and beta-adrenergic myocardial contraction. Our data suggest that nNOS is the myocardial constitutive isoform responsible for the NO-mediated autocrine regulation of myocardial inotropy and relaxation.
PRESERVED MECHANICS ON BETA BLOCKER THERAPY PREDICTS SYMPTOMATIC IMPROVEMENT AND MYOCARDIAL FUNCTIONAL STATUS IN OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY
Authors: Chiara Pisanello, Erik Su, Hongchang Luo, Iraklis Pozios, Niccolo’ Maurizi, Lars Sorensen, Roselle Abraham, Theodore Abraham
Journal: Journal of the American College of Cardiology (2015)
My months as a hatstand
Authors: A. Collinson
Journal: BMJ (2001)

In our encounters with strangers we follow protocols that are rooted in our cultural identity. These codes characterise countless fragments of our daily lives, which although mundane are no less dear to us. Living in Gambia I have once or twice astonished myself with a feeling of nostalgia for the blank anonymity of the London underground, where a lone commuter can almost be the only passenger in a carriage which is in fact crowded with others. The same void of interaction must encapsulate, to Gambians in Britain, all that separates them from the poetic greeting that accompanies every encounter between strangers back home.

> If the problem is not permanent it is not tragic; if not tragic then it is okay to ask 

Some months ago a less than dramatic surfing accident left me with an odontoid fracture and an abrupt suspension of my life as a research paediatrician in the Gambia. In Bristol five days later, wearing a halothoracic brace and …
Localized Coccidioidal Osteomyelitis
Authors: Timothy A. Lamphier
Journal: New England Journal of Medicine (1948)

COCCIDIOIDOMYCOSIS is a disease produced by the fungus Coccidioides immitis, which is present in large concentration in the soil of the San Joaquin Valley, California, and to a lesser degree in neighboring states. In its adult form, it is a spherule of about 50 microns in diameter, which has a doubly refractile capsule. The portal of entry is the respiratory tract or skin. The disease has both primary and secondary phases. Ordinarily, there is a primary pneumonic focus. The nodules produced by the endospores closely resemble those of tuberculosis.Once allergy is established, reinfection may bring out the disease in . . .
Anatomical and Hormonal Influences on Women's Dermatologic Health
Authors: June K Robinson
Journal: JAMA (2006)

BackgroundDermatological manifestations of sexually transmitted diseases (STDs) range from full body papulosquamous eruptions to genital ulcers and warts. The transmission, prevalence, and disease burden of STDs are not shared equally between the sexes.ObservationsWomen are more susceptible than men for the acquisition of the human immunodeficiency virus and other dangerous STDs because of economic, biological, and social factors, and often sustain more damage to their health from the disease.ConclusionThis review article elucidates the differential effect of STDs on women vs men to better understand what is required to protect women from the morbidity and mortality of STDs.
GMC imposes conditions on surgeon's registration after two babies die
Authors: C. Dyer
Journal: BMJ (2010)

Cadaveric hip joints were tested in a hip function simulator which subjected the femoral head to a cycle of loading and oscillation similar to that experienced during walking and measured the frictional torque transmitted to the acetabulum. Silicone fluids with viscosities from 10-2 Pa s (pascal second) to 30 Pa s were used as lubricants and the transition from mixed to full fluid film lubrication was observed around 5 x 10(-2) Pa s. Sodium carboxymethylcellulose solutions were also tested at the lower viscosities. Hyaluronidase digestion of samples of synovial fluid caused a significant increase in friction over the control samples. Trypsin digestion had no significant effect. No correlation between compliance of the cartilage and the frictional values was observed.