tbuckley/cabot-search huggingface dataset:
Factors Contributing to Increased Platelet Reactivity in People With Diabetes
Authors: David J. Schneider
Journal: Diabetes Care (2009)

eople with diabetes, particularly those with type 2 diabetes, exhibit increased platelet reactivity.Hyperglycemia contributes to greater platelet reactivity through direct effects and by promoting glycation of platelet proteins.Hypertriglyceridemia increases platelet reactivity.Both insulin resistance and insulin deficiency increase platelet reactivity.Insulin antagonizes activation of platelets.Thus, relative or absolute deficiency of insulin would be expected to increase platelet reactivity.Diabetes is associated with oxidative stress and inflammation.Resultant endothelial dysfunction promotes activation of platelets by decreasing production of nitric oxide (NO) that attenuates platelet reactivity.Oxidative stress accentuates this effect by attenuating activity of NO and promoting platelet activation.Inflammation and platelet activation are reciprocally related.Inflammation promotes platelet activation that, in turn, promotes inflammation.Accordingly, improved metabolic control achieved with regimens that improve insulin sensitivity and preserve pancreatic ␤-cell function is likely to decrease platelet reactivity and enhance effects of antiplatelet agents.Platelets from subjects with diabetes exhibit increased reactivity (i.e., increased propensity to activate in response to a stimulus) (1).This review highlights factors that contribute to increased platelet reactivity.Type 2 diabetes is more prevalent than type 1 diabetes and is associated with a substantially increased risk of macrovascular complications.Accordingly, this review focuses on platelet reactivity in subjects with type 2 diabetes.Key aspects of type 2 diabetes are insulin resistance, metabolic abnormalities including hyperglycemia, and systemic abnormalities including oxidative stress and inflammation.The influence of each of these abnormalities on platelet function is addressed.
The Pharmacologic Treatment of Portal Hypertension
Authors: R J Groszmann, C E Atterbury
Journal: Annual Review of Medicine (1985)

Variceal formation and rupture are dreaded complications of chronic liver disease and portal hypertension. The pharmacologic treatment of portal hypertension should be able to stop as well as to prevent variceal hemorrhage. There are two principal types of vasoactive drugs in the treatment of portal hypertension: vasoconstrictors and vasodilators. Vasoconstrictors reduce the splanchnic blood flow, thereby decreasing the portal blood flow and portal pressure. Vasodilators act by different mechanisms, including by relaxation of myofibroblasts in the fibrous septa and presinusoidal areas of the liver and by direct vasodilation of the collateral circulation. In addition, paradoxically, they could decrease portal flow and pressure by inducing a baroreflex-mediated mesenteric arterial vasoconstriction. A miscellaneous group of drugs is also available. These drugs reduce the blood flow and pressure in the gastroesophageal variceal system by mechanisms other than vasoconstriction or vasodilation. The success of these pharmacologic agents is limited once the varices have ruptured. The use of beta-blockers in the prophylaxis of the first variceal bleeding has been proven of benefit in this respect. Future research should be aimed at elucidating the role that humoral and endothelial factors play in development of the hyperdynamic circulatory state that characterizes patients with portal hypertension. Once these etiologic factors have been identified and new knowledge is acquired about their role in the complications of chronic liver disease, the challenge will rest on developing novel pharmacologic therapies specifically targeting these factors.
Molecular Mechanisms of Mitochondrial Autophagy/Mitophagy in the Heart
Authors: Toshiro Saito, Junichi Sadoshima
Journal: Circulation Research (2015)

