bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stimulation of Suicidal Erythrocyte Death by Fumagillin
Authors: Zbidah Mohanad , Lupescu Adrian , Jilani Kashif , Lang Florian 
Published: April 2013

AbstractFumagillin, a cyclohexane isolated from fungus Aspergillus fumigatus, has anti‐infective and anti‐cancer potency. Fumagillin is at least partially effective by inducing suicidal death or apoptosis. In analogy to apoptosis of nucleated cells, eryptosis is the suicidal death of erythrocytes characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Stimulators of eryptosis include increase of cytosolic Ca2+‐activity ([Ca2+]i) and ceramide. The present study explored whether fumagillin (5–100 μM) could stimulate eryptosis. To this end, [Ca2+]i was estimated from Fluo3 fluorescence, ceramide by utilizing specific antibodies, cell volume from forward scatter, phosphatidylserine exposure from annexin V binding and haemolysis from haemoglobin release. As a result, a 48‐hr exposure to fumagillin significantly increased [Ca2+]i (≥10 μM), enhanced ceramide abundance (100 μM), triggered annexin V binding (≥10 μM) and decreased forward scatter (≥10 μM). Fumagillin exposure was followed by slight but significant increase of haemolysis. Removal of extracellular Ca2+ significantly blunted but did not abolish the effect of fumagillin (100 μM) on annexin V binding. The present observations disclose a novel effect of fumagillin, that is, stimulation of eryptosis, paralleled by Ca2+ entry, ceramide formation, phosphatidylserine exposure and decrease of cell volume.
The Contractile Effect of Anandamide in the Guinea‐Pig Small Intestine is Mediated by Prostanoids but not TRPV1 Receptors or Capsaicin‐Sensitive Nerves
Authors: Dékány András , Benko Rita , Szombati Veronika , Bartho Lorand 
Published: April 2013

AbstractAlthough exogenous and endogenous cannabinoid receptor agonists have well‐documented inhibitory effects on gastrointestinal motility, a TRPV1 receptor‐mediated excitatory action of anandamide (arachidonoyl ethanolamide, AEA) in the guinea‐pig ileum strip has also been described. We used in vitro capsaicin desensitization for assessing the possible participation of sensory neurons in the contractile effect of anandamide on the guinea‐pig whole ileum, as well as autonomic drugs and a cyclooxygenase inhibitor for characterizing this response. Isolated organ experiments were used with isotonic recording. Contractions induced by anandamide (1 or 10 μM) were strongly inhibited by tetrodotoxin, indomethacin or atropine plus a tachykinin NK1 receptor antagonist, but weakly to moderately reduced by atropine alone and partly diminished by the fatty acid amide hydrolase inhibitor URB 597. Neither capsaicin pre‐treatment nor the TRPV1 receptor antagonist BCTC, the ganglionic blocking drug hexamethonium or cannabinoid (CB1 or CB2) receptor antagonists, influenced the effect of anandamide. It is concluded that the capsaicin‐insensitive, neuronal excitatory effect of anandamide in the intestine is most probably mediated by cyclooxygenase products. Such a mechanism may also play a role at other sites in the mammalian body.
Stigmatization and Denormalization as Public Health Policies: Some Kantian Thoughts
Authors: Dean Richard 
Published: April 2013

AbstractThe stigmatization of some groups of people, whether for some characteristic they possess or some behavior they engage in, will initially strike most of us as wrong. For many years, academic work in public health, which focused mainly on the stigmatization of HIV‐positive individuals, reinforced this natural reaction to stigmatization, by pointing out the negative health effects of stigmatization. But more recently, the apparent success of anti‐smoking campaigns which employ stigmatization of smokers has raised questions about whether stigmatization may sometimes be justified, because of its positive effects on public health. Discussion of the issue so far has focused on consequences, and on some Kantian considerations regarding the status of the stigmatized. In this article, I argue that further Kantian considerations regarding the treatment of the general public (the potential stigmatizers) also count against any public health policy involving stigmatization. Attempts to encourage stigmatization are likely to fail to appeal to the rational decision‐making abilities of the general public, and the creation of stigmatized groups (even if they are stigmatized for their voluntary behavior) is an obstacle to the self‐improvement of members of the general public.
Absolute Biological Needs
Authors: McLeod Stephen 
Published: April 2013

