gebhart/patrepeval huggingface dataset:
Proximal tibial osteotomy for osteoarthritis with varus deformity. A ten to thirteen-year follow-up study (1987)

The results in ninety-three knees that had been treated by proximal tibial opening-wedge osteotomy for varus deformity and osteoarthritis of the medial compartment were evaluated after a mean length of follow-up of 11.5 years (range, ten to thirteen years). After ten years, only forty-two (45 per cent) of the ninety-three knees had an excellent or good result, and in fifty-one knees there was recurrent pain for which seventeen had another operation. At five years, on the other hand, 90 per cent of the knees had a good result. Deterioration occurred at an average of seven years after the osteotomy and was always associated with recurrence of pain. Although the results deteriorated with time, time was not the only determinant of the result. Alignment, measured as the hip-knee-ankle angle on radiographs of the whole limb that were made with the patient bearing weight, was also a determinant of long-term results. The best results were obtained in the twenty knees that had a hip-knee-ankle angle of 183 to 186 degrees. In these knees, there was no pain and no progression of the arthrosis in either the medial or the lateral tibiofemoral compartment. Of the five knees that had an angle of more than 186 degrees, all five had progressive degenerative changes in the lateral compartment. In the sixty-eight undercorrected knees (an angle of less than 183 degrees), the results were less satisfactory, and there was a tendency toward recurrence of the varus deformity and progression of the arthritis of the medial compartment. However, when the correction was insufficient the deterioration was slow (average, seven years), and it was not associated with lateral laxity and deterioration of the lateral compartment, which are the changes that characterize the natural course of gonarthrosis as described by Hernborg and Nilsson. Therefore, proximal tibial osteotomy is a very suitable operation for patients who have gonarthrosis of the medial compartment, but a rigidly standardized and precise operative technique is required as well as accurate radiographic measurements of the mechanical axis of the limb, because exact postoperative alignment is the prerequisite for the longest possible period of relief of symptoms after osteotomy.
Antiviral Activity of 1-Adamantanamine (Amantadine) (1964)

I-Adamantanamine (amantadine) causes a selective, reproducible, dose-related inhibition of influenza infections in tissue culture, chick embryos, and mice. The compound is not virucidal and appears to act by interfering with the penetration of the host cell by the virus. In influenza infections of mice, greatest efficacy occurs with treatment at the time of infection; however, there is significant antiviral activity with treatment delayed up to 72 hours after infection. Virus inhibition is not complete and survivors are immune to a challenge infection with the original infecting virus.
ChemInform Abstract: 2,4,5‐Trisubstituted Imidazoles: Novel Nontoxic Modulators of P‐Glycoprotein Mediated Multidrug Resistance. Part 1. (2001)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Accurate quantification of hepatitis C virus (HCV) RNA from all HCV genotypes by using branched-DNA technology (1996)

In studies monitoring disease progression and therapeutic response, it is essential that the method used for hepatitis C virus (HCV) quantification not be influenced by genotypic variability. The branched DNA assay provides a reliable method for the quantification of HCV RNA. A modified set of oligonucleotide probes for the branched DNA assay was developed to enhance the efficiency of binding to genotypic variants of HCV. The improved branched DNA assay (HCV RNA 2.0) yielded highly reproducible quantification of hepatitis C virus RNA and displayed a nearly 600-fold dynamic range in quantification up to 120 Meq of HCV RNA per ml. The quantification limit was set at 0.2 Meg of HCV RNA per ml to ensure a specificity of > or = 95%. With this lowered quantification limit and the enhanced hybridization of the probes, the HCV RNA 2.0 assay exhibited a high level of sensitivity (96%) and was virtually unaffected by the genotypic variability of HCV. The HCV RNA 2.0 assay may be a useful tool for following HCV RNA levels throughout the course of disease, selecting patients for therapy, and evaluating therapeutic response.
Improved myocardial performance following high 2-3 diphosphoglycerate red cell transfusions. (1975)

