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Biomedical subjects

M A Martin

Publications and source records attributed to M A Martin.

At least 19 recordsLinked to original sources
PubMed2006

Can patients with McArdle's disease run?

Patients with McArdle's disease commonly adopt a sedentary lifestyle. This sedentary behaviour, however, usually worsens the limited exercise capacity of these patients. Although eccentric muscle work can be associated with rhabdomyolysis, supervised eccentric training with gradually increasing loads has important advantages compared with conventional concentric work, particularly for patients with a poor cardiorespiratory system. We report the beneficial effects (particularly, increased VO(2peak) (from 14.6 to 30.8 ml/kg/min) and increased gross muscle efficiency (from 13.8% to 17.2%)) induced by a supervised aerobic training programme of 7 months duration including 3-4 running sessions (< or =60 min/session) per week in a 38-year-old patient. These preliminary data suggest the potential therapeutic value of this type of exercise in these patients.

Adult↗
PubMed2006

Mobilisation of mesenchymal cells into blood in response to skeletal muscle injury.

Mesenchymal cells recruited to damaged tissues must circulate through the bloodstream. The absolute numbers of circulating mesenchymal stem cells (cMSCs) in two different models of acute and chronic skeletal muscle injury were determined. cMSCs were present in significantly higher numbers in both models than in healthy controls. These results support the hypothesis that MSCs are mobilised into the bloodstream after skeletal muscle tissue damage. These two models (acute and chronic) would be of value in the search for molecular mediators of mobilisation of MSCs into the circulation.

Adult↗
PubMed2006

Does the C34T mutation in AMPD1 alter exercise capacity in the elderly?

Ageing does affect functional capacity through several changes at the peripheral muscle level that impair the muscles capacity to produce energy and generate force. The skeletal muscle-specific isoform of AMP deaminase (AMPD) plays an important regulatory role in muscle metabolism and in determining energy charge. Since nearly 20 % of the general Caucasian population is heterozygous (CT) for the most common C34T mutation of the gene (AMPD1) encoding for this enzyme, it would be worthwhile to study if such a condition further increases the effects of ageing. Twenty-one women (61 - 80 yrs) served as subjects, and depending on the results of previous genotyping, were assigned to a group with the C34T mutation (heterozygous; n=4; mean+/-SEM age: 71+/-1 yrs) or with no mutation (n=17; 68+/-1 yrs). Several indices of maximal (peak oxygen uptake [V.O (2 peak)], peak power output) and submaximal endurance performance (ventilatory threshold, mechanical efficiency) and functional tests (one-mile walk test and a specific test of lower-body functional performance [sit-stand test]) were compared between the two groups. No significant differences were found in exercise capacity between both groups, e. g. V.O (2 peak) of 19.1+/-1.0 vs. 20.1+/-1.9 ml . kg (-1) . min (-1), V.O (2) at the VT of 11.9+/-0.6 vs. 12.9+/-1.0 ml . kg (-1) . min (-1), or time to complete the one-mile walk test (951+/-18 s vs. 962+/-61 s) and sit-stand test (9.9+/-0.2 vs. 9.2+/-0.2) (no mutation vs. C34T mutation, respectively). Although more research is necessary, it seems that the C34T mutation of the AMPD1, at least in heterozygous individuals, does not affect functional capacity in the elderly.

AMP Deaminase↗
PubMed2006

C34T mutation of the AMPD1 gene in an elite white runner.

The case is reported of an elite, male, white endurance runner (28 years of age), who is one of the best non-African runners in the world despite carrying the C34T mutation in the gene (AMPD1) that encodes the skeletal muscle specific isoform of AMP deaminase, an enzyme that plays an important role in muscle metabolism. The frequency of the mutant allele in sedentary white people is 8-11%. Previous research has shown that this mutation, at least in homozygotes, can impair the exercise capacity of untrained people and their trainability. The maximum oxygen uptake of the study subject was exceptionally high (83.6 ml/kg/min), whereas his ammonia and lactate concentrations at high submaximal running speeds were lower than those of other world class runners who are not carriers of the mutation. The partial metabolic deficiency of the study subject is possibly compensated for by his exceptionally favourable anthropometric characteristics (body mass index 18.2 kg/m2).

