Miracle-dz/UniFAR-FTUs huggingface dataset:
Characterization of Ryanodine Receptor–mediated Calcium Release in Human B Cells: Relevance to Diagnostic Testing for Malignant Hyperthermia

Background:Mutations in the ryanodine type 1 receptor (RyR1) are causative for malignant hyperthermia. Studies in human B lymphocytes have shown that measurement of RyR1-mediated intracellular Ca2+ (Ca2+i) release can differentiate between normal and malignant hyperthermia–susceptible individuals. The authors have further developed the B-cell assay by pharmacologically characterizing RyR1-mediated Ca2+ release in two normal human B-cell lines and demonstrating increased sensitivity of lymphocytes to the RyR1 agonist 4-chloro-m-cresol (4-CmC) in the porcine model of MH. Methods:Ca2+i was measured fluorometrically using fura-2 in populations of cells in suspension or with fluo-4 in single cells using confocal microscopy. The Dakiki and PP normal human B cell lines were used, as well as lymphocytes obtained from normal and malignant hyperthermia–susceptible pigs. 4-CmC was used to elicit RyR1-mediated Ca2+ release; all experiments were performed in the absence of external Ca2+. Results:EC50 values for 4-CmC were 0.98 and 1.04 mm for Dakiki and PP cells, respectively, demonstrating reproducibility. The 4-CmC–induced increase in Ca2+i was eliminated by thapsigargin and was unaffected by xestospongin C. The Ca2+i increase was separable from mitochondrial stores and was inhibited by azumolene. Caffeine did not induce Ca2+ i release, but ryanodine depleted intracellular stores by 50%. Lymphocytes from pigs carrying the Arg614Cys mutation in RyR1 showed increased sensitivity to 4-CmC (EC50 = 0.47 vs. 0.81 mm for cells derived from normal animals). Conclusions:RyR1-mediated Ca2+ signals can be pharmacologically distinguished from other intracellular sources in human B cells, and alterations of RyR1 function can be successfully detected using Ca2+ release from intracellular stores as an end point.
Promising new treatments for neovascular age-related macular degeneration

Angiogenesis, the growth of new blood vessels from existing blood vessels, is responsible for vision loss in a variety of ophthalmic diseases. In neovascular age-related macular degeneration (AMD), the leading cause for legal blindness in many industrialised countries, abnormal blood vessels grow in the macula and cause blindness. There are a number of factors important in the angiogenic cascade but VEGF-A has been implicated in recent years as the major factor responsible for neovascular and exudative diseases of the eye. Numerous antiangiogenic drugs are in development but anti-VEGF drugs have shown great promise in treating neovascular AMD and other ocular diseases, and many of these drugs have been adopted from oncology where antiangiogenic therapy is gaining wide acceptance. For the first time in neovascular AMD, anti-VEGF drugs have brought the hope of vision improvement to a significant proportion of patients. This review provides an overview on angiogenic mechanisms, potential antiangiogenic treatment strategies and different antiangiogenic drugs with special focus on neovascular AMD.
A systematic review of the effects of screening for colorectal cancer using the faecal occult blood test, hemoccult.

OBJECTIVE To review effectiveness of screening for colorectal cancer with faecal occult blood test, Hemoccult, and to consider benefits and harms of screening. DESIGN Systematic review of trials of Hemoccult screening, with meta-analysis of results from the randomised controlled trials. SUBJECTS Four randomised controlled trials and two non-randomised trials of about 330 000 and 113 000 people respectively aged >=40 years in five countries. MAIN OUTCOME MEASURES Meta-analysis of effects of screening on mortality from colorectal cancer. RESULTS Quality of trial design was generally high, and screening resulted in a favourable shift in the stage distribution of colorectal cancers in the screening groups. Meta-analysis of mortality results from the four randomised controlled trials showed that those allocated to screening had a reduction in mortality from colorectal cancer of 16% (relative risk 0.84 (95% confidence interval 0.77 to 0.93)). When adjusted for attendance for screening, this reduction was 23% (relative risk 0.77 (0.57 to 0.89)) for people actually screened. If a biennial Hemoccult screening programme were offered to 10 000 people and about two thirds attended for at least one Hemoccult test, 8.5 (3.6 to 13.5) deaths from colorectal cancer would be prevented over a period of 10 years. CONCLUSION Although benefits of screening are likely to outweigh harms for populations at high risk of colorectal cancer, more information is needed about the harmful effects of screening, the community's responses to screening, and costs of screening for different healthcare systems before widespread screening can be recommended.
Determinants of Agricultural Credit Demand and Supply among Small-Scale Farmers in Nigeria

