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At least 523 records · Page 29Linked to original sources
PubMed2002

Impact of ageing on the antinociceptive effect of reference analgesics in the Lou/c rat.

1. Research on the evolution of experimental pain perception and on the achievement of analgesia with ageing has led so far to contradictory results. 2. This study investigated in the rat the impact of ageing on the antinociceptive effect of reference analgesics, acetaminophen (50, 100, 200, 400 mg kg(-1) po), aspirin (50, 100, 200, 400 mg kg(-1) sc), clomipramine (5, 10, 20, 40 mg kg(-1) sc) and morphine (1.25, 2.5, 5, 10 mg kg(-1) sc). 3. Lou/c rats were chosen because they provide a model of healthy ageing and they do not develop obesity with age. Three groups of 40 rats each (mature (4 months), middle-aged (18 months) and old (26 months)), were treated with each drug at 14 days interval. Two tests were used: a thermal test (tail immersion in 48 degrees C water and measurement of reaction latency) and a mechanical test (paw pressure and measurement of struggle threshold). 4. Results confirm the increased mechanical sensitivity to pain and no change in thermal sensitivity for old rats compared to mature and middle-aged animals. They show a marked decrease in the effect of morphine with age and no age-related effect for acetaminophen, aspirin or clomipramine. Plasma levels of morphine and metabolites are not different in the three age groups. 5. It is likely that the influence of age on morphine analgesia is linked mainly to pharmacodynamic rather than pharmacokinetic changes.

Acetaminophen↗
PubMed2006

Plasmid-mediated VEGF gene transfer induces cardiomyogenesis and reduces myocardial infarct size in sheep.

We have recently reported that in pigs with chronic myocardial ischemia heart transfection with a plasmid encoding the 165 isoform of human vascular endothelial growth factor (pVEGF165) induces an increase in the mitotic index of adult cardiomyocytes and cardiomyocyte hyperplasia. On these bases we hypothesized that VEGF gene transfer could also modify the evolution of experimental myocardial infarct. In adult sheep pVEGF165 (3.8 mg, n=7) or empty plasmid (n=7) was injected intramyocardially 1 h after coronary artery ligation. After 15 days infarct area was 11.3+/-1.3% of the left ventricle in the VEGF group and 18.2+/-2.1% in the empty plasmid group (P<0.02). The mechanisms involved in infarct size reduction (assessed in additional sheep at 7 and 10 days after infarction) included an increase in early angiogenesis and arteriogenesis, a decrease in peri-infarct fibrosis, a decrease in myofibroblast proliferation, enhanced cardiomyoblast proliferation and mitosis of adult cardiomyocytes with occasional cytokinesis. Resting myocardial perfusion (99mTc-sestamibi SPECT) was higher in VEGF-treated group than in empty plasmid group 15 days after myocardial infarction. We conclude that plasmid-mediated VEGF gene transfer reduces myocardial infarct size by a combination of effects including neovascular proliferation, modification of fibrosis and cardiomyocyte regeneration.

Animals↗
PubMed2004

Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle.

Recent studies have shown that genes involved in oxidative phosphorylation (OXPHOS) exhibit reduced expression in skeletal muscle of diabetic and prediabetic humans. Moreover, these changes may be mediated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). By combining PGC-1alpha-induced genome-wide transcriptional profiles with a computational strategy to detect cis-regulatory motifs, we identified estrogen-related receptor alpha (Erralpha) and GA repeat-binding protein alpha as key transcription factors regulating the OXPHOS pathway. Interestingly, the genes encoding these two transcription factors are themselves PGC-1alpha-inducible and contain variants of both motifs near their promoters. Cellular assays confirmed that Erralpha and GA-binding protein a partner with PGC-1alpha in muscle to form a double-positive-feedback loop that drives the expression of many OXPHOS genes. By using a synthetic inhibitor of Erralpha, we demonstrated its key role in PGC-1alpha-mediated effects on gene regulation and cellular respiration. These results illustrate the dissection of gene regulatory networks in a complex mammalian system, elucidate the mechanism of PGC-1alpha action in the OXPHOS pathway, and suggest that Erralpha agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.

Animals↗
PubMed1987

Hepatocarcinogenicity of the woodchuck hepatitis virus.

