gebhart/patrepeval huggingface dataset:
The relationship between the design, position, and articular wear of acetabular components inserted without cement and the development of pelvic osteolysis. (1994)

Between 1983 and 1987, an acetabular component with a unique chamfered-cylinder design was inserted without cement in 134 hips. With use of this design, initial stability is achieved through a cylindrical interference fit with the peripheral rim of the acetabulum, without the need for pegs, spikes, or screws. At an average of sixty-four months (range, forty to ninety-six months) after implantation, follow-up data were available for 113 hips (ninety-three patients). No component had been revised for loosening or was radiographically loose. However, the prevalence of balloon-like osteolysis of the pelvis was 17 per cent (nineteen hips). This bone loss was generally not associated with pain or other symptoms. Ten of the nineteen hips that were associated with pelvic osteolysis (including six of the nine that were associated with osteolysis of the ilium) had been reconstructed with use of an acetabular component that had no holes in the shell (that is, the shell was completely solid). This finding indicates that, while elimination of holes through the acetabular shell may have advantages, it will not prevent pelvic osteolysis. The osteolysis of the ilium was associated with a lateral opening of the acetabular component of more than 50 degrees (p < 0.0001). All of the hips in this series had insertion of a porous-ingrowth femoral resurfacing component made of titanium alloy. These components are no longer used. Revision of the femoral side due to osteolysis provided a unique opportunity to inspect directly forty-two clinically well functioning acetabular components. All of the polyethylene liners and acetabular shells were found to be rigidly fixed. Inflammatory tissue at the periphery of the implant-bone interface resulted in circumferential resorption of periacetabular bone despite rigid fixation of the component. This is direct evidence that a process of bone resorption similar to that reported at the cement-bone interface of cemented acetabular components can occur at the implant-bone interface of components inserted without cement. At the reoperation, a communication that had led to the pelvic osteolysis was found through areas of bone resorption at the periphery of the implant-bone interface. These areas were essentially cystic and were filled with a mixture of fluid and friable, yellow-tan tissue. It appeared that the osteolytic process had expanded into the soft cancellous bone and marrow while being contained by the denser cortical shell of the pelvic bones.(ABSTRACT TRUNCATED AT 250 WORDS)
Improved Retroviral Vectors for Hematopoietic Stem Cell Protection and In Vivo Selection (1996)

Therapeutic gene transfer into hematopoietic cells is critically dependent on the evolution of methods that allow ex vivo expansion, high-frequency transduction, and selection of gene-modified long-term repopulating cells. Progress in this area needs elaboration of defined culture and transduction conditions for long-term repopulating cells and improvement of gene transfer systems. We have optimized retroviral vector constructions based on murine leukemia viruses (MuLV) to overcome the transcriptional repression encountered with the use of conventional Moloney MuLV (MoMuLV) vectors in early hematopoietic progenitor cells (HPC). Novel retroviral vectors, termed FMEV (for Friend-MCF/MESV hybrid vectors), were cloned that mediate greatly improved gene expression in the myeloerythroid compartment. Transfer of the selectable marker multidrug resistance 1 (mdr1), FMEV, in contrast to conventional MoMuLV-related vectors currently in use for clinical protocols, mediated background-free selectability of transduced human HPC in the presence of myeloablative doses of the cytostatic agent paclitaxel in vitro. Furthermore, FMEV also greatly improved chemo-protection of hematopoietic progenitor cells in a murine model system in vivo. Finally, when a second gene was transferred along with mdr1 in an FMEV-backbone, close to 100% coexpression was observed in multidrug-resistant colonies. These observations have significant consequences for a number of ongoing and planned gene therapy trials, for example, stem cell protection to reduce the myelotoxic side effects of anticancer chemotherapy, correction of inherited disorders involving hematopoietic cells, and antagonism of HIV infection.
Regulation of histidine and proline degradation enzymes by amino acid availability in Bacillus subtilis (1990)

