Biomedical subjects

A M Lynch

Publications and source records attributed to A M Lynch.

At least 19 recordsLinked to original sources

PubMed2003

Effectiveness and safety of a structured swimming program in previously sedentary women during pregnancy.

OBJECTIVE: To determine whether undertaking a swimming program in sedentary women during pregnancy would improve maternal fitness without adverse fetal consequences. METHODS: Prospective observational investigation of healthy sedentary pregnant women participating in a monitored swimming program. RESULTS: Twenty-three women attended swimming sessions from 16 to 28 weeks of gestation resulting in increasing distances swum and improved aerobic fitness as measured by physical work capacity (PWC170) (p = 0.003). Resting maternal heart rate decreased (p = 0.041) and resting systolic (p = 0.092) and diastolic (p = 0.971) blood pressures remained unchanged over gestation. The mean fetal heart rates decreased with advancing gestational age (p = 0.001), consistent with normal physiology. Non-stress tests and umbilical artery systolic/diastolic ratios were similar before and after swimming sessions, providing evidence that fetal well-being was unchanged. CONCLUSIONS: A structured swimming program in sedentary pregnant women increases maternal fitness without any alteration in maternal and fetal well-being.

Adult↗

PubMed2001

Flow cytometric enumeration of micronucleated reticulocytes: high transferability among 14 laboratories.

This laboratory previously described a single-laser flow cytometric method, which effectively resolves micronucleated erythrocyte populations in rodent peripheral blood samples. Even so, the rarity and variable size of micronuclei make it difficult to configure instrument settings consistently and define analysis regions rationally to enumerate the cell populations of interest. Murine erythrocytes from animals infected with the malaria parasite Plasmodium berghei contain a high prevalence of erythrocytes with a uniform DNA content. This biological model for micronucleated erythrocytes offers a means by which the micronucleus analysis regions can be rationally defined, and a means for controlling interexperimental variation. The experiments described herein were performed to extend these studies by testing whether malaria-infected erythrocytes could also be used to enhance the transferability of the method, as well as control intra- and interlaboratory variation. For these studies, blood samples from mice infected with malaria, or treated with vehicle or the clastogen methyl methanesulfonate, were fixed and shipped to collaborating laboratories for analysis. After configuring instrumentation parameters and guiding the position of analysis regions with the malaria-infected blood samples, micronucleated reticulocyte frequencies were measured (20,000 reticulocytes per sample). To evaluate both intra- and interlaboratory variation, five replicates were analyzed per day, and these analyses were repeated on up to five separate days. The data of 14 laboratories presented herein indicate that transferability of this flow cytometric technique is high when instrumentation is guided by the biological standard Plasmodium berghei.

Animals↗

PubMed2001

Effectiveness of a teaching programme in pain and symptom management for junior house officers.

The objectives of this study were (i) to assess the level of knowledge with respect to pain and symptom management among doctors in their first year after graduation and (ii) to measure the impact of a structured teaching programme on their level of knowledge. All 34 newly qualified junior house officers in one teaching hospital were offered a six-session teaching programme in pain and symptom management. A multiple-choice questionnaire was used to assess their level of knowledge at the beginning and at the end of a 6-month period over which the teaching sessions took place. Attendance at and satisfaction with the programme were high. There was a significant improvement in the level of knowledge at the end of the programme, with the greatest improvement in those who attended most sessions. The low scores recorded for the questionnaire administered before the teaching programme suggest that there is a critical need for improved education in palliative care amongst newly qualified doctors. We have shown that a simple in-service case-based teaching programme can meet this need effectively.

Education, Medical, Graduate↗

PubMed2001

Promoting intervention fidelity. Conceptual issues, methods, and preliminary results from the EARLY ALLIANCE prevention trial.

Fidelity refers to the demonstration that an experimental manipulation is conducted as planned. In outcome research, an intervention can be said to satisfy fidelity requirements if it can be shown that each of its components is delivered in a comparable manner to all participants and is true to the theory and goals underlying the research. Demonstrating the fidelity of an intervention is a key methodologic requirement of any sound prevention trial. This paper summarizes key conceptual and methodologic issues associated with intervention fidelity, and describes the steps taken to promote fidelity in EARLY ALLIANCE, a large-scale prevention trial currently testing the effectiveness of family, peer, and school interventions to promote competence and reduce risk for conduct disorder, substance abuse, and school failure. The paper presents preliminary results (Trial Year 1) that demonstrate content and process fidelity for two of these interventions, and discusses how the EARLY ALLIANCE methodology may be generalized to address fidelity issues in other prevention studies.

