Biomedical subjects

M Hancock

Publications and source records attributed to M Hancock.

At least 19 recordsLinked to original sources

PubMed2002

Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine.

Methotrexate is widely administered with mercaptopurine, a prodrug requiring activation into thioguanine nucleotides (TGN) to exert antileukemic effects. In vitro, methotrexate enhances TGN formation, but in vivo, such enhancement has yet to be demonstrated. We investigated whether TGN concentrations were related to methotrexate concentrations in children with acute lymphoblastic leukemia who received a weekly intravenous methotrexate (40 mg/m(2)) dose combined with daily mercaptopurine (75 mg/m(2)). A total of 141 erythrocyte TGN concentrations were measured with erythrocyte methotrexate polyglutamates (MTX-PG) concentrations in 87 patients. Average TGN concentrations ranged from 137 to 958 pmol/8 x 10(8) cells (median 389), average total MTX-PG concentrations (MTX- PG(1-7)) from 0.60 to 97.7 pmol/10(9)cells (median 29), and average long chain polyglutamate concentrations (MTX-PG(5-7)) from 0 to 8.35 pmol/10(9) cells (median 2.43). Higher TGN concentrations correlated with higher MTX-PG(5-7) concentrations (P = 0.002). These data support the practice of administering methotrexate with mercaptopurine during continuation therapy of acute lymphoblastic leukemia.

Algorithms↗

PubMed2001

Placental transport rather than maternal concentration of amino acids regulates fetal growth in monochorionic twins: implications for fetal origin hypothesis.

OBJECTIVE: The cause of discordant growth in monochorionic twins is not clear. We hypothesize that growth restriction of 1 monochorionic twin is due to fetal under-nutrition. STUDY DESIGN: We measured plasma amino acid concentrations by high performance liquid chromatography in maternal venous and fetal umbilical cord venous blood samples that were collected at birth from gestational age-matched monochorionic twins (n = 14) with a birth weight discordance of > or =20%. The concordant monochorionic twins with birth weight differences of < or =10% constitute a control group. RESULTS: In the intrauterine growth-restricted twins, fetal concentrations of essential amino acids valine (P <.01), leucine (P <.01), isoleucine (P <.01), phenylalanine (P <.01), and L-arginine (P <.05) were lower than the co-twins and concordant monochorionic twin pairs. Fetal concentrations of the nonessential amino acids taurine (P <.001), serine (P <.01), glycine (P <.01), tyrosine (P <.01), and aspartic acid (P <.01) were lower in the intrauterine growth-restricted twin than the co-twin or concordant monochorionic twins. No such differences were found between concordant monochorionic twin pairs. Maternal amino acid concentrations were similar between discordant and concordant groups. CONCLUSION: Concentrations of certain essential and nonessential amino acids in the intrauterine growth-restricted twins were lower than the co-twins. These differences support the hypothesis that intrauterine growth-restriction that affects 1 of the monochorionic twins is due to the impaired placental transport of amino acids rather than intertwin transfusion of blood.

Amino Acids↗

PubMed2001

Establishing process indicators for joint working in mental health: rationale and results from a national survey.

Effective joint working in mental health is a national concern as indicated by a series of governmental directives and initiatives aimed at improving practice in this area. Joint working is fundamental to the successful implementation of 'community care'. Many people, particularly the public, equate the introduction of the Community Care Act (Department of Health, 1990), with the beginning of community care as a social policy. In reality, however, community care has a much longer history in the UK involving the shift in the 1950s from providing care in the hospital to providing care in the community. Thus, one of the most obvious reasons for this concern expressed in the media and felt by the public is that 'community care' isn't working. While this is an important consideration, it is not the only explanation as to why joint working has come to occupy such a prominent position in the minds of health strategists and politicians. This paper explores our concern with joint working in mental health and proposes one way in which joint working can be effectively monitored and measured.

Community Mental Health Services↗

PubMed2001

The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants.