AMP Deaminase↗
PubMed2006

Exercise capacity in a 78 year old patient with McArdle's disease: it is never too late to start exercising.

The case is reported of a 78 year old man with McArdle's disease and a history of treated coronary heart disease. Despite the pre-exercise administration of sucrose allowing the patient to exercise with normal physiological responses, and without typical McArdle's symptoms or biochemical evidence of muscle damage, his exercise capacity was very low (V(O2)peak = 10.7 ml/min/kg), probably attributable to his lifetime of sedentary living. The data suggest that, with pre-exercise sucrose administration, such patients may be candidates for systematic reconditioning, which may improve functional capacity and quality of life.

Aged↗
PubMed2006

Applying a moving total mortality count to the cities in the NMMAPS database to estimate the mortality effects of particulate matter air pollution.

OBJECTIVES: To apply a new method for estimating the association between daily ambient particulate matter air pollution (PM) and daily mortality to data from over 100 United States cities contained in the National Morbidity, Mortality, and Air Pollution Study (NMMAPS) database and to see whether the results from the 90 cities NMMAPS analysis are robust to this different modelling approach. This new method has recently been shown to provide improved estimates for the association between PM and daily mortality when every-day PM data are unavailable. It avoids the need for selecting a lag of PM at which the mortality effects of PM are to be investigated. METHODS: With the aid of analytical methods and databases developed for NMMAPS, Poisson log linear models controlling for long term trends and weather effects were used to estimate the association between PM and mortality for cities in the NMMAPS database using the new method. A two stage Bayesian hierarchical model was then used to combine city specific estimates to form a national average PM mortality effect estimate. RESULTS: A 10 microg/m3 increase in PM was associated with a 0.12% increment in total mortality and a 0.17% increment in cardiovascular and respiratory mortality. These results are consistent with those found in the NMMAPS analysis. CONCLUSIONS: There is a statistically significant association between short term changes in PM and mortality on average for the cities contained in the NMMAPS database. These findings are further evidence that this widespread pollutant adversely affects public health.

Adult↗
PubMed2002

Tumour dose enhancement using modified megavoltage photon beams and contrast media.

This study examines the magnitude of tumour dose enhancement achieved by injection of gadolinium or iodine contrast media (CM) and treatment using modified x-ray photon spectra from linear accelerators. Monte Carlo modelling of the linear accelerator and patient geometry was used to explore the effect of removing the flattening filter for various beam qualities and the resultant effect on dose enhancement. In addition, ionization measurements were conducted to observe dose enhancement within a phantom containing CM. Simulation results indicate that for flattened 6-24 MV photon beams and realistic CM tumour concentrations, the dose enhancement remains below 5%. However, if the flattening filter is removed, dose enhancement is increased significantly. For a 30 mg ml(-1) gadolinium CM tumour concentration, for example, 8.4%, 10.8%, 13.7% and 23.1% dose enhancements are achieved for 18 MV, 6 MV, 4 MV and 2 MV unflattened beams, respectively. In contrast to the phototherapy technique, which uses the orthovoltage beam from a modified CT scanner to achieve dose enhancement, all unflattened spectra preserve the dose build-up at the surface, and thus the skin and bone are spared.

Chemotherapy, Adjuvant↗
PubMed2001

Macrophage are the principal reservoir and sustain high virus loads in rhesus macaques after the depletion of CD4+ T cells by a highly pathogenic simian immunodeficiency virus/HIV type 1 chimera (SHIV): Implications for HIV-1 infections of humans.

