History of biological warfare: catapults to capsomeres.
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Animals↗
Biomedical subjects
L A Miller
Publications and source records attributed to L A Miller.
Biological warfare: role of scientific societies.
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Biological Warfare↗
Effect of interleukin-1 alpha on lipoprotein lipids in cynomolgus monkeys: comparison to tumor necrosis factor.
Acute inflammation is associated with changes in lipoprotein metabolism. Cytokines are thought to mediate the metabolic effects of the inflammatory process. This study was undertaken to compare the effects of interleukin-1 alpha (IL-1 alpha) to tumor necrosis factor (TNF) on lipoprotein metabolism in non-human primates. Recombinant human IL-1 alpha (100 micrograms/kg), TNF alpha (20 micrograms/kg) and lipopolysaccharide (20 micrograms/kg) were injected into cynomolgus monkeys. Lipoprotein concentrations, plasma activities of post-heparin lipase (PHLA) and lecithin:cholesterol acyltransferase (LCAT) were measured prior to and 24 and 48 h after, injection. All three injections caused afebrile response in the animals. Interleukin-1 alpha had no effect on plasma lipoprotein concentrations, composition of lipoproteins or enzyme activity. In contrast, injection of TNF caused significant changes in lipoprotein concentrations. There was a 38% increase in plasma triacylglycerol and 30% decrease in plasma cholesterol at 48 h after injection. Concentrations of apolipoproteins A-I and B were decreased 20% and 44%, respectively, at 48 h. Compositional analyses of lipoprotein particles after TNF injection showed that both the LDL and HDL particles had decreased content of cholesterol ester and increased triacylglycerol after injection, and plasma activities of PHLA and LCAT were decreased. These changes were qualitatively similar to those seen after LPS injection. These data suggest that, unlike TNF, IL-1 alpha is not an important mediator of the inflammatory process on lipoprotein metabolism in cynomolgus monkeys.
Animals↗
Characteristics of taurine transport in cultured renal epithelial cell lines: asymmetric polarity of proximal and distal cell lines.
Taurine transport was determined in two continuous, renal epithelial cell lines: LLC-PK1 derived from the proximal tubule of the pig, and the Madin-Darby canine kidney cell (MDCK) from the distal tubule of the dog. In LLC-PK1, taurine transport is maximal at the apical surface, whereas in MDCK cells, transport is greatest at the basolateral surface. Transport is highly dependent on both sodium and chloride in the external medium, and is specific for beta-amino acids. The apical and basolateral surfaces of both cell lines show an adaptive response to extracellular taurine concentration, but only the basolateral surface of the MDCK cell responds to hyperosomolality by increased taurine accumulation. Thus, differential control of the beta-amino acid transport system by substrate and external tonicity exists. The role of the beta-amino acid transport system may differ according to the origin of the cell: in the proximal renal tubular cell, net transepithelial reabsorption of filtered taurine increases the body pool. By contrast, taurine accumulation by distal tubular cells may form a mechanism of cell volume regulation in response to osmotic stress.
Absorption↗
Impulsivity, risk-taking, and the ability to synthesize fragmented information after frontal lobectomy.
Patients with unilateral frontal- or temporal-lobe excisions and control subjects performed a cognitive risk-taking task in which target items (line-drawings or words) had to be guessed on the basis of partial-information clues. For each item, subjects chose to guess with either one, two, three, or all four clues, for a possible reward of 30, 20, 10, or 5 points, respectively. Two clue-presentation conditions were used to allow the differentiation of risk-taking from impulsivity. Whereas no group obtained high risk-taking scores, patients with frontal-lobe lesions demonstrated impulsive behaviour when manual responses were required. Only the left frontal-lobe group was impaired at solving the clues.
Adult↗
Denver's increase in HIV counseling after Magic Johnson's HIV disclosure.
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Basketball↗
Comparative trial of dapsone versus trimethoprim/sulfamethoxazole for primary prophylaxis of Pneumocystis carinii pneumonia.
