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Biomedical subjects

M Pickard

Publications and source records attributed to M Pickard.

13 recordsLinked to original sources
PubMed2006

Psychiatric symptoms and problem behaviours in people with intellectual disabilities.

BACKGROUND: Previous studies have suggested different patterns of associations between psychiatric symptoms and problem behaviours in people with intellectual disabilities (ID). The aim of this study was to investigate which problem behaviours are associated with specific psychiatric symptoms and the relative strength of these specific associations. METHOD: A cross sectional survey using the Psychiatric Assessment Schedule for Adults with Developmental Disabilities Checklist and the Disability Assessment Schedule was carried out in a sample of 214 adults with ID. RESULTS: Self-injurious and, to a lesser extent, aggressive problem behaviours were most associated with affective type symptoms. Screaming and destructive behaviours tended to be more associated with autism-related social impairment rather than conventional psychiatric symptoms. CONCLUSIONS: This study gives further evidence of associations between psychiatric symptoms and specific problem behaviours in people with ID. It may be particularly useful to consider the diagnosis of affective disorders if a person with ID shows self-injurious or aggressive behaviours.

Adult↗
PubMed2000

Alcohol and drug use in second-year medical students at the University of Leeds.

OBJECTIVE: In view of recent media attention concerning the high level of alcohol and drug use reported in a group of newly qualified junior doctors, the aim of the present study was to assess the alcohol and drug habits of a group of current medical students. METHODS: Information about alcohol and illicit drug use was obtained from 136 second-year medical students (46 men, 90 women) at the University of Leeds by means of a personally administered questionnaire. Levels of anxiety and depression were also assessed. RESULTS: 86% of the students drank alcohol and among those who drank, a high proportion (52.6% of the men and 50.6% of the women), exceeded the recommended weekly limit of alcohol consumption of 21 units for men and 14 units women per week). Illicit drug use was reported by 33.1% of students (28.3% of men, 35.6% of women). The drug most commonly used was cannabis. According to the Hospital Anxiety and Depression (HAD) scale, 41.2% of the students (37% of men, 43.3% of women) had anxiety ratings within the clinically significant range (HAD scale> 8); 9.5% of students demonstrated clinically significant levels of depression (HAD scale> 8). However, these high levels of anxiety and depression did not correlate with high levels of alcohol consumption or drug use.

Alcohol Drinking↗
PubMed2000

Thyroid hormone receptor gene expression in first trimester human fetal brain.

Maternal thyroid hormone is transferred to the fetus early in pregnancy and is postulated to regulate brain development. Thyroid hormone nuclear receptor (TR) proteins are present in fetal brain, but their isoformal composition is unknown. We therefore investigated the ontogeny of TR isoforms and related splice variants in first trimester human fetal brain (n = 9) by semi-quantitative reverse transcriptase-polymerase chain reaction analysis. Expression of the TRbeta1, TRalpha1 and c-erbAalpha2 isoforms was detected from 8.1 weeks gestation (wg). An additional truncated species was detected with the c-erbAalpha2 primer set, consistent with the c-erbAalpha3 splice variant previously described in the rat. All c-erbAalpha-derived transcripts were co-ordinately expressed and increased (ca. 8-fold) between 8.1 and 13.9 wg. A more complex ontogenic pattern was observed for TRbeta1, suggestive of a nadir between 8.4 and 12.0 wg. These findings point to an important role for the TRalpha1 isoform in mediating maternal thyroid hormone action during first trimester human fetal brain development.

Adult↗
PubMed1998

Calmodulin is essential for estrogen receptor interaction with its motif and activation of responsive promoter.

Calmodulin (CaM) has been reported to have affinity for the estrogen receptor (ER). Observations reported here reveal a direct physical interaction between purified CaM and ER. This direct ER-CaM interaction may be an initial event preceding the assembly of ER plus auxiliary proteins into the active ER complex with its DNA motif, the estrogen response element. We demonstrate that CaM is an integral component of this complex by using a system reconstituted from purified ER and nuclear extract from ER-negative breast cancer cells and also with ER-depleted nuclear extract of an ER-positive breast cancer cell line. Although CaM is essential for formation of this complex, it is not sufficient, suggesting roles also of auxiliary proteins. CaM also is functionally required for activation of an ER-responsive promoter, in the 17beta-estradiol-ER pathway of hormone action and regulation of 17beta-estradiol-responsive gene expression that is associated with proliferation of mammary epithelial cells.

Base Sequence↗
PubMed1997

Resistance to chemotherapeutic antimetabolites: a function of salvage pathway involvement and cellular response to DNA damage.

