Search PubMed⌕ Search

Biomedical subjects

L A Martin

Publications and source records attributed to L A Martin.

At least 37 records · Page 2Linked to original sources
PubMed1998

Phylogenetic analysis of African horse sickness virus segment 10: sequence variation, virulence characteristics and cell exit.

African horse sickness virus (AHSV) genome segment 10 encodes the non-structural proteins NS3/NS3a, which is involved in release of virus from cells. Full length segment 10 cDNAs were amplified by reverse transcription-polymerase chain reaction, from isolates of AHSV serotypes 2, 3, 4, 5, 7, 8 and 9. These cDNAs were cloned, sequenced and their phylogenetic relationships analysed. High levels of sequence homology were detected in segment 10 from some isolates of different serotypes, confirming that they could be grouped on this basis (serotypes 4, 5, 6 and 9 (group alpha); serotypes 3 and 7 (group beta); serotypes 1, 2, and 8 (group gamma). However, data from bluetongue virus (the prototype orbivirus) indicate that the AHSV serotype is determined exclusively by the structural outer coat proteins VP2 and VP5, encoded by genome segments 2 and 5 respectively. Therefore, as a direct consequence of genome segment reassortment between AHSV strains from different serotypes, the differences observed in segment 10 do not give a reliable indication of virus serotype. Segment 10 of AHSV 3 (virulent) and AHSV 3att (attenuated) were also analysed. These strains, together with AHSV 8, have been used to study of the genetic basis of virulence using reassortment (O'Hara et al., this publication). Virus release studies, using Culicoides cell cultures, indicate that differences in segment 10 of AHSV 3att and 8 can influence the timing of virus release from the infected cell.

African Horse Sickness Virus↗
PubMed1997

N-ethylmaleimide blocks depolarization-induced suppression of inhibition and enhances GABA release in the rat hippocampal slice in vitro.

Regulation of synaptic, GABAA receptor-mediated inhibition is a process of critical importance to normal brain function. Recently, we have described a phenomenon in hippocampus of a transient, yet marked, decrease in spontaneous, GABAA receptor-mediated IPSCs after depolarization activated Ca2+ influx into a pyramidal cell. This process, depolarization-induced suppression of inhibition (DSI), is absent in hippocampal cells that previously had been exposed to pertussis toxin in vivo, implicating a G-protein in the DSI process. To circumvent the problem that a single cell cannot be studied before and after G-protein block using the pertussis toxin pretreatment method, we have used the sulfhydryl alkylating agent N-ethylmaleimide (NEM), which blocks pertussis toxin-sensitive G-proteins, to determine whether acute inhibition of G-proteins can eliminate DSI of spontaneous IPSCs (sIPSCs). In whole-cell recordings from CA1 pyramidal cells that were first determined to express DSI, we have found that NEM does block DSI of sIPSCs. We also report that DSI of monosynaptic, evoked IPSCs is blocked by NEM, suggesting that a similar mechanism underlies both forms of DSI. It was of interest that DSI was abolished at a time when NEM had increased, not decreased, GABA transmission. Indeed, NEM greatly increased quantal GABA release by a Ca(2+)-independent mechanism, an observation with potentially important implications for understanding synaptic GABA release.

Analysis of Variance↗
PubMed1997

Pharmacokinetics of dolasetron after oral and intravenous administration of dolasetron mesylate in healthy volunteers and patients with hepatic dysfunction.

