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Biomedical subjects

P Martin

Publications and source records attributed to P Martin.

At least 19 recordsLinked to original sources
PubMed1992

Actin cables and epidermal movement in embryonic wound healing.

Skin wounds in embryos heal rapidly and perfectly. Even though the epidermis appears to be stretched taut over the surface of a structure such as a growing limb bud, its response to wounding is to close over the lesion, rather than to gape more widely. In adult wounds, the epidermis seems to migrate by means of lamellipodia, crawling over the exposed connective tissue. But in embryonic wounds we do not see lamellipodia. The epidermis at the edge of the wound looks smooth, as though under a circumferential tension. Here we show that a cable of filamentous actin appears to run continuously around most of the wound margin. It is confined to the single row of basal cells at the free edge of the epidermis. We suggest that the actin cable acts as a contractile 'purse string' to close up the embryonic wound.

Actins↗
PubMed1992

Antidepressant profile in rodents of SR 58611A, a new selective agonist for atypical beta-adrenoceptors.

beta 2-Adrenoceptor agonists possess antidepressant-like activity in animals and man, but their peripheral side-effects prevent their therapeutic use. Atypical beta-adrenoceptors have not been demonstrated in the central nervous system, but are known to exist in peripheral tissues such as the rat colon. We have now studied the antidepressant-like effects in rodents of a new selective atypical beta-adrenoceptor agonist, SR 58611A. SR 58611A was active with minimal effective doses of 0.1-0.3 mg kg-1 i.p. in several models (antagonism of the hypothermia induced by apomorphine and reserpine; potentiation of the toxicity produced by yohimbine; reversal of learned helplessness), but was inactive in the tests of reserpine-induced ptosis and behavioural despair. The antidepressant-like effect of SR 58611A was not antagonised by selective beta 1- or beta 2-adrenoceptor antagonists, but was blocked by high doses of the non-selective beta-adrenoceptor antagonists, propranolol and alprenolol. Unlike beta 2-adrenoceptor agonists, SR 58611A did not reduce locomotor activity or increase water intake at doses up to 10 mg kg-1. Therefore, SR 58611A may represent the prototype of a new class of antidepressant compounds.

Adrenergic beta-Agonists↗
PubMed1992

Differing effects of alpha-difluoromethylornithine and CGP 40116 on polyamine levels and infarct volume in a rat model of focal cerebral ischaemia.

Focal cerebral ischaemia was induced in rats by occlusion of the left middle cerebral artery. Two days later, infarct volume was determined by magnetic resonance imaging and the concentrations of the polyamines putrescine (PU), spermine and spermidine by HPLC. In control (occluded) animals, PU levels were elevated in infarcted and non-infarcted areas of the left hemisphere. Treatment with the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine, prevented the ischaemia-induced increase in tissue PU without affecting infarct volume. Conversely, administration of the N-methyl-D-aspartate (NMDA) receptor antagonist CGP 40116 decreased cortical infarction without changing the tissue content of PU. We conclude that there is no direct link between NMDA receptor activation and brain PU, or PU and post-ischaemic tissue damage, and that inhibitors of ODC are not cerebroprotective in this animal model of stroke.

2-Amino-5-phosphonovalerate↗
PubMed1992

Phase II trial of recombinant human granulocyte-macrophage colony-stimulating factor in patients undergoing allogeneic bone marrow transplantation from unrelated donors.

