Miracle-dz/UniFAR-FTUs huggingface dataset:
Decreases in anti-double-stranded DNA levels are associated with concurrent flares in patients with systemic lupus erythematosus.

OBJECTIVE To determine the degree to which changes in anti-double-stranded DNA (anti-dsDNA), as determined by Crithidia and enzyme-linked immunosorbent assays (ELISAs), precede or coincide with changes in systemic lupus erythematosus (SLE) activity, as measured by 5 clinical indices, the physician's global assessment (PGA), modified SLE Disease Activity Index (M-SLEDAI), modified Lupus Activity Index (M-LAI), Systemic Lupus Activity Measure (SLAM), and the modified British Isles Lupus Assessment Group (M-BILAG). METHODS Disease activity and anti-dsDNA were measured monthly in 53 SLE patients who were followed up for 1 year. Lupus flare was defined as an increase in PGA of > or = 1.0, M-SLEDAI > or = 3, M-LAI > or = 0.1, SLAM > or = 3, and M-BILAG > or = 4 within a 1-month period. Flare rates were calculated for groups, which were defined by "previous" (1 month prior to the flare) or "concurrent" (at the time of the flare) changes in anti-dsDNA. Logistic regression models were used to determine the significance of the association between recent changes in anti-dsDNA and flare, controlling for the prednisone dosage. RESULTS Flares occurred at 12% of visits, based on the PGA measure of disease activity. Using the other indices, flare rates were 19% (M-SLEDAI), 25% (M-LAI), 13% (SLAM), and 12% (M-BILAG). A concurrent decrease in anti-dsDNA (ELISA) was associated with significantly higher flare rates based on PGA (18 of 84, 21%; P = 0.0014), M-SLEDAI (27 of 89, 30%; P = 0.0019), M-LAI (37 of 89, 42%; P = 0.0001), and M-BILAG (19 of 89, 21%; P = 0.0264) scores. Flare rates were also significantly higher after a previous increase in anti-dsDNA (ELISA) based on M-SLEDAI (26 of 93, 30%; P = 0.0022) and M-LAI (34 of 93, 37%; P = 0.0117) scores. Flare rates tended to be lowest when there was a concurrent increase in anti-dsDNA (ELISA). Analysis of specific organ systems showed that a concurrent decrease in anti-dsDNA (ELISA) was significantly associated with increases in renal disease activity. Similar results were obtained using the Crithidia assay. CONCLUSION A previous increase in anti-dsDNA levels occurred before SLE flares, as measured by the M-SLEDAI and M-LAI only. However, during lupus flares, including the subset of renal flares, anti-dsDNA levels frequently decreased. We hypothesize that this decrease in anti-dsDNA represents deposition in tissue at the time of flare.
The adequacy of morphology for reconstructing the early history of placental mammals.

Systematic Biology Publication details, including instructions for authors and subscription information: http://www.informaworld. com/smpp/title~content=t713658732 The Adequacy of Morphology for Reconstructing the Early History of Placental Mammals Mark S. Springer a; Angela Burk-Herrick a; Robert Meredith a; Eduardo Eizirik b; Emma Teeling c; Stephen J. O'Brien d; William J. Murphy e a Department of Biology, University of California, Riverside, Riverside, CA, USA b Faculdade de Biociencias, PUCRS, Porto Allegre, RS, Brazil c School of Biological and Environmental Sciences, University College Dublin Belfield, Dublin, Ireland d Laboratory of Genomic Diversity, National Cancer Institute-Frederick, Frederick, MD, USA e Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA
GIAO/DFT evaluation of 13C NMR chemical shifts of selected acetals based on DFT optimized geometries

DFT/B3LYP calculations of the ground‐state conformation of eight cyclic and acyclic acetals are presented and compared with experimental data. Results of single‐point GIAO/DFT calculations at five different levels of theory show that isotropic shieldings need to be empirically scaled to achieve agreement with experimental chemical shifts. Statistical evaluation of data indicates that the most accurate prediction of 13C chemical shifts is achieved at the MPW1PW91/6–311G** level of theory. An empirical equation describing the relationship between δ values and shielding constants is postulated. This equation has been applied to the non‐chair ground‐state conformation of the six‐membered acetonide and to the conformationally flexible benzodioxonine derivative. The agreement observed between the experimental and predicted chemical shifts shows that calculations at the MPW1PW91/6–311G** level of theory are adequate for addressing questions of conformation. Copyright © 2004 John Wiley & Sons, Ltd.
Plasmid electrotransfer of eye ciliary muscle: principles and therapeutic efficacy using hTNF‐α soluble receptor in uveitis

