Homeobox genes and heart development.
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Animals↗
Biomedical subjects
S Palmer
Publications and source records attributed to S Palmer.
Antibiotic treatment for infective endocarditis.
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Anti-Bacterial Agents↗
Altruism by proxy: volunteering children for bone marrow donation.
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Bone Marrow Transplantation↗
Structural variation of the pseudoautosomal region between and within inbred mouse strains.
The pseudoautosomal region (PAR) is a segment of shared homology between the sex chromosomes. Here we report additional probes for this region of the mouse genome. Genetic and fluorescence in situ hybridization analyses indicate that one probe, PAR-4, hybridizes to the pseudoautosomal telomere and a minor locus at the telomere of chromosome 9 and that a PCR assay based on the PAR-4 sequence amplifies only the pseudoautosomal locus (DXYHgu1). The region detected by PAR-4 is structurally unstable; it shows polymorphism both between mouse strains and between animals of the same inbred strain, which implies an unusually high mutation rate. Variation occurs in the region adjacent to a (TTAGGG)n array. Two pseudoautosomal probes can also hybridize to the distal telomeres of chromosomes 9 and 13, and all three telomeres contain DXYMov15. The similarity between these telomeres may reflect ancestral telomere-telomere exchange.
Animals↗
Developmental differences and regional similarities in the responses of rat cardiac skinned muscles to acidosis, inorganic phosphate and caffeine.
The Ca2+ sensitivity of cardiac myofibrillar force production can be decreased by acidosis or inorganic phosphate (P(i)) and increased by caffeine. To investigate whether the source of tissue influences the potency of these agents, we compared the actions of acidosis (change of pH from 7.0 to 6.2), P(i) and caffeine (both 20 mM) on force production of skinned cardiac muscles from adult ventricle, adult atrium and neonate ventricle of the rat. Maximum Ca(2+)-activated force was reduced by all three interventions and the responses of the different muscle types to a given intervention were similar. Acidosis reduced myofibrillar Ca2+ sensitivity by 1.09 and 1.04 pCa units in adult ventricle and atrium, respectively, and P(i) reduced it by 0.19 and 0.22 pCa units. However, each effect was only one-third as great in the neonate ventricle, which showed falls of 0.33 pCa units for acidosis and 0.06 for P(i). In contrast, caffeine raised the Ca2+ sensitivity by the same amount (approximately 0.4 pCa units) in all three muscle types. The differential effect between adult and neonate seen with both acidosis and P(i) suggests some similarity in the mechanisms by which these factors decrease Ca2+ sensitivity. In contrast, the equal effects of caffeine on neonate and adult suggests that caffeine acts by a completely different mechanism. The lower pH- and P(i)-sensitivity of the neonatal ventricle can help to explain why neonatal and adult myocardium exhibit differential force responses to ischaemia (or hypoxia alone).
Acidosis↗
The novel inotropic agent CGP 48506 alters force primarily by Ca(2+)-independent mechanisms in porcine skinned trabeculae.
OBJECTIVES: The aim was to determine whether, and by what mechanism(s), a novel inotropic agent 5-methyl-6-phenyl-1,3,5,6-tetrahydro-3, 6-methano-1,5-benzodiazocine-2,4-dione (BA 41899) and its enantiomers directly alter the Ca2+ sensitivity of cardiac myofilaments. METHODS: Porcine ventricular trabeculae were permeabilised with Triton X-100. The relationship between force and pCa (-log[Ca2+]) was determined in the presence and absence of ATP. Troponin I was extracted, using vanadate, to produce unregulated maximally activated myofilaments. Force and actomyosin ATPase activity were measured simultaneously to determine tension cost (ATPase activity/tension). The effects of the (+) enantiomer (CGP 48506) on the twitch of intact muscle were demonstrated using rat papillary muscle. RESULTS: 100 microM BA 41899 had a pronounced Ca2+ sensitising effect on force production by porcine skinned cardiac fibres, increasing the pCa required for 50% maximal activation by 0.64 units, while suppressing maximum force by 18.3%. Resting tension was unaffected. These actions were primarily caused by CGP 48506 and were concentration dependent. At concentrations less than 100 microM, CGP 48506 also increased twitch amplitude in intact papillary muscles with no effect on resting tension, whereas 100 microM CGP 48506 increased resting force due to a slowing of relaxation. 100 microM CGP 48506 potentiated Ca(2+)-independent rigor tension in skinned trabeculae, indicating a Ca2+ sensitising mechanism unrelated to Ca2+ binding to troponin C. Tension cost was unaffected by 100 microM CGP 48506 over the entire range of activating Ca2+ concentrations. Suppression of maximum force by CGP 48506 was independent of both Ca2+ concentration and the regulatory troponin complex. CONCLUSIONS: Both the increase in Ca2+ sensitivity during submaximal activation and the depression of maximum force which are induced by CGP 48506 in skinned trabeculae occur at least partly through Ca(2+)-independent mechanisms.