The inherent or acquired (induced) resistance of certain tumours to cytotoxic drug therapy is a major clinical problem. There are many categories of cytotoxic agent: the antimetabolites, e.g. methotrexate (MTX), N-phosphonacetyl-L-aspartate (PALA), 5-fluorouracil (5-FU), 6-mercaptopurine (6-TG), hydroxyurea (HU) and 1-beta-D-arabinofuranosylcytosine (AraC); the alkylating agents, e.g. the nitrogen mustards and nitrosoureas; the antibiotics, e.g. doxorubicin and mitomycin C; the plant alkaloids, e.g. vincristine and vinblastine; and miscellaneous compounds, such as cisplatin. There are also many mechanisms of drug resistance elucidated principally from in vitro studies. These include mutation of target genes, amplification of target and mutated genes, differences in repair capacity, altered drug transport and differences in nucleoside and nucleobase salvage pathways (Fox et al, 1991). The aim of the present review is to evaluate in detail the mechanisms of response of both normal and tumour cells to three chemotherapeutic antimetabolites, MTX, PALA and 5-FU, which are routinely used in the clinic either alone or in combination to treat some of the commonest solid tumours, e.g. breast, colon, gastric and head and neck. The normal and tumour cell response to these agents will be discussed in relation to the operation of the known alternative 'salvage pathways' of DNA synthesis and current theories of DNA damage response.

Animals↗
PubMed1996

Influence of both salvage and DNA damage response pathways on resistance to chemotherapeutic antimetabolites.

The resistance of 3 human embryo fibroblast cell lines to the antimetabolites methotrexate (MTX), N-phosphonacetyl-L-aspartate (PALA) and 5-fluorouracil (5-FU) has been studied. The cell lines were of common genetic origin, all originating from the normal KMS parental cell line, which was irradiated with 60Co to produce the immortalised derivative KMST which, in turn, was transfected with an activated N-ras oncogene to produce the tumourigenic KN-NM cell line. Previous work from this group, using dialysed versus nondialysed serum, has provided evidence for the involvement of salvage pathways of purine and pyrimidine biosynthesis in the increased resistance to antimetabolites of those cell lines (KMST and KN-NM) tending towards increased tumourigenicity. The present study has extended this work by using the nucleoside and nucleobase transport inhibitor dipyridamole, to further assess the contribution of the salvage pathways to the increased cellular resistance to the three antimetabolites. The salvage pathways were found to contribute to the resistance of cell lines to PALA and MTX, but had no effect on the resistance to 5-FU. The addition of excess uridine in the case of PALA, and hypoxanthine plus thymidine in the case of MTX, could be used to "rescue" cells from the effects of dipyridamole-induced salvage pathway inhibition. The data will be discussed in relation to 1. the effect of limited substrate availability, 2. the induction of DNA damage and DNA damage-response pathways, and 3. DNA-damage protection by the salvage pathways of purine and pyrimidine biosynthesis.

Antimetabolites↗
PubMed1996

p53 protein overexpression and response to biomodulated 5-fluorouracil chemotherapy in patients with advanced colorectal cancer.

Biomodulated 5-flourouracil (5-FU) chemotherapy may limit disease progression in up to 50% of patients with metastatic or unresectable carcinoma of the colorectum. However, treatment is expensive and may be toxic. Thus any predictors of response may be clinically and economically valuable. The p53 gene is mutated in more than 50% of colorectal tumours, usually resulting in p53 overexpression. It may regulate cell cycle progression and cellular response to DNA damage. The principal anticancer activity of 5-FU is due to its ability to induce DNA damage. Fifty-nine patients received bolus intravenous 5-FU/folinic acid over 3 months. Response was assessed by CAT scan (WHO criteria). p53 protein overexpression was determined immunohistochemically from paraffin sections of the original primary tumour and resected metastases. Tumour over expression of p53 protein was associated with a lower rate of response and a higher rate of deterioration both radiologically (P < 0.03) and clinically (P < 0.05, chi 2 test for trend), but did not predict survival from start of treatment. Response was unrelated to age, sex, tumour grade, site of disease or chemotherapy schedule. Tumour p53 protein overexpression alone cannot be used to select advanced colorectal cancer patients for chemotherapy but may be useful in association with other markers of tumour biology.

Adult↗
PubMed1995

Differences in resistance to 5-fluorouracil as a function of cell cycle delay and not apoptosis.

A series of human embryo fibroblasts has previously been shown to display increasing resistance to the antimetabolites methotrexate (MTX) and N-phosphonacetyl-L-aspartate (PALA) with increasing tumorigenicity. This increased resistance was found to be further increased as a result of salvage pathway activity for purine and pyrimidine biosynthesis. A similar pattern of increasing resistance paralleling increasing tumorigenicity has now been shown to occur with 5-fluorouracil (5-FU), which is independent of salvage pathway activity. The KMS normal cell line was found to be more sensitive to 5-FU than either the immortalised KMST or tumorigenic KN-NM cell lines. Immunohistochemical analysis of the three cell lines demonstrated high levels of p53 protein in the KMST and KN-NM cell lines, but undetectable p53 levels in the KMS cell line. From these data it was hypothesised that a difference in p53 function may be causing the difference in the patterns of sensitivity observed in the three cell lines. P53 is now believed to function as a regulator of a G1 to S cell cycle checkpoint and as an inducer of apoptosis following DNA damage to the cell. The differences in sensitivity of the cell lines could not be explained by differences in the levels of apoptosis but could be attributed to differences in cell cycle response. Our evidence suggests that loss of cell cycle control, possibly through loss of p53 function, is an important factor in increasing the drug resistance of fibroblast cell lines.

