Miracle-dz/UniFAR-FTUs huggingface dataset:
Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus.

OBJECTIVE Peripheral blood lymphocytes (PBLs) from systemic lupus erythematosus (SLE) patients exhibit increased spontaneous and diminished activation-induced apoptosis. We tested the hypothesis that key biochemical checkpoints, the mitochondrial transmembrane potential (deltapsim) and production of reactive oxygen intermediates (ROIs), mediate the imbalance of apoptosis in SLE. METHODS We assessed the deltapsim with potentiometric dyes, measured ROI production with oxidation-sensitive fluorochromes, and monitored cell death by annexin V and propidium iodide staining of lymphocytes, using flow cytometry. Intracellular glutathione levels were measured by high-performance liquid chromatography, while ATP and ADP levels were assessed by the luciferin-luciferase assay. RESULTS Both deltapsim and ROI production were elevated in the 25 SLE patients compared with the 25 healthy subjects and the 10 rheumatoid arthritis patients. Intracellular glutathione contents were diminished, suggesting increased utilization of reducing equivalents in SLE. H2O2, a precursor of ROIs, increased deltapsim and caused apoptosis in normal PBLs. In contrast, H2O2-induced apoptosis and deltapsim elevation were diminished, particularly in T cells, and the rate of necrotic cell death was increased in patients with SLE. The intracellular ATP content and the ATP:ADP ratio were reduced and correlated with the deltapsim elevation in lupus. CD3:CD28 costimulation led to transient elevation of the deltapsim, followed by ATP depletion, and sensitization of normal PBLs to H2O2-induced necrosis. Depletion of ATP by oligomycin, an inhibitor of F0F1-ATPase, had similar effects. CONCLUSION T cell activation and apoptosis are mediated by deltapsim elevation and increased ROI production. Mitochondrial hyperpolarization and the resultant ATP depletion sensitize T cells for necrosis, which may significantly contribute to inflammation in patients with SLE.
Abnormal splicing of ABCA1 pre-mRNA in Tangier disease due to a IVS2 +5G>C mutation in ABCA1 gene Published, JLR Papers in Press, November 4, 2002. DOI 10.1194/jlr.M200248-JLR200

Two point mutations of ABCA1 gene were found in a patient with Tangier disease (TD): i) G>C in intron 2 (IVS2 +5G>C) and ii) c.844 C>T in exon 9 (R282X). The IVS2 +5G>C mutation was also found in the brother of another deceased TD patient, but not in 78 controls and 33 subjects with low HDL. The IVS2 +5G>C mutation disrupts ABCA1 pre-mRNA splicing in fibroblasts, leading to three abnormal mRNAs: devoid of exon 2 (Ex2−/mRNA), exon 4 (Ex4−/mRNA), or both these exons (Ex2−/Ex4−/mRNA), each containing a translation initiation site. These mRNAs are expected either not to be translated or generate short peptides. To investigate the in vitro effect of IVS2 +5G>C mutation, we constructed two ABCA1 minigenes encompassing Ex1–Ex3 region, one with wild-type (WTgene) and the other with mutant (MTgene) intron 2. These minigenes were transfected into COS1 and NIH3T3, two cell lines with a different ABCA1 gene expression. In COS1 cells, WTgene pre-mRNA was spliced correctly, while the splicing of MTgene pre-mRNA resulted in Ex2−/mRNA. In NIH3T3, no splicing of MTgene pre-mRNA was observed, whereas WTgene pre-mRNA was spliced correctly. These results stress the complexity of ABCA1 pre-mRNA splicing in the presence of splice site mutations.
HEPATITIS C VIRUS GENOTYPES IN CORDOBA , ARGENTINA UNEXPECTED HIGH PREVALENCE OF GENOTYPE

To determine hepatitis C virus (HCV) genotypes circulating in the central region of Argentina, 96 consecutive anti-HCV positive subjects were studied. The presence of HCV RNA was detected in 60 samples by RT-nested PCR of the 5’ noncoding region (5’ NCR). Genotyping was performed by restriction fragment length polymorphism analysis of 5’ NCR region combined with PCR using type-specific primers of the core region. The groups of individuals in this study included hemophilia and hemodialysis patients, injecting drug users, screened blood donors, and patients with acute or chronic liver disease, all from Córdoba, Argentina. Overall, genotype 2 was the most prevalent (55.0%), followed by genotypes 1 (38.3 %), and 3 (5.0%). Within genotype 1, subtype 1b was the most prevalent. An unexpected high prevalence of genotype 2 (61.9%) was found among patients with acute or chronic HCV infection (without known risk factors). These figures differ from other cohorts from East-Argentina where genotype 1 has been found as the most prevalent. This indicates that regional differences of genotype distribution might exist between Central and East Argentina.
Enhanced expression of the Flt‐1 and Flk‐1 receptor tyrosine kinases in a newborn piglet model of ischemic tolerance