The safety and possible efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) were evaluated in 40 consecutive patients who received transplants from unrelated donors. rhGM-CSF was administered by 2-hour daily intravenous infusion from day 0 to day 20 or day 27 after the marrow infusion. These patients were compared with 78 historical patients who received transplants from unrelated donors who did not receive rhGM-CSF. The rhGM-CSF-treated patients were older (P = .037) and were treated less frequently in laminar air flow rooms (P = .005) than were control patients. However, the rhGM-CSF-treated group had a higher proportion of "good risk" patients with chronic myelogenous leukemia in chronic phase (P = .006) than did the comparison group (P = .017), rendering comparisons of transplant-related complications not meaningful. rhGM-CSF was well tolerated and did not adversely increase the incidence of graft rejection or increase the incidence and severity of acute graft-versus-host disease. The median day the absolute neutrophil count reached 500/mm3 in patients who received rhGM-CSF was day 21, which was not different from that of historical patients. Nevertheless, the numbers of febrile days and septicemic episodes within the first 28 days in patients who received rhGM-CSF were less than in historical patients. The probability of nonrelapse mortality at 1 year in patients who received rhGM-CSF was 22%. In view of the retrospective nature of the control group, we cannot conclusively determine whether rhGM-CSF administration was beneficial. A prospective, randomized controlled study of rhGM-CSF is required to confirm these suggestive data.

Adult↗
PubMed1992

Mutations away from splice site recognition sequences might cis-modulate alternative splicing of goat alpha s1-casein transcripts. Structural organization of the relevant gene.

alpha s1-Casein variants F and D, synthesized in goat milk at lower levels than variant A, essentially differ from it by internal deletions of 37 and 11 amino acid residues, respectively. Northern blot analysis of mRNAs encoding alpha s1-casein F and A and sequencing of the relevant cloned cDNAs, as well as sequencing of in vitro amplified genomic fragments, revealed multiple alternatively processed transcripts, from the F allele. Although correctly spliced messengers were identified, most of the FmRNAs lacked three exons. These exons, further identified as exons 9, 10, and 11, together encode the 37 amino acid residues present in alpha s1-casein variant A but missing in variant F. Exon 9 codes for the sequence present in variant A but deleted in variant D. A single nucleotide deletion in exon 9 and two insertions, 11 and 3 base pairs in length, in the downstream intron, were identified as mutations potentially responsible for the alternative skipping of these 3 exons. From a computer-predicted secondary structure it appeared that the 11-base pair insertion might be involved in base-pairing interactions with the intron 5' splice site which might consequently be less accessible to U1 snRNA. We also report here the complete structural organization of the goat alpha s1-casein transcription unit, deduced from polymerase chain reaction experiments. It contains 19 exons scattered within a nucleotide stretch nearly 17-kilobase pairs long.

Amino Acid Sequence↗
PubMed1992

Exon-skipping is responsible for the 9 amino acid residue deletion occurring near the N-terminal of human beta-casein.

Interspecies comparison and alignment of the beta-casein N-terminal sequence, taking into account its exon modular splitting derived from the known structural organization of the relevant genes, has revealed that a 9 amino acid residue sequence, corresponding to that encoded by the third exon of the other species genes, is lacking in human beta-casein. Using the polymerase chain reaction technique, we have amplified a human genomic 1-kb fragment, spanning from exon 2 to exon 4, which was subsequently cloned and sequenced. One hundred base pairs (bp) upstream from exon 4 and 737 bp downstream of exon 2, a 27-bp virtual exon 3 sequence, probably skipped during the course of pre-mRNA splicing, was identified. We discuss the possibility that this out-splicing event might be due to the weak strength of the 3' acceptor site and/or to the secondary structure sequestering of the branch site sequence.

Amino Acid Sequence↗
PubMed1992

5-HT3 receptor antagonists reverse helpless behaviour in rats.

The effects of the 5-HT3 receptor antagonists, zacopride, ondansetron and ICS 205-930, were investigated in an animal model of depression, the learned helplessness test. Rats previously subjected to a session of 60 inescapable foot-shocks exhibited a deficit of escape performance in three subsequent shuttle-box sessions. The 5-HT3 receptor antagonists administered i.p. twice daily on a chronic schedule (zacopride 0.03-2 mg/kg per day; ondansetron and ICS 205-930: 0.125-2 mg/kg per day) reduced the number of escape failures at low to moderate daily doses. This effect was not observed with the highest dose(s) of zacopride, ondansetron and ICS 205-930 tested. These results indicate that 5-HT3 antagonists may have effects like those of conventional antidepressants in rats.