Adaptation, Psychological↗

PubMed2001

How much does physical appearance say about the psychological adjustment of competent and dysfunctional children?

Presents a study in which three sets of photographs of socially competent, aggressive, and anxious preschoolers were rated by college students (n = 150 raters per set), blind to the children's group membership. This was done to assess the extent to which adults are able to make valid and reliable evaluations of children's psychological adjustment on the basis of physical appearance alone. Sets 1 and 2 were photographs of different children taken under the same conditions and providing both facial and nonfacial cues. Sets 2 and 3 were of the same children taken under conditions that varied as to the amount of nonfacial cues they provided. Results showed that (a) socially competent children were judged to be better adjusted than their dysfunctional peers (i.e., more competent, less aggressive, less anxious, and less likely to have emotional or behavioral problems); (b) within the dysfunctional group, aggressive and anxious children were distinguished in ways that correspond closely to what is known about them from behavioral and clinical research; (c) irrespective of group membership, girls and boys were generally distinguished in ways that reflect normative beliefs about gender differences from social and developmental research; (d) group differences in ratings of psychological adjustment were generally comparable across photograph sets and could not be accounted for by differences in the children's perceived physical attractiveness; and (e) raters reported that they relied mainly on the children's expression, eyes, and posture to make their judgments of adjustment. These results replicate and extend earlier findings based on 1 of the 3 photograph sets (Serketich & Dumas, 1997). They suggest that when first impressions matter, competent children are at an advantage and their dysfunctional peers at a disadvantage even before their actual behavior comes to confirm or to invalidate these impressions. Theoretical and clinical implications of the findings are discussed.

Adaptation, Psychological↗

PubMed2001

Food-derived heterocyclic amine mutagens: variable metabolism and significance to humans.

The cooking of meat has been found to generate compounds that possess extreme mutagenicity when examined in short term tests. This observation led to the isolation and identification of a family of mutagenic chemicals, all of which are heterocyclic amines. These amines are potent bacterial and eukaryotic cell mutagens, and all of those tested have been found to induce tumors in laboratory animals. Metabolic activation of the heterocyclic amines predominantly involves CYP1-mediated N-hydroxylation and then O-esterification by phase II enzymes. In contrast, carbon oxidation, glucuronidation, and sulfation reactions at sites other than the hydroxylamine yield detoxication metabolites. In humans, the activities of these pathways are known to vary between individuals and are likely to influence susceptibility to the genetic toxicity of the heterocyclic amines. Clearly, accurate determination of human exposure to the heterocyclic amines and identification of the key enzyme systems involved and their regulation will be required for rational assessment of the risk and will help devise strategies to reduce such risk.

Amines↗

PubMed1999

Embryo survival, and fetal and placental growth following elevation of maternal estradiol blood concentrations in the rat.

High doses of estrogens cause embryonic mortality, and fetal and placental growth retardation in rats. This study addresses the physiological relevance of such findings. Estradiol benzoate (EB), by s.c. injection, or estradiol-17beta (E2), delivered by a miniosmotic pump, raised maternal E2 concentrations from only slightly above control values to 5-fold. EB (1 microgram/day) over Days 6-13, 8-13, and 11-13, and continuous infusion of E2 (15 ng/h; Days 10-13) reduced fetal survival to 0%, 0%, 22%, and 75%, respectively. Single injections of EB showed that its lethal effect declined rapidly over Days 9 (44% survival) to 13 (90% survival). Embryos died within 48 h, but death was not due to luteal failure since progesterone levels were maintained and progesterone administered with EB did not reduce mortality. Administration of EB at 1 microgram/day (Days 14-21) or E2 at 40 ng/h (Days 13-16) retarded fetal and placental growth but did not affect survival. The rat embryo is highly sensitive to elevated maternal estradiol concentrations over much of gestation. The early lethal effect implies that endogenous E2 production is carefully regulated to maintain pregnancy; the latter growth-retarding effect suggests that E2 may have a role in the normal control of fetal growth.