The purpose of this study was to compare the efficacy and safety of dapsone and trimethoprim/sulfamethoxazole in the primary prophylaxis of Pneumocystis carinii pneumonia (PCP) in patients infected with the human immunodeficiency virus (HIV) and having less than 200 CD4-positive cells per ml. This was a prospective, randomized, open-label study, using dapsone (100 mg p.o.) or trimethoprim/sulfamethoxazole (160 mg/800 mg p.o.) daily. Patients who developed toxicity requiring discontinuation were offered to cross over to the other study drug. They continued in the study until development of toxicity or documented PCP. Eighty-six patients were enrolled; 47 were randomized to receive dapsone and 39 to receive trimethoprim/sulfamethoxazole. Discontinuation of initial study drug occurred in 33 of the dapsone group and 25 of the trimethoprim/sulfamethoxazole group. Rash was the most common reason for discontinuation. Ten patients crossed over from dapsone to trimethoprim/sulfamethoxazole (4 successfully) and 11 patients crossed over from trimethoprim/sulfamethoxazole to dapsone (6 successfully). During 1,638 patient-months of observation (862 for dapsone and 776 for trimethoprim/sulfamethoxazole), one episode of PCP developed in each group. Both dapsone and trimethoprim/sulfamethoxazole are efficacious for the prophylaxis of PCP in HIV-infected persons with less than 200 CD4-positive cells per ml, but are each associated with significant toxicity. Development of toxicity to one drug does not invariably predict toxicity to the other.
Adult↗
Natural history of hematuria associated with hypercalciuria in children.
Hypercalciuria (HCU) is frequently found during the evaluation of children with hematuria; the long-term implications of untreated HCU in children are uncertain. Since 1981, we have identified HCU (urinary calcium, greater than 0.1 mmol.kg-1.d-1) in 58 patients (41 male) with hematuria; 64% had gross hematuria and 74% had a relative with urolithiasis. Renal HCU was diagnosed in 19 patients and absorptive HCU in 24 patients. In 15 children, the calcium loading test was nondiagnostic. In nine patients (16%), urolithiasis developed, and in one patient, a renal calcification developed. These 10 patients (seven male) were older (10.1 vs 7.5 years) than the other 48 patients and initially presented with gross hematuria (nine of 10). All 10 patients had a family history of urolithiasis. The initial urinary calcium value was similar between the 10 patients with stones (0.15 mmol.kg-1.d-1) and the patients without stones (0.14 mmol.kg-1.d-1); five had absorptive HCU and four had renal HCU. At least one follow-up urinary calcium measurement was available for 23 patients who were not receiving thiazide therapy during 1 to 6 years after diagnosis (mean, 3.1 years). At 1-year follow-up, 12 of 17 patients had HCU and five had hematuria. Twenty-one patients were studied 2 to 3 years from diagnosis; 11 had HCU and eight had hematuria. After 4 years, six of seven patients had HCU and three had hematuria. We concluded that children with HCU and hematuria are at significant risk for urolithiasis, especially if they have gross hematuria and a family history of urolithiasis. Hypercalciuria may be episodic in children with hematuria, and factors other than urinary calcium concentration may be responsible for urinary bleeding.
Calcium Metabolism Disorders↗
Arctiid moth clicks can degrade the accuracy of range difference discrimination in echolocating big brown bats, Eptesicus fuscus.
Four big brown bats (Eptesicus fuscus) born and raised in captivity were trained using the Yes/No psychophysical method to report whether a virtual sonar target was at a standard distance or not. At threshold bats were able to detect a minimum range difference of 6 mm (a delta t of 36 microseconds). Following threshold determinations, a click burst 1.8 ms long containing 5 pulses from the ruby tiger moth, Phragmatobia fuliginosa (Arctiidae), was presented randomly after each phantom echo. The sound energy of the click burst was -4 dB relative to that of the phantom echo. Clicks presented for the very first time could startle naive bats to different degrees depending on the individual. The bats' performance deteriorated by as much as 4000% when the click burst started within a window of about 1.5 ms before the phantom echo. Even when one of ten phantom echoes was preceded by a click burst, the range difference discrimination worsened by 200%. Hence, clicks falling within the 1.5 ms time window seem to interfere with the bat's neural timing mechanism. The clicks of arctiid moths appear to serve 3 functions: they can startle naive bats, interfere with range difference determinations, or they can signal the moth's distastefulness, as shown in earlier studies.