Mitochondrial quality is a crucial determinant of cell viability, and mitochondrial autophagy plays a central role in this control mechanism. Based on studies in yeast, numerous investigations of this process have been conducted, and the framework of mammalian mitochondrial autophagy is progressively appearing. However, many enigmas about the molecular mechanisms involved remain unsolved. Furthermore, the pathological significance of mitochondrial autophagy in the heart remains largely unclear. In this review, we discuss the current understanding of mitochondrial autophagy in mammals with reference to that in yeast. Regarding the process in yeast, some points of uncertainty have arisen. We also summarize recent advances in the research of autophagy and mitochondrial autophagy in the heart. This article is a part of a review series on Autophagy in Health and Disease .
Toward A Vaccine for AIDS: The Emergence of Immunobiology-Based Vaccine Development
Authors: K B Cease, J A Berzofsky
Journal: Annual Review of Immunology (1994)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
Will Focal Therapy Remain Only an Attractive Illusion for the Primary Treatment of Prostate Cancer?
Authors: Gianluca Giannarini, Giorgio Gandaglia, Francesco Montorsi, Alberto Briganti
Journal: Journal of Clinical Oncology (2014)

Focal therapy is an emerging treatment modality for clinically localized prostate cancer (PCa). It was introduced with the aim of reducing the morbidity associated with standard whole-gland therapy, such as radical prostatectomy (RP) and external beam radiation therapy, without jeopardizing cancer control. In particular, following the organ-preservation approach adopted for several other solid tumors, focal therapy strategies in PCa were conceived in an attempt to destroy the tumor while minimizing damage to noncancerous tissue and sparing key structures, such as the neurovascular bundles and the external urinary sphincter. Another advantage of this approach is that any future tumor lesions diagnosed at a later stage of the disease after the initial treatment are still amenable to re-treatment. Despite a dramatically increasing interest among clinicians and investigators, focal therapy is still in its infancy and should thus be regarded as an experimental approach. How long it will remain an investigational therapy is difficult to predict. However, we believe that several misconceptions and intrinsic limitations of this approach may prevent its further development as a possible treatment option for men with clinically localized PCa.
Archie Cochrane (1909-1988)
Authors: Iain Chalmers
Journal: Journal of the Royal Society of Medicine (2008)

Archibald Leman Cochrane was born in Galashiels, Scotland, on 12 January 1909, into a well-off Scottish tweed-making family, the first son of Walter Francis and Emma Mabel (nee Purdom) Cochrane. His father was killed at the Battle of Gaza when Archie was only eight years old; one of Archie's brothers (Walter) died aged two from pneumonia; the other (Robert) died aged 21 after a motorcycle accident. Unsurprisingly, Archie's lifelong relationship with his older sister, Helen, was very close, and it was her son and daughter-in-law - Joe and Maggie Stalker - who cared for Archie at their home in Somerset, England, in the years before his death on 18 June 1988.

That Archie's sister Helen outlived him was in part because he challenged a diagnosis of dementia made after she had been admitted to a psychiatric hospital. Further investigation led to the discovery that she and Archie both had porphyria. Because he was concerned that other members of the family scattered around the world might unknowingly have the condition and put themselves at risk, he solicited urinary and faecal samples from 153 relatives and succeeded in obtaining satisfactory specimens from 152 of them.

In some ways this anecdote encapsulates the essence of Archie Cochrane. He was always ready to challenge medical (and non-medical) authorities to provide better evidence about the basis for their diagnoses and treatments. Although he had an epidemiologist's interest in the wellbeing of communities, he was also deeply concerned for the welfare of individuals. And, as reflected in the survey of his relatives, he was known particularly for achieving very high rates of participation and follow-up in his epidemiological and clinical studies.
Regulation of thymocyte development through CD3. I. Timepoint of ligation of CD3 epsilon determines clonal deletion or induction of developmental program.
Authors: C N Levelt, A Ehrfeld, K Eichmann
Journal: The Journal of Experimental Medicine (1993)

