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Biomedical subjects

M Lynch

Publications and source records attributed to M Lynch.

At least 91 records · Page 5Linked to original sources
PubMed1998

Retention of the CDKN2A locus and low frequency of point mutations in primary and metastatic cutaneous malignant melanoma.

CDKN2A has been found mutated in melanoma families which show linkage to chromosome 9p21. In contrast, a low mutation rate has been found in melanomas, suggesting that CDKN2A might not be the first target for mutation in the development of this type of tumour. To elucidate the role of the CDKN2A gene and its alternative transcript p19ARF in the development of cutaneous malignant melanoma (CMM) we have analyzed 48 primary and metastasic CMM tumours for mutations and for loss of heterozygosity (LOH). Only one point mutation was detected (2%), while hemizygous deletions were identified in 20% of these tumours. Retention of the CDKN2A locus was found in 10 (47%) tumours with deletions at one or both sides of CDKN2A, suggesting that loss of this gene is not involved in CMM-tumour initiation and that another tumour-suppressor gene involved in melanoma is located at 9p21.

Gene Deletion↗
PubMed1998

Aberrant regulation of transforming growth factor-alpha during the establishment of growth arrest and quiescence of growth factor independent cells.

Autocrine transforming growth factor alpha (TGFalpha) is an important positive growth effector in malignant cells and plays a significant role in generating the growth factor-independent phenotype associated with malignant progression. However, the molecular mechanisms by which TGFalpha confers a growth advantage in progression is poorly understood. The highly tumorigenic cell line HCT116 up-regulates TGFalpha mRNA expression during growth arrest, whereas the poorly tumorigenic growth factor-dependent FET cell line down-regulates TGFalpha mRNA expression as it becomes quiescent. We have identified a 25-bp sequence at -201 to -225 within the TGFalpha promoter which mediates the differential regulation of TGFalpha expression during quiescence establishment in these two cell lines. This same sequence confers TGFalpha promoter responsiveness to exogenous growth factor or autocrine TGFalpha. The abberant upregulation of TGFalpha mRNA in quiescent HCT116 cells may allow them to return to the dividing state under more stringent conditions (nutrient replenishment alone) then quiescent FET cells (requires nutrients and growth factors). Antisense TGFalpha approaches showed that the dysregulated TGFalpha expression in quiescent HCT116 cells is a function of the strong TGFalpha autocrine loop (not inhibited by blocking antibodies) in these cells.

Base Sequence↗
PubMed1998

Synaptic and axonal remodeling of mossy fibers in the hilus and supragranular region of the dentate gyrus in kainate-treated rats.

Seizures evoked by kainic acid and a variety of experimental methods induce sprouting of the mossy fiber pathway in the dentate gyrus. In this study, the morphological features and spatial distribution of sprouted mossy fiber axons in the dorsal dentate gyrus of kainate-treated rats were directly shown in granule cells filled in vitro with biocytin and in vivo with the anterograde lectin tracer Phaseolus vulgaris leucoagglutinin (PHAL). Sprouted axon collaterals of biocytin-filled granule cells projected from the hilus of the dentate gyrus into the supragranular layer in both transverse and longitudinal directions in kainate-treated rats but were not observed in normal rats. The sprouted axon collaterals projected into the supragranular region for 600-700 microm along the septotemporal axis. Collaterals from granule cells in the infrapyramidal blade crossed the hilus and sprouted into the supragranular layer of the suprapyramidal blade. Sprouted axon segments in the supragranular layer had more terminal boutons per unit length than the axon segments in the hilus of both normal and kainate-treated rats but did not form giant boutons, which are characteristic of mossy fiber axons in the hilus and CA3. Mossy fiber axons in the hilus of kainate-treated rats had more small terminal boutons, fewer giant boutons, and there was a trend toward greater axon length compared with mossy fibers in the hilus of normal rats. With the additional length of supragranular sprouted collaterals, there was an overall increase in the length of mossy fiber axons in kainate-treated rats. The synaptic and axonal remodeling of the mossy fiber pathway could alter the functional properties of hippocampal circuitry by altering synaptic connectivity in local circuits within the hilus of the dentate gyrus and by increasing the divergence of the mossy fiber terminal field along the septotemporal axis.