Actin Cytoskeleton↗
Imaging of cervical spine trauma.
The cervical spine, supporting such critical structures as the medulla, spinal cord, and cervical nerve roots, can be very challenging to image properly because of its complex structural anatomy and superimposition of bony and soft tissue parts. In this article, the use and value of the various modalities that image the cervical spine are discussed. Plain radiography remains the best screening tool in the initial evaluation of the cervical spine after trauma. Additional views, such as swimmer's, pillar and lateral flexion, and extension, often are helpful in certain circumstances.
Adult↗
Problems in the diagnosis of foodborne infection in general practice.
The incidence of acute gastroenteritis and self suspected food poisoning in general practice populations was compared with consultation rates in four group practices during a 3-month winter period and a 2-month autumn period. The average monthly consultation rate for acute gastroenteritis and self suspected food poisoning was 0.3% and 0.06% respectively. However, over the same period, on average, an estimated 7% of the practice population per month reported an acute gastroenteritis illness, and 0.7% suspected a food poisoning illness. Only about one in 26 people who suffer an acute episode of gastroenteritis consult their general practitioner (GP). In two practices, faecal samples were sought from all patient cases; the isolation rate for salmonellas was 2% (3/191) and for campylobacters it was 12% (23/191). In the other two practices following routine management, the isolation rate for salmonellas was 9% (6/64) and for campylobacters it was 2% (1/64). Isolation of faecal pathogens was not associated with patients' suspicion of food poisoning. A history of eating out in the week before onset was associated with a significantly increased yield of salmonellas and campylobacters.
Adolescent↗
Photolysis of the novel inotropes EMD 57033 and EMD 57439: evidence that Ca2+ sensitization and phosphodiesterase inhibition depend upon the same enantiomeric site.
1. We studied the effects of flash photolysis on the novel enantiomeric cardiac inotropes EMD 57033 (a calcium sensitizer) and EMD 57439 (a phosphodiesterase III inhibitor) in rat isolated ventricular trabeculae. 2. In skinned trabeculae, EMD 57439 had no effect on force production, consistent with lack of an active cyclic AMP system in this preparation. In contrast, EMD 57033 potentiated force at partial and maximal activation. A single flash of near u.v. light given at partial activation (30-70%) reduced force potentiation by 52.4 +/- 5.2%. No effect was produced by flashes in the presence of EMD 57439 or in the absence of either drug. 3. The time course of relaxation induced by EMD 57033 photolysis was indistinguishable from that obtained on deactivating the muscle by rapidly lowering Ca2+ using photolysis of the caged chelator of calcium, diazo-2. 4. In intact, twitching trabeculae, EMD 57033 increased diastolic and peak force and slowed relaxation. These effects were simultaneously reduced by a light flash. In these muscles EMD 57439 reduced force, without affecting the twitch time course. These effects were also reduced by a light flash. 5. The u.v. absorbance spectra of EMD 57033 and EMD 57439 were identical. After photolysis optical density decreased substantially and the peak shifted from 320 nm to 280 nm. 6. The proton n.m.r. spectra of these compounds were identical. The main change post-photolysis was a decrease in the proton signal associated with the enantiomeric carbon atom. 7. This novel manipulation of the molecular structure of EMD 57033 and EMD 57439 within an experiment thus provides direct evidence linking calcium sensitization to a particular molecular structure. The three main effects of the sensitizer on the twitch were simultaneously abolished and may be mechanistically linked. Flash photolysis may be a useful tool for further investigations of the actions of these compounds. In particular, flash photolysis of the sensitizer represents a novel method of rapidly deactivating cardiac muscle.
Animals↗
Synergistic inhibition of human immunodeficiency virus isolates (including 3'-azido-3'-deoxythymidine-resistant isolates) by foscarnet in combination with 2',3'-dideoxyinosine or 2',3'-dideoxycytidine.
The combinations of foscarnet plus 2',3'-dideoxyinosine and foscarnet plus 2',3'-dideoxycytidine synergistically inhibit the replication of human immunodeficiency virus type 1 isolates, including two 3'-azido-3'-deoxythymidine-resistant isolates. The combination of 2',3'-dideoxyinosine plus 2',3'-dideoxycytidine showed additive inhibition of the majority of the human immunodeficiency virus isolates tested. All three combinations showed pronounced antagonistic cytotoxicity and thus were less toxic to the growth of peripheral blood mononuclear cells than the separate drugs.