Several recent observations suggest that successful rearrangement of the T cell receptor (TCR) beta locus induces several important events in thymocyte maturation. Allelic exclusion is achieved by interruption of further rearrangement of the beta locus, and CD4-8- interleukin (IL)-2R+ cells enter the CD4+8+IL-2R- stage. The actual molecular events regulating this important control point are unknown, but may be related to the expression of the TCR-beta locus in immature CD4-8- thymocytes. It is not clear whether maturation is induced by intracellular appearance of TCR-beta chain or by signal transduction through an immature TCR complex on the thymocyte membrane, possibly involving TCR-beta chain homodimers and CD3. Here we show that early addition of anti-CD3 mAb to fetal thymic organ cultures induces all known events associated with the acquisition of the CD4+8+ stage. Expression of CD4 and CD8 is accelerated, IL-2R alpha is downregulated, and the cells fail to produce TCR-beta, possibly based on premature cessation of beta gene rearrangement. Upon stimulation with anti-CD3 antibodies, we see calcium mobilization in 15% of all CD4-8- thymocytes with no detectable surface TCR expression. These results suggest that functional CD3 is expressed on immature thymocytes at very low concentrations before the appearance of a complete TCR-beta chain. Ligation of CD3 at this stage may mimic the maturation signal normally generated by the immature TCR-beta homodimer-CD3 complex. The results are consistent with the notion that acquisition of the CD4+8+ stage involves signal transduction through an immature TCR complex. Later in thymocyte development, ligation of CD3 results in deletion of CD4+8+ cells. Thus, signal transduction through CD3 may result in entirely different cellular responses, depending on the stage of thymocyte differentiation. These results suggest an involvement of CD3 as a link in signal transduction for at least two different decision points in the development of a thymocyte.
Effect of nitric oxide synthase inhibitor on allergen- and hyperventilation-induced bronchoconstriction in guinea-pigs
Authors: H Nogami, E Umeno, S Kano, T Hirose, S Nishima
Journal: European Respiratory Journal (1998)

To elucidate the role of endogenous nitric oxide (NO) in allergen- (AIB) and hyperventilation-induced bronchoconstriction (HIB), the effects of an NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on AIB and HIB were studied in guinea-pigs. In the AIB group, 21 anaesthetized guinea-pigs, actively sensitized with 1% ovalbumin, were challenged with aerosolized 0.1% ovalbumin solution under mechanical ventilation. In the HIB group, 14 guinea-pigs were challenged with hyperventilation (tidal volume of 12 mL x kg(-1) at 150 breaths x min(-1) with 21% O2 and 5% CO2 dry gas) for 5 min. In both groups, lung resistance (RL) was measured using a pressure-volume-sensitive body plethysmograph, with or without L-NAME pretreatment (8 mg x kg(-1) i.v. followed by 2 mg x kg(-1) x min(-1) i.v.). The NO precursor, L-arginine was injected at a rate of 15 mg x kg(-1) x min(-1) after L-NAME injection (10 mg x kg(-1)) in the AIB group. The results were as follows. In the AIB group, the maximal RL change was significantly potentiated by pretreatment with L-NAME. This potentiating effect of L-NAME was reversed by L-arginine. In the HIB group, the pretreatment with L-NAME had no effect on increases in RL. These findings suggest that endogenous nitric oxide may play an important role in the modulation of allergen-, but not hyperventilation-induced bronchoconstriction in guinea-pigs.
Third of men with treatment resistant prostate cancer respond to drug that targets gene defect, study finds
Authors: Susan Mayor
Journal: BMJ (2015)

One third of men with metastatic prostate cancer who do not respond to hormonal therapy show a response to olaparib, which targets inherited gene defects underlying the cancer in some people, says a study reported in the New England Journal of Medicine .1

The phase II trial included 50 men with metastatic prostate cancer that was resistant to androgen blockade. All of the men had previously been treated with docetaxel, and most (98%) had received abiraterone or enzalutamide. In the trial they were treated with olaparib tablets at a dose of 400 …
Inhibition of Vascular Smooth Muscle Cell K <sup>+</sup> Currents by Tyrosine Kinase Inhibitors Genistein and ST 638
Authors: Sergey V. Smirnov, Philip I. Aaronson
Journal: Circulation Research (1995)