Animals↗
Parallel processing of afferent input by identified interneurones in the auditory pathway of the noctuid moth Noctua pronuba (L.).
1. Interneurones 501 and 504 are identified sound-sensitive interneurones in the pterothoracic ganglion of the noctuid moth Noctua pronuba. Both neurones receive monosynaptic input from the A1 afferent and experiments with current injection suggest that the synapse is chemical. The EPSPs evoked in either IN 501 or 504 by the A1 afferent do not facilitate. 2. Temporal integration in INs 501 and 504 was compared by presenting the moth with tones at repetition rates found in the search, approach and terminal phases of the echolocating call of a hunting bat. INs 501 and 504 differ in their capacity to resolve stimulus repetition rates because the mean decay times of their compound EPSPs differ by a factor of three, although both interneurones receive monosynaptic input from the A1 afferent. 3. The features extracted from the authentic, prerecorded, call of an echolocating bat at the level of the pterothoracic ganglion were examined by recording sequentially from a range of interneurones in the same preparation. The capacity of INs 501 and 504 to encode the various phases of the call was examined in the light of their measured mean decay times and related to the avoidance behaviour of the insect.
Acoustic Stimulation↗
The bacteriophage resistance plasmid pTR2030 forms high-molecular-weight multimers in lactococci.
Lactococcus lactis ME2 can transfer a 46-kb plasmid, pTR2030, which encodes abortive phage infection (Hsp) and restriction/modification (R/M) activities. pTR2030 can be detected as a monomeric plasmid in transconjugants at low copy number, but not in ME2. pTR2030-specific probes were cloned and used to determine the location of the element in ME2. No homology was observed between these pTR2030-specific probes and the CsCl-purified plasmid content of ME2. However, probes specific for pTR2030 hybridized strongly to a high-molecular-weight moiety, and not to chromosomal DNA, in total DNA isolated by a gentle lysis procedure. The absence of junction fragments indicates that pTR2030 forms high-molecular-weight multimers in lactococci. A phage-sensitive derivative of ME2, L. lactis N1, is cured of pTR2030 and no longer possesses the high-molecular-weight species. When pTR2030 was reintroduced to N1 via conjugation, an ME2-like phage-insensitive phenotype was restored. pTR2030 could remain as a detectable monomeric plasmid in the N1 transconjugants or could revert to the high-molecular-weight structure.
Bacteriophages↗
Epitope mapping of the anti-human progesterone receptor monoclonal antibody, AB-52.
The monoclonal antibody AB-52 has high affinity and specificity for the two natural human progesterone receptor forms, receptor A (hPRA) and receptor B (hPRB), but it does not bind the PR of chick, mice, rats or rabbits. We have used a novel method to map its epitope. Based on a series of site-directed mutants of hPRA, together with immunoblotting, DNA gel mobility shift and antibody super shift assays, we have mapped the epitope of AB-52 to a 17 amino acid sequence lying between Val221 and Leu237 of the 933 amino acid hPRB protein. This N-terminal sequence is common to both hPRB and hPRA but is missing in chick PR and differs extensively from mouse PR. No anti-rabbit PR antibodies map to the homologous rabbit PR sequence which differs from hPR by four amino acids, suggesting that one or more of these four amino acids form a critical subset of residues in hPR that define the human specificity of AB-52. Knowledge of the AB-52 epitope is useful in structural analysis of PR, and in competition studies. Additionally, this 17 amino acid peptide whose antigenicity would not be predicted from computer analysis, should be useful for generating additional hPR specific antibodies.
Amino Acid Sequence↗
In vivo genetic exchange of a functional domain from a type II A methylase between lactococcal plasmid pTR2030 and a virulent bacteriophage.