Twenty-two matched coronary bypass surgery (CABS) patients were randomly divided into two groups; 11 patients in the control group received CPD-stored or fresh blood (mean age, 5.5 days) containing 70 percent of normal 2-3 diphosphoglycerate (2-3 DPG) and 11 patients received 2-3 DPG-enriched previously frozen, washed, concentrated red cells (2-3 DPG 150 percent of normal). Coming off cardiopulmonary bypass, when given a volume load, the high 2-3 DPG patients had a significant increase in cardiac index (2.95 L. per minute vs. 2.18 L. per minute, p smaller than 0.001) at similar filling pressures. At this time body oxygen consumption, in vivo P50, red cell 2-3 DPG, and arterial-venous oxygen content difference were all increased, but P minus vo2 was normal. Improved oxygen delivery occurred without decreasing mixed venous oxygen tension. The results suggest that, with volume loading, function in the heart with coronary artery disease is limited in part by available oxygen. By decreasing oxygen affinity for hemoglobin by altering red blood cells biochemically, myocardial performance can be improved safely.
Complete Regression of Advanced Primary and Metastatic Mouse Melanomas following Combination Chemoimmunotherapy (2009)

The development of therapeutic strategies which induce effective cellular antitumor immunity represents an important goal in cancer immunology. Here, we used the unique features of the genetically engineered Hgf-Cdk4(R24C) mouse model to identify a combination chemoimmunotherapy for melanoma. These mice develop primary cutaneous melanomas which grow progressively and metastasize in the absence of immunogenic foreign proteins such as oncogenes or antigens. Primary and metastatic tumors evade innate and adaptive immune defenses, although they naturally express melanocytic antigens which can be recognized by antigen-specific T cells. We found that primary melanomas continued to grow despite infiltration with adoptively transferred, in vivo-activated, tumor-specific CD8(+) T cells. To promote tumor immune defense, we developed a treatment protocol consisting of four complementary components: (a) chemotherapeutic preconditioning prior to (b) adoptive lymphocyte transfer and (c) viral vaccination followed by (d) adjuvant peritumoral injections of immunostimulatory nucleic acids. Lymphocyte ablation and innate antiviral immune stimulation cooperatively enhanced the expansion and the effector cell differentiation of adoptively transferred lymphocytes. The efficacy of the different treatment approaches converged in the tumor microenvironment and induced a strong cytotoxic inflammatory response enabling preferential recognition and destruction of melanoma cells. This combination chemoimmunotherapy caused complete regression of advanced primary melanomas in the skin and metastases in the lung with minimal autoimmune side effects. Our results in a clinically highly relevant experimental model provide a scientific rationale to evaluate similar strategies which unleash the power of innate and adaptive immune defense in future clinical trials.
Structurally Designed trans-2-Phenylcyclopropylamine Derivatives Potently Inhibit Histone Demethylase LSD1/KDM1,, (2010)

Lysine-specific demethylase 1 (LSD1/KDM1) demethylates histone H3, in addition to tumor suppressor p53 and DNA methyltransferase 1 (Dnmt1), thus regulating eukaryotic gene expression by altering chromatin structure. Specific inhibitors of LSD1 are desired as anticancer agents, because LSD1 aberrations are associated with several cancers, and LSD1 inhibition restores the expression of abnormally silenced genes in cancerous cells. In this study, we designed and synthesized several candidate compounds to inhibit LSD1, based on the structures of LSD1 and monoamine oxidase B (MAO-B), in complex with an antidepressant tranylcypromine (2-PCPA) derivative. Compound S2101 exhibited stronger LSD1 inhibition than tranylcypromine and the known small LSD1 inhibitors in LSD1 demethylation assays, with a k(inact)/K(I) value of 4560 M(-1) s(-1). In comparison with tranylcypromine, the compound displayed weaker inhibition to the monoamine oxidases. The inhibition modes of the two 2-PCPA derivatives, 2-PFPA and S1201, were identified by determination of the inhibitor-bound LSD1 structures, which revealed the enhanced stability of the inhibitor-FAD adducts by their interactions with the surrounding LSD1 residues. These molecules are potential pharmaceutical candidates for cancer or latent virus infection, as well as research tools for LSD1-related biological investigations.
Studies on the genetic and cellular control of sensitivity to enterotoxins in the sealed adult mouse model (1986)