Abstract The whole-cell patch-clamp technique was used to characterize the effects of several tyrosine kinase inhibitors on the voltage-gated K + current (I K ) in rat and rabbit pulmonary artery cells. I K was blocked in a dose-dependent manner by genistein (20 to 100 μmol/L) and ST 638 (0.5 to 40 μmol/L) but not by the inactive genistein analogue diadzein (100 μmol/L). This inhibition was not significantly altered when ATP was excluded from the patch pipette or when it was replaced by the poor tyrosine kinase substrate ATP-γ-S. The inhibition was also unaffected by inclusion of the tyrosine phosphatase inhibitor orthovanadate in either the bath (0.5 mmol/L) or pipette (0.2 mmol/L) solutions. In the rat, I K ordinarily inactivated negligibly over 300 ms. In the presence of 10 μmol/L ST 638, however, I K reached a peak ≈5 ms after depolarization (to +60 mV) and then decayed markedly. In the rabbit, I K demonstrated a prominent rapidly decaying initial component that was only slightly inhibited by ST 638, which preferentially blocked the sustained current; genistein showed the opposite selectivity. These observations indicated that I K blockade by genistein and ST 638 was not mediated by an inhibition of tyrosine kinase activity and further suggested that in both types of cells genistein and ST 638 preferentially blocked rapidly and slowly inactivating components of I K , respectively.
The prague C &amp; M criteria for grading barrett's oesophagus: a live endoscopy evaluation of observer agreement
Authors: J. Shutt, D. Chan, C. Boger, P. Patel
Journal: Gut (2011)

<h3>Introduction</h3> To validate the Prague C and M criteria for the endoscopic diagnosis and grading of Barrett9s oesophagus (BO) in a real-time clinical setting between two experienced endoscopists in a University teaching hospital in the UK. <h3>Methods</h3> Forty consecutive cases with BO were studied. A nurse endoscopist applied the Prague C and M criteria to record the Circumferential and Maximal extent of BO on push and pull endoscopy, this was repeated on pull endoscopy by a doctor (blinded to the initial assessment, with the nurse endoscopist not present). Landmark measurements were recorded by an independent observer. Intra- and inter-rater agreement regarding the length of C and M was evaluated by the correlation coefficient and Bland-Altman analysis. <h3>Results</h3> The Pearson correlation coefficients (r) for nurse pull against push endoscopy were 0.89 for C and 0.87 for M (p&lt;0.001), and for doctor against nurse were 0.76 for C and 0.80 for M (p&lt;0.001). Comparing pull against push endoscopy, the exact rates of agreement were 15/40 and 12/40 for C and M respectively, differing by 1 cm in 30/40 and 27/40, and by 2 cm in 30/40 and 36/40 respectively. There were 5 and 4 cases with differences of 3 or 4 cm for C and M respectively. Comparing doctor against nurse, the exact rates of agreement were 8/40 and 6/40 for C and M respectively, differing by 1 cm in 20/40 and 21/40, and by 2 cm in 30/40 and 29/40 respectively. There were 9 and 11 cases with differences of 3 or 4 cm for C and M respectively, and 1 case where C differed by 5 cm. From the Bland-Altman analysis, the mean difference in C between pull and push endoscopy was 0.33 cm (95% CI −0.22 to 2.00), with limits of agreement from −2.59 to 3.24 cm. For M, the mean difference between pull and push endoscopy was 0.63 cm (95% CI 0.07 to 2.03), with limits of agreement from −2.33 to 3.58 cm. The mean difference in C between doctor and nurse was −0.03 cm (95% CI −0.82 to 2.94), with limits of agreement from −4.31 to 4.26 cm. For M the mean difference between doctor and nurse was −0.33 cm (95% CI −1.09 to 2.81), with limits of agreement from −4.41 to 3.76 cm. <h3>Conclusion</h3> There was good agreement for interobserver C and M values of BO at live endoscopy, but with clinically significant limits of agreement that must be considered in any studies that use the Prague criteria, especially in trials that report a reduction in the length of BO as an end point. In this real-time clinical setting, patient movement and retching, compounded by the lack of 1 cm markings on the endoscope may well have contributed to this reduced degree of agreement.
Arterial Calcification in Chronic Kidney Disease: Key Roles for Calcium and Phosphate
Authors: Catherine M. Shanahan, Matthew H. Crouthamel, Alexander Kapustin, Cecilia M. Giachelli
Journal: Circulation Research (2011)