The highly pathogenic simian immunodeficiency virus/HIV type 1 (SHIV) chimeric virus SHIV(DH12R) induces a systemic depletion of CD4(+) T lymphocytes in rhesus monkeys during the initial 3-4 weeks of infection. Nonetheless, high levels of viral RNA production continue unabated for an additional 2-5 months. In situ hybridization and immunohistochemical analyses revealed that tissue macrophage in the lymph nodes, spleen, gastrointestinal tract, liver, and kidney sustain high plasma virus loads in the absence of CD4(+) T cells. Quantitative confocal immunofluorescence analysis indicated that greater than 95% of the virus-producing cells in these tissues are macrophage and less than 2% are T lymphocytes. Interestingly, the administration of a potent reverse transcriptase inhibitor blocked virus production during the early T cell phase but not during the later macrophage phase of the SHIV(DH12R) infection. When interpreted in the context of HIV-1 infections, these results implicate tissue macrophage as an important reservoir of virus in vivo. They become infected during the acute infection, gradually increase in number over time, and can be a major contributor to total body virus burden during the symptomatic phase of the human infection.

Adenine↗
PubMed2001

Thyroid hormone regulates oxidative phosphorylation in the cerebral cortex and striatum of neonatal rats.

We have previously shown that thyroid hormone (T(3)) regulates mitochondrial gene expression, morphology and transmembrane potential in the developing brain. Here, we have analysed the effect of thyroid hormone on mitochondrial function in different brain regions. For this purpose we have determined, in control, hypothyroid and T(3)-treated hypothyroid neonatal rats, the rate of oxidative phosphorylation in isolated mitochondria and the activity of the respiratory complexes in tissue homogenates. Our results showed a decrease in oxidative phosphorylation rate (only in the presence of NADH-generating substrates) and mitochondrial complexes I and III activity in the cerebral cortex and striatum of hypothyroid neonates, but not in the other areas analysed (hippocampus, cerebellum, thalamus, mid brain and brain stem). In parallel with mitochondrial activity, the levels of mitochondrially encoded transcripts were decreased only in the cerebral cortex and striatum of hypothyroid rats. The administration of T(3) corrected all these parameters. In summary, this study showed a down-regulation of mitochondrial gene expression accompanied by a decrease in mitochondrial activity in the cerebral cortex and striatum of developing hypothyroid neonatal rats.

Adenosine Triphosphatases↗
PubMed2001

N-linked glycosylation sites adjacent to and within the V1/V2 and the V3 loops of dualtropic human immunodeficiency virus type 1 isolate DH12 gp120 affect coreceptor usage and cellular tropism.

The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) is extensively glycosylated, containing approximately 23 asparagine (N)-linked glycosylation sites on its gp120 subunit. In this study, specific glycosylation sites on gp120 of a dualtropic primary HIV-1 isolate, DH12, were eliminated by site-directed mutagenesis and the properties of the resulting mutant envelopes were evaluated using a recombinant vaccinia virus-based cell-to-cell fusion assay alone or in the context of viral infections. Of the glycosylation sites that were evaluated, those proximal to the V1/V2 loops (N135, N141, N156, N160) and the V3 loops (N301) of gp120 were functionally critical. The glycosylation site mutations near the V1/V2 loop compromised the use of CCR5 and CXCR4 equally. In contrast, a mutation within the V3 loop preferentially inhibited the usage of CCR5; although this mutant protein completely lost its CCR5-dependent fusion activity, it retained 50% of the wild-type fusion activity with CXCR4. The replication of a virus containing this mutation was severely compromised in peripheral blood mononuclear cells, MT-4 cells, and primary monocyte-derived macrophages. A revertant virus, which acquired second site changes in the V3 loop that resulted in an increase in net positive charge, was isolated. The revertant virus fully recovered the usage of CXCR4 but not of CCR5, thereby altering the tropism of the parental virus from dualtropic to T-tropic. These results suggest that carbohydrate moieties near the V1/V2 and the V3 loops play critical roles in maintaining proper conformation of the variable loops for optimal interaction with receptors. Our results, combined with those of previously reported studies, further demonstrate that the function of individual glycans may be virus isolate dependent.