A sealed adult mouse (SAM) model was developed for studies on the effects of cholera enterotoxin (CT). With this system, 38 strains of outbred, inbred, congenic, recombinant, and mutant mice were starved for 24 h, anorectally occluded with cyanoacrylamide ester glue, given CT per os, and sacrificed at 6 h. Fluid accumulation (FA) values were calculated as gut weight to body weight ratios. At a saturating dose of CT (24 micrograms per mouse), FA responses were found to be independent of body weight and gut length. It was found, using recombinant and congenic mice, that mice which possess the H-2k haplotype (homozygous or heterozygous) are 2.5 to 3 times less responsive to CT than animals with the H-2b haplotype. The allele(s) responsible for this affect is located near the K end of the H-2 complex. Inbred and congenic mice given CT intravenously exhibited the same (b = responder, k = nonresponder) pattern in terms of weight loss and death, thus indicating that the H-2 effect is not limited just to the small intestinal epithelium. Mice given sublethal doses of CT intravenously and challenged after conversion to SAM 14 days later showed an immune response inversely related to weight loss (i.e., b haplotypes lost 10 to 15% body weight, recovered, but were not protected against challenge; k haplotypes lost little or no weight but were protected). To examine the possibility of a cellular basis for control of innate responses to CT, responder C57BL/10 (B10) mice were irradiated with 950 rads and immediately reconstituted with bone marrow from (B10 X B10.BR)F1 (nonresponder) mice. The chimeras became nonresponsive to CT when challenged 5 weeks after reconstitution. Reconstituted B10 controls responded normally. Outbred and inbred nude athymic mice also were nonresponsive when compared with normal responder controls. These data demonstrate a genetic basis for resistance to CT and that response and nonresponse is mediated, at least in part, by cells derived from bone marrow.
Diffuse hair loss: Its triggers and management (2009)

Diffuse hair loss can affect both sexes at any age. Anything that interrupts the normal hair cycle can trigger diffuse hair loss. Triggers include a wide variety of physiologic or emotional stresses, nutritional deficiencies, and endocrine imbalances. Loss of telogen-phase hairs is the most common. Hair loss during the anagen phase is usually caused by chemotherapy or radiation therapy. Finding the cause, or trigger, of the hair loss requires a thorough history and examination and will enable appropriate treatment. Patient education is key in the management of diffuse hair loss.
25-Hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway (2008)

The oxysterol receptor LXR is a key transcriptional regulator of lipid metabolism. LXR increases expression of SREBP-1, which in turn regulates at least 32 genes involved in lipid synthesis and transport. We recently identified 25-hydroxycholesterol-3-sulfate (25HC3S) as an important regulatory molecule in the liver. We have now studied the effects of 25HC3S and its precursor, 25-hydroxycholesterol (25HC), on lipid metabolism as mediated by the LXR/SREBP-1 signaling in macrophages. Addition of 25HC3S to human THP-1-derived macrophages markedly decreased nuclear LXR protein levels. 25HC3S administration was followed by dose- and time-dependent decreases in SREBP-1 mature protein and mRNA levels. 25HC3S decreased the expression of SREBP-1-responsive genes, acetyl-CoA carboxylase-1, and fatty acid synthase (FAS) as well as HMGR and LDLR, which are key proteins involved in lipid metabolism. Subsequently, 25HC3S decreased intracellular lipids and increased cell proliferation. In contrast to 25HC3S, 25HC acted as an LXR ligand, increasing ABCA1, ABCG1, SREBP-1, and FAS mRNA levels. In the presence of 25HC3S, 25HC, and LXR agonist T0901317, stimulation of LXR targeting gene expression was repressed. We conclude that 25HC3S acts in macrophages as a cholesterol satiety signal, downregulating cholesterol and fatty acid synthetic pathways via inhibition of LXR/SREBP signaling. A possible role of oxysterol sulfation is proposed.
Expression of Different Levels of Ethanologenic Enzymes from Zymomonas mobilis in Recombinant Strains of Escherichia coli (1988)