Vascular calcification contributes to the high risk of cardiovascular mortality in chronic kidney disease (CKD) patients. Dysregulation of calcium (Ca) and phosphate (P) metabolism is common in CKD patients and drives vascular calcification. In this article, we review the physiological regulatory mechanisms for Ca and P homeostasis and the basis for their dysregulation in CKD. In addition, we highlight recent findings indicating that elevated Ca and P have direct effects on vascular smooth muscle cells (VSMCs) that promote vascular calcification, including stimulation of osteogenic/chondrogenic differentiation, vesicle release, apoptosis, loss of inhibitors, and extracellular matrix degradation. These studies suggest a major role for elevated P in promoting osteogenic/chondrogenic differentiation of VSMC, whereas elevated Ca has a predominant role in promoting VSMC apoptosis and vesicle release. Furthermore, the effects of elevated Ca and P are synergistic, providing a major stimulus for vascular calcification in CKD. Unraveling the complex regulatory pathways that mediate the effects of both Ca and P on VSMCs will ultimately provide novel targets and therapies to limit the destructive effects of vascular calcification in CKD patients.
Contact allergy to formaldehyde
Authors: A.C. De Groot
Journal: British Journal of Dermatology (2011)

ORIGINAL ARTICLE, p 568 Formaldehyde is an important contact allergen in consumer products and in industry; 2–3% (Europe) to 8–9% (U.S.A.) of patients suspected of allergic contact dermatitis react to a patch test with this preservative. Patch testing with formaldehyde is problematic and the optimal test concentration has not been established. Formerly, test concentrations of 3–5% caused irritant reactions. In the 1980s, 2% was used; the current concentration of 1% in water was recommended by the International Contact Dermatitis Research Group. Because of a probable lack of scientific data behind this change, and also based on the impression that false‐negative results occur with the 1% concentration, two studies have previously compared the results of testing with 1% and 2% formaldehyde.1, 2 In the former study,1 no significant difference between the two test concentrations was found. More recently, 1397 patients with dermatitis were patch tested with 1% and 2% aqueous formaldehyde, using standardized amounts of 15 μL of the solutions applied with a micropipette to the filter paper discs in the test chambers (Finn Chamber).2 Sixty‐eight patients (4·9%) were found to have contact allergy to formaldehyde. Thirty‐seven of them reacted positively only to formaldehyde 2%, 29 patients reacted to both concentrations, and two reacted to the 1% concentration only. Thus, testing with 2% detected twice as many individuals with formaldehyde contact allergy.2
Three-dimensional intracellular calcium gradients in single human burst-forming units-erythroid-derived erythroblasts induced by erythropoietin.
Authors: R V Yelamarty, B A Miller, R C Scaduto, F T Yu, D L Tillotson, J Y Cheung
Journal: Journal of Clinical Investigation (1990)

We have previously shown that the intracellular free Ca2+ increase induced by erythropoietin is likely related to differentiation rather than proliferation in human BFU-E-derived erythroblasts (1989. Blood. 73:1188-1194). Since cell differentiation involves transcription of specific regions of the genome, and since nuclear endonucleases responsible for single strand DNA breaks observed in cells undergoing differentiation are Ca2+ dependent, we investigated whether the erythropoietin-induced calcium signal is transmitted from cytosol to nucleus in this study. To elucidate subcellular Ca2+ gradients, the technique of optical sectioning microscopy was used. After determining the empirical three-dimensional point spread function of the video imaging system, contaminating light signals from optical planes above and below the focal plane of interest were removed by deconvolution using the nearest neighboring approach. Processed images did not reveal any discernible subcellular Ca2+ gradients in unstimulated erythroblasts. By contrast, with erythropoietin stimulation, there was a two- to threefold higher Ca2+ concentration in the nucleus compared to the surrounding cytoplasm. We suggest that the rise in nuclear Ca2+ may activate Ca2(+)-dependent endonucleases and initiate differentiation. The approach described here offers the opportunity to follow subcellular Ca2+ changes in response to a wide range of stimuli, allowing new insights into the role of regional Ca2+ changes in regulation of cell function.