Analysis of Variance↗
PubMed1992

Therapies for hepatitis B virus: current status and future possibilities.

Alpha-interferon is the first agent with proven therapeutic efficacy in humans with chronic HBV infection. Obviously, further research is needed to clarify and expand the role of interferon in this setting. In addition, an overall response rate of less than 50% illustrates the need for continuing innovation in the treatment of HBV infection especially in patients with predictors of poor outcome. Despite the advent of effective vaccines against HBV, this pathogen is likely to remain a source of serious human morbidity and mortality for the foreseeable future. Continuing efforts must be directed towards finding more effective therapies against HBV. A recent preliminary report suggests that thymosin. like interferon on immune modulator, may also be efficacious in the treatment of chronic HBV and deserves further study.

Hepatitis B↗
PubMed1992

Experimental absence seizures: potential role of gamma-hydroxybutyric acid and GABAB receptors.

We have investigated whether the pathogenesis of spontaneous generalized non-convulsive seizures in rats with genetic absence epilepsy is due to an increase in the brain levels of gamma-hydroxybutyric acid (GHB) or in the rate of its synthesis. Concentrations of GHB or of its precursor gamma-butyrolactone (GBL) were measured with a new GC/MS technique which allows the simultaneous assessment of GHB and GBL. The rate of GHB synthesis was estimated from the increase in GHB levels after inhibition of its catabolism with valproate. The results of this study do not indicate significant differences in GHB or GBL levels, or in their rates of synthesis in rats showing spike-and-wave discharges (SWD) as compared to rats without SWD. Binding data indicate that GHB, but not GBL, has a selective, although weak affinity for GABAB receptors (IC50 = 150 microM). Similar IC50 values were observed in membranes prepared from rats showing SWD and from control rats. The average GHB brain levels of 2.12 +/- 0.23 nmol/g measured in the cortex and of 4.28 +/- 0.90 nmol/g in the thalamus are much lower than the concentrations necessary to occupy a major part of the GABAB receptors. It is unlikely that local accumulations of GHB reach concentrations 30-70-fold higher than the average brain levels. After injection of 3.5 mmol/kg GBL, a dose sufficient to induce SWD, brain concentrations reach 240 +/- 31 nmol/g (Snead, 1991) and GHB could thus stimulate the GABAB receptor. Like the selective and potent GABAB receptor agonist R(-)-baclofen, GHB causes a dose-related decrease in cerebellar cGMP. This decrease and the increase in SWD caused by R(-)-baclofen were completely blocked by the selective and potent GABAB receptor antagonist CGP 35348, whereas only the increase in the duration of SWD induced by GHB was totally antagonized by CGP 35348. The decrease in cerebellar cGMP levels elicited by GHB was only partially antagonized by CGP 35348. These findings suggest that all effects of R(-)-baclofen are mediated by the GABAB receptor, whereas only the induction of SWD by GHB is dependent on GABAB receptor mediation, the decrease in cGMP being only partially so. Taken together with the observations of Marescaux et al. (1992), these results indicate that GABAB receptors are of primary importance in experimental absence epilepsy and that GABAB receptor antagonists may represent a new class of anti-absence drugs.

4-Butyrolactone↗
PubMed1992

Wilson's disease: current status.

OBJECTIVE: To review current concepts about the pathogenesis, clinical manifestations, and treatment of Wilson's disease, with an emphasis on recent developments. DATA IDENTIFICATION: Published information was identified using MEDLINE and through extensive manual searching of bibliographies in identified sources. RESULTS: The basic biochemical alteration responsible for deranged hepatobiliary copper homeostasis in Wilson's disease has yet to be identified. The gene for Wilson's disease has been mapped to chromosome 13, but the function of its gene product has not yet been determined. The clinical manifestations of Wilson's disease are varied and often nonspecific and include a range of hepatic, neurologic, and psychiatric findings. Penicillamine remains the drug of choice for the treatment of Wilson's disease, but recent experience suggests that trientine and zinc may be safe, effective alternatives. All three drugs are probably safe for use in pregnant patients with Wilson's disease. Liver transplantation is the only effective treatment for Wilsonian fulminant hepatic failure and corrects the underlying metabolic defect. CONCLUSIONS: Wilson's disease is a disorder of hepatobiliary copper excretion manifested predominantly by hepatic and neurologic copper toxicosis and inherited in an autosomal recessive pattern. Although the specific underlying biochemical defect remains to be defined, specific therapy is available and usually successful. Maintaining a high index of suspicion is critical in diagnosing this readily treatable inherited disease.

