[Development of palliative care. Necessary guidelines for general health promotion].
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Attitude to Death↗
Biomedical subjects
J Martin
Publications and source records attributed to J Martin.
Inhibition of virus-encoded thymidine kinase suppresses herpes simplex virus replication in vitro and in vivo.
Both herpes simplex virus type 1 (HSV-1) and HSV-2 encode a thymidine kinase enzyme which differs from cellular thymidine kinase in substrate specificity. Viral thymidine kinase enables the virus to replicate in cells that lack cellular thymidine kinase, namely those of the sensory neurons where the virus establishes, and periodically reactivates from, a latent state. Thymidine kinase-dependent HSV replication following viral reactivation at the site of latency is thought to precede the emergence of virus at mucosal surfaces. The ability to inhibit such an essential viral enzyme would potentially prevent HSV from replicating within neuronal tissue, and thus stop the recurrent disease cycle. Ro 32-2313 was designed as a selective and competitive inhibitor of HSV thymidine kinase and in vitro studies have confirmed this mechanism of action. In vivo evaluation of a soluble prodrug of Ro 32-2313, Ro 32-4397, was undertaken in murine models where pathogenesis was dependent upon viral replication in neuronal tissue. It was shown that in vivo administration of Ro 32-4397 (i) significantly reduced the viral titre detected in isolated dorsal root ganglia; (ii) prevented HSV-2-induced lethality in a systemic infection model; and (iii) reduced zosteriform lesion development in a model of dermal infection. Administration of Ro 32-4397 produced dose-related changes in viral pathogenicity towards those of the phenotype of a thymidine kinase-deficient virus. Overall, the study confirmed that thymidine kinase inhibitors can suppress the replication of HSV in vivo, and suggest that such inhibitors may reduce reactivation of the virus from latency if used prophylactically in recurrent HSV infection.
Animals↗
[AIDS in the world: above all a problem of human rights and equality].
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Acquired Immunodeficiency Syndrome↗
A variable intron distribution in globin genes of Chironomus: evidence for recent intron gain.
The intron positions found in globin genes of plants, protozoa and invertebrates have been interpreted as evidence for a three-intron-four-exon structure of the ancestral globin gene. In particular, the so-called 'central' introns, which are not found in vertebrate globin genes but are present in a variety of invertebrate and plant species, have been used as an argument for an ancestral gene structure featuring three introns. We have analyzed the presence or absence of central introns in the Gb genes 2beta, 9 and 7A of various European and Australasian species of the insect Chironomus. We find unrelated central introns at different positions in some of the species investigated, while other species completely lack introns in these genes. This variable distribution of introns is parsimoniously explained by independent intron additions. Such a gain of introns may occur convergently at identical positions in unrelated taxa. Insertion by gene conversion may be a viable mechanism to explain intron gain.
Animals↗
Vascular endothelial growth factor stimulates prostacyclin production and activation of cytosolic phospholipase A2 in endothelial cells via p42/p44 mitogen-activated protein kinase.
Vascular endothelial growth factor (VEGF) stimulated a time- and concentration-dependent increase in PGI2 synthesis in human umbilical vein endothelial cells with a mean maximum increase of 2-fold above basal levels at 25 ng/ml after 60 min. VEGF also rapidly stimulated the release of arachidonic acid and phosphorylation and activation of cytosolic phospholipase A2 (cPLA2). The VEGF-related factor, placenta growth factor (PIGF), had little effect on PGI2 synthesis, arachidonic acid release or cPLA2 activation. PD98059, a selective inhibitor of MAP kinase kinase, caused complete inhibition of VEGF-stimulated MAP kinase activity, PGI2 synthesis and cPLA2 gel retardation, but had no effect on VEGF-induced vWF secretion. These findings provide the first evidence that VEGF can stimulate PGI2 synthesis via cPLA2-mediated arachidonic acid release and indicate that VEGF stimulation of this biosynthetic pathway may occur, at least in part, via activation of p42/p44 MAP kinases.