The first enzymes of the histidine (hut) and proline degradative pathways, histidase and proline oxidase, could not be induced in Bacillus subtilis cells growing in glucose minimal medium containing a mixture of 16 amino acids. Addition of the 16-amino-acid mixture to induced wild-type cells growing in citrate minimal medium repressed histidase synthesis 25- to 250-fold and proline oxidase synthesis 16-fold. A strain containing a transcriptional fusion of the hut promoter to the beta-galactosidase gene was isolated from a library of Tn917-lacZ transpositions. Examination of histidase and beta-galactosidase expression in extracts of a hut-lacZ fusion strain grown in various media showed that induction, catabolite repression, and amino acid repression of the hut operon were mediated at the level of transcription. This result was confirmed by measurement of the steady-state level of hut RNA in cells grown in various media. Since amino acid repression was not defective in B. subtilis mutants deficient in nitrogen regulation of glutamine synthetase and catabolite repression, amino acid repression appears to be mediated by a system that functions independently of these regulatory systems.
Detection of RAG Protein-V(D)J Recombination Signal Interactions Near the Site of DNA Cleavage by UV Cross-Linking (1999)

V(D)J recombination is initiated by double-strand cleavage at recombination signal sequences (RSSs). DNA cleavage is mediated by the RAG1 and RAG2 proteins. Recent experiments describing RAG protein-RSS complexes, while defining the interaction of RAG1 with the nonamer, have not assigned contacts immediately adjacent to the site of DNA cleavage to either RAG polypeptide. Here we use UV cross-linking to define sequence- and site-specific interactions between RAG1 protein and both the heptamer element of the RSS and the coding flank DNA. Hence, RAG1-DNA contacts span the site of cleavage. We also detect cross-linking of RAG2 protein to some of the same nucleotides that cross-link to RAG1, indicating that, in the binding complex, both RAG proteins are in close proximity to the site of cleavage. These results suggest how the heptamer element, the recognition surface essential for DNA cleavage, is recognized by the RAG proteins and have implications for the stoichiometry and active site organization of the RAG1-RAG2-RSS complex.
The pan‐caspase inhibitor Emricasan (IDN‐6556) decreases liver injury and fibrosis in a murine model of non‐alcoholic steatohepatitis (2014)

In conclusion, these data demonstrate that in a murine model of NASH, liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis and suggests that Emricasan may be an attractive antifibrotic therapy in NASH.
Protective Roles of Natural IgM Antibodies (2012)

Antibodies are a vital part of the armamentarium of the adaptive immune system for the fine-tuning of the recognition and response to foreign threats. However, in health there are some types of antibodies that instead recognize self-antigens and these contribute to the enhancement of primitive innate functions. This repertoire of natural IgM antibodies is postulated to have been selected during immune evolution for their contributions to critical immunoregulatory and housekeeping properties. The clearance of dying cells is one of the most essential responsibilities of the immune system, which is required to prevent uncontrolled inflammation and autoimmunity. In the murine immune system, natural IgM antibodies that recognize apoptotic cells have been shown to enhance the phagocytic clearance of dead and dying cells and to suppress innate immune signaling pathways. In the mouse, natural IgM are often the products of B-1 cell clones that arise during immune development without an absolute requirement for exogenous antigenic stimulation. In patients with systemic lupus erythematosus, IgM autoantibodies, which bind to neo-epitopes on apoptotic cells, have been demonstrated to be present at significantly higher levels in patients with lower disease activity and with less severe organ damage. While certain specificities of IgM autoantibodies correlate with protection from lupus renal disease, others may convey protective properties from lupus-associated atherosclerotic cardiovascular disease. New and unexpected insights into the functional roles of IgM antibodies are still emerging, especially regarding the functions of natural antibodies. Herein, we review recent progress in our understanding of the potential roles of natural IgM autoantibodies in the regulation of immune homeostasis and for protection from autoimmune and inflammatory diseases.
Risk Management in Global Finance (1995)

This special issue is devoted to a discussion of some major risks facing multinational companies (MNCs) in the operation of their global business. Multinational business is carried out in many ways including international trade and investment activities. Such enterprise may be confronted by a number of risks. Among these, the most important are foreign exchange risk, credit risk, interest rate risk, and political risk.
Implications of dynamic patterns of Delta and Notch expression for cellular interactions during Drosophila development (1993)