Base Sequence↗
PubMed2001

Polyvalent envelope glycoprotein vaccine elicits a broader neutralizing antibody response but is unable to provide sterilizing protection against heterologous Simian/human immunodeficiency virus infection in pigtailed macaques.

The great difficulty in eliciting broadly cross-reactive neutralizing antibodies (NAbs) against human immunodeficiency virus type 1 (HIV-1) isolates has been attributed to several intrinsic properties of their viral envelope glycoprotein, including its complex quaternary structure, extensive glycosylation, and marked genetic variability. Most previously evaluated vaccine candidates have utilized envelope glycoprotein from a single virus isolate. Here we compare the breadth of NAb and protective immune response following vaccination of pigtailed macaques with envelope protein(s) derived from either single or multiple viral isolates. Animals were challenged with Simian/human immunodeficiency virus strain DH12 (SHIV(DH12)) following priming with recombinant vaccinia virus(es) expressing gp160(s) and boosting with gp120 protein(s) from (i) LAI, RF, 89.6, AD8, and Bal (Polyvalent); (ii) LAI, RF, 89.6, AD8, Bal, and DH12 (Polyvalent-DH12); (iii) 89.6 (Monovalent-89.6); and (iv) DH12 (Monovalent-DH12). Animals in the two polyvalent vaccine groups developed NAbs against more HIV-1 isolates than those in the two monovalent vaccine groups (P = 0.0054). However, the increased breadth of response was directed almost entirely against the vaccine strains. Resistance to SHIV(DH12) strongly correlated with the level of NAbs directed against the virus on the day of challenge (P = 0.0008). Accordingly, the animals in the Monovalent-DH12 and Polyvalent-DH12 vaccine groups were more resistant to the SHIV(DH12) challenge than the macaques immunized with preparations lacking a DH12 component (viz. Polyvalent and Monovalent-89.6) (P = 0.039). Despite the absence of any detectable NAb, animals in the Polyvalent vaccine group, but not those immunized with Monovalent-89.6, exhibited markedly lower levels of plasma virus than those in the control group, suggesting a superior cell-mediated immune response induced by the polyvalent vaccine.

AIDS Vaccines↗
PubMed2000

Higher western blot immunoreactivity of glycoprotein 120 from R5 HIV type 1 isolates compared with X4 and X4R5 isolates.

The envelope glycoprotein of human immunodeficiency virus 1 (HIV-1) plays important roles in viral life cycle and pathogenesis. Understanding the immune responses the protein elicits during the course of a viral infection in patients is important in designing an effective vaccine candidate against the virus or for better diagnosis of the disease. In this study, we report that gp120 of R5 isolates have higher Western blot (WB) immunoreactivity to antibodies elicited against the protein in virus-infected human patients compared with that of X4 and X4R5 isolates. Analyses of WB immunoreactivity of chimeric gp120s constructed between R5 (AD8) and X4R5 (DH12) HIV-1 isolates indicate that there are complex tertiary interdomain interactions even after a complete denaturation of the protein. Our data suggest that the determinant(s) responsible for the high WB immunoreactivity might be present in all gp120s, but are accessible to antibodies only for R5 gp120s in the WB assay. The V1/V2 and/or V3 regions of X4 and X4R5 gp120s likely interfere with either the formation or surface exposure of the WB immunoreactive determinant. Supplementing HIV-1 WB diagnosis kits with purified R5 gp120 could improve their sensitivity and facilitate earlier diagnosis of virus infection.

Animals↗
PubMed2000

Quantification of thymic function by measuring T cell receptor excision circles within peripheral blood and lymphoid tissues in monkeys.