Arachidonic Acid↗
The preferential dopamine D3 receptor agonist cis-8-OH-PBZI induces limbic Fos expression in rat brain.
The affinity, selectivity and agonistic properties of a constrained dopaminergic compound, the benz[e]indole cis-8-hydroxy-3-(n-propyl)1,2,3a.4,5,9b-hexahydro-1H-benz[e]indole (cis-8-OH-PBZI), for the dopamine D3 receptor were evaluated in competition binding experiments with cloned human dopamine receptor subtypes and, to further extend its profile, in in vitro radioligand binding assays. The Ki value measured for competition binding of this compound to the dopamine D3 receptor was 27.4+/-3.1 nM; this was 775-fold, 550-fold, 90-fold and 10-fold higher affinity than that measured at dopamine D1A, D5, D2s and D4 receptors, respectively. Evidence of dopamine receptor activation by cis-8-OH-PBZI was obtained by measuring dose-dependent increases in extracellular acidification rates and decreases in cAMP synthesis. In vivo, cis-8-OH-PBZI potently induced Fos protein immunoreactivity in the rat medial prefrontal cortex and shell region of the nucleus accumbens, but only marginally in the motor dorsolateral striatum, indicating a selective limbic site of action. In conclusion, the present data identify cis-8-OH-PBZI as having preference for the dopamine D3 receptor in vitro, and as having dopamine agonist activity and limbic sites of action in vivo.
Animals↗
Expression of inducible nitric oxide synthase in human heart failure.
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Cardiac Output, Low↗
The effect of macromolecular crowding on chaperonin-mediated protein folding.
The cylindrical chaperonin GroEL and its cofactor GroES mediate ATP-dependent protein folding in Escherichia coli. Recent studies in vitro demonstrated that GroES binding to GroEL causes the displacement of unfolded polypeptide into the central volume of the GroEL cavity for folding in a sequestrated environment. Resulting native protein leaves GroEL upon GroES release, whereas incompletely folded polypeptide can be recaptured for structural rearrangement followed by another folding trial. Additionally, each cycle of GroES binding and dissociation is associated with the release of nonnative polypeptide into the bulk solution. Here we show that this loss of substrate from GroEL is prevented when the folding reaction is carried out in the presence of macromolecular crowding agents, such as Ficoll and dextran, or in a dense cytosolic solution. Thus, the release of nonnative polypeptide is not an essential feature of the productive chaperonin mechanism. Our results argue that conditions of excluded volume, thought to prevail in the bacterial cytosol, increase the capacity of the chaperonin to retain nonnative polypeptide throughout successive reaction cycles. We propose that the leakiness of the chaperonin system under physiological conditions is adjusted such that E. coli proteins are likely to complete folding without partitioning between different GroEL complexes. Polypeptides that are unable to fold on GroEL eventually will be transferred to other chaperones or the degradation machinery.
Chaperonin 10↗
Abnormal temporal dynamics of visual attention in spatial neglect patients.
When we identify a visual object such as a word or letter, our ability to detect a second object is impaired if it appears within 400ms of the first. This phenomenon has been termed the attentional blink or dwell time and is a measure of our ability to allocate attention over time (temporal attention). Patients with unilateral visual neglect are unaware of people or objects contralateral to their lesion. They are considered to have a disorder of attending to a particular location in space (spatial attention). Here we examined the non-spatial temporal dynamics of attention in patients, using a protocol for assessing the attentional blink. Neglect patients with right parietal, frontal or basal ganglia strokes had an abnormally severe and protracted attentional blink When they identified a letter, their awareness of a subsequent letter was significantly diminished for a length of time that was three times as long as for individuals without neglect. Our results demonstrate for the first time that visual neglect is a disorder of directing attention in time, as well as space.
Adult↗
Persistence is not always a virtue: tort reform, civil liability for health care, and the lack of empirical evidence.