During investigations of the evolution of experimental laboratory infections of woodchucks (Marmota monax) with the woodchuck hepatitis virus (WHV), eight hepatocellular carcinomas (HCC) were observed, six in newborns and two in young adult animals, all within 17-36 months after infection. The absence of an external cocarcinogenic effect in the well-monitored woodchucks indicates the carcinogenicity of WHV and suggests the same for the genetically and biologically similar human hepatitis B virus (HBV). Laboratory infections of woodchucks with two strains of WHV, not reported here in detail, resembled human and chimpanzee HBV infections histologically and serologically. In these studies, eight woodchucks became carriers of surface antigen of WHV for greater than 1 year. All eight woodchucks developed HCC, indicating a 100% risk of HCC in experimentally infected chronic WHV antigen carriers, which is analogous to the high risk of HCC in human hepatitis B surface antigen carriers. Histologically, the absence of cirrhosis in the examined pericarcinomatous tissue permits recognition of gradual transition from normal parenchyma to neoplastic nodules to HCC of rising anaplasia, indicating a continuum of increasingly more malignant neoplastic stages, as known for chemical carcinogenesis. The HCC developed in carrier woodchucks infected as newborns with only minor, if any, hepatitic changes but is associated with antigen-carrying hepatocytes and sometimes with hyperplastic nodules. This stage was preceded in infected adults by an early, acute, weeks-long hepatitis coinciding with the appearance of surface antigen. These findings are also analogous to typical HBV infection in human newborns and young adults, respectively. At the time of HCC development in all animals with adequate histologic material, an acute recent necroinflammation appeared around the tumor, associated with abnormal hematopoietic cells around and within the tumor. A promoting role in carcinogenesis of this necroinflammation of yet unestablished pathogenesis is being postulated, to be confirmed by determination of the status of the WHV DNA in the HCC and by prospective histologic study of the inflammatory reaction.

Animals↗
PubMed1989

An experimental approach to testing modular evolution: directed replacement of alpha-helices in a bacterial protein.

We have used oligonucleotide site-directed mutagenesis to ask whether certain structural motifs in proteins are determined mainly by local interactions among amino acids. Multiple consecutive amino acids in three alpha-helices in the alkaline phosphatase (EC 3.1.3.1) of Escherichia coli have been replaced with helical sequences from four other sources. Altogether, 12 distinct helical replacements were created, 9 of which retain enzymatic activity. Most short stretches of helical sequence can be replaced with unrelated helical sequences without eliminating enzyme activity. Replacements of the carboxyl half of an alpha-helix are less harmful than those of the amino half, and the two together are synergistic rather than additive. These results are consistent with the hypothesis that proteins originally evolved by the assembly of small functional folding units.

Alkaline Phosphatase↗
PubMed1978

Analysis of the effects of microwave energy on enzymatic activity of lactate dehydrogenase (LDH).

Interactions between microwave energy (3 GHz) and the enzyme Lactate Dehydrogenase (LDH) have been analyzed by monitoring the enzymatic activity during irradiation in steady-state or dynamic conditions, by irradiating the sample with variable power levels (up to 6 W into the sample) and, finally, by knowing accurately the true specific absorption rate. No permanent or temporary changes can be induced when the energy absorption does not cause a temperature variation. For higher energy values, effects are purely thermal in nature. Furthermore the thermal activation of the reaction velocity, caused by microwave irradiation, is in itself sufficient to give a good fit with the experimental time evolution of the enzymatic reaction.

Hot Temperature↗
PubMed1964

EVOLUTION OF THE IMMUNE RESPONSE. I. THE PHYLOGENETIC DEVELOPMENT OF ADAPTIVE IMMUNOLOGIC RESPONSIVENESS IN VERTEBRATES.