Animals↗
PubMed1998

Financial incentives and primary care provision in Britain: do general practitioners maximise their income?

The system of remunerating general practitioners (GPs) in Britain underwent significant changes in April 1990 with the implementation of a new contract between individual GPs and health authorities. The changes were a precursor to a wide-ranging programme of reforms of the British National Health Service. This paper investigates the relationship between financial incentives and the provision of primary health care services in Britain. A comprehensive anonymized data set was used, comprising information on 208 general practices in Scotland which serve just under one million people. An econometric model was tested to identify the determinants of cross-practice variation in the magnitude of the changes in GPs' remuneration levels between the two contracts. A linear programming model was used to examine the GPs' response to the financial incentives built into the new contract. The results of the econometric model indicated that the main beneficiaries of the 1990 contract were the practices which had expanded over the 1989-92 period, re-structured the GPs' partnership and made use of managerial skills by employing a practice manager; those practices also had larger lists in 1992 and relatively more patients attracting deprivation payments. The linear programming model showed that only a small minority of the practices (4.8%) maximised the remuneration from the new contract. Optimal solutions concerning income maximization strategies identified financial disincentives in the fee structure of the remuneration system associated with the provision of selected services and the care of particular groups of patients. The successful adoption of these strategies would involve cream skimming and selective service provision. However, there is no conclusive evidence of British GPs engaging in such activities.

Age Factors↗
PubMed1998

Actinomyces pyogenes septic arthritis in a diabetic farmer.

We report a case of septic arthritis and osteomyelitis of the left ankle due to Actinomyces pyogenes in a diabetic farmer. Few confirmed human cases of A. pyogenes infection have been reported, partly because of inadequate identification of this bacterium. Bacteriological characteristics of the organism, which resembles Arcanobacterium haemolyticum, are described with a review of previous case reports.

Animals↗
PubMed1998

Faecal progesterone metabolite analysis for non-invasive monitoring of reproductive function in the white rhinoceros (Ceratotherium simum).

The two subspecies of white rhinoceros, southern (Ceratotherium simum simum) and northern (Ceratotherium simum cottoni), breed poorly in captivity, and estimates of oestrous cycle length vary considerably (range, 25-90 days). To characterise reproductive patterns, faecal samples were collected 2-3 times/week for up to 56 months from non-pregnant animals (n=21) of both subspecies. Immununoreactive pregnanes containing a 20-oxo-group (20-oxo-P) were analysed in a group-specific enzyme immunoassay using an antibody against 5alpha-pregnane-3beta-ol-20-one 3HS:BSA. Reproductive patterns were highly variable among and within individual animals. However, rhinoceroses could be classified into four major categories on the basis of oestrous cycle length and luteal phase 20-oxo-P concentrations: (1) regular oestrous cycles of 10 weeks duration and > 800 ng/g (n=2 animals); (2) oestrous cycles between 4-10 weeks and 250-750 ng/g (n=6); (3) no apparent cycle regularity, but luteal activity indicated by 20-oxo-P concentrations of 100-200 ng/g (n=6); (4) no apparent luteal activity as indicated by 20-oxo-P of < 100 ng/g (n=7). In two attempts to induce ovarian activity, chlormadinone acetate was fed daily to one animal for 35 and 45 days, respectively. Each treatment was followed by a subsequent hCG injection which resulted in luteal phases of 17 and 18 days, respectively, beginning about 10 days after hCG. Concentration of faecal 20-oxo-P in one pregnant animal during the 4th and 5th month of gestation were markedly higher than those observed during the luteal phase of the cycle. In conclusion, two thirds of white rhinoceroses in this study had erratic or missing luteal activity, whereas variable cycles of 4-10 weeks in length were evident in six females, and regular oestrous cycles of 10 weeks in length were found in two animals.

Animals↗
PubMed1998

An ecological-transactional analysis of children and contexts: the longitudinal interplay among child maltreatment, community violence, and children's symptomatology.