In previous studies, dolasetron was shown to have both renal and hepatic elimination mechanisms. This study was conducted to determine the impact of varying degrees of hepatic dysfunction on the pharmacokinetics and safety of dolasetron and its reduced metabolites. Seventeen adults were studied: six healthy volunteers (group I), seven patients with mild hepatic impairment (Child-Pugh class A; group II), and four patients with moderate to severe hepatic impairment (Child-Pugh class B or C1; group III). Single 150-mg doses of dolasetron mesylate were administered intravenously and orally, with a 7-day washout period separating treatments. After intravenous administration, no differences were observed between healthy volunteers and patients with hepatic impairment in maximum plasma concentration (Cmax), areas under the plasma concentration-time curve (AUC), or elimination half-life (t1/2) of intact dolasetron. No significant differences were found in Cmax, AUC, or apparent clearance (C(lapp)) of hydrodolasetron, the primary metabolite of dolasetron. The mean t1/2 increased from 6.87 hours in group I to 11.69 hours in group III. After oral administration, C(lapp) of hydrodolasetron decreased by 42%, and Cmax increased by 18% in patients with moderate to severe hepatic impairment. There were less changes in patients with mildly hepatic impairment. Total percentage of dose excreted as metabolites was similar for healthy volunteers and patients with hepatic impairment, although urinary metabolite profiles differed slightly. Dolasetron was well tolerated and there were no apparent differences in adverse effects between groups or treatments. Because hepatic impairment did not influence Cl(app) of hydrodolasetron after intravenous administration, and the range of plasma concentrations of hydrodolasetron after oral administration was not different from those observed in healthy volunteers, dosage adjustments are not recommended for patients with hepatic disease and normal renal function.

Administration, Oral↗
PubMed1997

Neuropathic pain in cancer patients: mechanisms, syndromes, and clinical controversies.

The identification of a neuropathic pain syndrome in a cancer patient requires a focused clinical evaluation based on knowledge of common neuropathic pain syndromes. If a tumor is directly involved in the etiology of the pain, oncologic treatment is an initial consideration and may include surgery, radiation, or chemotherapy. There is no single accepted algorithm for the analgesic treatment of neuropathic pain and a systematic approach utilizing therapeutic trials of specific agents at gradually increasing doses is warranted. A trial of opioids, perhaps in combination with an NSAID, is warranted. If the pain is relatively unresponsive to an opioid, a trial with an adjuvant analgesic is reasonable. For example, a tricyclic antidepressant might be selected early for patients with continuous dysesthesia, and early treatment with an anticonvulsant might be used if the pain is predominantly lancinating or paroxysmal. Other adjuvant analgesics can be selected if there is insufficient response to these agents. A trial of sympathetic blockade, pharmacologic, anesthetic or surgical, should be considered in patients with evidence of causalgia or reflex sympathetic dystrophy. Physiatric modalities such as massage, heat, or cold; counterstimulation or transcutaneous electrical nerve stimulation (TENS), and orthopedic interventions, such as braces and splints may be useful. Epidural injections or neurostimulation of the spinal cord or brain can be considered in selected cases where appropriate expertise is available. Treatment of neuropathic pain remains a challenge for both clinicians and patients. The complexity of syndromes and underlying etiologic mechanisms warrants further clinical trials to determine the best treatment modalities for individual pain syndromes.

Diagnosis, Differential↗
PubMed1997

Use of transcriptional regulatory elements of the MUC1 and ERBB2 genes to drive tumour-selective expression of a prodrug activating enzyme.

In order to exploit differences in gene expression between normal and malignant cells for genetic prodrug-activation therapy, we have generated recombinant retroviruses containing the herpes simplex virus thymidine kinase coding region cloned downstream of sequences derived from the 5'-flanking regions of the MUC1 and ERBB2 genes. Transduction with retroviruses containing MUC1 promoters resulted in an increase in GCV sensitivity in MUC1 positive cells. A further increase in GCV sensitivity was achieved when MUC1-positive cells were transduced with retroviruses containing chimeric-MUC1/ERBB2 promoters. No significant sensitization to GCV was observed when MUC1-negative cells were transduced with these recombinant retroviruses. These results suggest that one may be able to develop a tumour-selective therapy by utilizing the transcriptional regulatory regions of the MUC1 and ERBB2 genes to drive the expression of suicide genes.

Antiviral Agents↗
PubMed1996

Retrograde signalling in depolarization-induced suppression of inhibition in rat hippocampal CA1 cells.