This paper analyses the factors determining the demand for and supply of agricultural credit (loans) among small-scale farmers in south-western Nigeria. Empirical data were obtained from 270 farmers who used credit. The data were analysed using descriptive statistics and statistical models. Analysis revealed that farmers who used credit were younger (average: 47 years old), and that cultivated farm sizes (average: 3.8 ha) were larger than the national average. The statistical models showed that the interest rate, farm expenditure, the amount borrowed from alternative sources, farm size and savings were the main determinants of credit demand, while interest rates charged, the level of savings of respondents, the amount of loan demanded and the proportion of previous loans repaid were the major determinants of credit supply. In order to improve the agricultural sector, formal lending institutions should target younger farmers, including women, use group and social assets as collateral rather than physical assets, charge commercial interest rates, mobilize savings through their rural outposts and give medium-term rather than short-term loans.
An examination of factors which may affect the water holding capacity of dietary fibre

1. Dietary fibre has a water holding capacity (WHC) and this is a function of the fibre source and method of measurement. Water can be associated with fibre either as trapped water or bound water. This makes it difficult to predict the ability of fibre to influence stool weight in humans. 2. Examination of various fibre concentrates for chemical composition, as neutral detergent fibre (NDF), acid detergent fibre (ADF) and lignin; structure, by scanning electron microscopy; WHC, by centrifugation, suggests that WHC is more a function of fibre structure than chemical composition. Cereal fibre and vegetable fibre have a different chemical composition and are structurally very distinct. Structure is also dependent on the method of fibre preparation. 3. Measurement of WHC by centrifugation gives an estimate of the water which can be bound and also trapped by the fibre. The amount of trapped water will depend on the structure of the fibre whereas bound water will depend on the chemical composition.
Disturbed Development of the Preimplantation Embryo in the Insulin-Dependent Diabetic BB/E Rat

Although improved regulation of maternal IDDM during pregnancy has resulted in a major fall in the stillbirth rate, the rates for other problems, such as spontaneous preterm labor, fetuses small for gestational age, congenital malformation, and the incidence of large placentas, remain raised. This has suggested the possibility that the damaging effect of conventionally treated but poorly regulated IDDM may operate primarily at the earliest stages of gestation, even before the diagnosis of pregnancy has been made. This study shows that spontaneous autoimmune IDDM in the Bio Breeding/Edinburgh (BB/E) rat is associated with severe disturbance in the development of the preimplantation embryo in a majority of pregnancies, as indicated by a fivefold increase in the incidence of degenerate fragmented embryos and a 33% reduction in the number of expanded blastocysts and in those blastocysts that reach the expanded stage a 20% cellular deficit in the inner-cell mass without any change in trophectoderm cell number. In addition, we find that blastocysts removed from diabetic rats and cultured in vitro for 24 h show no sign of “catch-up” growth of the inner-cell mass, although under these conditions, the trophectoderm exhibits a 25% cellular accretion. It is tempting to speculate that these phenomena are a presage of the characteristic combination of fetal growth retardation and large placentas, which are a feature of both BB/E rat and human IDDM pregnancy.
Involvement of the central nucleus of the amygdala and nucleus accumbens core in mediating Pavlovian influences on instrumental behaviour

Pavlovian conditioned cues exert a powerful influence on instrumental actions directed towards a common reward, this is known as Pavlovian‐to‐instrumental transfer (PIT). The nucleus accumbens (NAcc) has been hypothesized to function as an interface between limbic cortical structures required for associative conditioning, like the amygdala, and response mechanisms through which instrumental behaviour can be selected and performed. Here we have used selective excitotoxic lesions to investigate the involvement of subnuclei of the amygdala as well as the core and shell regions of the nucleus accumbens on PIT in rats. Within the amygdala, selective lesions of the central nucleus (CeN), but not of the basolateral nucleus (BLA), abolished the PIT effect. In addition, selective lesions of the NAcc core, but not the NAcc shell, also abolished PIT. None of the lesions impaired the acquisition of Pavlovian food cup approaches or instrumental responding itself. These data demonstrate that the CeN and NAcc core are central components of the neural system mediating the impact of Pavlovian cues on instrumental responding. We suggest that this effect may depend upon the regulation of the dopaminergic innervation of the NAcc core by projections from the CeN to the ventral tegmental area.
Differential effects of polycyclic aromatic hydrocarbons on transactivation of AP‐1 and NF‐κB in mouse epidermal cl41 cells