Animals↗

PubMed1999

Analysis of gene mutations and clastogenicity following short-term treatment with azathioprine in MutaMouse.

The mutagenicity and clastogenicity of the immunosuppressive drug azathioprine (AZA), a multitissue rodent carcinogen and IARC-classified human carcinogen, was investigated using transgenic lacZ mice (MutaMouse). Male animals (n = 5 per group) were dosed with AZA (10, 50, 100 mg/kg p.o. daily for 5 days), vehicle (n = 10), or the positive control, chlorambucil (15 mg/kg i.p., n = 3), and killed 24 hr or 25 days after the last treatment. Micronucleus assays were performed with bone marrow (24-hr samples) or peripheral blood (24-hr and 25-day samples) and DNA was extracted from bone marrow and liver for gene mutation analysis at the transgenic lacZ locus. AZA induced 5.3-111.3-fold increases in %MNPCE (P < 0.01) in bone marrow compared with vehicle control, accompanied by 4.4-5. 6-fold increases in %MNRETs (P < 0.01) in peripheral blood. Chlorambucil caused a 14.5-fold increase in %MNRET and there was evidence of significant stem cell toxicity in both positive control and AZA treatment groups. By day 25, however, there was evidence of substantial recovery of the bone marrow as determined by the frequency of RET, and the %MNRET in all treatment groups was the same as the vehicle control. Analysis of lacZ MF showed 1.4-1.6-fold increases in AZA 24-hr bone marrow samples, increasing to approximately 2.0-fold above concurrent controls by day 25 (medium dose P < 0.05, high dose P < 0.01). For liver, there was a 2-fold increase in MF (P < 0.05) in the 24-hr sample at the highest dose only, and increases of 1.3-1.5-fold by day 25 in the medium (P < 0. 05) and high (P = 0.055) dose groups, respectively. The positive control, chlorambucil, induced 2-3-fold increases (P < 0.01) in mean MF in both bone marrow (25-day sample) and liver (24-hr and 25-day samples). These data confirm the clastogenicity of AZA in the mouse, and show that this compound induces gene mutations in bone marrow and liver, in vivo, at the highest dose and supports the view that AZA is a genotoxic carcinogen.

Animals↗

PubMed1998

Genetic analysis of PHIP intestinal mutations in MutaMouse.

The mutagenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was investigated in male MutaMouse mice administered 20 mg/kg per o.s. for 4 days and killed 7 days later. Genomic DNA was extracted from liver, kidney and small and large intestine and the mutation frequency (MF) at the lacZ locus was determined using a positive selection assay. Mutant lacZ clones from the intestine were characterized further by direct PCR amplification and DNA sequencing. A total of 57 lacZ mutants from PhIP-treated (40) and untreated (18) mice were analysed. In mutants from the PhIP group, 33% were G:C-->T:A transversions from a total of 65% base substitutions (cf. 17% in the vehicle control group). In untreated control mice, 39% of mutants were G:C-->A:T transitions from a total of 72 % base substitutions (cf. 25 % in the PhIP group). Interestingly, 20% of the PhIP group mutations were due to G:C base pair (-G) deletions (cf. none in controls). This study confirms that PhIP is mutagenic to the intestine of the MutaMouse and induces a spectrum of mutations which are clearly distinct from those spontaneously generated. Also, the PhIP mutation signature in vivo is very similar to that observed for the HPRT and DHFR loci in hamster and human cells in vitro. This suggests that the mutational characteristics of PhIP are well conserved over different reporter genes and between species and that the mutation signature could be of value in molecular epidemiology studies.

Animals↗

PubMed1998

Do hospital palliative care teams improve symptom control? Use of a modified STAS as an evaluation tool.