Due to its small size and particular isolating barriers, the eye is an ideal target for local therapy. Recombinant protein ocular delivery requires invasive and painful repeated injections. Alternatively, a transfected tissue might be used as a local producer of transgene‐encoded therapeutic protein. We have developed a nondamaging electrically mediated plasmid delivery technique (electrotransfer) targeted to the ciliary muscle, which is used as a reservoir tissue for the long‐lasting expression and secretion of therapeutic proteins. High and long‐lasting reporter gene expression was observed, which was restricted to the ciliary muscle. Chimeric TNF‐α soluble receptor (hTNFR‐Is) electrotransfer led to elevated protein secretion in aqueous humor and to drastic inhibition of clinical and histological inflammation scores in rats with endotoxininduced uveitis. No hTNFR‐Is was detected in the serum, demonstrating the local delivery of proteins using this method. Plasmid electrotransfer to the ciliary muscle, as performed in this study, did not induce any ocular pathology or structural damage. Local and sustained therapeutic protein production through ciliary muscle electrotransfer is a promising alternative to repeated intraocular protein administration for a large number of inflammatory, degenerative, or angiogenic diseases.
Do Parents Understand Immunizations? A National Telephone Survey

Background. Immunization may now be undervalued because vaccines have largely eliminated the threat of serious infectious diseases in childhood. As the incidence of vaccine-preventable diseases has declined, concern about vaccine safety has increased. Significant erosion of public confidence in vaccine safety could lead to reduced immunization rates and a resurgence of vaccine-preventable diseases. Objective and Methods. To assess parents' understanding of vaccine-preventable diseases, vaccines, immunization practices, and policies, we conducted a telephone survey in the United States with a nationally representative sample (n = 1600) of parents with children ≤6 years of age, and expectant parents in April and May 1999. Results. Eighty-seven percent of respondents deemed immunization an extremely important action that parents can take to keep their children well. Although respondents' overall rating of immunization safety was high, a substantial minority held important misconceptions. For example, 25% believed that their child's immune system could become weakened as a result of too many immunizations, and 23% believed that children get more immunizations than are good for them. Children's health care providers were cited as the most important source of information on immunizations. Conclusions. Although the majority of parents understand the benefits of immunization and support its use, many parents have important misconceptions that could erode their confidence in vaccines. A systematic educational effort addressing common misconceptions is needed to ensure informed immunization decision-making. Physicians, nurses, and other providers of primary care have a unique opportunity to educate parents because parents see them as the most important source of information about immunizations. vaccination, immunization, pediatric, safety, health beliefs.
Rasmussen's encephalitis: a role for autoimmune cytotoxic T lymphocytes

The present review describes advances in Rasmussen's encephalitis (also known as Rasmussen's syndrome), an unihemispheric intractable epileptic disease with persistent inflammation. Specific attention is given to the recent recognition of cytotoxicity by CD8+/granzyme-B-positive T lymphocytes as a new pathogenic mechanism of neuronal damage.
What Does it Cost to Make a Payment?

We survey the limited data that exists concerning the cost of making/receiving a payment by banks, retailers, and other parties to a transaction. Since an electronic payment costs between one-third and onehalf that of a paper-based instrument, a country may save 1% of its GDP annually as it shifts from a fully paper-based to a fully electronic-based payment system. Some gains have already been realized. Additional analysis indicates that bank costs of making a payment may have fallen by 45% in Europe as the share of electronic transactions in 12 countries rose from . 43 to . 79 over 1987-1999.
Posterior Cramér-Rao bounds for discrete-time nonlinear filtering with finitely correlated noises