Antiviral Agents↗
A short peptide eluted from the H-2Kb molecule of a polyomavirus-positive tumor corresponds to polyomavirus large T antigen peptide at amino acids 578 to 585 and induces polyomavirus-specific immunity.
A short peptide in complex with the H-2Kb molecule on PyRMA, a polyomavirus transfectant of the mouse lymphoma cell line RMA, was identified as a polyomavirus tumor-specific transplantation antigen. The peptide was obtained by affinity chromatography, acidic extraction, and reverse-phase high-pressure liquid chromatography (HPLC). In one HPLC fraction, a peptide sequence in which 5 of 8 amino acids, GKxGLxxA, corresponded to residues 578 to 585 of polyomavirus large T antigen was identified. In tumor rejection assays, we therefore tested three related synthetic peptides, corresponding to the octapeptide LT 578-585, GKTGLAAA; the nonapeptide LT 578-586, GKTGLAAAL; and the decapeptide LT 578-587, GKTGLAAALI. The octapeptide was found to give the most effective immunization against the outgrowth of the polyomavirus DNA-positive PyRMA tumor. However, none of the three peptides immunized against the original polyoma-virus-negative RMA line.
Amino Acid Sequence↗
Induction of a novel conformation in the progesterone receptor by ZK299 involves a defined region of the carboxyl-terminal tail.
Progesterone receptor antagonists are a promising class of therapeutic drugs indicated for the treatment of a variety of reproductive conditions. Understanding their mechanism of action at the molecular level is an important prerequisite for the development of future generations of these drugs. Using limited proteolytic analysis to monitor conformational changes in the progesterone receptor, we can detect three distinct classes of progestin antagonist. The effect of the first, RU486, on the conformation of the carboxyl terminus of the receptor has been previously described. The second, exemplified by RWJ 47626, a nonsteroidal compound with in vitro antiprogestin activity, induces a proteolytic fragment pattern indistinguishable from that induced by the agonist R5020. Finally, ZK299 induces a fragment pattern intermediate between that induced by R5020 and RU486. Site-directed mutagenesis of the carboxyl-terminal tail of the progesterone receptor indicates that the region containing the putative activation function AF-2 is differentially exposed to proteolytic attack depending on the nature of the antagonist bound. The differentially exposed region is most accessible when the antagonist RU486 is bound, less accessible when the antagonist ZK299 is bound, and least accessible when the antagonist RWJ47626 or agonist R5020 is bound. The results suggest that multiple types of antiprogestin can be defined in terms of their effects on the conformation of the carboxyl-terminal activation function of the progesterone receptor.
Amino Acid Sequence↗
The effects of EMD 57033 on rigor tension in porcine skinned cardiac trabecula.
5-[1-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolyl]-6-methy l-3,6- dihydro-2H-1,3,4-thiadiazin-2-one (EMD 57033) is a cardiotonic agent which acts directly on the myofilaments, increasing their sensitivity to Ca2+. We studied the effects of EMD 57033 on porcine cardiac skinned fibres to investigate the roles of Ca2+ and crossbridges in its Ca2+ sensitisation. EMD 57033 potentiated resting and maximum tensions and caused a leftward shift of the force-Ca2+ relationship. Under rigor conditions, in which fibres developed Ca(2+)-independent force, EMD 57033 was still able to potentiate tension, provided the compound was added prior to rigor development. These results show that EMD 57033 increases force by a Ca(2+)-independent mechanism in the intact myofilament lattice and that the Ca2+ sensitiser acts during the transition of crossbridge state rather than on crossbridges that are fixed in the strongly attached state corresponding to rigor.
Adenosine Triphosphate↗
Guidelines for the use of granulocyte colony stimulating factor (G-CSF)
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Drug Utilization↗
A contravention of Ohno's law in mice.
The chloride channel gene, CLCN4, has been previously mapped to the X chromosome in humans. We isolated a cDNA clone for mouse Clcn4 and used this to map the gene in an interspecific backcross. This revealed the surprising finding that the gene maps to the X chromosome in Mus spretus but to chromosome 7 in C57BL/6 mice. This is the first example of a gene that contravenes Ohno's law--it is a gene unique to the X chromosome in one eutherian species but autosomal in another. The consequence of this chromosomal rearrangement is that the gene is lost by mendelian segregation in a subset of the male progeny of a (C57BL/6 x Mus spretus) x Mus spretus backcross.
Amino Acid Sequence↗
Intracellular activation and cytotoxicity of three different combinations of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine.