AbstractAbsolute needs (as against instrumental needs) are independent of the ends, goals and purposes of personal agents. Against the view that the only needs are instrumental needs, David Wiggins and Garrett Thomson have defended absolute needs on the grounds that the verb ‘need’ has instrumental and absolute senses. While remaining neutral about it, this article does not adopt that approach. Instead, it suggests that there are absolute biological needs. The absolute nature of these needs is defended by appeal to: their objectivity (as against mind‐dependence); the universality of the phenomenon of needing across the plant and animal kingdoms; the impossibility that biological needs depend wholly upon the exercise of the abilities characteristic of personal agency; the contention that the possession of biological needs is prior to the possession of the abilities characteristic of personal agency. Finally, three philosophical usages of ‘normative’ are distinguished. On two of these, to describe a phenomenon or claim as ‘normative’ is to describe it as value‐dependent. A description of a phenomenon or claim as ‘normative’ in the third sense does not entail such value‐dependency, though it leaves open the possibility that value depends upon the phenomenon or upon the truth of the claim. It is argued that while survival needs (or claims about them) may well be normative in this third sense, they are normative in neither of the first two. Thus, the idea of absolute need is not inherently normative in either of the first two senses.
Prion Disease: A Tale of Folds and Strains
Authors: Kretzschmar Hans , Tatzelt Jörg 
Published: April 2013

AbstractResearch on prions, the infectious agents of devastating neurological diseases in humans and animals, has been in the forefront of developing the concept of protein aggregation diseases. Prion diseases are distinguished from other neurodegenerative diseases by three peculiarities. First, prion diseases, in addition to being sporadic or genetic like all other neurodegenerative diseases, are infectious diseases. Animal models were developed early on (a long time before the advent of transgenic technology), and this has made possible the discovery of the prion protein as the infectious agent. Second, human prion diseases have true equivalents in animals, such as scrapie, which has been the subject of experimental research for many years. Variant Creutzfeldt–Jakob disease (vCJD) is a zoonosis caused by bovine spongiform encephalopathy (BSE) prions. Third, they show a wide variety of phenotypes in humans and animals, much wider than the variants of any other sporadic or genetic neurodegenerative disease. It has now become firmly established that particular PrPSc isoforms are closely related to specific human prion strains. The variety of human prion diseases, still an enigma in its own right, is a focus of this article. Recently, a series of experiments has shown that the concept of aberrant protein folding and templating, first developed for prions, may apply to a variety of neurodegenerative diseases. In the wake of these discoveries, the term prion has come to be used for Aβ, α‐synuclein, tau and possibly others. The self‐propagation of alternative conformations seems to be the common denominator of these “prions,” which in future, in order to avoid confusion, may have to be specified either as “neurodegenerative prions” or “infectious prions.”
Cell injury and Premature Neurodegeneration in Focal Malformations of Cortical Development
Authors: Iyer Anand , Prabowo Avanita , Anink Jasper , Spliet Wim G. M. , van Rijen Peter C. , Aronica Eleonora 
Published: April 2013

AbstractSeveral lines of evidence suggest that cell injury may occur in malformations of cortical development associated with epilepsy. Moreover, recent studies support the link between neurodevelopmental and neurodegenerative mechanisms. We evaluated a series of focal cortical dysplasia (FCD,n = 26; typeIandII) and tuberous sclerosis complex (TSC,n = 6) cases. Sections were processed for terminal deoxynucleotidyl transferase‐mediated 2′‐deoxyuridine 5′‐triphosphate nick‐end labeling (TUNEL) labeling and immunohistochemistry using markers for the evaluation of apoptosis signaling pathways and neurodegeneration‐related proteins/pathways. In bothFCD IIandTSCspecimens, we observed significant increases in bothTUNEL‐positive and caspase–3‐positive cells compared with controls andFCD I. Expression ofβ‐amyloid precursor protein was observed in neuronal soma and processes inFCD IIandTSC. In these specimens, we also observed an abnormal expression of death receptor‐6. Immunoreactivity for phosphorylated tau was only found in older patients withFCD IIandTSC. In these cases, prominent nuclear/cytoplasmic p62 immunoreactivity was detected in both dysmorphic neurons and balloon/giant cells. Our data provide evidence of complex, but similar, mechanisms of cell injury in focal malformations of cortical development associated with mammalian target of rapamycin pathway hyperactivation, with prominent induction of apoptosis‐signaling pathways and premature activation of mechanisms of neurodegeneration.
Smooth muscle relaxation and activation of the large conductance Ca++ – activated K+ (BKCa) channel by novel oestrogens
Authors: Maher J , Hunter A C , Mabley J G , Lippiat J , Allen M C 
Published: April 2013