In this paper, a recursive formula of the mean-square error lower bound for the discrete-time nonlinear filtering problem when noises of dynamic systems are temporally correlated is derived based on the Van Trees (posterior) version of the Cramér-Rao inequality. The approximation formula is unified in the sense that it can be applicable to the multi-step correlated process noise, multi-step correlated measurement noise and multi-step cross-correlated process and measurement noise simultaneously. The lower bound is evaluated by two typical target tracking examples respectively. Both of them show that the new lower bound is significantly different from that of the method which ignores correlation of noises. Thus, when they are applied to sensor selection problems, number of selected sensors becomes very different to obtain a desired estimation performance.
Conceptualizing agriculture: a critique of post-productivism as the new orthodoxy

It has become fashionable to conceptualize recent shifts in agrarian priorities as a ‘postproductivist’ transition from a previously ‘productivist’ agriculture. This notion became more popular throughout the 1990s as a way to capture in one convenient package the complex changes experienced by both the agricultural sector specifically and within rural areas more generally. However, the widespread and uncritical use of such an all-encompassing term is rather surprising given debates elsewhere in human geography on the rejection of dualistic thinking. Yet, in agricultural and rural studies, the active creation and reinforcement of a productivist/post-productivist dualism has emerged as a means of explaining the uneven development of rural areas. This paper develops a critique of post-productivism to demonstrate its invalidity, presenting empirical evidence to refute five supposed characteristics relating to quality food, pluriactivity, sustainability, production dispersion and regulation. It is argued that future progress in agricultural research will only be made if post-productivism is abandoned. Effort should be refocused upon understanding deeper processes underpinning agricultural change using existing theoretical perspectives developed in human geography but which lack application in the agricultural context. Ecological modernization is provided as a brief exemplar of how such progress may be achieved.
Further characterization, by a combined high-performance liquid chromatography/1H-NMR approach, of the heterogeneity displayed by the neutral carbohydrate chains of human bronchial mucins.

From bronchial mucins of cystic fibrosis patients with blood group O, the carbohydrate chains were released in the form of oligosaccharide-alditols by alkaline borohydride treatment. Application of high-performance liquid chromatography directly on the pool of neutral oligosaccharides afforded 23 fractions. Twenty oligosaccharide structures were characterized by employing 500-MHz 1H-NMR spectroscopy in conjunction with sugar analysis. Thirteen among these had been revealed before to occur in human bronchial mucins [Van Halbeek, H. , Dorland, L. , Vliegenthart, J. F. G. , Hull, W. E. , Lamblin, G. , Lhermitte, M. , Boersma, A. , and Roussel, P. (1982) Eur. J. Biochem. 127, 7-20], when paper-chromatographic fractionation of this pool of neutral oligosaccharides was employed. High-performance liquid chromatography enabled to obtain another seven pentasaccharide and hexasaccharide alditols; the largest-size representatives are: (Formula see text). Thereby, this approach afforded deeper insight into the structural heterogeneity displayed by the carbohydrate chains of bronchial mucins.
Phosphoinositide 3-OH Kinase (PI3K) and PKB/Akt Delay the Onset of p53-mediated, Transcriptionally Dependent Apoptosis*

The phosphoinositide 3-OH kinase (PI3K)-PKB/Akt signaling pathway has been shown to mediate both Ras- and cytokine-induced protection from apoptosis. In addition, apoptosis induced by the p53 tumor suppressor protein can be inhibited by Ras- and cytokine-mediated signaling pathways. It was therefore of interest to determine if the PI3K-PKB/Akt signaling pathway was capable of conferring protection from apoptosis induced by p53. We demonstrate in this report that constitutively active PI3K and PKB/Akt are capable of significantly delaying the onset of p53-mediated apoptosis. This was manifested as a delay in the kinetics of DNA degradation and cell death as well as a profound attenuation in the accumulation of cells with a sub-G1 DNA content. Moreover, we found that this effect is mediated in the absence of changes in expression of Bcl-2, Bcl-Xl, and the pro-apoptotic protein Bax. Our results provide the first direct and unambiguous link between p53-mediated apoptosis and the PI3K-PKB/Akt signaling pathway.
IL‐12 is involved in the induction of experimental autoimmune myasthenia gravis, an antibody‐ mediated disease