Cicchetti and Lynch have conceptualized ecological contexts as consisting of nested levels with varying degrees of proximity to the individual. These levels of the environment interact and transact with each other over time in shaping individual development and adaptation. With a sample of maltreated (n = 188) and nonmaltreated (n = 134) children between the ages of 7 and 12 years, this investigation employed a 1-year longitudinal design to conduct an ecological-transactional analysis of the mutual relationships among community violence, child maltreatment, and children's functioning over time. Indicators of children's functioning were externalizing and internalizing behavior problems and self-rated traumatic stress reactions, depressive symptomatology, and self-esteem. Either full or partial support was obtained for the study's primary hypotheses. Rates of maltreatment, particularly physical abuse, were related to levels of child-reported violence in the community. In addition, child maltreatment and exposure to community violence were related to different aspects of children's functioning. Specific effects were observed for neglect and sexual abuse and for witnessing and being victimized by violence in the community. Finally, there was evidence that children and their contexts mutually influence each other over time. Results were discussed within the framework of an ecological-transactional model of development.

Aggression↗
PubMed1998

Trauma, mental representation, and the organization of memory for mother-referent material.

Research on the effects of child maltreatment and exposure to community violence suggests that children who experience these types of traumatic events may be at risk for alterations and biases in attention and memory similar to those that have been observed in adults suffering from traumatic stress reactions. Along these lines, attachment theory posits that representational models of relationships also may act as moderators of similar cognitive biases by selectively guiding children's attention to and processing of interpersonal stimuli. Building upon the trauma and attachment literatures, the present investigation examined the links among trauma, representational models of caregivers, and children's memory for mother-relevant information using an incidental recall task in a sample of maltreated (n = 71) and nonmaltreated (n = 102) children between the ages of 8 and 13 years. Results were consistent with the hypothesis that experiences of trauma and representational models of caregivers are associated with differences in the way children process and retrieve information about positive and negative mother attribute words. In particular, experiences of trauma initially were associated with increased insecurity in children's representational models. Moreover, the interaction of traumatic experience and security of mental representation predicted children's recall for mother attribute words: victimized children with insecure models recalled the highest proportion of negative mother stimuli. Trauma and mental representation did not have a consistent effect on structurally encoded aspects of recall. Results were discussed in terms of the ways in which children who have experienced trauma process information about their worlds. The importance of assessing functioning in multiple developmental domains when studying memory also was discussed.

Adolescent↗
PubMed1998

The anti-proliferative effect of suramin towards tamoxifen-sensitive and resistant human breast cancer cell lines in relation to expression of receptors for epidermal growth factor and insulin-like growth factor-I: growth stimulation in the presence of tamoxifen.