Polycyclic aromatic hydrocarbons (PAHs) and their derivatives, such as benzo[a]pyrene (B[a]P), (±)‐anti‐benzo[a]pyrene‐7,8‐diol‐9,10‐epoxide (B[a]PDE), and 5‐methylchrysene‐1,2‐diol‐3,4‐epoxide (5‐MCDE), are complete carcinogens. However, the tumor promotion effects of PAHs remain unclear. We therefore investigated the possible activation of activator protein‐1 (AP‐1) and nuclear factor‐κB (NFκB) in mouse epidermal Cl41 cells after different PAHs treatments, including B[a]P, B[a]PDE, chrysene‐1,2‐diol‐3,4‐epoxid (CDE), and 5‐MCDE. The results showed that B[a]PDE and 5‐MCDE were able to activate AP‐1 and NF‐κB, whereas B[a]P showed only marginal effect on AP‐1 activation, and B[a]P and CDE had no effect on NF‐κB activation. Treatment with either B[a]PDE or 5‐MCDE also resulted in mitogen‐activated protein kinases (MAPKs) activation as well as inhibitory subunit kappa‐B (IκBα) phosphorylation and degradation, whereas B[a]P and CDE had no effect. Pretreatment with PD98059, a specific inhibitor for extracellular signal‐regulated protein kinases (ERKs) upstream kinase MEK1/2, or SB202190, a p38 kinase inhibitor, resulted in a dramatic inhibition of B[a]PDE‐induced AP‐1 transactivation. In addition, B[a]PDE‐induced AP‐1 activation was also inhibited by overexpressing a dominant negative mutant of JNK1 in the cells. All these suggest ERKs, c‐jun N‐terminal kinases (JNKs), and p38 kinase signal transduction pathways are required for AP‐1 induction by B[a]PDE. Taken together, B[a]PDE and 5‐MCDE are the active compounds of PAHs to initiate signaling pathways. Considering the important roles of AP‐1 and NF‐κB in tumor promotion, we speculated the activation of AP‐1 and NF‐κB by B[a]PDE and 5‐MCDE may involve in their or their parent compounds' tumor promotion effects. This study may help in better understanding the tumor promotion effects of PAHs. © 2004 Wiley‐Liss, Inc.
Pitfalls in Salivary Gland Fine-Needle Aspiration Cytology

Introduction: Fine needle aspiration cytology (FNAC) of salivary gland lesion is being increasingly used. Major salivary glands and some minor salivary glands are optimal targets for fine-needle aspiration (FNA). In some instances the final histology of these lesions differs from the FNA result. Objective: To determine the diagnostic accuracy of FNAC in salivary gland lesions and identify the salivary gland FNA cases having discordant histological diagnosis so that most common diagnostic pitfalls can be avoided. Material and Methods: In Pathology department, PIMS, 61 salivary gland FNAC cases from Jan 2008 to Sep 2009 were retrospectively reviewed to identify the cytological characteristics that may have contributed to this discrepancy. Results: 31 were males and age ranges from 04-76 years (mean 38.84 ± 14). 25(43.1%) were diagnosed non-neoplastic, 31(55.1%) were rendered benign while 02 (3.44%) were malignant on cytology. Positive predictive value of FNAC was 100% and negative predictive value was 91.4%. 08 FNAC cases show discordant diagnosis in specific typing of the lesion. 6/8 cases were misdiagnosed as pleomorphic adenoma. The most common missed diagnosis was mucoepidermoid carcinoma. Conclusion: Pleomorphic adenoma and mucoepidermoid carcinoma are common in occurrence and create problems in diagnosis. Experience cytopathologist should review all the cytology slides
Confidence in Prescription Writing among Junior Physicians in Trinidad and Tobago.