The pregnane X receptor (PXR)/steroid and xenobiotic receptor (SXR) transcriptionally activates cytochrome P4503A4 (CYP3A4) when ligand activated by endobiotics and xenobiotics. We cloned the human PXR gene and analysed the sequence in DNAs of individuals whose CYP3A phenotype was known. The PXR gene spans 35 kb, contains nine exons, and mapped to chromosome 13q11-13. Thirty-eight single nucleotide polymorphisms (SNPs) were identified including six SNPs in the coding region. Three of the coding SNPs are non-synonymous creating new PXR alleles [PXR*2, P27S (79C to T); PXR*3, G36R (106G to A); and PXR*4, R122Q (4321G to A)]. The frequency of PXR*2 was 0.20 in African Americans and was never found in Caucasians. Hepatic expression of CYP3A4 protein was not significantly different between African Americans homozygous for PXR*1 compared to those with one PXR*2 allele. PXR*4 was a rare variant found in only one Caucasian person. Homology modelling suggested that R122Q, (PXR*4) is a direct DNA contact site variation in the third alpha-helix in the DNA binding domain. Compared with PXR*1, and variants PXR*2 and PXR*3, only the variant PXR*4 protein had significantly decreased affinity for the PXR binding sequence in electromobility shift assays and attenuated ligand activation of the CYP3A4 reporter plasmids in transient transfection assays. However, the person heterozygous for PXR*4 is normal for CYP3A4 metabolism phenotype. The relevance of each of the 38 PXR SNPs identified in DNA of individuals whose CYP3A basal and rifampin-inducible CYP3A4 expression was determined in vivo and/or in vitro was demonstrated by univariate statistical analysis. Because ligand activation of PXR and upregulation of a system of drug detoxification genes are major determinants of drug interactions, it will now be useful to extend this work to determine the association of these common PXR SNPs to human variation in induction of other drug detoxification gene targets.

Alleles↗

PubMed2000

Identification of genetic heterogeneity in Refsum's disease.

Refsum's disease (MIM 266500) is a recessive disorder characterised by defective peroxisomal alpha-oxidation of phytanic acid. A Refsum's disease gene, phytanoyl-CoA hydroxylase (PAHX), has been localised to chromosome 10p13 between the markers D10S226-D10S223. This study investigated whether all cases of Refsum's disease were linked with chromosome 10p13. Eight genetically informative families comprising 92 individuals including 17 living patients with a Refsum's disease phenotype and initial plasma phytanic acid > 200 micromol/L were recruited. Linkage to the 10pter-10p11.2 region was investigated using a panel of eight dinucleotide repeat markers. Linkage analysis of this phenotypically identical cohort suggested that Refsum's disease was genetically heterogeneous (Zmax = 5.28, alpha = 0.45). Two subgroups were identified. One group of four families with eight affected individuals had a maximum multipoint lod score for linkage of 3.89 in the region D10S547 to D10S191, whilst in another three families with nine affected individuals linkage to this region was definitely excluded. Our results show that Refsum's disease is genetically heterogeneous, with up to 55% of cases not being linked to the PAHX gene locus at D10S547 to D10S223. This suggests that Refsum's disease, in common with other peroxisomal 'diseases', may be more accurately described as a heterogeneous syndrome.

Chromosome Mapping↗

PubMed2000

Discordant amino acid profiles in monochorionic twins with twin-twin transfusion syndrome.

To test the hypothesis that discordant growth in monochorionic (MC) twins occurs at least in part due to disparity in placental amino acid transporter function, we measured plasma amino acid levels by HPLC in maternal and fetal blood samples collected at birth from gestational age matched twins with (n = 12) and without (n = 12) twin-twin transfusion syndrome (TTTS). In the donor twin, fetal plasma concentrations and feto-maternal ratios of five essential amino acids-valine (p < 0.001), leucine (p < 0.001), iso-leucine (p < 0.05), histidine (p < 0.001) and L-arginine (p < 0. 001)-were lower than the recipient and non-TTTS twin pairs. Fetal concentrations of the nonessential amino acids taurine (p < 0.001), serine (p < 0.01), glycine (p < 0.001) and tyrosine (p < 0.05) were also markedly lower in the donor than the recipient and non-TTTS twin pairs. In contrast, the fetal alanine level in the donor twin was higher than the recipient (664 +/- 64 versus 396 +/- 23 microM; p < 0.001) and the non-TTTS twin pairs (p < 0.01). No such differences between amino acid profiles in non-TTTS MC twin pairs were found. Maternal plasma amino acid levels between TTTS and non-TTTS groups were comparable. This study provides the first evidence that certain amino acids in the donor twin of chronic TTTS differ significantly from those of the co-twin while others were comparable between twin pairs. These data, therefore, argue against inter-twin transfusion as the sole cause of growth restriction of the donor twin and suggests instead that impaired placental transport of amino acids may be a likely mechanism.