BACKGROUND: A significant proportion of breast cancer patients receiving tamoxifen therapy relapse during treatment following acquisition of tamoxifen-resistant or oestrogen-independent phenotypes. The mechanism behind this rapid progression to oestrogen autonomy is at present unclear and further treatment modalities are limited. Suramin represents a novel potential second line therapy. The mechanism of the antineoplastic activity of suramin is not completely understood, although the drug binds to many growth factors including epidermal growth factor and insulin-like growth factors and can also dissociate growth factors from their receptors. In this study we have related suramin sensitivity to the expression of receptors for epidermal growth factor and insulin-like growth factor-I in a number of breast cancer cell lines including lines resistant to tamoxifen. MATERIALS AND METHODS: The anti-proliferative effects of suramin were investigated in two oestrogen dependent breast cancer lines (ZR-75-1 and MCF-7), oestrogen independent (ZR-PR-LT) and tamoxifen resistant (ZR-75-9a1) variants of ZR-75-1 and a tamoxifen resistant (LY2) variant of MCF-7. Full dose response curves were constructed and IC50 values determined for each cell line. Sensitivity to suramin was correlated with the level of expression of receptors for epidermal growth factor (EGFR) and insulin-like growth factor-I (IGFR). On observing stimulation of cell proliferation by suramin in the tamoxifen resistant cell lines in the presence of tamoxifen we also investigated the possible role of suramin sequestration of transforming growth factor-beta in mediating this effect. RESULTS: All cell lines exhibited a dose- and time-dependent response to suramin treatment. Tamoxifen resistant ZR-75-9a1 cells (day 6 IC50 85 micrograms ml-1) were more resistant to suramin than oestrogen independent ZR-PR-LT cells (day 6 IC50 45 micrograms ml-1), and the parent ZR-75-1 line (day 6 IC50 56 micrograms ml-1). Increased sensitivity to suramin was associated with increased expression of IGFR and decreased expression of EGFR. Tamoxifen resistant LY2 cells were significantly more sensitive to suramin (day 6 IC50 70 micrograms ml-1) than MCF-7 cells (day 6 IC50 350 micrograms ml-1). Both IGFR and EGFR expression by LY2 cells was lower than in the parent line. The antioestrogen-resistant ZR-75-9a1 and LY2 lines grown in the presence of 8 microM tamoxifen were growth stimulated by concentrations of the drug below 100 micrograms/ml. As growth stimulation observed in the presence of tamoxifen may have been due to suramin sequestration of tamoxifen induced TGF-beta 1 secretion we also investigated the response of the cells to this peptide in the presence and absence of suramin. All cell lines were growth inhibited by TGF-beta 1 except ZR-75-9a1 which was unresponsive. Responses to TGF-beta 1 were modified in the presence of 100 micrograms suramin ml-1 although TGF-beta 1 was unable to mimic the ability of tamoxifen to stimulate proliferation in the presence of suramin. CONCLUSIONS: These results suggest that for ZR-75-1 cells and variants, increased sensitivity to suramin is associated with an increase in expression of IGFR and a decrease in EGFR numbers. However, tamoxifen resistant LY2 cells, in which both IGFR and EGFR expression is reduced were considerably more sensitive than parental MCF-7 cells suggesting that there is no clear relationship between EGFR and IGFR expression and suramin sensitivity. The unexpected stimulation of cell proliferation of the tamoxifen resistant variants by suramin in the presence of tamoxifen could not be explained by suramin sequestration of transforming growth factor-beta and the mechanism of this interaction remains unclear.

Antineoplastic Agents↗
PubMed1998

Regulation of transforming growth factor alpha expression in a growth factor-independent cell line.

Aberrant transcriptional regulation of transforming growth factor alpha (TGF alpha) appears to be an important contributor to the malignant phenotype and the growth factor independence with which malignancy is frequently associated. However, little is known about the molecular mechanisms responsible for dysregulation of TGF alpha expression in the malignant phenotype. In this paper, we report on TGF alpha promoter regulation in the highly malignant growth factor-independent cell line HCT116. The HCT116 cell line expresses TGF alpha and the epidermal growth factor receptor (EGFR) but is not growth inhibited by antibodies to EGFR or TGF alpha. However, constitutive expression of TGF alpha antisense RNA in the HCT116 cell line resulted in the isolation of clones with markedly reduced TGF alpha mRNA and which were dependent on exogenous growth factors for proliferation. We hypothesized that if TGF alpha autocrine activation is the major stimulator of TGF alpha expression in this cell line, TGF alpha promoter activity should be reduced in the antisense TGF alpha clones in the absence of exogenous growth factor. This was the case. Moreover, transcriptional activation of the TGF alpha promoter was restored in an antisense-TGF alpha-mRNA-expressing clone which had reverted to a growth factor-independent phenotype. Using this model system, we were able to identify a 25-bp element within the TGF alpha promoter which conferred TGF alpha autoregulation to the TGF alpha promoter in the HCT116 cell line. In the TGF alpha-antisense-RNA-expressing clones, this element was activated by exogenous EGF. This 25-bp sequence contained no consensus sequences of known transcription factors so that the TGF alpha or EGF regulatory element within this 25-bp sequence represents a unique element. Further characterization of this 25-bp DNA sequence by deletion analysis revealed that regulation of TGF alpha promoter activity by this sequence is complex, as both repressors and activators bind in this region, but the overall expression of the activators is pivotal in determining the level of response to EGF or TGF alpha stimulation. The specific nuclear proteins binding to this region are also regulated in an autocrine-TGF alpha-dependent fashion and by exogenous EGF in EGF-deprived TGF alpha antisense clone 33. This regulation is identical to that seen in the growth factor-dependent cell line FET, which requires exogenous EGF for optimal growth. Moreover, the time response of the stimulation of trans-acting factor binding by EGF suggests that the effect is directly due to growth factor and not mediated by changes in growth state. We conclude that this element appears to represent the major positive regulator of TGF alpha expression in the growth factor-independent HCT116 cell line and may represent the major site of transcriptional dysregulation of TGF alpha promoter activity in the growth factor-independent phenotype.