The thymus is the primary organ responsible for the production of mature TCR alpha / beta T cells. Quantification of a DNA excision circle that is produced during TCR rearrangement, termed a signal joint TCR rearrangement excision circle (sjTREC) can be used as a measure of thymic function. Here sjTREC measurement has been applied to two monkey species used as animal models of human disease, rhesus macaques (Asian origin) and sooty mangabeys (African origin). Initial PCR analysis determined that the TCR deltaRec-PsiJalpha rearrangement leading to sjTREC formation occurs in both species. Primers to a DNA sequence conserved in macaques, mangabeys and humans were used in a quantitative competitive PCR assay to quantify sjTREC. We found that as in humans, sjTREC in these two monkey species decline with age. sjTREC are first generated in thymocytes during the early stages of TCR rearrangement. Lymph node CD4(+) and CD8(+) T cells contain more sjTREC than peripheral blood T cell populations, suggesting that recent thymic emigrants home to the lymphoid tissues. The sjTREC level is significantly higher within the peripheral blood CD4(+) and CD8(+) T cells of mangabeys compared to macaques. Removal of the thymus in four macaques led to a profound decrease in peripheral blood sjTREC level by 1 year post-thymectomy, indicating the lack of a significant extra-thymic source of peripheral naive T cells in macaques. Our results indicate that production, trafficking, and proliferation of recent thymic emigrants in these two monkey species represents a useful animal model system for understanding human immunological disorders.

Aging↗
PubMed2000

Emergency coronary artery bypass graft surgery in abciximab-treated patients.

BACKGROUND: Although the platelet antiaggregant abciximab is frequently used with percutaneous coronary interventions, results of emergency coronary artery bypass graft operations in patients recently treated with abciximab are poorly characterized. METHODS: During a 29-month period, 12 patients required emergency coronary artery bypass grafting within 12 hours (mean, 1.9 hours) of abciximab therapy. Our full standard heparin dose regimen was used (mean heparin dose, 53,000 U per patient). Each patient received a single platelet transfusion dose after protamine administration, and further blood products were transfused as necessary. Clinical outcome and transfusion requirements were compared with predicted results based on risk-adjusted historical patients. RESULTS: No patients died and none were returned to the operating room for coagulopathy-related bleeding. Per patient transfusion requirements were as follows: red blood cells, 3.6 units; apheresis platelets, 1.4 units; and fresh frozen plasma, 1.5 units. As compared with predicted values, there was no excessive incidence of mortality, stroke, or red blood cell transfusion requirements. CONCLUSIONS: Emergency coronary artery bypass graft operations using full-dose heparin can be performed successfully in acutely ischemic abciximab-treated patients. Prophylactic transfusion of platelets after protamine administration appears to be useful.

Abciximab↗
PubMed2000

Vaginal clindamycin and oral metronidazole for bacterial vaginosis: a randomized trial.

OBJECTIVE: To compare the efficacy and safety of clindamycin vaginal ovules with oral metronidazole for treatment of bacterial vaginosis. METHODS: Women with bacterial vaginosis received either 100-mg ovules of clindamycin (intravaginally for 3 consecutive days) plus placebo capsules (orally twice daily for 7 days) or metronidazole 500 mg (two 250-mg capsules orally twice daily for 7 days) plus placebo ovules (intravaginally for 3 consecutive days). The sample was determined prospectively to provide a probability of.84 of correctly concluding that the rate of success for clindamycin is not more than 15% less than the expected 75% success rate for metronidazole. Clinical outcome was determined on the basis of vaginal fluid amine odor and clue cells. RESULTS: Of the 399 patients enrolled, 233 could be evaluated for efficacy. Of those, 77 (68.1%) of 113 patients were cured with clindamycin, compared with 80 (66. 7%) of 120 who were cured with metronidazole (95% confidence interval -10.6%, 13.4%; P =.810). Treatment-related adverse events were reported more frequently in the metronidazole treatment group. Systemic symptoms, such as nausea and taste perversion, accounted for most of the difference between groups. CONCLUSION: A 3-day regimen of clindamycin, given as intravaginal ovules, was as effective as and better tolerated than a 7-day regimen of oral metronidazole 500 mg, given twice daily, for treatment of bacterial vaginosis.

Administration, Intravaginal↗
PubMed2000

Effect of ABC transporters on HIV-1 infection: inhibition of virus production by the MDR1 transporter.

