Miracle-dz/UniFAR-FTUs huggingface dataset:
Some Factor VIII (FVIII) Inhibitors Recognise a FVIII Epitope(s) that Is Present only on FVIII-vWF Complexes

Summary A mild haemophilia A patient (LE) with an Arg2150His mutation in the C1 domain of the factor VIII (FVIII) light chain was shown to have anti-FVIII antibodies inhibiting wild type but not self FVIII. Polyclonal anti-FVIII antibodies of this patient were purified by affinity adsorption using recombinant FVIII (rFVIII) and/or plasma-derived FVIII-von Willebrand factor (vWF) complexes. A distinct population of antibodies was obtained that bound to FVIII-vWF complexes but not to rFVIII, indicating that an epitope was created by the association of FVIII to vWF. Such antibodies belonged to the IgG2 isotype, but the FVIII epitopes to which they bind could not be mapped with precision due to vWF dependency. Depletion experiments showed that anti-FVIII antibodies recognising FVIII-vWF complex also distinguished wild-type from mutated self FVIII, indicating that the Arg2150His mutation alters the B cell epitope formed by the association of FVIII to vWF. To determine whether the Arg2150His substitution also alters the formation of the FVIII-vWF complex, the interaction between mutated or normal FVIII with vWF was evaluated in plasma. The dissociation rate of mutated FVIII from vWF was found to be significantly increased. The presence of an Arg2150His mutation therefore results in the disappearance of a FVIII B cell epitope generated by the association of FVIII with vWF. Patients carrying such an Arg2150His mutation and receiving infusion of wild-type FVIII may therefore be at risk of developing inhibitors to allogeneic FVIII only.
Improving Asthma Management among African-American Children via a Community Health Worker Model: Findings from a Chicago-Based Pilot Intervention

Objectives. Asthma affects 25–30% of children living in certain disadvantaged Chicago neighborhoods, a rate twice the national prevalence (13%). Children living in poor, minority communities tend to rely heavily on the emergency department (ED) for asthma care and are unlikely to be properly medicated or educated on asthma self-management. A pilot project implemented and evaluated a community health worker (CHW) model for its effectiveness in reducing asthma morbidity and improving the quality of life among African-American children living in disadvantaged Chicago neighborhoods. Methods. Trained CHWs from targeted communities provided individualized asthma education during three to four home visits over 6 months. The CHWs also served as liaisons between families and the medical system. Seventy children were enrolled into the pilot phase between 15 November 2004 and 15 July 2005, of which 96% were insured by Medicaid and 54% lived with a smoker. Prior to starting, the study was approved by an institutional review board. Data on 50 children (71.4%) who completed the entire 12-month evaluation phase were analyzed using a before and after study design. Results. Findings indicate improved asthma control. Specifically, symptom frequency was reduced by 35% and urgent health resource utilization by 75% between the pre- and post-intervention periods. Parental quality of life also improved by a level that was both clinically and statistically significant. Other important outcomes included improved asthma-related knowledge, decreased exposure to asthma triggers, and improved medical management. The intervention was also shown to be cost-effective, resulting in an estimated $5.58 saved per dollar spent on the intervention. Conclusions. Findings suggest that individualized asthma education provided by a trained, culturally competent CHW is effective in improving asthma management among poorly controlled, inner-city children. Further studies are needed to affirm the findings and assess the model’s generalizability.
Magnet Therapy: What's the Attraction?

Purpose To review the current state of the science of magnet therapy with respect to pain management and to view magnet therapy from a nursing perspective. Data Sources Extensive review of the world‐wide scientific literature and of scientific peer‐reviewed journals regarding magnet therapy. Conclusions Magnet therapy is gaining popularity; however, the scientific evidence to support the success of this therapy is lacking. More scientifically sound studies are needed in order to fully understand the effects that magnets can have on the body and the possible benefits or dangers that could result from their use. Implications for Practice Credibility for advanced practice will be established across disciplines as nurses demonstrate their ability to critically evaluate practices. Alternative therapies are accepted and used by many patients today. While magnet therapy is popular, the scientific evidence to support its use is limited, at best. Advanced practice nurses have more effective treatment modalities in their repertoire and are advised to avoid practices for which efficacy is unsupported.
Peroxovanadium‐mediated protection against murine leishmaniasis: role of the modulation of nitric oxide