The efficacy of reforms in the civil system, including professional liability in the health care arena, depends upon the accuracy with which problems are defined. A growing empirical literature argues that the description of the civil justice system underlying the movement for tort reform in the health care arena is not an accurate one. Regardless, that description continues to be used successfully as the basis for a variety of enacted reforms. The interesting question now posed by some researchers is why that description persists despite its lack of empirical verification. This article summarizes the reformers' description; provides an overview of relevant empirical findings; and then draws on a theoretical literature in political science dealing with agenda-setting in the public policy process to answer that interesting question. The article concludes that the image persists because it is successful in a political, not rational, process in which appeals to emotion overshadow reasoned argument.
Causality↗
Ca(2+)-dependent and Ca(2+)-independent regulation of contractility in isolated human myocardium.
UNLABELLED: Changes in contractile force of the myocardium may depend on changes in the intracellular Ca2+ concentration, changes in the responsiveness of the myofibrils for Ca2+, or a combination of both. We investigated in isolated muscle strip preparations from human nonfailing and endstage failing hearts the influence of physical (changes in preload, stimulation rate, or rhythm), and pharmacological interventions (alpha- or beta-adrenoceptor-stimulation, endothelin) on developed force of contraction and the corresponding intracellular Ca2+ transients. METHODS: Isometric contraction, electrical stimulation, 37 degrees C. Simultaneous registration of force of contraction and intracellular Ca2+ transients (aequorin method). RESULTS: Increases in preload, alpha- and endothelin-receptor stimulation resulted in increases in force of contraction without increasing aequorin light emission. Increasing stimulation rate or increasing rest intervals resulted in parallel increases (nonfailing myocardium) or decreases (failing myocardium) of force of contraction and aequorin light emission. beta-Adrenoceptor-stimulation exerted inotropic and lusitropic effects in human failing myocardium associated with a large, overproportional increase in aequorin light emission. CONCLUSION: The human heart regulates intrinsic contractility via several subcellular mechanisms. Increases in preload (Frank-Starling-mechanism) and alpha- or endothelin-receptor-stimulation enhance myocardial contractility by increasing the Ca2+ responsiveness of the myofilaments; rate- and rhythm-dependent modulation of the contractile state directly depend on changes in the intracellular Ca(2+)-transients; beta-adrenoceptor stimulation results in an overproportional large increase in intracellular Ca2+ transients, probably due to additional cAMP-dependent Ca(2+)-desensitizing effects on the level of the myofibrils.
Calcium↗
Extraordinary conservation of cysteines among homologous Chironomus silk proteins sp185 and sp220.
Aquatic larvae of the midge, Chironomus tentans, synthesize a 185-kDa silk protein (sp185) with the cysteine-containing motif Cys-X-Cys-X-Cys (where X is any residue) every 20-28 residues. We report here the cloning and full-length sequence of cDNAs encoding homologous silk proteins from Chironomus pallidivittatus (sp185) and Chironomus thummi (sp220). Deduced amino acid sequences reveal proteins of nearly identical mass composed of 72 blocks of 20-28 residues, 61% of which can be described by the motif X5-8-Cys-X5-(Trp/Phe/Tyr)-X4-Cys-X-Cys-X-Cys. Spatial arrangement of these residues is preserved more than surrounding sequences. cDNA clones enabled us to map the genes on polytene chromosomes and identify for the first time the homolog of the Camptochironomus Balbiani ring 3 locus in Chironomus thummi. The apparent molecular weight difference between these proteins (185 vs 220 kDa) is not attributable to primary structure and may be due to differential N-linked glycosylation. DNA distances and codon substitutions indicate that the C. tentans and C. pallidivittatus genes are more related to each other than either is to C. thummi; however, substitution rates for the 5'- and 3'-halves of these genes are different. Blockwise sequence comparisons suggest intragenic variation in that some regions evolved slower or faster than the mean and may have been subjected to different selective pressures.
Amino Acid Sequence↗
Antibody-directed enzyme prodrug therapy: pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial.