We measured the intracellular activation and cytotoxicity of 3'-azido-3'-deoxythymidine (zidovudine, ZDV) and 2',3'-dideoxyinosine (ddI) when combined at three different clinically relevant combinations of 1:1, 1:10, and 10:1 (ZDV:ddI). The activation of ddI to ddA-TP was increased in all three combinations with ZDV, compared to ddI alone. A maximum twofold increase in ddA-TP was observed, which could not be further increased by raising the concentration of ZDV in the combination. On the other hand, the concentration of ZDV in the combination could be reduced to one-tenth while retaining increased activation of ddI. We also examined the cytotoxicity of these combinations in CEM cells, phytohemagglutinin (PHA)-stimulated and resting human peripheral blood mononuclear cells (PBMCs). CEM cells were the least sensitive overall to the drugs. ZDV showed greater cytotoxicity in stimulated PBMCs than resting PBMCs, whereas the reverse was true for ddI. This could be explained by the different activation pathways of these two drugs. The 1:1 and 10:1 ZDV:ddI combinations showed reduced toxicity compared to the separate drugs. These results indicate that ZDV and ddI need not necessarily be combined together at a ratio of ZDV:ddI of 1:1, but that some alteration in the dosages of ZDV or ddI in patients could be possible without loss of the benefits of combined ZDV:ddI therapy.
Antiviral Agents↗
The role of troponin C in modulating the Ca2+ sensitivity of mammalian skinned cardiac and skeletal muscle fibres.
1. We investigated the effects of acidosis, inorganic phosphate (Pi) and caffeine on the Ca2+ affinity of isolated fast-twitch skeletal and cardiac troponin C (TnC), labelled with fluorescent probes to report Ca2+ binding to the regulatory sites. We also measured the effects of these interventions on the maximum force development and the Ca2+ sensitivity of skinned fibres from fast-twitch skeletal muscle and cardiac muscle, as has been done previously. The two types of experiment were carried out under similar solution conditions, so that we could assess the contribution of any direct actions on TnC to the modulation of Ca2+ sensitivity in the skinned muscle fibres. 2. In skinned fibres, acidosis (decreasing pH from 7.0 to 6.2) and Pi (20 mM) suppressed maximum force to the same extent within a given muscle type, but had greater effects on cardiac fibres compared with skeletal fibres. Caffeine (20 mM) depressed maximum force equally in cardiac and skeletal muscle. Thus, the fall of force induced by acidosis or Pi may involve a different mechanism from that induced by caffeine. 3. Skinned skeletal fibres were more Ca2+ sensitive than cardiac fibres by 0.29 pCa units (pCa = -log10[Ca2+]). Isolated skeletal TnC also had a greater Ca2+ affinity than cardiac TnC, by 0.20 pCa units. These results suggest that the Ca2+ sensitivity of skinned fibres is at least partly determined by the type of TnC present. 4. Acidosis reduced the Ca2+ sensitivity of force in skinned fibres profoundly and had a 2-fold greater effect in cardiac muscle than skeletal muscle (falls in pCa for 50% activation, pCa50, were 1.09 and 0.55, respectively). Acidosis also reduced the Ca2+ affinity of TnC, again having double the effect on the pCa50 for cardiac TnC (0.58) as on that for skeletal TnC (0.28). The greater effect of acidosis on cardiac skinned fibres, compared with skeletal, may be partly explained, therefore, by the type of TnC present, and one-half of the effect on fibres may be attributed to the direct effect of H+ on TnC. 5. Pi reduced the Ca2+ sensitivity of force in skeletal and cardiac skinned fibres by 0.30 and 0.19 pCa units, respectively. However, the Ca2+ affinity of isolated cardiac and skeletal TnC was unaffected by Pi, indicating that the decrease in muscle Ca2+ sensitivity is not mediated by a direct action of Pi on TnC. 6. Caffeine increased the Ca2+ sensitivity of cardiac skinned fibres by 0.31 pCa units, which was 3 times greater than for the skeletal fibres (0.09 pCa units).(ABSTRACT TRUNCATED AT 400 WORDS)
Acidosis↗
Comparison of extraction procedures for high-performance liquid chromatographic determination of cellular deoxynucleotides.
For the determination of cellular deoxynucleoside triphosphates (dNTPs) by high-performance liquid chromatography, the choice of extracting agent and periodate oxidation procedure is important for accurate results. Different extraction methods were compared using either cold methanol or trichloroacetic acid for extraction of dNTPs from lymphoblastoid cells. The recoveries of the dNTPs varied with the different extraction methods. A modification of the periodate oxidation procedure for degrading ribonucleoside triphosphates to their bases was also compared with the original method. Both methods gave accurate results when trichloroacetic acid was used as extracting agent, but when methanol was used interfering peaks were present on the chromatogram when the original method was used. These peaks were absent when the modified periodate procedure was used.
Chromatography, High Pressure Liquid↗