IL‐12 has been shown to be involved in the pathogenesis of Th1‐mediated autoimmune diseases, but its role in antibody‐mediated autoimmune pathologies is still unclear. We investigated the effects of exogenous and endogenous IL‐12 in experimental autoimmune myasthenia gravis (EAMG). EAMG is an animal model for myasthenia gravis, a T cell‐dependent, autoantibody‐mediated disorder of neuromuscular transmission caused by antibodies to the muscle nicotinic acetylcholine receptor (AChR). Administration of IL‐12 with Torpedo AChR (ToAChR) to C57BL/6 (B6) mice resulted in increased ToAChR‐specific IFN‐γ production and increased anti‐ToAChR IgG2a serum antibodies compared with B6 mice primed with ToAChR alone. These changes were associated with earlier and greater neurophysiological evidence of EAMG in the IL‐12‐treated mice, and reduced numbers of AChR. By contrast, when IL‐12‐deficient mice were immunized with ToAChR, ToAChR‐specific Th1 cells and anti‐ToAChR IgG2a serum antibodies were reduced compared to ToAChR‐primed normal B6 mice, and the IL‐12‐deficient mice showed almost no neurophysiological evidence of EAMG and less reduction in AChR. These results indicate an important role of IL‐12 in the induction of an antibody‐mediated autoimmune disease, suggest that Th1‐dependent complement‐fixing IgG2a anti‐AChR antibodies are involved in the pathogenesis of EAMG, and help to account for the lack of correlation between anti‐AChR levels and clinical disease seen in many earlier studies.
Simulating sequential multiple assignment randomized trials to generate optimal personalized warfarin dosing strategies

Background Due to the cost and complexity of conducting a sequential multiple assignment randomized trial (SMART), it is desirable to pre-define a small number of personalized regimes to study. Purpose We proposed a simulation-based approach to studying personalized dosing strategies in contexts for which a therapeutic agent’s pharmacokinetic and pharmacodynamics properties are well understood. We take dosing of warfarin as a case study, as its properties are well understood. We consider a SMART in which there are five intervention points in which dosing may be modified, following a loading phase of treatment. Methods Realistic SMARTs are simulated, and two methods of analysis, G-estimation and Q-learning, are used to assess potential personalized dosing strategies. Results In settings where outcome modelling may be complex due to the highly non-linear nature of the pharmacokinetic and pharmacodynamics mechanisms of the therapeutic agent, G-estimation provides for which the more promising method of estimating an optimal dosing strategy. Used in combination with the simulated SMARTs, we were able to improve simulated patient outcomes and suggest which patient characteristics were needed to best individually tailor dosing. In particular, our simulations suggest that current dosing should be determined by an individual’s current coagulation time as measured by the international normalized ratio (INR), their last measured INR, and their last dose. Tailoring treatment only based on current INR and last warfarin dose provided inferior control of INR over the course of the trial. Limitations The ability of the simulated SMARTs to suggest optimal personalized dosing strategies relies on the pharmacokinetic and pharmacodynamic models used to generate the hypothetical patient profiles. This approach is best suited to therapeutic agents whose effects are well studied. Conclusion Prior to investing in a complex randomized trial that involves sequential treatment allocations, simulations should be used where possible in order to guide which dosing strategies to evaluate.
DESIGNED EXTENSION OF SURVIVAL STUDIES: APPLICATION TO CLINICAL TRIALS WITH UNRECOGNIZED HETEROGENEITY

It is well known that unrecognized heterogeneity among patients, such as is conferred by genetic subtype, can undermine the power of a randomized trial, de- signed under the assumption of homogeneity, to detect a truly beneficial treatment. We consider the conditional power approach to allow for recovery of power under unexplained heterogeneity. While Proschan and Hunsberger (1995) confined the application of conditional power design to normally distributed observations, we consider more general and difficult settings in which the dataare in the framework of continuous time and are subject to censoring. In particular, we derive a procedure appropriate for the analysis of the weighted log rank test under the assumption of a proportional hazards frailty model. The proposed method is illustrated through application to a brain tumor trial.
Clostridial neurotoxins compromise the stability of a low energy SNARE complex mediating NSF activation of synaptic vesicle fusion.