The phosphotyrosine phosphatase inhibitor bpV(phen) has the ability to markedly decrease the progression of leishmaniasis in vivo. Here, we have identified the mechanisms that are responsible for this protective effect. We report that two potent peroxovanadium (pV) compounds, bpV(phen) and bpV(pic), control progression of leishmaniasis in a similar manner by modulating NO‐dependent microbicidal action. We observed that their injection can rapidly and transiently induce the expression of inducible NO synthase (iNOS) in livers of mice and enhance circulating nitrate levels. Treatment of mice with bpV(phen) or bpV(pic) completely controlled progression of leishmaniasis in an NO‐dependent manner, since inhibition of iNOS with aminoguanidine completely reversed this pV‐mediated protection. This NO‐dependent pV‐mediated protection was further demonstrated by the incapacity of bpV(phen)‐treated Nramp–/–, iNOS–/– mutant mice to control Leishmania major infection. Using an air pouch model, we showed that bpV(phen) can strongly modulate secretion of L. major‐induced pro‐inflammatory molecules and neutrophil recruitment. In addition, we observed that bpV(phen) per se can strongly induce the expression of Th1 type cytokines over Th2 in spleens of animals. Overall, this study has allowed us to establish the in vivo functional and immunological events involved in pV‐mediated protective mechanism against leishmaniasis and that NO plays a pivotal role in this process.
Organization and dynamics of tryptophan residues in erythroid spectrin: Novel structural features of denatured spectrin revealed by the wavelength‐selective fluorescence approach

We have investigated the organization and dynamics of the functionally important tryptophan residues of erythroid spectrin in native and denatured conditions utilizing the wavelength‐selective fluorescence approach. We observed a red edge excitation shift (REES) of 4 nm for the tryptophans in the case of spectrin in its native state. This indicates that tryptophans in spectrin are localized in a microenvironment of restricted mobility, and that the regions surrounding the spectrin tryptophans offer considerable restriction to the reorientational motion of the water dipoles around the excited state tryptophans. Interestingly, spectrin exhibits a REES of 3 nm even when denatured in 8 M urea. This represents the first report of a denatured protein displaying REES. Observation of REES in the denatured state implies that some of the structural and dynamic features of this microenvironment around the spectrin tryptophans are retained even when the protein is denatured. Fluorescence quenching data of denatured spectrin support this conclusion. In addition, we have deduced the organization and dynamics of the hydrophobic binding site of the polarity‐sensitive fluorescent probe PRODAN that binds erythroid spectrin with high affinity. When bound to spectrin, PRODAN exhibits a REES of 9 nm. Because PRODAN binds to a hydrophobic site in spectrin, such a result would directly imply that this region of spectrin offers considerable restriction to the reorientational motion of the solvent dipoles around the excited state fluorophore. The results of our study could provide vital insight into the role of tryptophans in the stability and folding of spectrin.
Reorganization of the femoral cortex due to age-, sex-, and endoprosthetic-related effects emphasized by osteonal dimensions and remodeling.