Administration, Oral↗
PubMed1992

Response to heparinization in adults and children undergoing cardiac operations.

The activated clotting time is an unreliable index of anticoagulation status during cardiopulmonary bypass procedures. However, modern instrumentation (Hemotec Hepcon HMS) now allows the monitoring of free heparin levels via automated protamine titration. In the present study, the standard procedure of anticoagulation at Killingbeck Hospital, Leeds, was investigated. Twenty-two pediatric patients and 20 adult patients undergoing open heart procedures involving cardiopulmonary bypass were given empirical doses of heparin (3 mg/kg body weight bolus), and activated clotting time was maintained at a level greater than 450 seconds using the Hemochron Timer. Heparin neutralization was performed at the termination of the bypass period using an empirical equivalent (3 mg/kg) of protamine sulfate. Mean free heparin concentration (+/- standard deviation) fell from 2.26 (+/- 0.45) mg/kg to 1.39 (+/- 0.34) mg/kg over the period 10 to 40 minutes on bypass in children. In adults, free heparin level declined from 2.56 (+/- 0.58) mg/kg to 1.81 (+/- 0.58) mg/kg over the same period. The biological half-life for heparin was 60 minutes in adults and 35 minutes in pediatric patients. Empirical protamine dosing resulted in excess protamine administration when compared with Hepcon titrated dose requirements: for children: median (range), 80 (12 to 350) versus 33 (12 to 97) mg, p less than 0.001; and for adults: 350 (200 to 500) versus 130 (61 to 237) mg, p less than 0.001. In conclusion, empirical heparin administration (3 mg/kg) does not result in "steady-state" anticoagulation during cardiopulmonary bypass, and empirical administration of protamine takes no account of interindividual differences in heparin sensitivity and biological half-life, which may be assessed using the Hepcon HMS.

Adult↗
PubMed1992

Acute esophageal hemorrhage from a vagal neurilemoma.

A man with known systemic neurofibromatosis developed an acute upper gastrointestinal hemorrhage while hospitalized after a neurosurgical procedure. Endoscopic evaluation showed a vascular lesion with an appearance consistent with a Dieulafoy-type lesion in the distal esophagus. Despite multiple endoscopic procedures with attempted coagulation of the bleeding lesion, the patient continued to have life-threatening hemorrhaging. At thoractomy, a tumor was found to arise from the vagus nerve at the site of bleeding. This tumor was resected and histologically determined to be a neurilemoma. Acute bleeding into the esophagus associated with this type of tumor has not been previously reported.

Cranial Nerve Neoplasms↗
PubMed1992

An early molecular component of the wound healing response in rat embryos--induction of c-fos protein in cells at the epidermal wound margin.

The spreading of epithelial sheets plays a pivotal role in normal embryonic morphogenesis but the cellular and molecular mechanisms underlying these processes are not very well understood. One way of directly examining epithelial spreading in the embryo is to excise a piece of tissue and follow the epithelial wound healing process. In this paper we report our studies of the healing of a simple excisional lesion to the E12.5 rat embryo hindlimb. The wounded, living embryo is cultured in a roller bottle and under such conditions the lesion is completely re-epithelised by 24 h. We find that epidermal cells specifically at the margin of the wound rapidly (within 15 min of wounding) and transiently express the nuclear transcription factor c-fos. This induction occurs whether or not serum is included in the culture medium. We speculate that local induction of c-fos at the wound site may play a role in regulating transcription of genes involved in the healing process.

Animals↗