Intriguing structure-activity relations underlie the potent inhibition of HIV protease by norstatine-based peptides.
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Aminocaproates↗
Biomedical subjects
H Chan
Publications and source records attributed to H Chan.
Different spatial tunings for ON and OFF pathway stimulation.
We compared the spatial tuning of sensitivity to luminance increments and decrements in three types of localized stimulus presentation with a smooth spatiotemporal envelope. The first type consisted of spatiotemporal Gabor grating functions with either a positive or a negative bias in luminance. The spatial tuning showed a substantially narrower bandwidth and greater peak sensitivity for the positive Gabors. A similar description could be applied to the results for detection of spots with a 2-D difference-of-Gaussian profile, although the shape of the tuning function differed in several respects. We also used the biased Gabor modulation in a contrast self-masking paradigm, where the increment (or decrement) was presented against a steady background with the same spatial configuration, over a range of base contrasts. At medium spatial frequencies the biased masking functions were similar to those typically found for unbiased gratings, in showing a threshold facilitation (dipper) at low contrast, and sub-Weber masking behaviour at higher contrasts. At low spatial frequencies, however, a pronounced asymmetry appeared. Stimuli with a positive bias again showed typical masking behaviour, but a virtually flat masking function was obtained for negative bias stimuli. We conclude that stimuli without abrupt luminance transients reveal pronounced differences in the spatial tuning of responses to positive and negative stimuli, which probably reflect differences in the neural connectivity of the ON and OFF processing systems.
Contrast Sensitivity↗
Sonography in thyroid carcinoma in children.
This paper reviews the clinical, sonographic and pathological findings of 20 children with thyroid carcinoma in an attempt to determine the value and limitations of sonography in thyroid neoplasms in this age group. Although sonography is an excellent technique for the evaluation of thyroid disorders and masses, certain limitations must be kept in mind. Microscopic foci of tumour might be missed and sonography cannot predictably differentiate benign from malignant disease. Previous radiation exposure should increase the level of suspicion for malignancy.
Adenocarcinoma↗
Color appearance across the retina: effects of a white surround.
Hue and saturation scaling was used to measure the appearance of spectral lights as a function of stimulus size at loci spaced across the horizontal meridian. At a given locus, each hue (red, yellow, green, and blue) grew as a function of stimulus size to some asymptotic value. Growth functions fitted to the hue data were used to derive the sizes of perceptive fields of the hue mechanisms. We had previously investigated the size scales of these fields by using stimuli presented on a dark background: Field sizes for all mechanisms increased with eccentricity, this increase was greater on the temporal than on the nasal retina, and the retinal size scales of the different hue mechanisms were not the same. We now report the results of repeating the study with stimuli embedded in a white surround rather than in darkness. The main effects of the white surround were as follows: Sizes of perceptive fields of all mechanisms were smaller everywhere than with the dark surround. For small fields, stimuli appeared everywhere more saturated with the white surround, but larger stimuli appeared less saturated.
Adolescent↗
Cationic lipids enhance cellular uptake and activity of phosphorothioate antisense oligonucleotides.
We have investigated the use of a cationic lipid preparation to enhance antisense oligonucleotide activity in human umbilical vein endothelial cells. A liposomal preparation containing the cationic lipid N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) was found to increase by at least 1000-fold the potency of an antisense oligonucleotide (ISIS 1570) that hybridizes to the AUG translation initiation codon of human intercellular adhesion molecule-1. In the presence of 8 microM DOTMA, 6-15-fold more 35S-ISIS 1570 associated with cells, at oligonucleotide concentrations from 0.01 to 5 microM, than did in the absence of DOTMA. Both 35S-ISIS 1570 association with cells and antisense activity were increased as a function of DOTMA concentration and with increasing time of incubation with the cationic lipid. Fluorescein-labeled ISIS 1570 was used to assess the intracellular distribution of the oligonucleotide in the presence and absence of DOTMA. In the absence of DOTMA, the oligonucleotide localized to discrete structures in the cytoplasm of the cell, resulting in a punctate fluorescence pattern. In the presence of DOTMA, cellular fluorescence markedly increased and the oligonucleotide localized within the nucleus, as well as to discrete structures in the cytoplasm. Accumulation of the oligonucleotide in the nucleus in the presence of DOTMA was time and temperature dependent. Nuclear accumulation was inhibited by preincubation of the cells with monensin but not chloroquine, NH4Cl, nocodazole, colcemid, or brefeldin A. These data demonstrate that cationic lipids increase antisense activity by increasing the amount of oligonucleotide associated with cells and altering intracellular distribution of the oligonucleotide.