1. We have investigated the phenomenon of 'depolarization-induced suppression of inhibition' (DSI) using whole-cell voltage-clamp techniques in Ca1 pyramidal cells of rat hippocampal slices. DSI was induced by eliciting voltage-dependent calcium (Ca2+) currents with 1 s voltage steps of +60 to +90 mV from the holding potential. DSI was apparent as a reduction in synaptic GABAA responses for a period of about 1 min following the voltage step. 2. TTX-sensitive spontaneous IPSCs (sIPSCs) were susceptible to DSI, while TTX-resistant miniature inhibitory postsynaptic current (mIPSCs) were not. Miniature IPSCs are ordinarily infrequent and independent of external Ca2+ in the CA1 region. To increase the frequency of mIPSCs and to induce a population of Ca(2+)-sensitive mIPSCs, we increased the bath K+ concentration to 15 mM. The increased mIPSCs were also insensitive to DSI, however. 3. T whole-cell pipette-filling solution contained 5 mM 2(triethylamino-N-(2,6-dimethyl-phenyl)acetamide (QX-314) to block voltage-dependent Na+ currents and caesium to block K+ currents. Nevertheless, bath application of 50 microM 4-aminopyridine (4-AP) or 250 nM veratridine both clearly reduced DSI, evidently by acting at presynaptic sites. 4. The amplitudes of monosynaptically evoked IPSCs (elicited in the presence of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 50 microM 2-amino-5-phosphonovaleric acid (APV)) were dramatically reduced during the DSI period. Weak stimulation produced small IPSCs and occasional 'failures' of transmission during the control period. The percentage of failures increased markedly during the DSI period. Moderate-intensity stimulation produced larger IPSCs that were often composed of distinguishable multiquantal components. All-or-none failures of multiquantal IPSC components also occurred during DSI. 5. The degree of paired-pulse IPSC depression did not change during DSI, whereas it was decreased, as expected, by baclofen. 6. We conclude that the data represent novel evidence that DSI is mediated by a retrograde signalling process possibly involving presynaptic axonal conduction block.

Animals↗
PubMed1996

Direct cell killing by suicide genes.

Cell death can be induced by genetic intervention in a variety of ways. We review genetic prodrug activation therapies using both mammalian and non-mammalian enzyme systems as well as the expression of toxin genes and apoptotic triggers. Targeting of the genetic intervention using both transductional restriction and transcriptional control elements is examined in both in vitro and in vivo systems, and the present state of clinical trials is reviewed.

Animals↗
PubMed1996

Dose-ranging evaluation of the antiemetic efficacy of intravenous dolasetron in patients receiving chemotherapy with doxorubicin or cyclophosphamide.

Selective 5-HT3 antagonists have proven to be safe and effective for the prevention of chemotherapy-induced nausea and vomiting. Dolasetron is a new highly selective addition to this class of antiemetics that has been shown to have significant antiemetic activity in patients receiving cisplatin-containing regimens. This pilot study was designed to evaluate the antiemetic efficacy of dolasetron in cancer patients receiving doxorubicin and/or cyclophosphamide. This study used an open-label, non-randomized design to evaluate the efficacy and safety of intravenous dolasetron in the prevention of emesis in patients receiving doxorubicin (25-75 mg/m2) and/or cyclophosphamide (400-1200 mg/m2). Sixty-nine patients received a single, intravenous dose of dolasetron over 15-20 min beginning 30 min prior to the start of chemotherapy. Dose levels of dolasetron studied were: 0.3, 0.6, 1.2, 1.8 and 2.4 mg/kg. Patients were monitored for emesis, nausea and adverse events for 24h after the start of chemotherapy. Overall, 61% of patients experienced complete control of emesis. No significant trend towards increased antiemetic efficacy (P = 0.076) or nausea control with increasing dolasetron dose was noted, although the power to detect significant differences was limited by the small number of patients on the 0.3-mg/kg and 2.4-mg/kg dose levels. Age, gender, and type of chemotherapy were significant predictors of complete antiemetic control. Adverse events were generally mild and included headache, chills, lightheadedness, fever, diarrhea, dizziness, and asymptomatic prolongation of ECG intervals. Intravenous dolasetron is safe and effective in the prevention of emesis induced by doxorubicin and/or cyclophosphamide.

Adult↗
PubMed1996

NIRCA: a rapid robust method for screening for unknown point mutations.