Cell Division↗
PubMed1998

Should doctors practise resuscitation skills on newly deceased patients? A survey of public opinion.

Trainee doctors must acquire skills in resuscitation, but opportunities for learning on real patients are limited. One option is to practise these skills in newly deceased patients. We sought opinions from 400 multiethnic guests at an open-access dinner dance for members of a local community. The questionnaire could elicit the responses strongly agree, agree, unsure, disagree or strongly disagree. 332 (83%) guests responded. For non-invasive techniques, 32% of responders supported practice without consent, 74% with consent. Support diminished with increasing invasiveness of procedure. 91% of the sample were uncomfortable about the procedures, the commonest reason being 'respect for the body' (264/302). 86% of responders felt that practice should last for no more than 5 minutes. The most popular solutions were for people to carry a personal card giving consent (89%) and establishment of a central register of individuals consenting to be practised upon after death (79%).

Adult↗
PubMed1998

Deleterious mutation accumulation in organelle genomes.

It is well established on theoretical grounds that the accumulation of mildly deleterious mutations in nonrecombining genomes is a major extinction risk in obligately asexual populations. Sexual populations can also incur mutational deterioration in genomic regions that experience little or no recombination, i.e., autosomal regions near centromeres, Y chromosomes, and organelle genomes. Our results suggest, for a wide array of genes (transfer RNAs, ribosomal RNAs, and proteins) in a diverse collection of species (animals, plants, and fungi), an almost universal increase in the fixation probabilities of mildly deleterious mutations arising in mitochondrial and chloroplast genomes relative to those arising in the recombining nuclear genome. This enhanced width of the selective sieve in organelle genomes does not appear to be a consequence of relaxed selection, but can be explained by the decline in the efficiency of selection that results from the reduction of effective population size induced by uniparental inheritance. Because of the very low mutation rates of organelle genomes (on the order of 10(-4) per genome per year), the reduction in fitness resulting from mutation accumulation in such genomes is a very long-term process, not likely to imperil many species on time scales of less than a million years, but perhaps playing some role in phylogenetic lineage sorting on time scales of 10 to 100 million years.

Animals↗
PubMed1998

Inferring the major genomic mode of dominance and overdominance.

The mode of within-locus gene action in most genomic regions is termed as the major genomic mode, i.e., it is the within-locus allelic effects in most regions of the genome. Determining whether dominance or overdominance is the major genomic mode is important for two long-standing evolutionary genetics issues: 1. How is the genetic variation in most genomic regions maintained? 2. What is the major mechanism for heterosis? Many efforts have been made, but almost all of them suffer some explanational difficulties. Here we propose an alternative inference approach. It is based on the existent theoretical results on the correlation of the recombination rate and the level of neutral variation in different genomic regions. Positive and negative correlation suggest dominance and overdominance, respectively, as the major genomic mode. Zero correlations imply either few selected sites or about equal composition and distribution of dominant and overdominant regions in the genome, depending on the data distribution. This approach not only avoids all the problems associated with earlier approaches, but it is also particularly useful in organisms where controlled breeding is difficult. Well-corroborated data in Drosophila and recently emerging data in mice and humans all suggest dominance as the major genomic mode.

Animals↗
PubMed1997

Chimeric CLL-1 antibody fusion proteins containing granulocyte-macrophage colony-stimulating factor or interleukin-2 with specificity for B-cell malignancies exhibit enhanced effector functions while retaining tumor targeting properties.