Base Sequence↗
Copper deficiency and microcytic anemia resulting from prolonged ingestion of over-the-counter zinc.
Isolated copper deficiency occurred in a 57-yr-old man who had ingested massive quantities of zinc for more than 18 months. The patient presented with microcytic anemia and had normal gastrointestinal function with no evidence of occult blood loss. Dietary zinc in large doses leads to copper deficiency by antagonizing copper absorption. With discontinuance of zinc, the anemia and hypocupremia promptly corrected. The relationship between zinc, copper deficiency, and iron metabolism is reviewed.
Anemia↗
Antisense oligonucleotides inhibit intercellular adhesion molecule 1 expression by two distinct mechanisms.
Intercellular adhesion molecule 1 (ICAM-1) is a glycoprotein expressed on the surface of both hemopoietic and nonhemopoietic cells that mediates, in part, the emigration of leukocytes out of the vasculature. Expression of ICAM-1 on the surface of human umbilical vein endothelial cells and a human lung carcinoma cell line (A549) was increased by interleukin-1 beta, tumor necrosis factor alpha, and interferon gamma in a concentration-dependent manner. Phosphorothioate antisense oligonucleotides designed to hybridize to 10 target sites on the human ICAM-1 mRNA were tested for inhibition of ICAM-1 expression in both cell lines by an ICAM-1 enzyme-linked immunosorbent assay. Based upon potency and unique mRNA target sites, two oligonucleotides were studied in greater detail: ISIS 1570, which targeted the AUG translation initiation codon, and ISIS 1939, which targeted specific sequences in the 3'-untranslated region of the mRNA. Both oligonucleotides specifically inhibit expression of ICAM-1 as analyzed by immunoprecipitation of 35S-labeled proteins. Treatment of cells with ISIS 1939 promoted a reduction in ICAM-1 mRNA, whereas ISIS 1570 did not change the level of ICAM-1 mRNA, suggesting that the two oligonucleotides may be inhibiting ICAM-1 expression by two different mechanisms. The activity of both oligonucleotides was blocked by hybridization of the oligonucleotide to its complementary sense strand prior to addition to the cells. Neither ISIS 1570 nor ISIS 1939 changed the transcriptional rate of the ICAM-1 gene, demonstrating that both oligonucleotides were working through a post-transcriptional mechanism. 2'-O-Methyl phosphorothioate analogs, which do not support RNase H-mediated cleavage of target mRNA, were used to determine if the active antisense oligonucleotides inhibited ICAM-1 expression by an RNase H-dependent mechanism. The 2'-O-methyl phosphorothioate analog of ISIS 1939 did not significantly reduce interleukin-1 beta-induced ICAM-1 expression, whereas the 2'-O-methyl phosphorothioate analog of ISIS 1570 did inhibit ICAM-1 expression, suggesting that the reduction of ICAM-1 mRNA following treatment with ISIS 1939 was due, in part, to RNase H-mediated hydrolysis. Adherence of HL-60 cells to human umbilical vein cell monolayers was inhibited by ISIS 1570 and ISIS 1939, demonstrating that the reduced levels of ICAM-1 impact on ICAM-1-associated function.
Amino Acid Sequence↗
Preoperative chemotherapy for children with Wilms' tumor.
Five years ago, the use of preoperative chemotherapy for Wilms' tumor was adopted at this institution. Thirty children ranging in age from 5 months to 9 years had histologically confirmed Wilms' tumor (needle biopsy, n = 26; open biopsy, n = 4). Stage was determined by chest and abdominal computed tomography (CT) scan. Bilateral tumors were present in 6 children. All children received actinomycin D and vincristine from 3 weeks to 6 months before surgery. Seven children with bilateral tumors or stage IV disease also received adriamycin. CT-measured tumor masses shrunk in most cases. Subsequently, nephrectomy was performed in 23 patients and partial nephrectomy in 4, 2 of whom had bilateral disease. In 2 patients, residual bilateral well-differentiated epithelial tumor was not surgically resected. One child died before surgery. Reevaluation at delayed total or partial nephrectomy resulted in a downstaging of disease in 12 (41%). Further chemotherapy and radiation was based on the surgical stage. Postoperative chemotherapy (4 months to 2 years) was administered to all patients. The chest and/or abdomen were radiated in 12. Four patients (13%) died, 1 of radiation pneumonitis and 3 of the disease progression (2 with unfavorable histology, 1 of whom had bilateral disease). Two of 4 with unfavorable histology and 4 of 6 with stage IV disease have survived. It is concluded that this preoperative chemotherapy protocol is as effective as the National Wilms' Tumor Study (NWTS) protocol. The treated tumor is smaller, less friable, and easier to remove. Furthermore, because of downstaging, less radiation is necessary for cure.