Amino Acids↗

PubMed1999

Private or NHS General Dental Service care in the United Kingdom? A study of public perceptions and experiences.

BACKGROUND: Recent changes in the NHS General Dental Service have led to a reduction in the availability of NHS dental care and increased charges. This study explores public and user views and experiences of NHS and private dental care in the light of these changes. METHODS: The study employed a combination of quantitative and qualitative methods. The first phase involved a postal survey of a random sample of adults on the electoral registers in a county in Southern England, which yielded a response rate of 55 per cent (n = 1506). Follow-up face-to-face interviews were carried out with sub-samples (n = 50) selected from survey respondents. RESULTS: The evidence shows greater satisfaction with certain aspects of private care than with NHS dental care and suggests that the decline in perceived quality of NHS care is less to do with the quality of dental technical skills and more to do with perceived access and availability. However, there was general support for the egalitarian principles associated with NHS dentistry, although payment for dental care by users was acceptable even though dentistry on the NHS was preferred. CONCLUSION: The shift in the balance of NHS and private dental care reflects the interests and preferences of dentists rather than of the public. It suggests, however, that a continued shift towards private practice is a trend that the public will not find acceptable, which might limit the extent of expansion of private practice.

Adult↗

PubMed1997

12p abnormalities and the TEL gene (ETV6) in childhood acute lymphoblastic leukemia.

Although abnormalities involving the short arm of chromosome 12 (12p) are one of the most frequently observed rearrangements in childhood acute lymphoblastic leukemia (ALL), little is known about the frequency of different structural abnormalities and their relationship to the status of the ETV6 (also named TEL) gene in this region. Of 815 children with newly diagnosed ALL, 94 (11.5%) had a total of 104 cytogenetic 12p abnormalities. Loss of genetic material was observed in 67 (64%) of these abnormalities. Cases with 12p alterations had a much lower frequency of hyperdiploidy greater than 50 (7%) than did the ALL population in general, but these cases had a similar distribution of immunophenotype and similar 5-year event-free survival (70% +/- 5% SE v 64% +/- 2%, P = .64). Rearrangement of the ETV6 gene was identified in 36 (56%) of 64 cases evaluated. The ETV6-CBFA2 (TEL-AML1) fusion transcript was found in 25 (66%) of 38 cases evaluated, and all but one of these showed ETV6 rearrangement. Importantly, ETV6 rearrangement was associated with a favorable prognosis (5-year event-free survival: 89% +/- 6% v 60% +/- 1%, P < .01). We conclude that most but not all 12p cytogenetic abnormalities in childhood ALL involve ETV6, and that rearrangement of ETV6 is associated with a favorable treatment outcome.

Adolescent↗

PubMed1997

XYY syndrome in children with acute lymphoblastic leukemia.

Certain constitutional chromosomal abnormalities increase the risk of malignancy and/or decrease treatment tolerance. We identified two patients with the XYY syndrome among a total of 444 male children with acute lymphoblastic leukemia who had complete cytogenetics studies. In both cases, the leukemic cell karyotype suggested a constitutional XYY abnormality that was confirmed in studies of lymphocytes obtained during remission. The incidence rate in our series is higher than that of the XYY syndrome in the general population (0.0045 vs. 0.001), but not significantly so. This finding and a literature review failed to confirm an increased frequency of the XYY syndrome among children with acute lymphoblastic leukemia. Both of our patients remain in remission 24 and 28 months, respectively, postdiagnosis. Their tolerance of intensive treatment, including high-dose methotrexate, suggests that the untoward treatment toxicity seen in patients with chromosomal abnormalities such as trisomy 21 does not extend to the XYY syndrome.