We describe a method for screening for dispersed point mutations, based on the observation that RNase frequently cleaves both strands of base pair mismatches in duplex RNA targets. The mismatched substrates are generated by in vitro transcription of wild-type and mutant templates amplified by the PCR or reverse transcription (RT)-PCR; bacteriophage promoters are incorporated into the PCR primers to permit both strands of the products to be transcribed into RNA. Complementary wild-type and mutant transcripts are hybridized and treated with RNase, and the cleavage products are separated on agarose gels and detected by visualization of the ethidium-stained sample under UV light. The method is thus non-isotopic, and since the cleavage products remain double-stranded during analysis, the labor-intensive RNase inactivation steps required in the original procedure can be eliminated. Also, nonspecific background cleavage is reduced so that longer target regions (1 kb) can be screened in a single step. The Non-Isotopic RNase Cleavage Assay (NIRCA) achieved a detection rate of 88%-90% in blind studies in a Factor IX model system, and it was also used to detect unknown p53 mutations in breast tumor samples. NIRCA provides a rapid method for sensitive, non-isotopic, high-throughput genetic screening.

Base Sequence↗
PubMed1996

MDL 201,307: a novel benzothiazepine modulator of multiple drug resistance.

A series of novel benzothiazepine derivatives were evaluated for their relative potential to reverse multiple drug resistance (MDR) phenotype in vitro as well as for their relative cardiovascular activity and neurotoxicity. Compounds were evaluated for antiMDR activity using Chinese hamster ovary cells with derived resistance to either vincristine or doxorubicin, or a human lymphoblastic leukemia line with resistance to vinblastine. Lead compounds with good antiMDR activity were further evaluated for their relative potential to exhibit cardiovascular and neurological pharmacodynamic activity. A single compound, MDL 201,307 with good antiMDR activity and low cardiovascular and neurologic activity was chosen for further study. In contrast to (R)-verapamil, MDL 201,307 showed only a weak potential to block calcium channels. Using a series of related murine fibrosarcoma cell lines (UV-2237M) with varying levels of resistance to doxorubicin, it was shown that MDL 201,307 augmented inhibition of growth due to doxorubicin. The antiMDR compound was also effective in enhancing the cytotoxicity of actinomycin-D and vinblastine although it was ineffective in increasing cytotoxicity of the nonMDR compound, 5FU. MDL 201,307 increased uptake and decreased efflux of doxorubicin suggesting that MDL 201,307 blocks the GP170-mediated efflux pump mechanism. MDL 201,307 represents a novel antiMDR agent with diminished potential for cardiovascular activity and neurologic interactions which presently limit many of the currently available first and second generations of antiMDR compounds.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Influence of a sampling review process for radiation oncology quality assurance in cooperative group clinical trials--results of the Radiation Therapy Oncology Group (RTOG) analysis.

The Radiation Therapy Oncology Group (RTOG) designed a random sampling process and observed its influence upon radiotherapy review mechanisms in cooperative group clinical trials. The method of sampling cases for review was modeled from sampling techniques commonly used in pharmaceutical quality assurance programs, and applied to the initial (on-study) review of protocol cases. 'In control' (IC) status is defined for a given facility as the ability to meet minimum compliance standards. Upon achieving IC status, activation of the sampling process was linked to the rate of continued patient accrual for each participating institution in a given protocol. The sampling design specified that > or = 30% cases not in compliance would be detected with 80% power. A total of 458 cases was analyzed for initial review findings in four RTOG Phase III protocols. Initial review findings were compared with retrospective (final) review results. Of the 458 cases analyzed, 370 underwent initial review at on-study, while 88 did not require review as they were enrolled from institutions that had demonstrated protocol compliance. In the group that had both initial and final review, 345/370 (93%) were found to have followed the protocol or had a minor variation. Of the exempted cases, 79/88 (90%) were found to be per protocol or a minor variant. The sampling process proved itself to be cost-effective and resulted in a noticeable reduction in the workload, thus providing an improved approach to resource allocation for the group. Continued evaluation of the sampling mechanism is appropriate as study designs and participants vary over time, and as more data become available to study.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Protocols↗
PubMed1995

Erythrocyte polyamine levels: an indication of successful engraftment of bone marrow in children.