Although monoclonal antibody (MoAb) therapy of the human malignant lymphomas has shown success in clinical trials, its full potential for the treatment of hematologic malignancies has yet to be realized. To expand the clinical potential of a promising human-mouse chimeric antihuman B-cell MoAb (chCLL-1) constructed using the variable domains cloned from the murine Lym-2 (muLym-2) hybridoma, fusion proteins containing granulocyte-macrophage colony-stimulating factor (GM-CSF) (chCLL-1/GM-CSF) or interleukin (IL)-2 (chCLL-1/IL-2) were generated and evaluated for in vitro cytotoxicity and in vivo tumor targeting. The glutamine synthetase gene amplification system was employed for high level expression of the recombinant fusion proteins. Antigenic specificity was confirmed by a competition radioimmunoassay against ARH-77 human myeloma cells. The activity of chCLL-1/GM-CSF was established by a colony formation assay, and the bioactivity of chCLL-1/IL-2 was confirmed by supporting the growth of an IL-2-dependent T-cell line. Antibody-dependent cellular cytotoxicity against ARH-77 target cells demonstrated that both fusion proteins mediate enhanced tumor cell lysis by human mononuclear cells. Finally, biodistribution and imaging studies in nude mice bearing ARH-77 xenografts indicated that the fusion proteins specifically target the tumors. These in vitro and in vivo data suggest that chCLL-1/GM-CSF and chCLL-1/IL-2 have potential as immunotherapeutic reagents for the treatment of B-cell malignancies.

Animals↗
PubMed1997

The SH3 domain of amphiphysin binds the proline-rich domain of dynamin at a single site that defines a new SH3 binding consensus sequence.

Amphiphysin is an SH3 domain-containing neuronal protein that is highly concentrated in nerve terminals where it interacts via its SH3 domain with dynamin I, a GTPase implicated in synaptic vesicle endocytosis. We show here that the SH3 domain of amphiphysin, but not a mutant SH3 domain, bound with high affinity to a single site in the long proline-rich region of human dynamin I, that this site was distinct from the binding sites for other SH3 domains, and that the mutation of two adjacent amino acids in dynamin I was sufficient to abolish binding. The dynamin I sequence critically required for amphiphysin binding (PSRPNR) fits in the novel SH3 binding consensus identified for the SH3 domain of amphiphysin via a combinatorial peptide library approach: PXRPXR(H)R(H). Our data demonstrate that the long proline-rich stretch present in dynamin I contained multiple SH3 domain binding sites that recognize interacting proteins with high specificity.

Amino Acid Sequence↗
PubMed1997

Right-sided cardiac tumors detected by transesophageal echocardiography and its usefulness in differentiating the benign from the malignant ones.

Eighteen patients (3 men and 15 women; mean age 63 years) with right-sided tumors were evaluated by both transthoracic and transesophageal echocardiography from 1989 to 1996. The indications for echocardiographic studies included evaluation for a presumed mass and further evaluation of ventricular function and valvular function. Fifteen patients had right atrial tumors. These included 5 hypernephromas, 4 myxomas, 2 angiosarcomas, 1 lipoma, 1 cavernous hemangioma, 1 hepatoma, and 1 chondrosarcoma. Three patients had right ventricular (RV) tumors: 1 metastatic olfactory neuroblastoma, a leiomyosarcoma, a chondrosarcoma, and a fourth patient had infiltration of the RV free wall of unknown etiology. Biopsy of either right atrial or RV masses was performed with transesophageal echocardiographic guidance in 2 patients, and allowed histologic diagnosis before surgical resection. These findings indicate that tumors are more often found in the right atrium than in the right ventricle, and females predominate. Most tumors arising within the right atrium are benign, whereas those extending into the right atrium from outside are malignant. RV tumors are rarely encountered; when present, they are likely to be malignant.

Adult↗
PubMed1997

Adaptation and extinction in changing environments.

The extinction risk of a population is determined by its demographic properties, the environmental conditions to which it is exposed, and its genetic potential to cope with and adapt to its environment. All these factors may have stochastic as well as directional components. The present chapter reviews several types of models concerned with the vulnerability of small populations to demographic stochasticity and to random and directional changes of the environment. In particular, the influence of mutation and genetic variability on the persistence time of a population is explored, critical rates for environmental change are estimated beyond which extinction on time scales of tens to a few thousand generations is virtually certain, and the extinction risks caused by the above mentioned factors are compared.

Adaptation, Physiological↗