BACKGROUND A fundamental skill in the practice of medicine is the ability to safely and rationally prescribe drugs. This research aims to estimate the percentage of newly registered medical officers who reported confidence in writing prescriptions. METHODS A questionnaire was distributed to 200 medical officers employed at public health tertiary institutions throughout Trinidad and Tobago. These comprised medical interns (provisionally registered) and house officers (fully registered). Participants indicated their confidence or reluctance to prescribe with or without supervision. Estimates and comparisons between the two groups were obtained using Fisher's exact and Chi-squared tests. RESULTS The response rate was 73.5%. More medical interns (68%; n = 41) than house officers (56%; n = 42) stated that they were 'Confident' or 'Very Confident' (p = 0.126) to prescribe. Approximately eighty-four per cent (83.6%; n = 51) of medical interns and 89.2% (n = 66) of house officers felt confident to prescribe antibiotics (p = 0.465). A greater percentage of medical interns (84.2%; n = 50) than house officers (66.7%; n = 49) agreed that undergraduate training equipped them to write prescriptions safely and rationally (c² = 6.17, df = 1; p = 0.012). CONCLUSIONS While most recent medical graduates felt confident about their prescription writing, there is a need to objectively measure this ability.
Just add a pinch of salt!--current directions for the use of salt in recipes in Australian magazines.

BACKGROUND Australians currently consume too much salt causing adverse consequences for health. The media play an important role in the provision of nutrition advice to consumers. Previous research shows that many foods advertized in consumer magazines are high in salt, but little research has examined magazine recipes in this context. The aim of this project was to summarize directions for salt use in recipes in leading Australian magazines. METHODS In August 2007 and 2008, the top 10 magazines by circulation that included at least five recipes, were examined. Standardized information was collected about directions for salt use in recipes. RESULTS Three hundred and thirty recipes were identified in 2007 and 417 in 2008. About 68% of recipes included high-salt ingredients, 37% instructed to season with salt, 10% instructed to add a specific quantity of salt and 15% recommended selection of low-salt ingredients. There was substantial variability in directions for salt use in recipes between magazines, but no clear differences between 2007 and 2008. CONCLUSION Many recipes advised to add salt in direct contradiction to national dietary guidelines. There is clear potential for editorial guidelines on salt use in recipes to play a role in advancing public health efforts in Australia and other such nations.
Recombinant Transforming Growth Factor‐β1 Induces Endochondral Bone in the Baboon and Synergizes with Recombinant Osteogenic Protein‐1 (Bone Morphogenetic Protein‐7) to Initiate Rapid Bone Formation

Several members of the bone morphogenetic protein (BMP) and transforming growth factor‐β (TGF‐β) families are molecular regulators of cartilage and bone regeneration, although their actual roles and combined interactions in skeletal repair are poorly understood. The presence of several molecular forms suggests multiple functions in vivo as well as synergistic interactions during both embryonic bone development and regeneration of cartilage and bone in postfetal life. Here we show for the first time that recombinant human transforming growth factor‐β1 (TGF‐β1) induces endochondral bone formation in extraskeletal sites of adult baboons. We also show that TGF‐β1 and recombinant human osteogenic protein‐1 (OP‐1, bone morphogenetic protein‐7) synergize in inducing large ossicles in extraskeletal sites of the primate as early as 15 days after implantation. A single application of OP‐1, in conjunction with an insoluble collagenous matrix as carrier (5, 25, and 125 μg/100 mg of carrier matrix) induced bone differentiation in the rectus abdominis of the baboon. This level of tissue induction was raised several‐fold by the simultaneous addition of comparatively low doses of TGF‐β1 (0.5, 1.5, and 5 μg), which by itself induces bone formation in the rectus abdominis at doses of 5 μg/100 mg of carrier matrix. Combinations of OP‐1 and TGF‐β1 yielded a 2‐ to 3‐fold increase in cross‐sectional area of the newly generated ossicles, with markedly elevated key parameters of bone formation, and corticalization of the newly formed bone by day 15, culminating in bone marrow generation by day 30. The tissue generated by the combined application of OP‐1 and TGF‐β1 showed distinct morphological differences when compared with OP‐1–treated specimens, with large zones of endochondral development and extensive bone marrow formation. At the doses tested, synergy was optimal at a ratio of 1:20 by weight of TGF‐β1 and OP‐1, respectively. These results provide evidence for a novel function of TGF‐β1 in the primate and the scientific basis for synergistic molecular therapeutics for the rapid regeneration of cartilage and bone.
Dual Regulation of Rho and Rac by p120 Catenin Controls Adipocyte Plasma Membrane Trafficking*