The expression of Zymomonas mobilis genes encoding pyruvate decarboxylase and alcohol dehydrogenase II in Escherichia coli converted this organism from the production of organic acids to the production of ethanol. Ethanol was produced during both anaerobic and aerobic growth. The extent to which these ethanologenic enzymes were expressed correlated with the extent of ethanol production. The replacement of organic acids with ethanol as a metabolic product during aerobic and anaerobic growth resulted in dramatic increases in final cell density, indicating that these acids (and the associated decline in pH) are more damaging than the production of ethanol. Of the plasmids examined, the best plasmid for growth and ethanol production expressed pyruvate decarboxylase and alcohol dehydrogenase II at levels of 6.5 and 2.5 IU/mg of total cell protein, respectively.
A 200‐amino acid ATPase module in search of a basic function (1995)

A fast growing family of ATPases has recently been highlighted. It was named the AAA family, for ATPases Associated to a variety of cellular Activities. The key feature of the family is a highly conserved module of 230 amino acids present in one or two copies in each protein. Despite extensive sequence conservation, the members of the family fulfil a large diversity of cellular functions: cell cycle regulation, gene expression in yeast and HIV, vesicle-mediated transport, peroxisome assembly, 26S protease function etc. In addition, several members of this family can be found in the same organism (up to 17 in S. cerevisiae). The contrast between functional diversity and structural conservation of the module, from archaebacteria to mammals, suggests that it plays an essential, but as yet unknown, role at key points of the cellular machinery. Two (non-exclusive) such possibilities are: (1) ATP-dependent proteasome function and (2) ATP-dependent anchorage of proteins. Finally, the basic biochemical activity of the AAA module is still a matter of speculation, and we propose that it acts as an ATP-dependent protein clamp.
Protected areas systems review of the Indo-Malayan Realm (1997)

This report documents the growth and changing character of the protected areas systems of the Indo-Malayan Realm over the period 1986-96 with a view to: 1) evaluate the representational coverage and conservation importance of the existing protected areas system; 2) identify gaps and shortcomings in the existing system; 3) identify sites of global priority for conservation ; and 4) monitor progress on the development of protected areas within the Realm. The report evaluates the protected areas systems from the following viewpoints: how much of each country and its bio-geographical sub-divisions are under protection status; the management effectiveness in individual countries; the coverage in relation to species richness, centers of endemism, and in relation to threats to habitat. It also provides specific suggestions on how the present approaches and initiatives relating to protected areas management could be improved throughout the Realm.
Pathogenic mechanisms of myotonic dystrophy (2009)

DM (myotonic dystrophy) is a dominantly inherited genetic disorder that is the most common cause of muscular dystrophy in adults affecting 1 in 8500 individuals worldwide. Different microsatellite expansions in two loci cause different forms of the disease that share similar features: DM1 (DM type 1) is caused by a tri- (CTG) nucleotide expansion within the DMPK (dystrophia myotonica protein kinase) 3'-untranslated region and DM2 (DM type 2) is caused by a tetra- (CCTG) nucleotide expansion within intron 1 of the ZNF9 (zinc finger 9) gene. The pathogenic mechanism of this disease involves the RNA transcribed from the expanded allele containing long tracts of (CUG)(n) or (CCUG)(n). The RNA results in a toxic effect through two RNA-binding proteins: MBNL1 (muscleblind-like 1) and CUGBP1 (CUG-binding protein 1). In DM1, MBNL1 is sequestered on CUG repeat-containing RNA resulting in its loss-of-function, while CUGBP1 is up-regulated through a signalling pathway. The downstream effects include disrupted regulation of alternative splicing, mRNA translation and mRNA stability, which contribute to the multiple features of DM1. This review will focus on the RNA gain-of-function disease mechanism, the important roles of MBNL1 and CUGBP1 in DM1, and the relevance to other RNA dominant disorders.
Microstructure identification during crystallization of charged colloidal suspensions (1990)

Abstract We use a polarized light microscope in its orthoscopic and conoscopic arrangements and laser light diffraction to study the effect of particle volume fraction and cell thickness on the microstructure of crystallizing suspensions of negatively charged polystyrene microspheres. Deionized suspensions of these particles nucleate at random sites in the bulk of the suspension to give a variety of structures, orientations and sizes. Orthoscopic observation of the Bragg diffraction colors between crossed polars and conoscopic inspection of the interference figures reveal structural details. We find that the crystallites grow by parallel stacking of the (111) layers to single and twin fcc structures. At moderate volume fractions, Φ ≈ 0.09, the structures are essentially “frozen” in space by their neighbors. At lower concentrations, Φ ≈ 0.05, the crystallites are larger with smoother boundaries and exhibit a range of colors. In thick cells, L ≥ 200 μm, and Φ ≤ 0.05, the colored crystallites become dark with time as they align with the (111) planes parallel to the cell walls. In thin, 50μm cells and Φ ≤ 0.05, this alignment is enhanced. We demonstrate that striated crystallites with lamellae of alternating colors and varying width are polysynthetic fcc twins with (111) twin plane. The number density of twin crystals and the frequency of striations decrease with decreasing volume fraction.
The E-loop Is Involved in Hydrogen Peroxide Formation by the NADPH Oxidase Nox4 (2011)