Background and PurposeOestrogens can interact directly with membrane receptors and channels and can activate vascular BKCa channels. We hypothesized that novel oestrogen derivatives could relax smooth muscle by an extracllular effect on the α and β1 subunits of the BKCa channel, rather than at an intracellular site.Experimental ApproachWe studied the effects of novel oestrogens on the tension of pre‐contracted isolated rat aortic rings, and on the electrophysiological properties of HEK 293 cells expressing the hSloα or hSloα+β1 subunits. Two of the derivatives incorporated a quaternary ammonium side‐chain making them membrane impermeable.Key ResultsOestrone, oestrone oxime and Quat DME‐oestradiol relaxed pre‐contracted rat aorta, but only Quat DME‐oestradiol‐induced relaxation was iberiotoxin sensitive. However, only potassium currents recorded in HEK 293 cells over‐expressing both hSloα and hSloβ1 were activated by oestrone, oestrone oxime and Quat DME‐oestradiol.Conclusion and ImplicationsThe novel oestrogens were able to relax smooth muscle, but through different mechanisms. In particular, oestrone oxime required the presence of the endothelium to exert much of its effect, whilst Quat DME‐oestradiol depended both on NO and BKCa channel activation. The activation of BKCa currents in HEK 293 cells expressing hSloα+β1 by Quat DME‐oestradiol is consistent with an extracellular binding site between the two subunits. The binding site resides between the extracellular N terminal of the α subunit and the extracellular loop between TM1 and 2 of the β1 subunit. Membrane‐impermeant Quat DME‐oestradiol lacks an exchangeable hydrogen on the A ring obviating antioxidant activity.
No difference in phenotype of the main Dutch SDHD founder mutations
Authors: van Hulsteijn L. T. , den Dulk A. C. , Hes F. J. , Bayley J. P. , Jansen J. C. , Corssmit E. P. M. 
Published: April 2013

SummaryObjectiveSDHD mutations predispose carriers to hereditary paraganglioma syndrome. The objective of this study was to assess the genotype–phenotype correlation of a large Dutch cohort of SDHD mutation carriers and evaluate potential differences in clinical phenotypes due to specific SDHD gene mutations.DesignRetrospective, descriptive single‐centre study.PatientsAll consecutive SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center were included.MeasurementsSubjects were investigated according to structured protocols used for standard care, including repetitive biochemical and radiological screening for paragangliomas.ResultsTwo hundred and one SDHD mutation carriers with a mean age at presentation of 42·6 ± 14·4 years and a mean follow‐up of 5·8 ± 5·4 years were evaluated. Eighty‐one percent carried the SDHD c.274G>T (p.Asp92Tyr) mutation and 13% the SDHD c.416T>C (p.Leu139Pro) mutation. No differences in clinical phenotype between these two specific SDHD mutations were found. Ninety‐one percent developed one or multiple paragangliomas in the head and neck region (HNPGLs), of which the carotid body tumour was the most prevalent (85%). Eighteen carriers developed pheochromocytomas, fifteen sympathetic paragangliomas and nine carriers (4%) suffered from malignant paraganglioma. By end of follow‐up, sixteen SDHD mutation carriers (8%) displayed no biochemical or radiological evidence of manifest disease.ConclusionsThe two main Dutch SDHD founder mutations do not differ in clinical expression. SDHD mutations are associated with the development of multiple HNPGLs and predominantly benign disease.
Dimethylfumarate: potency prediction and clinical experience
Authors: Basketter David A. , White Ian R. , Burleson Florence G. , Burleson Gary R. , Kimber Ian 
Published: April 2013