Adolescent↗

PubMed1997

A comparative outcome study of frequent, moderate, occasional, and nonattenders of Alcoholics Anonymous.

The purpose of this project was to identify the outcomes associated with frequent, moderate, occasional, and nonparticipation in Alcoholics Anonymous by male alcohol dependents during the first month after treatment. Informants reported nonparticipants consumed far more alcohol during a 48 week followup than moderate or occasional participants. Moderate and occasional participants were rated as abstinent more often than nonparticipants. Nonparticipants were also reported jailed more often than participants. All other consumption and quality of life comparisons between the groups were nonsignificant. Occasional and moderate AA attendance appear to be associated with better outcomes than nonattendance, but frequent participation was not associated with additional improvement.

Adult↗

PubMed1997

A comparison of the symptoms associated with early and late onset alcohol dependence.

This study was designed to determine whether the prevalences of the DSM-III alcohol abuse/dependence symptoms in 87 early and 73 late onset male alcoholics differ from one another. The authors administered a 19-item alcohol abuse/dependence symptom checklist with items based on the DSM-III criteria. Nine of the 19 symptoms were reported significantly more often in the early than in the late onset alcoholics. Antisocial behaviors were reported to have been particularly frequent in the early onset group.

Adult↗

PubMed1997

Indirect calorimetry, body composition and small bowel function in asymptomatic HIV-seropositive women.

Extrapolation of data from energy balance studies in HIV-seropositive men to HIV-seropositive women may be inaccurate due to gender differences in body composition, hormones and metabolism. If women have a different metabolic response to the human immunodeficiency virus (HIV), nutritional advice may differ from HIV-seropositive men. Ten asymptomatic HIV-seropositive women were matched with 10 heterosexual female controls from low-risk groups. Subjects and controls had assessment of energy and protein intake, resting energy expenditure (REE) and substrate oxidation, small bowel absorption and permeability and body composition. There were no significant differences in REE, substrate oxidation and body composition. Energy and protein intake and small bowel permeability were increased and sugar absorption decreased in HIV-seropositive women (all P < 0.05). Unlike asymptomatic HIV-seropositive men, asymptomatic HIV-seropositive women do not have significant alterations in metabolism or body composition. Therefore, nutritional advice may need to vary according to the gender of the asymptomatic HIV-seropositive subject.

Adult↗

PubMed1996

A 48-week natural history follow-up of alcoholics who do and do not engage in limited drinking after treatment.

The research on the controversial Alcoholics Anonymous tenet that limited drinking rapidly leads alcoholics to inebriety is inconclusive. We conducted 48-week follow-ups on 51 posttreatment alcohol dependents who had reportedly engaged in limited drinking and 51 paired controls who apparently had not. According to the informants, the limited drinkers consumed 16 times as much alcohol and were 4 times as likely to regress to unacceptable drinking as controls. They were also more often rehospitalized and attended fewer Alcoholics Anonymous meetings than the controls. They were, however, usually (62%) categorized as abstinent or moderate drinkers when assessed during the follow-up period. The groups did not differ in risk of jailing, detoxification, or job loss, nor did limited drinkers ordinarily regress quickly to inebriety. The outcomes of our limited drinkers were inferior to those of controls but much less negative than those Wilson's Alcoholics Anonymous maintains.

Adult↗

PubMed1994

The isolation of activin from ovine amniotic fluid.

During a study of the levels of inhibin and follistatin in ovine amniotic fluid, we noted that although detectable levels of immunoactive inhibin and follistatin were found throughout gestation, the addition of amniotic fluid to a rat anterior pituitary cell culture resulted in a stimulation, rather than the expected suppression, of FSH concentrations. These data suggested the possibility that activin was present in amniotic fluid. We, therefore, set out to isolate the molecules responsible for this activin-like activity and determine their structure. Amniotic fluid, collected from pregnant sheep between 120-140 days gestation, was used as starting material in the purification and diluted in parallel to a human activin-A standard in the activin RIA employed to monitor the purification. A total pool of 7.4 liters amniotic fluid was processed by dye affinity chromatography, hydrophobic interactive chromatography, gel filtration, and a series of reverse phase HPLC steps. Polyacrylamide gel electrophoresis of fractions from the final HPLC step, which showed both activin immunoactivity and bioactivity, revealed a band with a mol wt of 25.3 kilodaltons (kDa), which reduced to 15.8 kDa, and a minor band of 45 kDa, which reduced to 25 kDa. NH2-terminal amino acid sequences of several active fractions from the same region were identical to the known sequence of ovine activin-A. The identification of immunoactive activin, follistatin, and inhibin in amniotic fluid raises the question of the sites of production of these proteins and their interactions and role in fetal physiology.