A 20S complex composed of the cytosolic fusion proteins NSF and SNAP and the synaptosomal SNAP receptors (SNAREs) synaptobrevin, syntaxin and SNAP‐25 is essential for synaptic vesicle exocytosis. Formation of this complex is thought to be regulated by synaptotagmin, the putative calcium sensor of neurotransmitter release. Here we have examined how different inhibitors of neurotransmitter release, e.g. clostridial neurotoxins and a synaptotagmin peptide, affect the properties of the 20S complex. Cleavage of synaptobrevin and SNAP‐25 by the neurotoxic clostridial proteases tetanus toxin and botulinum toxin A had no effect on assembly and disassembly of the 20S complex; however, the stability of its SDS‐resistant SNARE core was compromised. This SDS‐resistant low energy conformation of the SNAREs constitutes the physiological target of NSF, as indicated by its ATP‐dependent disassembly in the presence of SNAP and NSF. Synaptotagmin peptides caused inhibition of in vitro binding of this protein to the SNAREs, a result that is inconsistent with synaptotagmin's proposed role as a regulator of SNAP binding. Our data can be reconciled by the idea that NSF and SNAP generate synaptotagmin‐containing intermediates in synaptic vesicle fusion, which catalyse neurotransmitter release.
Fatty Liver in Liver Transplantation and Surgery

Steatosis of the liver is common in Western countries, affecting about 25% of donors for liver transplantation and 20% of patients undergoing liver resection. Transplantation of livers with severe steatosis (> 60%) is associated with a high risk of primary nonfunction, and these livers should not be used for organ donation. In contrast, transplantation with livers containing mild steatosis (< 30%) yields results similar to those of transplantation performed with nonfatty livers. The outcome of livers with moderate steatosis (30 to 60%) are varying, and the use of these organs depends on the existence of additional risk factors. Similarly, liver resection in patients with steatosis is associated with a risk of postoperative mortality when compared with patients with nonfatty livers (14% versus 2%). Although hepatic steatosis is an important risk factor for surgery, little is known about the mechanisms of injury. In animal experiments, steatosis is associated with decreased ATP production and a disturbance of sinusoidal flow. Further contributing factors may include Kupffer cell dysfunction and leukocyte adhesion. Fatty hepatocytes have reduced tolerance against ischemic injury with a predominant necrotic form of cell death. In addition, the ability of hepatocytes to regenerate after major tissue loss is impaired in the steatotic liver. Very few protective strategies are known. Ischemic preconditioning and intermittent clamping protect the human liver against prolonged periods of ischemia. These techniques appear to be particularly protective in the steatotic liver. New insights into the mechanisms of liver failure in steatotic organs are needed to decrease the risk of surgery and increase the pool of organ donors.
Development of a Novel Reference Plane for the Heidelberg Retina Tomograph with Optical Coherence Tomography Measurements

PurposeTo develop an ideal reference plane for the Heidelberg Retina Tomograph (HRT) with the assistance of optical coherence tomography (OCT) measurements of the mean retinal nerve fiber layer (RNFL) thickness. Patients and MethodsThe mean RNFL thickness was measured with OCT in eyes with early glaucoma (n = 50) and age-matched normal eyes (n = 40) at a circle as close as possible to the disc margin without touching it. Glaucomatous eyes were enrolled from chronic open-angle glaucoma patients with reproducible glaucomatous visual field defects with standard automated perimetry. One eye of each patient was randomly selected. A new reference plane was defined as located posteriorly from the mean height of the contour line by the amount of mean RNFL thickness measured with the OCT. Receiver-operating characteristic (ROC) curves were generated to compare the ability of parameters obtained with the conventional and the new reference plane to differentiate glaucomatous eyes from normal eyes. The same analysis was performed for early glaucomatous eyes with myopic refractive errors (n = 25). ResultsThe areas under the ROC curves (AUCs) were greater for rim area, rim area/disc area, and rim volume with the new reference plane compared with those with the conventional reference plane, but they were not significantly different. When the same analysis was performed for myopic glaucomatous eyes, the AUCs for rim area, rim area/disc area, and rim volume with the new reference plane were greater than those with the conventional reference plane (P = 0.002, 0.010, and 0.034, respectively). ConclusionA novel reference plane for the HRT defined by OCT measurements may improve the ability of the HRT to detect early glaucoma, especially in eyes with tilted discs.