Background. Dimethylfumarate (DMF) was the cause of a major outbreak of allergic contact dermatitis as a consequence of its use as an antifungal agent in leather products, particularly in furniture, with what became known as ‘toxic sofa dermatitis'.Objectives. To determine whether the frequency and severity of reactions to DMF arose as a function of its intrinsic potency and/or the nature and extent of exposure.Methods. The intrinsic potency of DMF was measured with the standard local lymph node assay (LLNA), with determination of an EC3 value, which is the threshold in the LLNA and serves as an indicator of relative skin‐sensitizing potency in humans.Results. The EC3 value for DMF was 0.35% when tested in dimethylformamide as a vehicle, indicating that DMF is a strong, but not an extreme, skin sensitizer in this mouse model.Conclusions. DMF appears to have a sensitizing potency in the mouse that is very similar to that of formaldehyde, which is also a strong human skin sensitizer. However, the frequency and intensity of allergic contact dermatitis reactions to DMF suggest that it was the prolonged, repeated and occlusive exposure to this chemical over large skin areas, combined with the strong sensitizing potency, that generated the ‘perfect storm’ conditions that caused the DMF epidemic.
The role of faecal diversion in low rectal cancer: a review of 1791 patients having rectal resection with anastomosis for cancer, with and without a proximal stoma
Authors: Nurkin S. , Kakarla V. R. , Ruiz D. E. , Cance W. G. , Tiszenkel H. I. 
Published: April 2013

AbstractAimThe morbidity of anastomotic dehiscence may be mitigated by a defunctioning stoma, but it is unclear if it is required for most low rectal anastomoses. Preoperative risk factors leading to anastomotic complications and the indications for faecal diversion have yet to be clearly defined.MethodUsing the American College of Surgeons‐National Surgical Quality Improvement Project (ACS‐NSQIP) participant‐use file, patients were identified who underwent low anterior resection with anastomosis for cancer at the 211 participating hospitals in 2005–08.ResultsA total of 1791 patients underwent low anterior resection. Patients were subdivided into two groups based on the level of the anastomosis. Of these 1266 patients had a low pelvic anastomosis (LPA) and 525 a coloanal anastomosis (CAA). In the LPA group, 606 patients had a stoma and 660 had no stoma. There were no differences in wound complications, sepsis or septic shock. Patients who had a stoma were more likely to have postoperative acute renal failure (1.7 vs 0.5%, P = 0.0485, OR 3.674). In the CAA group, 352 had a stoma and 173 had no stoma. In patients without faecal diversion, there was a significantly greater incidence of sepsis (8.7 vs 3.7%, P = 0.022, OR 2.47), septic shock (3.5 vs 0.57%, P = 0.018, OR 6.29) and need for reoperation (11 vs 1.7%, P = 0.0001, OR 7.11). Hospital length of stay was significantly longer with CAA and no stoma. On multivariate analysis, not having a stoma with a CAA was a risk factor for serious postoperative morbidity.ConclusionWhile a defunctioning stoma with a coloanal anastomosis seems to protect from postoperative sepsis, septic shock and need for reoperation, it is likely that it is overused in rectal cancer surgery.
Non‐symbolic halving in an Amazonian indigene group
Authors: McCrink Koleen , Spelke Elizabeth S. , Dehaene Stanislas , Pica Pierre 
Published: April 2013

AbstractMuch research supports the existence of an Approximate Number System (ANS) that is recruited by infants, children, adults, and non‐human animals to generate coarse, non‐symbolic representations of number. This system supports simple arithmetic operations such as addition, subtraction, and ordering of amounts. The current study tests whether an intuition of a more complex calculation, division, exists in an indigene group in the Amazon, the Mundurucu, whose language includes no words for large numbers. Mundurucu children were presented with a video event depicting a division transformation of halving, in which pairs of objects turned into single objects, reducing the array's numerical magnitude. Then they were tested on their ability to calculate the outcome of this division transformation with other large‐number arrays. The Mundurucu children effected this transformation even when non‐numerical variables were controlled, performed above chance levels on the very first set of test trials, and exhibited performance similar to urban children who had access to precise number words and a surrounding symbolic culture. We conclude that a halving calculation is part of the suite of intuitive operations supported by the ANS.
In‐treatment HDL cholesterol levels and development of new diabetes mellitus in hypertensive patients: The LIFE Study
Authors: Okin P. M. , Hille D. A. , Wiik B. P. , Kjeldsen S. E. , Lindholm L. H. , Dahlöf B. , Devereux R. B. 
Published: April 2013