The conjugative plasmid pTR2030 confers bacteriophage resistance to lactococci by two independent mechanisms, an abortive infection mechanism (Hsp+) and a restriction and modification system (R+/M+). pTR2030 transconjugants of lactococcal strains are used in the dairy industry to prolong the usefulness of mesophilic starter cultures. One bacteriophage which has emerged against a pTR2030 transconjugant is not susceptible to either of the two defense systems encoded by the plasmid. Phage nck202.50 (phi 50) is completely resistant to restriction by pTR2030. A region of homology between pTR2030 and phi 50 was subcloned, physically mapped, and sequenced. A region of 1,273 bp was identical in both plasmid and phage, suggesting that the fragment had recently been transferred between the two genomes. Sequence analysis confirmed that the transferred region encoded greater than 55% of the amino domain of the structural gene for a type II methylase designated LlaI. The LlaI gene is 1,869 bp in length and shows organizational similarities to the type II A methylase FokI. In addition to the amino domain, upstream sequences, possibly containing the expression signals, were present on the phage genome. The phage phi 50 fragment containing the methylase amino domain, designated LlaPI, when cloned onto the shuttle vector pSA3 was capable of modifying another phage genome in trans. This is the first report of the genetic exchange between a bacterium and a phage which confers a selective advantage on the phage. Definition of the LlaI system on pTR2030 provides the first evidence that type II systems contribute to restriction and modification phenotypes during host-dependent replication of phages in lactococci.
Amino Acid Sequence↗
Regulation of taurine transporter activity in LLC-PK1 cells: role of protein synthesis and protein kinase C activation.
Taurine transporter activity increases after exposure of cultured renal epithelial cells to taurine-free medium for 24 h and decreases after incubation in high (500 microM) taurine. This adaptive response mimics that observed in rat kidney after manipulation of dietary taurine. In order to elucidate potential mechanisms involved in the regulation of beta-amino acid transporter activity, the role of RNA transcription, protein synthesis, and protein import (trafficking), as well as protein kinase C activation, on the control of taurine transport was examined in the continuous proximally derived LLC-PK1 renal cell line. Inhibition of RNA transcription with actinomycin D did not alter the up-regulatory and down-regulatory adaptive responses. Inhibition of protein synthesis with cycloheximide prevented the increased taurine transport in response to taurine-free medium as well as the decrease in taurine transport after exposure to high taurine. Colchicine prevented the response to taurine-free medium but had no effect on the response to high-taurine medium. Exposure of confluent cell monolayers to the active phorbol esters, phorbol 12-myristate 13-acetate and phorbol 12,13 dibutyrate, resulted in a reduction in taurine uptake. The effect was seen within minutes of exposure but was not observed in the presence of the inactive phorbol 4-alpha. This inhibitory action was blocked by staurosporin, an inhibitor of protein kinase C (PKC). Treatment of cells with the diacylglycerol kinase inhibitor R59022, which results in increased intracellular diacylglycerol, a natural stimulant of PKC, also inhibited taurine uptake, providing further evidence for a specific effect of PKC activation.(ABSTRACT TRUNCATED AT 250 WORDS)
Amiloride↗
The future of calcium channel blocker therapy in diabetes mellitus.
Diabetes mellitus is associated with significant morbidity and mortality caused by the micro- and macro-vascular complications that all too frequently develop during the lifetime of the diabetic patient. In attempts to treat the complications of diabetes, several different treatment strategies have been investigated. The role of tight blood glucose control in the treatment of diabetic vascular complications has recently been challenged, as the existing data in support of this mode of therapy are currently inconclusive. Perhaps more effective in preventing many of the vascular complications is the rigorous treatment of hypertension that frequently accompanies diabetes mellitus. Epidemiological studies have demonstrated that the presence of hypertension significantly contributes to the development and progression of diabetic nephropathy, retinopathy, cardiovascular disease, and possibly neuropathy. Preliminary clinical studies demonstrate that the progression of diabetic renal disease can be slowed by vigorous antihypertensive therapy. Among the various antihypertensive agents used to treat the hypertension associated with diabetes mellitus, calcium channel blockers are emerging as one of the agents of first choice. This is because of their very low side effect profile and their absence of detrimental effects on serum lipid levels and glucose tolerance. Calcium channel blockers may be of additional potential benefit to the diabetic patient by slowing the progression of atherosclerosis, reversing the intracellular calcium defects that may contribute to the pathogenesis of diabetic cardiomyopathy, and protecting against the progression of chronic renal disease.
Calcium Channel Blockers↗
T47DCO cells, genetically unstable and containing estrogen receptor mutations, are a model for the progression of breast cancers to hormone resistance.