Biopsy, Needle↗
Differences in mediator release between allergic rhinitis and asthma.
To determine why patients with allergic rhinitis alone differ in their airway response to inhaled allergen compared to patients with allergic asthma, bronchial lavage was performed in 10 subjects with allergic asthma and in five subjects with allergic rhinitis, before and after inhalation challenge with antigen to produce an immediate asthmatic reaction. Before antigen challenge, the subjects with asthma had higher absolute neutrophil counts in the lavage fluid. After antigen challenge, the subjects with asthma released significant amounts of bronchoconstrictive mediators, such as histamine and thromboxane B2 into the lavage fluid, whereas subjects with rhinitis alone did not. There was also a significant increase in prostaglandin E2 in the subjects with asthma after antigen challenge. Nonimmunologic bronchoconstriction with methacholine inhalation challenge in six other subjects with asthma did not demonstrate an increase in any of the lavage fluid mediator levels that were measured. A positive correlation was found between methacholine provocative concentration causing a 20% drop in FEV1 and the concentration of prostaglandin E2 in the lavage fluid before challenge. The significance of this observation has yet to be determined. The results suggest that subjects with allergic asthma differ from subjects with rhinitis alone in their capacity to release more mediators into the airways on antigen challenge. It is not known whether this increase in mediators is due to increase in the number of mast cells in the airways or due to increase in mediator releasability from the mast cells of subjects with asthma.
Adult↗
Reassessment of the temporal patterns of bronchial obstruction after exposure to occupational sensitizing agents.
Typical asthmatic reactions after exposure to common or occupational allergens have been classified as isolated immediate, early late, late, and dual (Pepys and Hutchcroft, 1975). Atypical reactions can also occur, but their temporal behavior and frequency are unknown. We analyzed 69 bronchospastic reactions after exposure to three types of occupational sensitizers in the laboratory: isocyanates, western red cedar, and IgE sensitizing agents. Graphs of the reactions were presented to three observers in a blind, randomized way. Reactions were defined as follows: (1) typical patterns, that is, isolated immediate, early late, late, and dual, as put forward by Pepys and Hutchcroft, and (2) atypical patterns including progressive (onset, during, or minutes after exposure, progressing to a maximum reaction 5 to 6 hours later) and square waved (similar to a dual reaction but with only partial recovery [less than 10%] between the immediate and late falls in FEV1). Some curves were also analyzed by polynomial regression. The three observers agreed in 59/69 cases (86%), and a consensus was reached after discussion for the remaining subjects. Fifteen of 63 (22%) reactions were atypical. IgE-mediated reactions and reactions to red cedar were, respectively, mainly of the immediate and late types. The distribution of reactions to isocyanates, however, was significantly different (chi-square, 6.1; p = 0.01), the "progressive" pattern occurring in 7/23 instances (30%). There was a satisfactory concordance between visual assessment and polynomial fit analysis in distinguishing dual from square-waved reactions. We conclude that isocyanates frequently cause atypical progressive bronchospastic reactions that are rarely observed after exposure to IgE agents and western red cedar.
Adult↗
The release of platelet-activating factor into plasma during allergen-induced bronchoconstriction.
Plasma histamine and platelet-activating factor (PAF) were measured in six subjects with mild seasonal asthma before and after allergen-induced bronchoconstriction, and in six other patients with asthma before and after methacholine-induced bronchoconstriction. A significant increase in plasma histamine and PAF levels was found in patients with mild seasonal asthma after allergen-induced bronchoconstriction but not in patients with asthma after bronchoconstriction induced by methacholine. There was a significant correlation between the baseline plasma PAF levels and the degree of bronchial hyperresponsiveness to methacholine. These findings suggests that PAF may be an important mediator in the pathogenesis of asthma and bronchial hyperresponsiveness.