Cortical remodeling is of particular importance to femoral strength. However, osteonal morphology and its quantitative changes are still poorly understood. Therefore, osteons as the cortexes basic structural units should serve for histomorphometrical assessment of reorganization mechanisms. Total hip replacement (THR) cases as well as relevant controls were investigated to gain insight into changes within stress shielded as well as age- and sex-associated bone with emphasis on the underlying osseous cell interactions. Control (n = 23) and THR (lifetime Ø14 months, n = 8) femora were prepared to grinding specimen. Osteon density (On.Dn.), osteon area (On.Ar.), haversian canal area (H.Ar.), osteon mean wall thickness (MWT), and cortical porosity (Ct.Po.) were evaluated periosteal and endosteal. Osteonal activity (OA) was determined by mineralization differentiation of active and quiescent osteons. Sex- and age-related differences in osteonal remodeling were evident in controls. Females showed age-dependent increases of H.Ar. during concomitant changes of On.Ar. and MWT resulting in elevated Ct.Po. at the entire cortex. Males showed this occurrence only periosteal. Increased OA and therefore higher remodeling rates were found in females above 70 years. THR led to decreased On.Dn. at the entire cortex. Periosteal increased OA represented increased periprosthetic remodeling resulting in elevated H.Ar. , which enhanced Ct.Po. Massive losses of endosteal circular osteonal structures following THR are reflected in a spongy reorganized cortex leading to increased Ct.Po. Imbalances in osteoblast-osteoclast interactions whose intensity is related to the respective cortex regions occur in both stress shielded and aging bone and may thus contribute to implant failure and fracture risk.
Comparison of cost-effectiveness and utility of exercise ECG, single photon emission computed tomography, positron emission tomography, and coronary angiography for diagnosis of coronary artery disease.

BACKGROUND To compare cost-effectiveness and utility of four clinical algorithms to diagnose obstructive coronary atherosclerotic heart disease (CAD), we compared exercise ECG (ExECG), stress single photon emission computed tomography (SPECT), positron emission tomography (PET), and coronary angiography. METHODS AND RESULTS Published data and a straightforward mathematical model based on Bayes' theorem were used to compare strategies. Effectiveness was defined as the number of patients with diagnosed CAD, and utility was defined as the clinical outcome, ie, the number of quality-adjusted life years (QALY) extended by therapy after the diagnosis of CAD. Our model used published values for costs, accuracy, and complication rates of tests. Analysis of the model indicates the following results. (1) The direct cost (fee) for each test differs considerably from total cost per delta QALY. (2) As pretest likelihood of CAD (pCAD) in the population increases, there is a linear increase in cost per patient tested but a hyperbolic decrease in cost per effect and cost per utility unit, ie, increased cost-effectiveness and decreased cost per utility unit. (3) At pCAD < 0.70, analysis of the model indicates that stress PET is the most cost-effective test, with the lowest cost per utility, followed by SPECT, ExECG, and angiography, in that order. (4) Above a threshold value of pCAD of 0.70 (for example, middle-aged men with typical angina), proceeding directly to angiography as the first test showed the lowest cost per effect or utility. This quantitative model has the advantage of estimating a threshold value of pCAD (0.70) at which the rank order of cost-effectiveness and cost per utility unit change. The model also allows substitution of different values for any variable as a way to account for the uncertainties of clinical data, ie, changing costs, test accuracy and risk, etc. This procedure, called sensitivity analysis, showed that the rank order of cost-effectiveness did not change despite changes in several variables. CONCLUSIONS (1) Estimation of total costs of diagnostic tests for CAD requires consideration not only of the direct cost of the test per se (eg, test fees) but also of the indirect and induced costs of management algorithms based on the test (eg, cost/delta QALY). (2) It is essential to consider the clinical history (pCAD) when selecting the clinical algorithm to make a diagnosis with the lowest cost per effect or cost per utility unit. (3) Stress PET shows the lowest cost per effect or cost per utility unit in patients with pCAD < 0.70. (4) Angiography shows the lowest cost per effect or cost per utility unit in patients with pCAD > 0.70.
Asset Integration, Risk Taking and Loss Aversion in the Laboratory

We report on a laboratory experiment testing for the presence of loss aversion, as separate from risk aversion, utilizing an asset integration protocol designed to ensure that a loss of cash provided by the experimenter is viewed as a real loss by experimental participants. Our experimental design augments the Holt-Laury risk preference elicitation methodology to assess how individuals choose between a safe option and a riskier lottery. When the money at stake is viewed as the individualâ€™s own money, one of the lottery outcomes is in the domain of losses. Our results confirm that individuals display an additional reluctance to participate in a mixed domain lottery beyond that predicted by risk aversion. We show that only preference functions incorporating loss aversion are able to generate predicted behaviour that matches our results.
Phosphorylation and Desensitization of Human Endothelin A and B Receptors