Vascular endothelial growth factor (VEGF), an angiogenic factor induced by hypoxia, also exerts direct effects on neural tissues. VEGF up‐regulation after hypoxia coincides with expression of its two tyrosine kinase receptors Flt‐1(VEGFR‐1) and Flk‐1 (KDR/VEGFR‐2), which are the key mediators of physiological angiogenesis. We have recently shown that hypoxic‐preconditioning (PC) leading to tolerance to hypoxia–ischemia in neonatal piglet brain resulted in increased expression of VEGF. In this study, we used a hypoxic‐preconditioning model of ischemic tolerance to analyze the expression and cellular distribution of VEGF receptors and phosphorylation of cAMP‐response element‐binding protein (CREB) in newborn piglet brain. The response of Flt‐1 and Flk‐1 mRNA to PC alone was biphasic with peaks early (6 h) and late (1 week) after PC. The mRNA expression of Flt‐1 and Flk‐1 in piglets preconditioned 24 h prior to hypoxia–ischemia was significantly higher than non‐preconditioned piglets and remained up‐regulated up to 7 days. Furthermore, PC prior to hypoxia–ischemia significantly increased the protein levels of Flt‐1 and Flk‐1 compared with hypoxia–ischemia in a time‐dependent manner. Double‐immunolabeling indicated that both Flt‐1 and Flk‐1 are expressed in neurons and endothelial cells with a similar time course of expression following PC and that PC leads to the growth of new vessels. Finally, our data demonstrate that PC significantly phosphorylated and activated cAMP‐response element‐binding protein in nucleus. These results suggest that mechanism(s) initiated by PC can induce VEGF receptor up‐regulation in newborn brain and that VEGF–VEGF receptor‐coupled signal transduction pathways could contribute to the establishment of tolerance following hypoxia–ischemia.
Clinical Implications of Expression of ETS-1 Related to Angiogenesis in Metastatic Lesions of Ovarian Cancers

Objective: ETS-1 has been identified as a proto-oncogene and a transcription factor for tumor angiogenesis, which is essential for the growth, invasion and metastasis of solid tumors. The aim is to investigate the clinical implications of ETS-1 expression in peritoneal metastatic lesions of ovarian cancers. Methods: In primary tumors and peritoneal metastatic lesions from 30 patients with stage III ovarian cancers, ETS-1 histoscores and ets-1 mRNA levels were determined by immunohistochemistry and competitive RT-PCR-Southern blot analysis using recombinant RNA, respectively. Results: Immunohistochemical staining revealed that ETS-1 was expressed in the cancer cells and vascular endothelial cells. ETS-1 histoscores in the endothelial cells and ets-1 mRNA levels were significantly (p < 0.05) increased in 20 of 30 peritoneal metastatic lesions of ovarian cancers. There was a significant correlation between microvessel counts (MVCs) and ETS-1 histoscores in the endothelial cells (p < 0.001) and between MVCs and ets-1 mRNA levels in the primary tumor and the peritoneal metastatic lesion of ovarian cancers (p < 0.001). Furthermore, the 24-month survival rate of patients with significantly increased ets-1 mRNA level (2/20, 10%) was significantly (p < 0.01) lower than that of patients with no change in the level (6/10, 60%) from the primary tumor to the peritoneal metastatic lesion. Conclusions: ETS-1 might be associated with peritoneal metastasis dominantly as an angiogenic mediator and additionally as an oncogene product to activate tumor invasion in ovarian cancers.
FoxO3a and BCR-ABL Regulate cyclin D2 Transcription through a STAT5/BCL6-Dependent Mechanism