Activins↗

PubMed1994

Partial characterization of inhibin, activin, and follistatin in the term human placenta.

To determine whether the human term placenta contains inhibin, activin, and follistatin, placental homogenates from normal placentae were subjected to several fractionation procedures: 1) dye affinity chromatography; 2) hydrophobic interaction chromatography using phenyl sepharose; 3) gel filtration under acid conditions; 4) reversed phase-high pressure liquid chromatography (RP-HPLC); and 5) preparative polyacrylamide gel electrophoresis and electroelution. Purification was followed by RIA for inhibin, activin, and follistatin as well as in vitro bioassay based on the FSH cell content of rat anterior pituitary cells in culture. Two peaks of immunoactive and bioactive inhibin with differing elution patterns on RP-HPLC were shown to have molecular weights of 33K and 32K on polyacrylamide gel electrophoresis. These peaks may represent inhibin A and B. Three peaks of immunoactive activin on RP-HPLC had molecular weights of 26.5K, 25.5K, and 27K and may represent activin A, AB, and B. Immunoactive follistatin eluted on RP-HPLC as a broad peak, which on polyacrylamide gel electrophoresis consisted of three main activities consistent with molecular weights of 31K, 35K, and 38K. These studies demonstrate that the term placenta contains inhibin, activin, and follistatin, which have been partially characterized. The presence of these substances within the placenta raises the possibility of their function in local paracrine interactions.

Activins↗

PubMed1993

Guiding STARS.

Explore the source record for details and available documents.

Aircraft↗

PubMed1993

Expression of activation antigens CD38 and CD71 is not clinically important in childhood acute lymphoblastic leukemia.

Cell activation antigen expression, because it is related to cell proliferation, may offer useful information about tumor characteristics and treatment outcome. To assess the clinical utility of assays for the plasmocyte activation antigen CD38 (T10) and the thymocyte activation antigen CD71 (transferrin receptor; T9) in childhood acute lymphoblastic leukemia (ALL), we reviewed the presenting features and clinical outcomes of 325 ALL patients treated on a single protocol at St Jude Children's Research Hospital. T-cell ALL cases were more likely than B-lineage ALL cases to express CD38 (100% versus 90.5%, p < 0.01) and CD71 (92% versus 32%, p < 0.01). However, expression of these antigens was not related to any clinical or biologic feature within the immunophenotypic subgroups. More importantly, event-free survival did not differ significantly between CD38+ and CD38- cases or between CD71+ and CD71- cases in the study group as a whole or in immunophenotypic subgroups. Studies of CD38 and CD71 expression in childhood ALL provide no clinically useful information beyond that obtained from standard immunophenotyping studies.

ADP-ribosyl Cyclase↗

PubMed1990

A comparison of placement techniques and complications of externalized catheters and implantable port use in children with cancer.

The complications associated with the placement and use of Hickman catheters (n = 120), Broviac catheters (n = 146), and implantable ports (n = 93) in children with cancer were analyzed. Percutaneously placed central venous access devices (CVADs) tended to fail less often (P = .86) and to develop infections less often (P = .056) than surgically placed CVADs. The difference in complications with percutaneous versus surgically placed CVADs requires confirmation in a randomized trial to assure they are not a result of differences in patient characteristics. When all catheter failures (removal due to infection, obstruction, or dislodgement) were considered, ports had a significantly longer failure-free duration of use than externalized Hickman and Broviac catheters (P = .0009). Ports also remained infection-free longer than externalized catheters (P = .0014). The greatest risk of infection occurs in the first 100 days of use, particularly for ports. This study demonstrates that for long-term use (greater than 100 days) ports are superior to externalized catheters in children with cancer.

Bacterial Infections↗