We studied the evolution of erythrocyte polyamine levels after 17 autologous bone marrow transplants (BMT) in 16 children with malignant diseases. We found that the time to the end of aplasia (0.5 x 10(9) granulocytes per liter) could be divided into 2 distinct periods. The first is characterized by low erythrocyte spermidine (Spd) and spermine (Spm) levels; the second is characterized by normal levels of polyamines. Spd and Spm levels were correlated (r = 0.74) during the second period, but not during the first period or in the control group. Furthermore, the time when Spd concentration was > or = 7 nmol/8 x 10(9) erythrocytes (19 +/- 7) was correlated (r = 0.64) with the advent of end of aplasia (30 +/- 10). We found no correlation between the numbers of CFU-GM and duration of aplasia levels or the duration of period A. The establishment of normal erythrocyte spermidine levels is the earliest index of successful marrow engraftment.

Adolescent↗
PubMed1994

Hippocampal theta rhythm in behaving rats following ibotenic acid lesion of the septum.

The effects of ibotenic acid lesion of the septum were studied in rats implanted with chronically indwelling electrodes and septal cannula. Each rat served as its own control and the properties of the hippocampal theta rhythm were studied before and after ibotenic acid and control saline infusion into the medial septal area. Ibotenic acid preferentially killed neurons in the lateral septum, and significantly attenuated the hippocampal theta rhythm about 50% bilaterally, at both surface and deep electrodes. The coherence and the phase of the theta rhythm at the CA1 apical dendrites, with respect to a superficial electrode, also declined significantly after ibotenic acid lesion. Pilocarpine (25 mg/kg i.p.) induced a theta rhythm of 7-9 Hz during immobility in the lesioned rats that was significantly higher in frequency than that induced in intact rats (4-6 Hz). In lesioned rats, the theta rhythm during tail pinch under urethane anesthesia was largely abolished, and the theta during walking was attenuated by atropine sulfate (50 mg/kg i.p.). Phencyclidine (10 mg/kg i.p.) or parachlorophenylalanine (PCPA) alone, which was inferred to abolish an atropine-resistant theta input, did not affect the power of the walking theta rhythm in either the lesioned or the normal rat. It was concluded that the theta in the behaving rats after ibotenic acid lesion in the septum has a strong atropine-sensitive component, and that it is not predominantly atropine-resistant, as suggested previously. The lack of PCPA effect on the theta phase in intact and lesioned rats also suggested a different view of the atropine-resistant theta in hippocampal region CA1. One possible mechanism of the atropine-resistant theta at the distal dendrites of pyramidal cells may result from rhythmic inhibition by stratum lacunosum-moleculare interneurons which may be activated by either serotonergic or cholinergic inputs.

Animals↗
PubMed1994

Mouse strain differences in the behavioral effects of corticotropin-releasing factor (CRF) and the CRF antagonist alpha-helical CRF9-41.

The effect of the corticotropin-releasing factor (CRF) antagonist alpha-helical CRF9-41 (alpha H CRF9-41; 25 and 50 micrograms) was examined in four strains of mice (BALB/C, NIH Swiss, CF-1, and CD) in the elevated plus-maze anxiolytic test and found to significantly increase percent open arm activity in only the BALB/C mice. A marginal anxiolytic response was obtained in NIH Swiss, while no effect of the antagonist was noted in CF-1 or CD mice in this test. Diazepam (1-4 mg/kg IP) significantly increased percent open arm activity in all four mouse strains. Thus, all strains were sensitive to the effects of a known anxiolytic in this test. The locomotor-suppressing effect of the agonist CRF was assessed in the four strains of mice. While CRF suppressed locomotor activity in each of the strains, the peptide was more efficacious and more potent in the BALB/C strain than in any of the other three strains. The behavioral differences in responsiveness to CRF and the antagonist alpha H CRF9-41 could not be explained on the basis of differential binding of CRF to forebrain membranes in the four mouse strains. These data suggest that the BALB/C mouse is more sensitive to the behavioral effects of CRF and its antagonist than other strains and may be a useful strain for examining the effects of CRF and/or stress.