ABSTRACT Cell cycle arrest by FoxO transcription factors involves transcriptional repression of cyclin D, although the exact mechanism remains unclear. In this study, we used the BCR-ABL-expressing cell line BV173 as a model system to investigate the mechanisms whereby FoxO3a regulates cyclin D2 expression. Inhibition of BCR-ABL by STI571 results in down-regulation of cyclin D2 expression, activation of FoxO3a activity, and up-regulation of BCL6 expression. Using reporter gene assays, we demonstrate that STI571, FoxO3a, and BCL6 can repress cyclin D2 transcription through a STAT5/BCL6 site located within the cyclin D2 promoter. We propose that BCR-ABL inhibition leads to FoxO3a activation, which in turn induces the expression of BCL6, culminating in the repression of cyclin D2 transcription through this STAT5/BCL6 site. This process was verified by mobility shift and chromatin immunoprecipitation analyses. We find that conditional activation of FoxO3a leads to accumulation of BCL6 and down-regulation of cyclin D2 at protein and mRNA levels. Furthermore, silencing of FoxO3a and BCL6 in BCR-ABL-expressing cells abolishes STI571-mediated effects on cyclin D2. This report establishes the signaling events whereby BCR-ABL signals are relayed to cyclin D2 to mediate cell cycle progression and defines a potential mechanism by which FoxO proteins regulate cyclin D2 expression.
Genetic polymorphisms of drug transporters: pharmacokinetic and pharmacodynamic consequences in pharmacotherapy

There has been increasing appreciation of the role of drug transporters in pharmacokinetic and pharmacodynamic consequences in pharmacotherapy. The clinical relevance of drug transporters depends on the localisation in human tissues (i.e., vectorial movement), the therapeutic index of the substrates and inherent interindividual variability. With regard to variability, polymorphisms of drug transporter genes have recently been reported to be associated with alterations in the pharmacokinetics and pharmacodynamics of clinically useful drugs. A growing number of preclinical and clinical studies have demonstrated that the application of genetic information may be useful in individualised pharmacotherapy for numerous diseases. However, the reported effects of variants in certain drug transporter genes have been inconsistent and, in some cases, conflicting among studies. Furthermore, the incidence of almost all known variants in transporter genes tends to be racially dependent. These observations suggest the necessity of considering interethnic variability before extrapolating pharmacokinetic data obtained in one ethic group to another, especially in the early phase of drug development. This review focuses on the impact of genetic variations in the function of drug transporters (ABC, organic anion and cation transporters) and the implications of these variations for pharmacotherapy from pharmacokinetic and pharmacodynamic viewpoints.
The catabolism of human G immunoglobulins of different heavy chain subclasses. 3. The catabolism of heavy chain disease proteins and of Fc fragments of myeloma proteins.

The catabolism of 131I and 125I paired labelled Fc fragments of myeloma proteins and of H chain disease proteins of different heavy chain subclasses was studied in men and monkeys. In contrast to the previously demonstrated catabolic heterogeneity of intact γG immunoglobulins, the Fc fragments and H chain disease proteins of all subclasses tested were catabolized at a similar rate. These data suggest that structures not present on the Fc fragments are responsible for the faster turnover rate of γG3 immunoglobulins and for the differences in half-lives of myeloma proteins within a given subclass. The catabolic features of the H chain disease proteins differed from those of intact γG. Although the whole body half-lives of the two proteins were similar, the fractional turnover rate of the H chain disease proteins was higher than that of γG, on the average 8% of the intravascular pool/day as compared to 4% for γG. One-half to 1% of the intravascular pool of the H chain disease protein and less than 0·1% of the γG was excreted into the urine. An average of 24% of the H chain disease proteins and 44% of the γG equilibrated into the intravascular compartment.
Comparison of the likelihood ratios of two binary diagnostic tests in paired designs

The performance of two binary diagnostic tests is traditionally compared by their respective sensitivities and specificities. Other measures to describe the performance of a binary diagnostic test are likelihood ratios, defined as the ratio between the likelihood of a diagnostic test result in a group of diseased patients and the likelihood of a diagnostic test result in a group of non‐diseased patients. In this study, we propose a method, based on the log‐transformation of the ratio of the likelihood ratios, to compare the likelihood ratios of two binary diagnostic tests in paired designs. We have deduced hypothesis tests to compare the likelihood ratios and we have carried out simulation experiments to study the power and the type I error of the hypothesis tests deduced. We have also deduced a joint hypothesis test to simultaneously compare the likelihood ratios. The procedure used has been extended to the situation in which more than two binary diagnostic tests are applied to the same sample, and the situation in which two diagnostic tests with multilevel results are compared. Copyright © 2007 John Wiley & Sons, Ltd.
Design for Usability in Virtual Environment