Although endothelin-1 can elicit prolonged physiologic responses, accumulating evidence suggests that rapid desensitization affects the primary G protein-coupled receptors mediating these responses, the endothelin A and B receptors (ETA-R and ETB-R). The mechanisms by which this desensitization proceeds remain obscure, however. Because some intracellular domain sequences of the ETA-R and ETB-R differ substantially, we tested the possibility that these receptor subtypes might be differentially regulated by G protein-coupled receptor kinases (GRKs). Homologous, or receptor-specific, desensitization occurred within 4 min both in the ETA-R-expressing A10 cells and in 293 cells transfected with either the human ETA-R or ETB-R. In 293 cells, this desensitization corresponded temporally with agonist-induced phosphorylation of each receptor, assessed by receptor immunoprecipitation from 32Pi-labeled cells. Agonist-induced receptor phosphorylation was not substantially affected by PKC inhibition but was reduced 40% (p < 0.03) by GRK inhibition, effected by a dominant negative GRK2 mutant. Inhibition of agonist-induced phosphorylation abrogated agonist-induced ETA-R desensitization. Overexpression of GRK2, -5, or -6 in 293 cells augmented agonist-induced ET-R phosphorylation ∼2-fold (p < 0.02), but each kinase reduced receptor-promoted phosphoinositide hydrolysis differently. While GRK5 inhibited ET-R signaling by only ∼25%, GRK2 inhibited ET-R signaling by 80% (p < 0.01). Congruent with its superior efficacy in suppressing ET-R signaling, GRK2, but not GRK5, co-immunoprecipitated with the ET-Rs in an agonist-dependent manner. We conclude that both the ETA-R and ETB-R can be regulated indistinguishably by GRK-initiated desensitization. We propose that because of its affinity for ET-Rs demonstrated by co-immunoprecipitation, GRK2 is the most likely of the GRKs to initiate ET-R desensitization.
Endogenous Testosterone and Mortality in Men: A Systematic Review and Meta-Analysis

Context Low testosterone levels have been associated with outcomes that reduce survival in men. Objective Our objective was to perform a systematic review and meta-analysis of published studies to evaluate the association between endogenous testosterone and mortality. Data sources Data sources included MEDLINE (1966 to December 2010), EMBASE (1988 to December 2010), and reference lists. Study selection Eligible studies were published English-language observational studies of men that reported the association between endogenous testosterone and all-cause or cardiovascular disease (CVD) mortality. A two-stage process was used for study selection. 1) Working independently and in duplicate, reviewers screened a subset (10%) of abstracts. Results indicated 96% agreement, and thereafter, abstract screening was conducted in singlicate. 2) All full-text publications were reviewed independently and in duplicate for eligibility. Data extraction Reviewers working independently and in duplicate determined methodological quality of studies and extracted descriptive, quality, and outcome data. Data synthesis Of 820 studies identified, 21 were included in the systematic review, and 12 were eligible for meta-analysis [n = 11 studies of all-cause mortality (16,184 subjects); n = 7 studies of CVD mortality (11,831 subjects)]. Subject mean age and testosterone level were 61 yr and 487 ng/dl, respectively, and mean follow-up time was 9.7 yr. Between-study heterogeneity was observed among studies of all-cause (P Conclusion Low endogenous testosterone levels are associated with increased risk of all-cause and CVD death in community-based studies of men, but considerable between-study heterogeneity, which was related to study and subject characteristics, suggests that effects are driven by differences between cohorts (e.g. in underlying health status).
The tale of the tail: limb function and locomotor mechanics in Alligator mississippiensis