Delta and Notch function are required for cell fate specification in numerous tissues during embryonic and postembryonic Drosophila development. Delta is expressed by all members of interacting cell populations within which fates are being specified and is subsequently down-regulated as cells stably adopt particular fates. Multiphasic expression in the derivatives of many germ layers implies successive requirements for Delta function in a number of tissues. At the cellular level, Delta and Notch expression are generally coincident within developing tissues. At the subcellular level, Delta and Notch are localized in apparent endocytic vesicles during down-regulation from the surfaces of interacting cells, implying an interaction consistent with their proposed roles as signal and receptor in cellular interactions during development.
Imipramine and fluoxetine prevent the stress-induced escape deficits in rats through a distinct mechanism of action (1995)

A large body of evidence indicates that brain monoamines are involved in the pathogenesis of mental depression, as well as in the mechanism of action of most antidepressant treatments. The present report shows that long-term exposure to imipramine (IMI) or fluoxetine (FLX) was equally potent in preventing the escape deficits produced in rats by repeated unavoidable shocks. The acute administration of SCH 23390, a selective D1 dopamine receptor blocker, shortly before the inescapable shock session, entirely prevented IMI effect on escape performance, but only partially prevented that of FLX. Moreover, pindolol (an antagonist of beta-adrenoceptors and of serotonin 5-HT(1A) and 5-HT(1B) receptors) completely antagonized the efficacy of FLX in preventing escape deficits, whereas it did not effect the activity of IMI. The acute administration of propranolol failed to alter the effect of either antidepressant. It was concluded that in rats, the efficacy of IMI in counteracting the stress-induced behavioral sequelae is mainly mediated by the activation of D1 dopamine receptors, whereas that of FLX is largely dependent upon the stimulation of post-synaptic 5-HT(1A) receptors. Finally, the effects of the two drugs appear to be totally unrelated to activation of beta-adrenoceptors.
Development of Fourth Generation ABC Inhibitors from Natural Products: A Novel Approach to Overcome Cancer Multidrug Resistance (2015)

Multidrug resistance (MDR) in cancer caused due to overexpression of ABC drug transporters is a major problem in modern chemotherapy. Molecular investigations on MDR have revealed that the resistance is due to various transport proteins of the ABC superfamily which include Phosphoglycoprotein (P-gp/MDR1/ ABCB1), multidrug resistance-associated protein-1 (MRP1), and the breast cancer resistance protein (BCRP). They have been characterized functionally and are considered as major players in the development of MDR in cancer cells. These ATP-dependent transporter proteins cause MDR either by decreased uptake of the drug or increased efflux of the drug from the target organelles. Several MDR-reversing agents are being developed and are in various stages of clinical trials. The first three generations of ABC modulators such as quinine, verapamil, cyclosporine-A, tariquitor, PSC 833, LY335979, and GF120918 required to be administered in high doses to reverse MDR and were associated with adverse effects. Additionally, these modulators non-selectively inhibit ABC and adversely accumulate chemotherapeutic drugs in brain and kidney. Currently, research has stepped up towards reversing MDR by using natural products which exhibitted potential as chemosensitizers. Globally, there is a rich biodiversity of natural products which can be sourced for developing drugs. These products may provide more lead compounds with superior activity, foremost to the development of more effective therapies for MDR cancer cells. Here, we briefly review the status of natural products for reversing MDR modulators, and discuss the long term goal of MDR strategies in current clinical settings.
Extreme value modelling of laboratory safety data from clinical studies (2012)

Most clinical studies collect several safety-related laboratory variables. Generally, it is the extreme values of these variables that indicate potential safety issues. We illustrate the novel application of extreme value modelling to such data, with the aim of predicting the incidence of severe adverse drug reactions. By applying the methods to a clinical trial data set, we identify a dose-response relationship and use Bayesian techniques to identify a potential safety concern by making predictions from the fitted model, despite the small sample size.
Apoptosis induced by HIV-1 infection of the central nervous system. (1996)