Design for Usability (DFU) is a well known concept in computer science, since it refers to an important topic for the Human-Computer-Interaction research community. In the industrial design field this term is not so widely employed although the product usability is considered one of the most important factors for a product to be successful on the market. The importance of usability addresses the relationship between the interface of a product and its users. The success of several products on the market depends on complex interfaces, which require the user’s intense interaction. Often such devices, which the designer sees as being extremely efficient, are too complex and incomprehensible to the user. Usability should be one of the peculiar aims of the design, and thus assessed throughout the design itself. It should work on the assumption that final users should be involved during all the phases of the development of a product. The present study proposes a methodology of participatory design based on the user-product interaction in a virtual environment, and developed by involving users in the definition of the interface of an interactive product for household use.
Using errorless learning to treat letter-by-letter reading: Contrasting word versus letter-based therapy

Some pure alexic readers have been shown to activate lexical and semantic knowledge under brief presentation conditions. This ability is not seen when letter-by-letter reading accuracy is high or the reading impairment is very severe. It is also unlikely to occur under normal untimed presentation because the pure alexic will make deliberate use of their letter-by-letter strategy. This paper presents data from a moderately severe letter-by-letter reader, FD, who had visual processing problems affecting reading. He also had other mild aphasic characteristics. FD showed implicit reading abilities under brief presentation conditions, being able to make lexical decisions and semantic categorisations well above chance. FD was given two therapy programmes, the first, whole word therapy to exploit this implicit ability and the second to improve letter-by-letter accuracy and speed. FD showed some improvement in reading ability after both therapy programmes, particularly for words of personal interest to him. His letter naming accuracy and reading of visually similar words were the most resistant to change. A striking effect of therapy was the cessation of FD's letter-by-letter reading and the emergence of some of the characteristics of deep dyslexia. Even when therapy concentrated on letter accuracy, FD did not revert back to his original letter-by-letter reading strategy.The results are discussed with reference to the two theories of pure alexia. Some conclusions are drawn about the need for therapists to examine and exploit all residual reading skills when devising therapeutic programmes.
Ovulation side and occurrence of mittelschmerz in spontaneous and induced ovarian cycles.

Molland EA. Experimental renal papillary necrosis. Kidney Int 1978;13: 5-14. 2 Nanra RS, Stuart-Taylor J, De Leon AH, White KH. Analgesic nephropathy; etiology, clinical syndrome, and clinicopathologic correlations in Australia. Kidney Int 1978;13 :79-92. 3New Zealand Rheumatism Association Study. Aspirin and the kidney. Br MedJ 1974;i:593-6. 4 Macklon AF, Craft AW, Thompson M, Kerr DNS. Aspirin and analgesic nephropathy. Br Med J 1974 ;i:597-600. 5 Chantler C, Garnett ES, Parsons V, Veall N. Glomerular filtration rate measurement in man by the single injection method using 5"Cr-EDTA. Clin Sci 1969;37:169-80.
A Systematic Review of Third-Generation Hydroxyethyl Starch (HES 130/0.4) in Resuscitation: Safety Not Adequately Addressed