Antibody-directed enzyme prodrug therapy (ADEPT) was administered to ten patients in a phase I clinical trial. The aim was to measure plasma levels of the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-L-glutamic acid (CMDA) and the bifunctional alkylating drug (CJS11) released from it by the action of tumour-localised carboxypeptidase G2 (CPG2) enzyme. New techniques were developed to extract the prodrug and drug from plasma by solid-phase absorption and elution and to measure CPG2 activity in plasma and tissue. All extracts were analysed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). CPG2 activity was found in metastatic tumour biopsies but not in normal tissue, indicating that localisation had been successful. The clearing agent SB43-gal, given at 46.5 mg/m2, achieved the aim of clearing non-tumour-localised enzyme in the circulation, indicating that conversion of prodrug to drug could take place only at the site of localised conjugate. Plasma prodrug did not always remain above its required threshold of 3 microM for the "therapeutic window" of 120 min after dosing, but the presence of residual prodrug after the first administration of each day indicated that this could be achieved during the remaining four doses over the following 8 h. Despite considerable inter-patient prodrug plasma concentration variability, the elimination half-life of the prodrug was remarkably reproducible at 18 +/- 8 min. Rapid appearance of the drug in plasma indicated that successful conversion from the prodrug had taken place, but also undesirable leakback from the site of localisation into the bloodstream. However, drug plasma levels fell rapidly by at least 50% at between 10 and 60 min with a half-life of 36 +/- 14 min. Analysis of the plasma extracts by LC/MS indicated that this technique might be used to confirm qualitatively the presence of prodrug, drug and their metabolites.
Antibodies, Monoclonal↗
Biodistribution of an antibody-enzyme conjugate for antibody-directed enzyme prodrug therapy in nude mice bearing a human colon adenocarcinoma xenograft.
The enzyme carboxypeptidase G2 (CPG2) can be targeted to tumors by antibodies and used to activate prodrugs in a treatment called antibody-directed enzyme prodrug therapy (ADEPT). Different doses of CPG2 conjugated to the anti-CEA antibody A5B7 were administered i.v. to nude mice bearing the LS174T human colon adenocarcinoma xenograft, and the biodistribution of conjugate activity 48 and 72 h later was determined using a novel high-performance liquid chromatography (HPLC) method. Conjugate doses of 2,500 and 625 U/kg gave tumor enzyme levels of 0.5-0.6 U/g. Lower doses of 300 and 150 U/kg gave tumor enzyme levels of 0.1-0.3 U/g. Intriguingly, the best tumor:blood ratio of conjugate activity at both 48 and 72 h was achieved after administration of the 625-U/kg dose, not the 2,500-U/kg dose. After 48 h this ratio was 3.8, whereas after 72 h the value was 5.5. This conjugate dose also gave the greatest tumor:tissue ratios in all other tissues examined. After 72 h the tumor:colon ratio was 105, whereas the tumor:kidney ratio was 36. In ADEPT, to obtain maximal tumor damage to LS174T xenografts in nude mice with minimal systemic toxicity using the A5B7-CPG2 conjugate, prodrug should therefore be administered at least 72 h after a conjugate dose of 625 U/kg.
Adenocarcinoma↗
A candidate model for Angelman syndrome in the mouse.
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are well-recognized examples of imprinting in humans. They occur most commonly with paternal and maternal 15q11-13 deletions, but also with maternal and paternal disomy. Both syndromes have also occurred more rarely in association with smaller deletions seemingly causing abnormal imprinting. A putative mouse model of PWS, occurring with maternal duplication (partial maternal disomy) for the homologous region, has been described in a previous paper but, although a second imprinting effect that could have provided a mouse model of AS was found, it appeared to be associated with a slightly different region of the chromosome. Here, we provide evidence that the same region is in fact involved and further demonstrate that animals with paternal duplication for the region exhibit characteristics of AS patients. A mouse model of AS is, therefore, strongly indicated.
Aneuploidy↗
Defaecography in patients with irritable bowel syndrome and healthy volunteers.