The support team assessment schedule (STAS) has previously been validated as an evaluation tool for community palliative care teams and inpatient units. This study reports on use of an expanded STAS (E-STAS) to determine symptom prevalence and outcome for inpatients and outpatients referred to a multiprofessional hospital palliative care team. E-STAS forms were completed on patients at referral and twice weekly thereafter. Between August 1996 and May 1997, 352 patients had one or more E-STAS forms completed; 122 of this group had three or more assessments. One-hundred-and-eighty-two patients were male and 170 were female, the median age was 68.5 years (range 26-101 years) and all but 27 (8%) had malignant disease. Of the symptoms assessed on referral, the most common were psychological distress 93%, anorexia 73%, pain 59%, mouth discomfort 59%, depression 40%, constipation 36%, breathlessness 32%, nausea 24% and vomiting 13%. In the 122 patients where three or more assessment were completed, statistically significant improvements from first to last assessment were seen in all symptoms except depression. This study suggests that E-STAS may be a useful tool to evaluate interventions by a hospital palliative care team in patients with advanced disease.

Adult↗

PubMed1997

Assessing human risk to heterocyclic amines.

Heterocyclic amines such as MeIQx and PhIP are potent genotoxic chemicals which are formed at part per billion levels when meat is cooked. Using assays based on gas chromatography/mass spectrometry with stable isotope labelled analogues as internal standards we have demonstrated MeIQx and PhIP, are efficiently absorbed into the systemic circulation after ingestion of fried beef. Using a potent and selective inhibitor of human CYP1A2, furafylline, we have shown that N-hydroxylation catalysed by this enzyme is the major pathway of metabolism of MeIQx and PhIP and is solely responsible for their oxidation to mutagenic species. This is in contrast to the situation in laboratory animals in which both activation by N-hydroxylation and deactivation by C-oxidation occurs. When furafylline was administered to human volunteers before ingestion of fried beef, we showed that > 90% of MeIQx and approximately 70% of PhIP elimination could be inhibited, demonstrating the extent to which activation occurred in man. MeIQx is a very powerful mutagen in bacterial assays whereas PhIP is a more potent mammalian cell mutagen. Using a mammalian cell target gene, hprt, we have shown that PhIP induces a characteristic mutational 'fingerprint' which is identical to that detected in the Apc gene of 5/8 colonic tumours induced by PhIP in rats. These studies support a biological association between HA exposure and diet-related tumours but emphasise that information obtained from animal studies does not always reflect the situation in humans.

Animals↗

PubMed1996

Duration-dependent increase in striatal glutamate following prolonged fluphenazine administration in rats.

Chronic neuroleptic administration has been shown to selectively increase striatal extracellular glutamate concentration. In the current study, age-matched female rats were administered chronic oral fluphenazime or no drug via their drinking water for 3 or 32 weeks. Microdialysis probes were inserted into the ventrolateral caudate putamen and the medial nucleus accumbens and dialysis samples were analyzed for glutamate and gamma-aminobutyric acid (GABA) concentrations Glutamate levels were significantly increased only in the ventrolateral caudate putamen after 32 weeks. No significant effects were seen for GABA levels. Neuroleptic-induced enhancement of striatal glutamate levels thus appears to increase with chronic exposure and this increase may relate to late onset motor side effects.

Animals↗

PubMed1996

Enzymic and interindividual differences in the human metabolism of heterocyclic amines.

Heterocyclic amines (HAs) present in cooked meat (PhIP and MeIQx) are activated only by CYP1A2 in the liver of most species, including man. This enzyme exhibits marked interindividual differences in its expression, due to induction and possibly also genetically. The absence of CYP1A2 appears to protect from HA-(PhIP and MeIQx) induced cancer, as exemplified by results in the cynomolgus monkey. Differences in the potency of these HAs are not due to differences in the kinetics of their activation. The catalytic efficiency of CYP1A2 towards HAs and their oxidative fate varies amongst species, in both cases increasing the susceptibility of humans compared to that of the rat. Interindividual and inter-organ differences in the further metabolism of N-hydroxy-HAs appear to be important determinants of cancer susceptibility, as does the glutathione S-transferase catalysed detoxication of esters of N-hydroxy-PhIP. There is a need for an effective means of quantifying the in vivo activation of HAs in man to enable the possible risk posed by these compounds to be assessed effectively.

Animals↗

PubMed1996

Subchronic administration of clozapine, but not haloperidol or metoclopramide, decreases dopamine D2 receptor messenger RNA levels in the nucleus accumbens and caudate-putamen in rats.