Antimetabolites, Antineoplastic↗
PubMed1989

The reactions of chloroperoxidase in the presence of xanthine/xanthine oxidase.

Spectral data are presented which indicate that chloroperoxidase is converted to compound II during the reaction with superoxide/hydrogen peroxide generated in the xanthine/xanthine oxidase system. Upon completion of compound II formation, compound II returns back to the native state of chloroperoxidase without formation of detectable intermediates. It is shown that chloroperoxidase acts as a superoxide scavenger but less effectively than superoxide dismutase. Addition of chloride ion enhances the rate of decay of compound II to native enzyme, showing that chloride ion is oxidized to a chlorine atom in the presence of compound II.

Chloride Peroxidase↗
PubMed1989

Effect of maternal hypothyroxinaemia during fetal life on the calmodulin-regulated phosphatase activity in the brain of the adult progeny in the rat.

Calmodulin-regulated phosphatase activity was measured in the brain of 2-month-old rats born from hypothyroid and normal dams, using a fluorometric enzyme assay developed for this purpose. Calmodulin content was measured in the same brain regions by radioimmunoassay. Significant differences between groups in weight and protein content, basal phosphatase and calmodulin-regulated phosphatase activity were found. The brain region most affected was the cerebellum, where basal and calmodulin-regulated phosphatase activities, and protein content were increased. The data point towards a lasting effect of maternal hypothyroxinaemia on the brain function of the progeny.

Animals↗
PubMed1988

Mechanism of azide binding to chloroperoxidase and horseradish peroxidase: use of an iodine laser temperature-jump apparatus.

The kinetics of azide binding to chloroperoxidase have been studied at eight pH values ranging from 3.0 to 6.6 at 9.5 +/- 0.2 degrees C and ionic strength of 0.4 M in H2O. The same reaction was studied in D2O at pD 4.36. In addition, results were obtained on azide binding to horseradish peroxidase at pD 4.36 and pH 4.56. Typical relaxation times were in the range 10-40 microseconds. The value of kH/kD(on) for chloroperoxidase is 1.16, and kH/kD(off) is 1.7; corresponding values for horseradish peroxidase are 1.10 and 2.4. The H/D solvent isotope effects indicate proton transfer is partially rate controlling and is more important in the dissociation of azide from the enzyme-ligand complex. A mechanism is proposed in which hydrazoic acid binds to chloroperoxidase in a concerted process in which its proton is transferred to a distal basic group. Hydrogen bonding from the newly formed distal acid to the bound azide facilitates formation of hydrazoic acid as the leaving group in the dissociation process. The binding rate constant data, kon, can be fit to the equation kon = k3/(1 + KA/[H+]), where k3 = 7.6 X 10(7) M-1 S-1 and KA, the dissociation constant of hydrazoic acid, is 2.5 X 10(-5) M. The same mechanism probably is valid for the ligand binding to horseradish peroxidase.

Azides↗
PubMed1987

On the mechanism of chlorination by chloroperoxidase.

Spectral-scan results obtained on the millisecond time scale are reported for reactions of chloroperoxidase with peracetic acid and chloride ion in both the presence and the absence of monochlorodimedone. A multimixing experiment is performed in which stoichiometric amounts of chloroperoxidase and peracetic acid are premixed for 0.7 s before the resultant compound I is reacted with chloride ion. The combined results show that the only detectable enzyme intermediate species is compound I (except in very late stages of the reaction), that the disappearance of compound I is accelerated by the presence of chloride ion, and that it is further accelerated if both chloride and monochlorodimedone are present. It is concluded that compound I is an obligate intermediate species in the reaction. Experiments are performed on the reaction of monochlorodimedone with hypochlorous acid in both the presence and the absence of added chloride ion, but in the absence of chloroperoxidase. The presence of chloride ion greatly accelerates the reaction rate apparently by setting off a chlorine chain reaction. This reaction would be important in the enzyme-catalyzed reaction if hypochlorous acid were liberated into the solution. A careful analysis of steady-state kinetic results shows that in the chlorination of monochlorodimedone at least, liberation of free hypochlorous acid is not important in the enzyme-catalyzed pathway. Rather the reaction proceeds from compound I to formation of iron(III)-OCl by chloride ion addition to the ferryl oxygen atom. This obligate intermediate species then chlorinates the substrate. It is well described as enzyme-activated hypochlorous acid, in which replacement of the proton in HOCl by the heme iron ion produces a Cl+ species of great potency. Thus the enzyme controls chlorination of monochlorodimedone rather than unleashing an uncontrolled chain reaction in which it would be rapidly destroyed.

Chemical Phenomena↗