We postulate that one mechanism for the progression of breast cancers to hormone resistance involves the acquisition of mutant estrogen receptors (ER)4 by genetically unstable cell subpopulations. The T47D human breast cancer cell line may be a model for such progression, having sublines that are ER positive and estrogen responsive, ER positive and estrogen resistant, or ER negative. Also, T47D cells can be either hyperdiploid (HD) or hypertetraploid (HT) or persistently alternate between these states. T47DCO cells are a HD and ER-positive, but estrogen-resistant, subline of T47D cells that undergoes spontaneous tetraploidization. Such a stable variant, designated T47Dv, is 85% HT (Cancer Res., 49: 3943, 1989). We now show that single-cell clones derived from the mixed HD/HT T47Dv can be either HD or HT, and can be either estrogen responsive or estrogen resistant, for growth and for progesterone receptor regulation. To begin the study of ER in this model system of T47DCO and their derivatives, we have generated complementary DNA libraries from the parental HD T47DCO cells and have isolated three ER complementary DNA mutants. These include two frame-shift/termination mutants that would encode ERs truncated in the DNA-binding domain and in the hormone-binding domain and a third mutant with a large in-frame deletion spanning the hinge region and a part of the hormone-binding domain. If expressed, these mutant ERs would lack hormone-binding capacity and would be undetected by the anti-ER antibodies currently in clinical use. Genetic instability, when associated with mutant ERs in subpopulations of breast tumor cells, may provide the selective pressure leading to hormone resistance. T47DCO cells and their clonal derivatives provide a model for the systematic study of ER mutations and other mechanisms of hormone resistance in Stage IV breast cancer.
Amino Acid Sequence↗
Adaptive regulation of taurine transport in two continuous renal epithelial cell lines.
Taurine is actively transported by a beta-amino acid transporter located on the proximal tubule apical surface. We have characterized taurine transport into confluent monolayers of two continuous renal epithelial cell lines: LLC-PK1, a cell of porcine proximal tubular origin, and the Madin-Darby canine kidney cell line (MDCK) of distal origin. Taurine uptake is linear up to 90 minutes in LLC-PK1 cells and 180 minutes in MDCK cells. This process is highly dependent upon Na+ as the cation and either Cl- or Br- as the anion. Taurine uptake is inhibited by another beta-amino acid, beta-alanine, to a greater extent than the alpha-analog, L-alanine or other alpha-amino acids. Incubation of cell monolayers with taurine-free medium (0 microM taurine) induces an increase in Na(+)-dependent taurine uptake when compared to cells exposed to standard medium (50 microM taurine). When cells were incubated in medium containing high taurine (500 microM), uptake was decreased as compared to control cells. This adaptive response is evident by 12 hours in both cell lines and is the result of changes in the apparent transport maximum (Jmax) rather than the apparent Km for taurine. The changes in transport observed after manipulation of medium taurine concentration were not associated with differences in taurine efflux. In summary, taurine is transported by a beta-specific, Na-Cl dependent process in both renal epithelial cell lines. Although the factors which regulate taurine transport are not known, an increased transport maximum is observed in cells which have been taurine-starved, and a decreased Jmax is seen in cells supplied with excess taurine.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Transport Systems↗
Nucleotide sequence and distribution of the pTR2030 resistance determinant (hsp) which aborts bacteriophage infection in lactococci.
The lactococcal plasmid pTR2030 encodes resistance to bacteriophage attack via two mechanisms, an abortive-infection mechanism, designated Hsp, and a restriction and modification system. We present the complete sequence of the hsp structural gene. The gene is 1,887 base pairs in length and encodes a protein with a predicted molecular mass of 73.8 kilodaltons. The upstream region was cloned in a promoter-screening vector and shown to direct the constitutive expression of the cat-86 gene. An internal probe was used to determine the distribution of the hsp sequence in industrially significant lactococcal strains and to evaluate its relatedness to another lactococcal plasmid implicated in an abortive-infection-type mechanism, pNP40. No homology was detected, suggesting that this gene is not widely distributed in lactococci. Therefore, there are at least two independent abortive-infection genotypes in lactococci.
Amino Acid Sequence↗