Apoptosis plays a role in AIDS pathogenesis in the immune system, but its role in HIV-1-induced neurological disease is unknown. In this study, we examine apoptosis induced by HIV-1 infection of the central nervous system (CNS) in an in vitro model and in brain tissue from AIDS patients. HIV-1 infection of primary brain cultures induced apoptosis in neurons and astrocytes in vitro as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and propidium iodide staining and by electron microscopy. Apoptosis was not significantly induced until 1-2 wk after the time of peak virus production, suggesting induction by soluble factors rather than by direct viral infection. Apoptosis of neurons and astrocytes was also detected in brain tissue from 10/11 AIDS patients, including 5/5 patients with HIV-1 dementia and 4/5 nondemented patients. In addition, endothelial cell apoptosis was frequently detected in the brain of AIDS patients and was confirmed by electron microscopy. Most of the apoptotic cells were not localized adjacent to HIV-1-infected cells, providing further evidence for induction by soluble factors. In six non-AIDS control patients with normal brain, apoptotic cells were absent or limited to rare astrocytes. However, TUNEL-positive neurons and astrocytes were frequently detected in seven patients with Alzheimer's disease or abundant senile plaques. These studies suggest that apoptosis is a mechanism of CNS injury in AIDS which is likely to be induced by soluble factors. The apoptosis of endothelial cells in the CNS raises the possibility that some of these factors may be blood-derived.
Ablation of eosinophil and IgE responses with anti-IL-5 or anti-IL-4 antibodies fails to affect immunity against Schistosoma mansoni in the mouse. (1990)

To investigate the role of anaphylactic immune responses in protective immunity against schistosomiasis, mice vaccinated with irradiated cercariae of Schistosoma mansoni were treated with neutralizing mAb antibodies against either IL-5 or IL-4 before and during challenge infection. Anti-IL-5-treated vaccinated mice showed a complete ablation of circulating as well as tissue eosinophils present in inflammatory reactions to migrating schistosomula in the skin and lungs but nevertheless eliminated challenge infections as effectively as vaccinated animals treated with a control mAb. Similarly, treatment of vaccinated mice with an anti-IL-4 mAb markedly reduced serum IgE although failing to diminish immunity. The effect of anti-IL-5 mediated eosinophil depletion was also assessed in a second model in which resistance is induced by concomitant chronic infection. Again, normal, unaltered protection was observed in the absence of circulating and tissue eosinophils. In contrast to the above findings, treatment with anti-IFN-gamma was found to cause a partial depletion of immunity in vaccinated mice whereas, paradoxically, increasing the numbers of inflammatory reactions against invading schistosomula in the lungs. These observations argue against a requirement for either eosinophils or IgE in the anti-schistosome immunity induced by vaccination with irradiated cercariae or for eosinophils in the resistance resulting from previous infection in mice and support previous data suggesting a role for an IFN-gamma dependent cell-mediated effector mechanism in vaccine-induced resistance.
Magnetic Resonance Imaging of the Lumbar Spine in People without Back Pain (1994)

On MRI examination of the lumbar spine, many people without back pain have disk bulges or protrusions but not extrusions. Given the high prevalence of these findings and of back pain, the discovery by MRI of bulges or protrusions in people with low back pain may frequently be coincidental.
Saturation of cyclotron maser instability driven by an electron loss-cone distribution (1985)

The resonance diffusion of electrons in velocity space caused by the excited EM wave fields is considered to be the dominant saturation process of cyclotron maser instability that is driven by an electron loss-cone distribution. An upper-bound of the saturation level is derived analytically.
Power efficiency of voltage scaling in multiple clock, multiple voltage cores (2002)