The MDR1 multidrug transporter P-gp (P-glycoprotein) is an efflux pump that extrudes diverse hydrophobic drugs and peptides from cells. Since the entry of HIV-1 into cells involves an initial interaction of the viral gp41 hydrophobic peptide with the plasma membrane, a potential effect of P-gp on HIV-1 infectivity was explored. Virus production was greatly decreased when P-gp was overexpressed at the surface of a continuous CD4(+) human T-leukemic cell line (12D7) infected with HIV-1(NL4-3), a T-tropic molecular clone of HIV-1. P-gp overexpression did not significantly alter the surface expression or distribution of either the HIV-1 receptor CD4 or the coreceptor CXCR4. Reduction of HIV-1 infectivity in P-gp-expressing cells occurred both during the fusion of viral and plasma membranes and at subsequent step(s) in the HIV-1 life cycle.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Short- and long-term clinical outcomes in rhesus monkeys inoculated with a highly pathogenic chimeric simian/human immunodeficiency virus.

A highly pathogenic simian/human immunodeficiency virus (SHIV), SHIV(DH12R), isolated from a rhesus macaque that had been treated with anti-human CD8 monoclonal antibody at the time of primary infection with the nonpathogenic, molecularly cloned SHIV(DH12), induced marked and rapid CD4(+) T cell loss in all rhesus macaques intravenously inoculated with 1.0 50% tissue culture infective dose (TCID(50)) to 4.1 x 10(5) TCID(50)s of virus. Animals inoculated with 650 TCID(50)s of SHIV(DH12R) or more experienced irreversible CD4(+) T lymphocyte depletion and developed clinical disease requiring euthanasia between weeks 12 and 23 postinfection. In contrast, the CD4(+) T-cell numbers in four of five monkeys receiving 25 TCID(50)s of SHIV(DH12R) or less stabilized at low levels, and these surviving animals produced antibodies capable of neutralizing SHIV(DH12R). In the fifth monkey, no recovery from the CD4(+) T cell decline occurred, and the animal had to be euthanized. Viral RNA levels, subsequent to the initial peak of infection but not at peak viremia, correlated with the virus inoculum size and the eventual clinical course. Both initial infection rate constants, k, and decay constants, d, were determined, but only the latter were statistically correlated to clinical outcome. The attenuating effects of reduced inoculum size were also observed when virus was inoculated by the mucosal route. Because the uncloned SHIV(DH12R) stock possessed the genetic properties of a lentivirus quasispecies, we were able to assess the evolution of the input virus swarm in animals surviving the acute infection by monitoring the emergence of neutralization escape viral variants.

Amino Acid Substitution↗
PubMed2000

Identification of gp120 regions targeted by a highly potent neutralizing antiserum elicited in a chimpanzee inoculated with a primary human immunodeficiency virus type 1 isolate.

We have previously reported that a chimpanzee infected with a primary human immunodeficiency virus type 1 (HIV-1) isolate (HIV-1(DH12)) developed an extremely potent virus-neutralizing antibody. Immunoglobulin G purified from this animal conferred sterilizing immunity following passive transfer to macaques which were subsequently challenged with simian immunodeficiency virus/HIV-1 chimeric virus strain DH12. In addition to being highly strain specific, the chimpanzee antiserum did not bind to the V3 loop peptide of HIV-1(DH12), nor did it block the interaction of gp120 with the CD4 receptor. When neutralization was examined in the context of virus particles carrying chimeric envelope glycoproteins, the presence of all five hypervariable regions (V1 to V5) was required for optimal neutralization. Virions bearing chimeric gp120 containing the V1-V2 and V4 regions of HIV-1(DH12) could also be neutralized, but larger quantities of the chimpanzee antiserum were needed to block infection. These results indicate that the HIV-1 gp120 epitope(s) targeted by the chimpanzee antiserum is highly conformational, involving surface elements contributed by all of the hypervariable domains of the envelope glycoprotein.

Animals↗