Animals↗
PubMed1994

Improved detection of persistent foot-and-mouth disease infection in cattle by the polymerase chain reaction.

Persistent foot-and-mouth disease (FMD) infection of cattle was established by exposure to infected pigs. Oesophageal-pharyngeal fluid samples collected ante-mortem and tissue samples obtained post-mortem were tested for virus by conventional means and for viral RNA by the polymerase chain reaction (PCR). The results showed that the PCR was superior for detecting the carrier state in tissue samples. A high neutralising activity in tissues probably influenced the yields of virus obtained by infectivity assay.

Animals↗
PubMed1993

The effects of structural analogs of putrescine on proliferation, morphology and karyotype of glioblastoma cells in culture.

In a previous study, we identified regions on the surface of tumor cells which act as acceptor sites for putrescine (Put) and studied the competition between structural analogs of Put (N,N'-tetramethyl-alpha,omega-diaminoalkanes) and Put bound to latex microspheres. A chain of four to seven carbons was necessary for inhibition of Put-latex binding to the cell surface of human glioblastoma (U251) cells. We show here that under the experimental conditions, N,N'-tetramethyl-1,4-butanediamine and N,N'-tetramethyl-1,7-heptanediamine exhibit an antitumor effect. In a first step (1-48 h after treatment), cells exposed to these compounds show large intracellular vacuoles. We failed to detect any acid phosphatase activity in these intracellular structures revealing that they were not lysosomes. Electron microscopy observations argue for the conclusion that these vacuoles are an hypertrophy of the endoplasmic reticulum (ER) and/or of the Golgi vesicles. Our hypothesis is that this typical effect of the analogs reveals that ER could be a physiological target of endogenous polyamines. At a later stage (6 days after treatment), the cells undergo morphological and biochemical changes: thin and long expansions characterize the cells and the GFA protein is overexpressed. Correlated to both these effects, karyotypic modifications are found in chromosomes 3 and 6. These changes evoke a differentiation of the treated cells. The work provides evidence that N-methylated polyamine analogs taking the place of endogenous putrescine demonstrate a hopeful antitumor effect.

Cell Differentiation↗
PubMed1993

Survival comparison of radiosurgery-eligible and -ineligible malignant glioma patients treated with hyperfractionated radiation therapy and carmustine: a report of Radiation Therapy Oncology Group 83-02.

PURPOSE: The purpose is twofold: (1) to identify the malignant glioma patients treated in a trial of hyperfractionated radiotherapy (RT) and carmustine (BCNU) who may have been eligible for a stereotactic radiosurgery (SRS) boost; and (2) to compare survival of such patients with that of those considered SRS-ineligible. PATIENTS AND METHODS: From January 1983 to July 1989, 778 malignant glioma patients were enrolled on Radiation Therapy Oncology Group (RTOG) 83-02, a randomized phase I/II hyperfractionated RT dose-escalation trial with BCNU chemotherapy. The SRS criteria used in a single-institution trial were applied to these patients; they are: Karnofsky performance status (KPS) of greater than 60; well-circumscribed tumor less than 4.0 cm; no subependymal spread; and a location not adjacent to brainstem or optic chiasm. RESULTS: Eighty-nine patients (11.9%) were identified as potentially SRS-eligible. The median survival times (MST) and 18-month survival rates of the 89 eligible and 643 ineligible patients were 14.4 versus 11.7 months and 40% versus 27%, respectively (P = .047). The MST and 18-month survival rate of the 544 SRS-ineligible patients with KPS greater than 60 were 12.1 months and 29%, respectively, and were not statistically inferior to the survival of the SRS-eligible group (P = .21). Multivariate analysis revealed age, KPS, and histopathology to be strongly predictive of survival, and SRS eligibility was also significantly predictive (P = .047). CONCLUSION: SRS-eligible patients enrolled on RTOG 83-02 had survival superior to that of the SRS-ineligible group, and this advantage is mainly due to the selection of a subgroup with a high minimum KPS.

Carmustine↗