AbstractAimsAlthough hypertensive patients with low baseline HDL cholesterol levels have a higher incidence of diabetes mellitus, whether changing levels of HDL over time are more strongly related to the risk of new diabetes in hypertensive patients has not been examined.MethodsIncident diabetes mellitus was examined in relation to baseline and in‐treatment HDL levels in 7485 hypertensive patients with no history of diabetes randomly assigned to losartan‐ or atenolol‐based treatment.ResultsDuring 4.7 ± 1.2 years follow‐up, 520 patients (6.9%) developed new diabetes. In univariate Cox analyses, compared with the highest quartile of HDL levels (> 1.78 mmol/l), baseline and in‐treatment HDL in the lowest quartile (< 1.21 mmol/l) identified patients with > 5‐fold and > 9 fold higher risks of new diabetes, respectively; patients with baseline or in‐treatment HDL in the 2nd and 3rd quartiles had intermediate risk of diabetes. In multivariable Cox analyses, adjusting for randomized treatment, age, sex, race, prior anti‐hypertensive therapy, baseline uric acid, serum creatinine and glucose entered as standard covariates, and in‐treatment non‐HDL cholesterol, Cornell product left ventricular hypertrophy, diastolic and systolic pressure, BMI, hydrochlorothiazide and statin use as time‐varying covariates, the lowest quartile of in‐treatment HDL remained associated with a nearly 9‐fold increased risk of new diabetes (hazard ratio 8.7, 95% CI 5.0–15.2), whereas the risk of new diabetes was significantly attenuated for baseline HDL < 1.21 mmol/l (hazard ratio 3.9, 95% CI 2.8–5.4).ConclusionsLower in‐treatment HDL is more strongly associated with increased risk of new diabetes than baseline HDL level.
Trends in selection and timing of first‐line pharmacotherapy in older patients with Type 2 diabetes diagnosed between 1994 and 2006
Authors: Foster P. D. , Mamdani M. M. , Juurlink D. N. , Shah B. R. , Paterson J. M. , Gomes T. 
Published: April 2013

AbstractAimsTo characterize temporal trends in the selection and timing of first‐line pharmacotherapy among older patients with Type 2 diabetes.Design and methodsWe studied five population‐based cohorts every 3 years, from 1994 to 2006. In each of those years, we identified all subjects aged 66 years or older newly diagnosed with diabetes and determined the initial glucose‐lowering drug and the time between diagnosis and drug initiation. We calculated the proportion of patients prescribed each agent and estimated time from diagnosis to initiation using Kaplan–Meier survival analysis.ResultsWe identified a total of 64 368 eligible people who initiated drug therapy during the study period. From 1994 to 2006, first‐line metformin use increased from 20.1 to 79.0%. Glyburide (glibenclamide) decreased from 71.1% of all first‐line therapies in 1994 to 9.8% in 2006, while first‐line use of insulin or combination therapy have changed little at approximately 5% each. No other medication exceeded 2% of first‐line therapies. The median time from diagnosis to initiation of pharmacotherapy increased dramatically during the study period, from 1.8 years in 1994 to 4.6 years in 2006.ConclusionsMetformin has become the most commonly used initial medication for the treatment of diabetes. Although guidelines have evolved to recommend more aggressive initiation and intensification of pharmacotherapy, our results suggest that the time from diagnosis to initiation has increased substantially.
Workplace Friendships among Bank Employees in Eastern Libya
Authors: Bader Hind A. M. , Hashim Intan H. M. , Zaharim Norzarina Mohd 
Published: April 2013

AbstractThe purpose of this study was to examine workplace friendships among 536 employees of Wahda Bank in four cities in Eastern Libya. In this study, a Workplace Friendship Scale (WFS) was used to assess opportunities for and the presence of friendships. Participants in this study reported mainly positive friendships at the workplace. Participants of different gender, ages, education levels, cities, and durations of work in different departments reported various opportunities for workplace friendships. However, marital status and type of occupation were not significantly related to friendships at the workplace. Findings suggest both similar and unique patterns of friendships compared to those studied outside Libya.