During 3T3L1 adipogenesis there is a marked reduction in β-catenin and N-cadherin expression with a relatively small decrease in p120 catenin protein levels. Cell fractionation demonstrated a predominant decrease in the particulate (membrane-bound) pool of p120 catenin with little effect on the soluble pool, resulting in a large redistribution from the plasma membrane to the cytosol. Reexpression of p120 catenin inhibited constitutive (transferrin receptor) and regulated mannose 6-phosphate receptor and GLUT4 trafficking to the plasma membrane. The inhibition of membrane trafficking was specific for p120 catenin function as this could be rescued by co-expression of N-cadherin. Moreover, overexpression of a p120 catenin deletion mutant (p120Δ622–628) or splice variant (p120-4A), neither of which could regulate Rho or Rac activity, showed no significant effect. The inhibition of GLUT4 translocation was also observed upon the simultaneous expression of a constitutively active Rac mutant (Rac1/Val12) in combination with a dominant-interfering Rho mutant (RhoA/Asn19). This was recapitulated by expression of the Rho ADP-ribosylation factor (C3ADP) in combination with constitutively active Rac1/Val12. Moreover, siRNA-mediated knockdown of p120 catenin resulted in increased basal state accumulation of GLUT4 at the plasma membrane. Together, these data demonstrate that p120 catenin plays an important role in maintaining the basal tone of membrane protein trafficking in adipocytes through the dual regulation of Rho and Rac function and accounts for reports implicating Rho or Rac in the control of GLUT4 translocation.
Empirical research on consumers' intention to purchase online

In e-commerce, customers' perceived value is considered pivotal determinant of consumers' intention to purchase online. Using perceived product quality, website service quality and perceived cost as the three aspects of customer perceived value, this paper presents a theoretical model which discusses how customers' perceived value affects their online purchase intention. Research results have shown that: perceived product quality, website service quality significantly positively affect consumers' perceived trust, which further positively influence consumers' intention to purchase online, but the effect of perceived cost on perceived trust and purchase intention doesn't demonstrate statistic significance. At last, we discuss the relationships among the three aspects of perceived value, perceived trust and purchase intention.
Ca2+‐independent phospholipase A2‐dependent sustained Rho‐kinase activation exhibits all‐or‐none response

Sustained contraction of cells depends on sustained Rho‐associated kinase (Rho‐kinase) activation. We developed a computational model of the Rho‐kinase pathway to understand the systems characteristics. Thrombin‐dependent in vivo transient responses of Rho activation and Ca2+ increase could be reproduced in silico. Low and high thrombin stimulation induced transient and sustained phosphorylation, respectively, of myosin light chain (MLC) and myosin phosphatase targeting subunit 1 (MYPT1) in vivo. The transient phosphorylation of MLC and MYPT1 could be reproduced in silico, but their sustained phosphorylation could not. This discrepancy between in vivo and in silico in the sustained responses downstream of Rho‐kinase indicates that a missing pathway(s) may be responsible for the sustained Rho‐kinase activation. We found, experimentally, that the sustained phosphorylation of MLC and MYPT1 exhibit all‐or‐none responses. Bromoenol lactone, a specific inhibitor of Ca2+‐independent phospholipase A2 (iPLA2), inhibited sustained phosphorylation of MLC and MYPT1, which indicates that sustained Rho‐kinase activation requires iPLA2 activity. Thus, the systems analysis of the Rho‐kinase pathway identified a novel iPLA2‐dependent mechanism of the sustained Rho‐kinase activation, which exhibits an all‐or‐none response.
Choosing between internal and external development for innovation projects: antecedents and consequences

Abstract Unlike alliance proponents, we posited that high-tech small firms (HTSFs) may not prefer interfirm collaboration for innovation activities. Drawing on the transaction cost and corporate entrepreneurship perspectives, we proposed that boundary decisions in innovation activities are determined by the perceived uncertainties of innovation projects and entrepreneurial orientation (EO). We also examined the consequences of collaborative innovation. In a sample of 178 Korean HTSFs in software development, we found that some aspects of perceived uncertainty prevented collaborative innovation, and that EO moderated this effect, enhancing the outcomes of collaborative innovation. We discuss theoretical and practical insights of these findings.