The effects of unique profile antipsychotic drugs on dopamine D2 receptors and D2 receptor messenger RNA were assessed following subchronic administration in rats. Male, Sprague-Dawley rats were administered oral haloperidol, clozapine, metoclopramide or no drug for three weeks via their drinking water. Tissue from the medial nucleus accumbens and dorsolateral caudate-putamen was dissected and analyzed by Northern blot analysis for levels of dopamine D2 receptor messenger RNA and binding assays conducted with [3H]spiperone for dopamine D2 receptors. Haloperidol and metoclopramide, but not clozapine, significantly increased [3H]spiperone in the caudate-putamen, but not the nucleus accumbens. Clozapine significantly decreased D2 messenger RNA levels in the caudate-putamen and the nucleus accumbens, while metoclopramide and haloperidol had no significant effect in either brain region. The finding of decreased D2 receptor messenger RNA levels produced by subchronic clozapine may account for the lack of striatal D2 receptor up-regulation, which was robustly observed after subchronic haloperidol and metoclopramide. Furthermore, since haloperidol and metoclopramide have a high liability for motor side effects, the current results relate favorably to the low motor side effect profile of clozapine.

Actins↗

PubMed1996

Physical enhancement of dermatologic drug delivery: iontophoresis and phonophoresis.

Iontophoresis and phonophoresis are emerging technologies capable of enhancing drug penetration through the stratum corneum, the principal barrier to percutaneous absorption. With utilization of applied electric current or ultrasonic waves, respectively, iontophoresis and phonophoresis have shown efficacy in an increasing number of clinical applications. This article reviews the underlying principles, current status, and potential of iontophoresis and phonophoresis in dermatologic therapy.

Anesthetics, Local↗

PubMed1996

Overwhelming postsplenectomy infection.

The incidence of overwhelming sepsis in asplenic patients is low. It carries, however, an unacceptably high morbidity rate and mortality rate. The risk of development is related to the age of the patient as well as the duration since and the reason for splenectomy. It may also occur in functionally hyposplenic states. The rapidly lethal clinical course demands intense efforts toward prevention by both physician and patient, rapid recognition within the initial medical setting, and aggressive intervention with broad-spectrum antibiotics and other supportive measures.

Humans↗

PubMed1996

Heterocyclic amines: evaluation of their role in diet associated human cancer.

1. Heterocyclic amines are formed in parts per billion levels when meat is cooked. 2. The heterocyclic amines MeIQx and PhIP are efficiently absorbed into the systemic circulation after ingestion of cooked food. 3. We have shown that MeIQx and PhIP, both in vitro and in vivo, are substrates for human hepatic CYP1A2, which exclusively and efficiently catalyses their conversion to genotoxic hydroxylamines. 4. MeIQx and PhIP are promutagens. MeIQx is a very powerful bacterial mutagen whereas PhIP is a more potent mammalian cell mutagen. Using a mammalian cell target gene, hprt, we have shown that PhIP induces a characteristic mutational 'fingerprint'. 5. MeIQx and PhIP are carcinogenic in bioassays. The PhIP mutational 'fingerprint' has been detected in the Apc gene of 5/8 colonic tumours induced by PhIP in rats.

Animals↗

PubMed1996

Organ distinctive mutagenicity in MutaMouse after short-term exposure to PhIP.

We have investigated PhIP-induced mutagenicity in various tissues (kidney, liver, large and small intestine) using a transgenic mouse model (MutaMouse). In addition to tissue specific mutagenesis, we measured the binding of [14C]PhIP to MutaMouse mice blood proteins (haemoglobin and albumin), to obtain a quantitative estimate of carcinogen exposure and activation and their relationship to mutagenesis. Short-term (4 days) treatment of MutaMouse mice with [14C]PhIP by oral gavage resulted in the dose-dependent accumulation of radiolabelled material bound to haemoglobin and serum albumin. PhIP, at the highest dose (20 mg/kg), caused a 5.9-fold increase in the mutation frequency in the large intestine, a 4.2-fold increase in the mutation frequency in the small intestine but only a marginal 1.6-fold increase in the liver. However, there was no significant increase in mutations in the kidney at this dose. In contrast, there were no significant differences in any of these tissues between the vehicle control and the two lower doses (2.0 and 0.2 mg/kg respectively). These results are discussed in relationship to those previously reported for PhIP at the Dlb-1 locus.

Administration, Oral↗