Due to increasing clock speeds, increasing design sizes and shrinking technologies, it is becoming more and more challenging to distribute a single global clock throughout a chip. In this paper we study the effect of using a Globally Asynchronous Locally Synchronous (GALS) organization for a superscalar, out-of-order processor, both in terms of power and performance. To this end, we propose a novel modeling and simulation environment for multiple clock cores with static or dynamically variable voltages for each synchronous block. Using this design exploration environment we were able to assess the power/performance tradeoffs available for Multiple Clock, Single Voltage (MCSV), as well as Multiple Clock, Dynamic Voltage (MCDV) cores. Our results show that MCSV processors are 10% more power efficient when compared to single-clock single voltage designs with a performance penalty of about 10%. By exploiting the flexibility of independent dynamic voltage scaling the various clock domains, the power efficiency of GALS designs can be improved by 12% on average, and up to 20% more in select cases. The power efficiency of MCDV cores becomes comparable with the one of Single Clock, Dynamic Voltage (SCDV) cores, while being up to 8% better in some cases. Our results show that MCDV cores consume 22% less power at an average 12% performance loss.
A neurohistological correlate of schizophrenia. (1984)

We report an apparently consistent alteration of pyramidal cell orientation in ten chronic schizophrenic patients compared with eight nonschizophrenic controls from a Veterans Administration Medical Center. A blind study based upon measurement of over 13,000 cells indicates highly significant differences between the two groups, particularly in anterior and middle hippocampal regions. Cell disarray is most pronounced at the CA 1-prosubiculum and CA 1/CA 2 interfaces. Smaller degrees of deviation, noted in the controls, together with more extreme deviation reported in a previous qualitative study of chronic schizophrenics from a state hospital, could be interpreted as suggesting a histopathological continuum ranging from the clinically nonpsychotic individual, through borderline states to the intractable long-term psychotic.
α-Methylacyl Coenzyme A Racemase, Ki-67, and Topoisomerase IIα in Cystoprostatectomies With Incidental Prostate Cancer (2007)

alpha-Methylacyl coenzyme A racemase (AMACR), Ki-67, and topoisomerase IIalpha were immunohisto-chemically evaluated in prostate carcinoma (PCa), high-grade prostatic intraepithelial neoplasia (HPIN), normal-looking epithelium (NEp), and atrophy in 20 cystoprostatectomy (CyP) and 20 radical prostatectomy (RP) specimens with pT2a Gleason score 6 PCa. The aim was to see whether there were differences in marker expression between CyP and RP specimens. The results showed that the proportions of AMACR-, Ki-67-, and topoisomerase IIalpha-positive cells in the CyP and RP specimens increased from NEp and atrophy through HPIN, away from and adjacent to PCa, to PCa. AMACR expression in PCa in CyP specimens was slightly lower than in RP specimens, but the differences were not significant; there were significant differences in Ki-67 and topoisomerase IIalpha indices. Our findings in marker expression in NEp, atrophy, and HPIN suggest that there are some differences in the field effects in terms of prostatic carcinogenesis between CyP and RP specimens.
Metabolic Characterization of Polarized M1 and M2 Bone Marrow-derived Macrophages Using Real-time Extracellular Flux Analysis (2015)

Specific metabolic pathways are increasingly being recognized as critical hallmarks of macrophage subsets. While LPS-induced classically activated M1 or M(LPS) macrophages are pro-inflammatory, IL-4 induces alternative macrophage activation and these so-called M2 or M(IL-4) support resolution of inflammation and wound healing. Recent evidence shows the crucial role of metabolic reprogramming in the regulation of M1 and M2 macrophage polarization. In this manuscript, an extracellular flux analyzer is applied to assess the metabolic characteristics of naive, M1 and M2 polarized mouse bone marrow-derived macrophages. This instrument uses pH and oxygen sensors to measure the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), which can be related to glycolytic and mitochondrial oxidative metabolism. As such, both glycolysis and mitochondrial oxidative metabolism can be measured in real-time in one single assay. Using this technique, we demonstrate here that inflammatory M1 macrophages display enhanced glycolytic metabolism and reduced mitochondrial activity. Conversely, anti-inflammatory M2 macrophages show high mitochondrial oxidative phosphorylation (OXPHOS) and are characterized by an enhanced spare respiratory capacity (SRC). The presented functional assay serves as a framework to investigate how particular cytokines, pharmacological compounds, gene knock outs or other interventions affect the macrophage's metabolic phenotype and inflammatory status.