In contrast to the NADPH oxidases Nox1 and Nox2, which generate superoxide (O(2)(·-)), Nox4 produces hydrogen peroxide (H(2)O(2)). We constructed chimeric proteins and mutants to address the protein region that specifies which reactive oxygen species is produced. Reactive oxygen species were measured with luminol/horseradish peroxidase and Amplex Red for H(2)O(2) versus L-012 and cytochrome c for O(2)(·-). The third extracytosolic loop (E-loop) of Nox4 is 28 amino acids longer than that of Nox1 or Nox2. Deletion of E-loop amino acids only present in Nox4 or exchange of the two cysteines in these stretches switched Nox4 from H(2)O(2) to O(2)(·-) generation while preserving expression and intracellular localization. In the presence of an NO donor, the O(2)()-producing Nox4 mutants, but not wild-type Nox4, generated peroxynitrite, excluding artifacts of the detection system as the apparent origin of O(2)(·-). In Cos7 cells, in which Nox4 partially localizes to the plasma membrane, an antibody directed against the E-loop decreased H(2)O(2) but increased O(2)(·-) formation by Nox4 without affecting Nox1-dependent O(2)(·-) formation. The E-loop of Nox4 but not Nox1 and Nox2 contains a highly conserved histidine that could serve as a source for protons to accelerate spontaneous dismutation of superoxide to form H(2)O(2). Mutation of this but not of four other conserved histidines also switched Nox4 from H(2)O(2) to O(2)(·-) formation. Thus, H(2)O(2) formation is an intrinsic property of Nox4 that involves its E-loop. The structure of the E-loop may hinder O(2)(·-) egress and/or provide a source for protons, allowing dismutation to form H(2)O(2).
Immune response to type III group B streptococcal polysaccharide-tetanus toxoid conjugate vaccine. (1996)

Group B Streptococcus (GBS) is an important perinatal pathogen. Because transplacentally acquired maternal antibodies to the GBS capsular polysaccharides (CPS) confer protection, prevention of infant disease may be possible after immunization of women. Unfortunately, the purified CPS of GBS are only variably immunogenic in adults; therefore to enhance immunogenicity we have designed and developed a CPS-protein conjugate vaccine. The lability of a conformationally dependent epitope on the III CPS containing a critical sialic acid residue was important to consider in vaccine design. 100 women were randomized to receive GBS type III CPS-tetanus toxoid conjugate (III-TT) vaccine at one of three doses; unconjugated GBS type III CPS; or saline. Serum samples were obtained before immunization and 2, 4, 8, and 26 wk thereafter, and specific antibody to type III CPS was measured. Vaccines were well tolerated. In sera from recipients of the highest dose of III-TT, CPS-specific IgG levels rose from a geometric mean of 0.09 microg/ml before immunization to 4.53 microg/ml 8 wk later, whereas levels in recipients of unconjugated type III CPS rose from 0.21 microg/ml to 1.41 microg/ml. Lower doses resulted in lower antibody levels. A > or = 4-fold rise in antibody concentration was achieved in 90% of recipients of III-TT compared with 50% of those that received III CPS (P = 0.0015). Antibodies evoked by the conjugate vaccine recognized a conformationally dependent epitope of the III-CPS, promoted opsonophagocytosis and killing of GBS, and, after maternal immunization, protected neonatal mice from lethal challenge with type III GBS. We conclude that directed coupling of type III GBS polysaccharide to a carrier protein yielded a conjugate vaccine with preserved expression of a highly labile conformational epitope involving sialic acid and enhanced immunogenicity compared with uncoupled CPS.