1. The California hagfish, Eptatretus stoutii, seems to be completely lacking in adaptive immunity: it forms no detectable circulating antibody despite intensive stimulation with a range of antigens; it does not show reactivity to old tuberculin following sensitization with BCG; and gives no evidence of homograft immunity. 2. Studies on the sea lamprey, Petromyzon marinus, have been limited to the response to bacteriophage T(2) and hemocyanin in small groups of spawning animals. They suggest that the lamprey may have a low degree of immunologic reactivity. 3. One holostean, the bowfin (Amia calva) and the guitarfish (Rhinobatos productus), an elasmobranch, showed a low level of primary response to phage and hemocyanin. The response is slow and antibody levels low. Both the bowfin and the guitarfish showed a vigorous secondary response to phage, but neither showed much enhancement of reactivity to hemocyanin in the secondary response. The bowfin formed precipitating antibody to hemocyanin, but the guitarfish did not. Both hemagglutinating and precipitating antibody to hemocyanin were also observed in the primary response of the black bass. 4. The bowfin was successfully sensitized to Ascaris antigen, and lesions of the delayed type developed after challenge at varying intervals following sensitization. 5. The horned shark (Heterodontus franciscii) regularly cleared hemocyanin from the circulation after both primary and secondary antigenic stimulation, and regularly formed hemagglutinating antibody, but not precipitating antibody, after both primary and secondary stimulation with this antigen. These animals regularly cleared bacteriophage from the circulation after both the primary and secondary stimulation with bacteriophage T(2). Significant but small amounts of antibody were produced in a few animals in the primary response, and larger amounts in the responding animals after secondary antigenic stimulation. 6. Studies by starch gel and immunoelectrophoresis show that the hagfish has no bands with mobilities of mammalian gamma globulins; that the lamprey has a single, relatively faint band of this type; and that multiple gamma bands are characteristic of the holostean, elasmobranchs, and teleosts studied. By this method of study, the bowfin appeared to have substantial amounts of gamma(2) globulin. 7. We conclude that adaptive immunity and its cellular and humoral correlates developed in the lowest vertebrates, and that a rising level of immunologic reactivity and an increasingly differentiated and complex immunologic mechanism are observed going up the phylogenetic scale from the hagfish, to the lamprey, to the elasmobranchs, to the holosteans, and finally the teleosts.

Adaptation, Physiological↗
PubMed1990

Effects of long term metoprolol administration on the electrocardiogram of rats infected with T cruzi.

STUDY OBJECTIVE: The aim of the study was to evaluate the role of beta receptor antagonists in the evolution of experimental Chagas' disease. DESIGN: Rats were infected with T cruzi, 2000 parasites.g-1 body weight, soon after weaning. One group was then given metoprolol, 100 mg.kg-1.d-1, in drinking water. A comparison group received no metoprolol. Two control groups of non-infected rats were also studied, one with and one without metoprolol in the same dose. SUBJECTS: Adult male albino rats were used: 144 were infected with T cruzi and received metoprolol (group IM), 137 were infected and received no metoprolol (group IW), 46 non-infected rats received metoprolol (group CM), and 43 non-infected rats did not receive metoprolol (group CW). MEASUREMENTS and main results--30 d after infection, resting ECG was performed in all surviving rats. (There were 63 deaths in the infected groups and none in the non-infected groups.) Abnormal ECG was found in 20/81 infected rats in group IM and in 30/74 in group IW (p less than 0.05). No ECG changes were found in the non-infected rats. Of rats in group IM with normal resting ECG, 31 continued to take metoprolol (group IMNM), while 30 similar rats did not (group IMNW); in group IM with abnormal ECG, 10 rats continued to take metoprolol (group IMAM), while 10 similar rats did not (group IMAW). Of rats in group IW with normal ECG, 22 were started on metoprolol (group IWNM), while 22 similar rats were not (group IWNW); in group IW with abnormal ECG, 15 rats were started on metoprolol (group IWAM), while 15 similar rats did not (group IWAW). After 120 d and 300 d infection there were no differences in mortality rate and Ajmaline test in any of the matched groups (IMNM X IMNW; IMAM X IMAW; IWNM X IWNW; IWAM X IWAW). After 120 d there was no difference in ECG between the groups, but after 300 d there was a decrease in abnormal ECG in group IWAM (IWAM v IWAW, 0/12 v 5/12, p less than 0.05). No histological differences were found. CONCLUSIONS: Metoprolol decreases the proportion of rats with abnormal resting ECG in both the acute and the chronic stage of T cruzi infection.

Animals↗
PubMed2003

Experimental prediction of the natural evolution of antibiotic resistance.

The TEM family of beta-lactamases has evolved to confer resistance to most of the beta-lactam antibiotics, but not to cefepime. To determine whether the TEM beta-lactamases have the potential to evolve cefepime resistance, we evolved the ancestral TEM allele, TEM-1, in vitro and selected for cefepime resistance. After four rounds of mutagenesis and selection for increased cefepime resistance each of eight independent populations reached a level equivalent to clinical resistance. All eight evolved alleles increased the level of cefepime resistance by a factor of at least 32, and the best allele improved by a factor of 512. Sequencing showed that alleles contained from two to six amino acid substitutions, many of which were shared among alleles, and that the best allele contained only three substitutions.

Biological Evolution↗