Biological Assay↗
Binding of IgG to B cell via HLA molecules.
Binding of immunoglobulins to major histocompatibility complex (MHC) molecules was demonstrated by two different assays: the binding of IgG to B cells by flow cytometry, and purified MHC antigens with an Elisa assay. Fc fragment from immune-complex binds to the Fc receptor on B lymphocytes. Here, Fab was also shown to bind to B cells. This binding was inhibited by specific human allo anti-HLA Class I and II sera directed at the polymorphic sites. Thus, in addition to the Fc receptor, MHC can also serve as a binding site for IgG. In an Elisa assay using purified antigens, IgG was shown to bind to HLA Class I and II molecules. Other proteins such as transferrin, human serum albumin, gelatin, etc., did not bind to the MHC proteins. Immunoglobulins bound to MHC molecules by sites on the Fab fragment independent of the hypervariable region. This was demonstrated by the retention of antibody activity even after binding of antibody (anti-lactoferrin) to MHC. The relative avidity between Fab and HLA Class I and II was 4-8 x 10(5) M-1.
B-Lymphocytes↗
Retrovirus-induced interference with collagen I gene expression in Mov13 fibroblasts is maintained in the absence of DNA methylation.
We have studied the role of DNA methylation in repression of the murine alpha 1 type I collagen (COL1A1) gene in Mov13 fibroblasts. In Mov13 mice, a retroviral provirus has inserted into the first intron of the COL1A1 gene and blocks its expression at the level of transcriptional initiation. We found that regulatory sequences in the COL1A1 promoter region that are involved in the tissue-specific regulation of the gene are unmethylated in collagen-expressing wild-type fibroblasts and methylated in Mov13 fibroblasts, confirming and extending earlier observations. To directly assess the role of DNA methylation in the repression of COL1A1 gene transcription, we treated Mov13 fibroblasts with the demethylating agent 5-azacytidine. This treatment resulted in a demethylation of the COL1A1 regulatory sequences but failed to activate transcription of the COL1A1 gene. Moreover, the 5-azacytidine treatment induced a transcription-competent chromatin structure in the retroviral sequences but not in the COL1A1 promoter. In DNA transfection and microinjection experiments, we found that the provirus interfered with transcriptional activity of the COL1A1 promoter in Mov13 fibroblasts but not in Xenopus laevis oocytes. In contrast, the wild-type COL1A1 promoter was transcriptionally active in Mov13 fibroblasts. These experiments showed that the COL1A1 promoter is potentially transcriptionally active in the presence of proviral sequences and that Mov13 fibroblasts contain the trans-acting factors required for efficient COL1A1 gene expression. Our results indicate that the provirus insertion in Mov13 can inactivate COL1A1 gene expression at several levels. It prevents the developmentally regulated establishment of a transcription-competent methylation pattern and chromatin structure of the COL1A1 domain and, in the absence of DNA methylation, appears to suppress the COL1A1 promoter in a cell-specific manner, presumably by assuming a dominant chromatin structure that may be incompatible with transcriptional activity of flanking cellular sequences.
Animals↗
Occupational asthma caused by exposure to neurospora in a plywood factory worker.
A 24 year old man developed severe asthma two years after starting to work in a plywood plant. Four years later the patient had to stop working because of the increasing severity of his asthma. Three months after leaving his job, the patient's asthma was greatly improved. His job consisted of placing plywood sheets into a drying machine. The plywood sheets had stayed outside in wet conditions for at least four to six weeks and were usually covered with moulds. Drying the plywood sheets changed the mould into a fine orange powder. Exposure to this in the laboratory induced an isolated immediate asthmatic reaction. The same reaction was seen when the patient was challenged with an extract of the mould powder at a 0.1% w/v concentration. Skin prick test with the mould extract induced a weal and flare reaction and IgE antibodies against the dry mould powder were identified. A control patient with the same degree of bronchial hyperreactivity did not have any asthmatic reaction when challenged with the same mould extract. Culture of the dry mould powder on Sabouraud agar plates grew pure Neurospora sp. This mould has not been previously reported as a cause of occupational asthma. The immunological mechanism is probably related to an IgE mediated mast cell allergy.
Adult↗
Color appearance in the peripheral retina: effects of stimulus size.