BACKGROUND: In patients with IBS, many symptoms have their origin in the recto-anal segment, with motility changes in the rectum and in the internal anal sphincter, and alterations in rectal sensitivity. However, up to now, it is not known if these clinical and physiological changes are equated with morphological changes in the recto-anal segment. METHODS: Sixteen consecutive patients with IBS (mean age 22, range 18-33 years; 13 females) and 10 healthy volunteers (mean age 34.5, range 19-50 yr.; 6 males) were evaluated prospectively with defaecography. RESULTS: 1) Anorectal angle: No significant differences were observed in the anorectal angle during rest (91.6 +/- 3.5 degrees vs 92.6 +/- 2.5 degrees) and during defaecation (92 +/- 5.5 degrees vs 98.7 +/- 2.6 degrees) between patients with IBS and healthy volunteers. However, patients with IBS were unable to widen the angle during defaecation, remaining the same at rest (91.6 +/- 3.5 degrees) as during defaecation (92 +/- 5.5 degrees). IBS patients with constipation (n = 2) compared to those with normal frequency defaecation (n = 13) showed no significant differences at rest (95 +/- 6 vs 89.8 +/- 4.1 degrees) and during defaecation (100 +/- vs 88.9 +/- 6.4 degrees). Healthy volunteers widened the angle by more than 5 degrees during defaecation. 2) Perineometry: although not significant, patients with IBS had less perineal descent during the simulated defaecation (1.98 +/- 0.37 cm) than healthy subjects (2.1 +/- 0.3 cm). Nevertheless, during squeeze there was significantly less mobility or perineal descent in patients with IBS than in control subjects (0.21 +/- 0.17 vs 0.95 +/- 0.21 cm; P = 0.01). CONCLUSIONS: The findings of this study suggest that patients with IBS as a whole, whether constipation predominant or not, showed changes in pelvic-floor mobility.
Adolescent↗
[Successful treatment of fulminant myocarditis with the biventricular MEDOS Assist System (MEDOS HIA-VAD)].
BACKGROUND: Successful weaning from biventricular mechanical support with full recovery of the myocardial function is extremely rare in fulminant myocarditis. We report on our experience with the new MEDOS HIA ventricular assist device. METHODS AND RESULTS: We used the MEDOS assist system to support a 30-year-old woman with profound circulatory impairment caused by acute myocarditis. The device provided adequate hemodynamics and recovery of myocardial function. Despite anticoagulation therapy we had to change either the left or right ventricular pump chamber because of clot formation on the surface of the outflow tract. On the 14th postoperative day a surgical reintervention was necessary for bleeding from the cannulation site of the pulmonary artery. After 17 days the myocardial function had recovered and we could remove the assist system. The following parameters were measured before implantation of the MEDOS assist system and after weaning from circulatory support: ejection fraction 15 vs. 45%, cardiac index 0.7 vs. 2.6 L/min/m2, arterial pressure (systolic/diastolic/mean) 81/55/66 vs. 113/66/82 mm Hg, pulmonary artery pressure 33/25/29 vs. 34/20/28 mm Hg, pulmonary capillary wedge pressure 24 vs. 19 mm Hg. CONCLUSIONS: Despite severe cardiac failure in fulminant myocarditis requiring biventricular mechanical support full recovery of the myocardium is possible.
Adult↗
Testing technical skill via an innovative "bench station" examination.
BACKGROUND: A new approach to testing operative technical skills, the Objective Structured Assessment of Technical Skill (OSATS), formally assesses discrete segments of surgical tasks using bench model simulations. This study examines the interstation reliability and construct validity of a large-scale administration of the OSATS. METHODS: A 2-hour, eight-station OSATS was administered to 48 general surgery residents. Residents were assessed at each station by one of 48 surgeons who evaluated the resident using two methods of scoring: task-specific checklists and global rating scales. RESULTS: Interstation reliability was 0.78 for the checklist score, and 0.85 for the global score. Analysis of variance revealed a significant effect of training for both the checklist score, F(3,44) = 20.08, P <0.001, and the global score, F(3,44) = 24.63, P <0.001. CONCLUSIONS: The OSATS demonstrates high reliability and construct validity, suggesting that we can effectively measure residents' technical ability outside the operating room using bench model simulations.
Clinical Competence↗