BACKGROUND:Hydroxyethyl starches (HES) are widely used for intravascular volume therapy in surgical, emergency, and intensive care patients. There are safety concerns with regard to coagulopathy, renal failure, pruritus, tissue storage, and mortality. Third-generation HES 130/0.4 is considered to have an improved risk profile. A common rationale for the use of HES is the belief that 3 to 4 times more crystalloid than colloid volume is needed to achieve similar hemodynamic end points. Our goal was to assess whether published studies on HES 130/0.4 resuscitation are sufficiently well designed to draw conclusions about the safety of this compound. In addition, we wanted to assess crystalloid-to-colloid fluid ratios in studies with goal-directed fluid regimen. METHODS:Systematic review of randomized controlled trials in which HES 130/0.4 is used for resuscitation. RESULTS:We identified 56 randomized controlled trials (RCTs) with HES 130/0.4 in. acute hypovolemia, mainly from the elective surgical setting (n = 45). Surgical studies were small-sized (median 25 patients in the HES groups, range 10 to 90) and of short duration (median 12 hours, range 0.5 to 144 hours). The median cumulative HES dose was 2465 mL (range 328 to 6229 mL), corresponding to 35 mL/kg in a 70-kg patient, the daily dose limit being 50 mL/kg. End points mostly addressed variable surrogate outcomes. Sixty percent of control fluids were other HES solutions, gelatins, or dextran, which have a similar risk profile. Without exception, these studies were not designed for clinically important safety outcomes, primarily because they were too small, used mostly inadequate control fluids, and had inappropriately short observation periods. Therefore, and also because of heterogeneity of patient groups and outcome definitions, results from these studies cannot be pooled. These studies do not allow any conclusion about the safety of HES 130/0.4. There is a common belief that 3 to 4 times more crystalloid than colloid volume is necessary to achieve similar hemodynamic effects. We found a considerably lower ratio in surgical studies (mean 1.8, SD 0.1). CONCLUSIONS:In summary, the extent of fluid load reduction that can be achieved by HES 130/0.4 is overestimated. Use of older HES solutions may be associated with serious side effects, and clinicians should be aware that there is no convincing evidence that third-generation HES 130/0.4 is safe in surgical, emergency, or intensive care patients despite publication of numerous clinical studies.
Determination of the Optical Properties of Native Joint Cartilage with NIR – Spectroscopy

Current research work at the fzmb deals with the tissue optics and spectral properties of biological tissue. To determine the optical properties of biological tissue, a measurement setup was established, which con- forms to the tissue properties absorption, scattering and anisotropy as well as to the underlying requirements of the calculation models. As an example, in this work the optical properties of native joint cartilage are measured.
Nitric oxide and bronchial reactivity

Nitric oxide (NO), is a small diatomic free reactive radical (accurately designated as N O ) which was previously only regarded as an atmospherie pollutant but now appears to play a erucial role in regulatory functions of the body including the respiratory tract. It has for a long time been regarded as a reactive by-product of fossil burning that can contribute to the formation of photochemical smog and acid rain. Furthermore, it can be found in high amounts in cigarette smoke [1]. The discovery that endothelium derived relaxant factor was similar to nitric oxide [2-4] has induced an explosion of research demonstrating that nitric oxide plays a central role in the regulation of a great number of physiological and pathophysiological processes in the body. It is now clear that this inorganic gas is synthesized by a diverse range of cells in animals and man from the semi-essential amino aeid L-arginine by different stereosf>ecifie enzymes called nitric oxide synthases [5-8]. Physiological processes in which nitric oxide is involved are vascular regulation, blood clotting, neurotransmission. host defense, immunological reactions, inflammation, nocieeption. ciliary beat frequency in ciliated epithelial cells and memory. Furthermore, it is involved in the pathogenesis of septic shock, neuronal damage in stroke and neuro-degenerative diseases. Increasing evidence now also points to an important role for nitric oxide in the regulation of pulmonary functions and a role in pulmonary disease [9-14], Nitric oxide is present in exhaled air of animals and man [12.13]. In the respiratory tract, nerves, endothelial cells, vascular and airway smooth muscle cells, inflammatory cells (macrophages. neutrophils, mast cells) and the airway epithelium are sources of nitric oxide [9]. The different effects of nitric oxide are mediated by the activation of soluble guanylyl cyclase. which consequently, increase cyclic guanosine monophosphate (cGMP) in the target cell.
Contribution to the study of the vasculature of submandibular and sublingual glands and lymph nodes of rats by corrosion cast technique combined with scanning electron microscopy

The study of anatomical structures in their normal state allows the identification of pathological changes that can occur in them. Angiogenesis and the vasculature have been widely studied, mainly because of their association with the development of neoplasms. One of the methods applied for such purposes is the corrosion cast technique, which provides a copy of the vessels with normal as well as pathological structures. The replica of the vasculature provided by this technique allows the three‐dimensional analysis of vessels by means of scanning electron microscopy. The aim of the present study was to demonstrate, by means of corrosion casts, the angioarchitecture of the submandibular and sublingual glands and lymph nodes. Scanning electron microscopy showed that the three structures have distinct vascular patterns. The corrosion cast technique can be employed in the study of the angioarchitecture of the submandibular and sublingual glands and lymph nodes, but requires specific precautions. The removal of the structures en bloc and the handling of the replicas with the aid of a stereoscopic magnifier reduce the risk of fractures. Microsc. Res. Tech., 2008. © 2008 Wiley‐Liss, Inc.