Hue and saturation scaling were used to measure the appearance of spectral lights as a function of stimulus size for nine loci across the horizontal retinal meridian. At a given locus, each hue (R, Y, G, and B) grew as a function of stimulus size up to some asymptotic value. The parameter values of Michaelis-Menten growth functions fitted to the hue data were used to derive the sizes of the so-called perceptive fields of the hue mechanisms. The fields for all mechanisms increased with eccentricity, and this increase was greater on the temporal than on the nasal retina. By increasing stimulus size it was possible to achieve fovealike color vision to eccentricities of 20 deg. However, even the largest stimuli failed to produce fully saturated hues at 40 deg. The retinal size scales of the four hue mechanisms were not the same; those for R and B were similar, and these mechanisms had the smallest perceptive fields everywhere. The perceptive fields of the hue mechanisms at all loci were larger than anatomical estimates of the sizes of retinal receptive fields.
Adolescent↗
Hodgkin's disease in children: treatment with MOPP and low-dose, extended field irradiation without laparotomy. Late results and toxicity.
The 10 year results of a trial of bimodal treatment of Hodgkin's disease in children with 6 cycles of MOPP and low-dose extended field irradiation, without staging laparotomy, were for 57 children in all stages as follows: survival 85%, relapse-free survival 80%, and survival-free of second relapse 86%. There were three fatal toxic events, two due to viral infection and one to a second malignant tumor (NHL). Three other patients developed a second malignant tumour, and one developed a thyroid adenoma. No patient developed acute leukemia. These results are compared with the results of treatment of surgically staged children by extended field irradiation alone, with bimodal treatment reserved for relapse or advanced disease at diagnosis. Initial bimodal treatment improved the overall 10 year survival free from a second relapse rate by 20% (86% vs. 66%). No major difference in treatment toxicity between these two groups has emerged during the first 10 years of follow-up. We conclude that, except for favourable CS-1 presentations, children with Hodgkin's disease confined to the lymphatic system should be given bimodal treatment, but that the least morbid effective combination remains to be determined.
Adolescent↗
Human beta nerve growth factor obtained from a baculovirus expression system has potent in vitro and in vivo neurotrophic activity.
A baculovirus expression vector, which contains the coding sequences for human prepro (beta) nerve growth factor under control of the viral polyhedrin promoter, was constructed. Upon infection of insect cells with the recombinant virus, mature human beta nerve growth factor (rhNGF) was released into the culture fluid. The mature rhNGF was biologically active since rat pheochromocytoma (PC12) and human neuroblastoma (SH-SY5Y) cells were induced to extend neurites upon treatment with this material. This activity was abolished by treating with antiserum prepared against mature mouse beta NGF (mNGF). When compared with mNGF, rhNGF more rapidly elicited the differentiation response in both PC12 and SH-SY5Y cells. In an in vivo assay of cholinergic cell survival, rhNGF was nearly as potent as mNGF in protecting cholinergic neurons from degeneration following a fimbria-fornix lesion. These results show that the baculovirus expression system provides quantities of biologically potent human beta NGF suitable for a comprehensive program of research to ascertain beta NGF's potential as a therapeutic agent for the treatment of Alzheimer's disease.
Animals↗
Two-pulse monocular and binocular interactions at the differential luminance threshold.
Interaction between two pulses at the differential luminance threshold was studied for stimuli pairs presented to the same eye or to opposite eyes with an interocular delay. With monocular stimuli, the results replicated the earlier observations by Ikeda (1965) and Rashbass (1970) indicating linear interaction followed by rectification occurring at about 50-60 msec into the integration epoch. Binocular results were different, in accord with observations made in the contrast domain by Green and Blake (1981). Binocular stimuli of opposite polarity showed no cancellation. Binocular facilitation at threshold was found when either the stimuli of the same sign (+ + or - -) occurred with little interocular delay (stimulus onset asynchrony, SOA less than 15 msec), or the stimuli of the opposite sign (+ - or - +) were presented with an interocular delay between 15 and 100 msec SOA; the latter effect was at maximum with flashes 50 msec in duration presented with 50 msec interocular SOA. These results imply that binocular interaction takes place between rectified internal effects of luminance pulses. From the two-channel binocular model of Cogan (1987), binocular facilitation is attributed to the "fused" response derived from multiplicative excitation between same-sign (half-wave rectified), internal pulse responses. The absence of cancellation between simultaneous opposite-sign dichoptic stimuli is attributed to the "either-eye" binocular process dealing with full-wave rectified internal pulse responses to transient stimuli.
Humans↗