SUMMARY Crocodilians tow their large muscular tail behind them during terrestrial bouts when they high walk (a walking trot). Analysis of ground reaction forces in the American alligator (Alligator mississippiensis) revealed the consequences of tail-dragging. Individual limb and tail ground reaction force records show that the hindlimbs of Alligator take on a substantial role in body mass support consistent with the more caudal location of its center of mass due to the presence of a particularly heavy tail (representing nearly 28% of total body mass). Furthermore, because the constant drag imposed by the tail is substantial, both fore- and hindlimbs in Alligator have a heightened propulsive role as a means of countering the net braking effect of the tail. Ground reaction forces of the whole body were used to assess how well Alligator was able to utilize mechanical energy-saving mechanisms (inverse pendulum or mass-spring). A high-walking Alligator recovers, on average, about 20% of its mechanical energy by inverse pendulum mechanics. These modest energy recovery levels are likely to be due to a combination of factors that may include low locomotor speed, imprecise coordination of contralateral limbs in the trot, frequent dragging of feet of protracting limbs during swing phase and, possibly, tail dragging.
The Role of the Invariant His-1069 in Folding and Function of the Wilson's Disease Protein, the Human Copper-transporting ATPase ATP7B*

The copper-transporting ATPase ATP7B is essential for normal distribution of copper in human cells. Mutations inATP7B lead to Wilson's disease, a severe disorder with neurological and hepatic manifestations. One of the most common disease mutations, a H1069Q substitution, causes intracellular mislocalization of ATP7B (the Wilson's disease protein, WNDP). His-1069 is located in the nucleotide-binding domain of WNDP and is conserved in all copper-transporting ATPases from bacteria to mammals; however, the specific role of this His in the structure and function of WNDP remains unclear. We demonstrate that substitution of His-1069 for Gln, Ala, or Cys does not significantly alter the folding of the WNDP nucleotide-binding domain or the proteolytic resistance of the full-length WNDP. In contrast, the function of WNDP is markedly affected by the mutations. The ability to form an acylphosphate intermediate in the presence of ATP is entirely lost in all three mutants, suggesting that His-1069 is important for ATP-dependent phosphorylation. Other steps of the WNDP enzymatic cycle are less dependent on His-1069. The H1069C mutant shows normal phosphorylation in the presence of inorganic phosphate; it binds an ATP analogue, β,γ-imidoadenosine 5′-triphosphate (AMP-PNP), and copper and undergoes nucleotide-dependent conformational transitions similar to those of the wild-type WNDP. Although binding of AMP-PNP is not disrupted by the mutation, the apparent affinity for the nucleotide is decreased by 4-fold. We conclude that His-1069 is responsible for proper orientation of ATP in the catalytic site of WNDP prior to ATP hydrolysis.
Permittivity and Conductivity Measured Using a Novel Toroidal Split-Ring Resonator

We describe and demonstrate the use of a novel toroidal split-ring resonator to make accurate and precise measurements of the permittivity of liquids and gases. We first analytically show how the resonance frequency and quality factor of the resonator are related to the complex permittivity of the material filling its gap. We then use the resonator to experimentally determine the permittivity of a number of different materials. First, the compact and high- ${Q}$ resonator is used to measure both the real and imaginary parts of the complex permittivity of methyl alcohol at 185 MHz. Second, the resonator was placed inside a vacuum-tight Dewar. We measured the resonance frequency with the resonator suspended in vacuum and then immersed in an atmosphere of air. From these data, the dielectric constant of air was accurately determined. Next, the resonator was submerged in liquid nitrogen, and the boiling temperature of the nitrogen bath was manipulated by regulating its vapor pressure. This system allowed for a precise measurement of the dielectric constant of liquid nitrogen over a temperature range of 64 to 77 K. Finally, we monitored the quality factor of the copper resonator as its temperature drifted from 80 K to room temperature. From these data, we extracted the linear temperature dependence of copper’s resistivity.
Getting out of the starting gate on the right foot: employment effects of investment in human capital

The technological progress and the globalisation process reshape the nature of jobs inducing a substantial drop in the incidence of permanent employment occupations. This paper estimates whether employers could be less reluctant to hire workers on a permanent basis in presence of a human capital investment, which they partly finance. We find that the permanent employment rate of cohorts affected by law no. 92/2012 at the age threshold of 30 years increased by about 1% when compared to the permanent employment rate of similar untreated cohorts. This difference in discontinuity impact can be generated by the vocational apprenticeship labour contract only. After 36 months from the baseline, this positive effect persists and increases to about 5%. We interpret our results as evidence that a labour contract that invests in human capital serves as a stepping stone into permanent employment.