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Biomedical subjects

M Grey

Publications and source records attributed to M Grey.

At least 37 records · Page 2Linked to original sources
PubMed1999

Conceptual and technical considerations when combining large data sets.

Secondary analysis provides a useful method for the development of new knowledge. Larger samples can be constructed, and secondary analysis can be enhanced when data sets are combined. A standardized method for combining large data sets is crucial, yet literature on methods for combining large data sets for secondary analysis is lacking. The purpose of this article is to outline and explain the process of combining two or more large data sets (n = 276, n = 125) for secondary analysis by using these authors' previous work with large oncology and AIDS caregiver data sets.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Continuous subcutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes.

OBJECTIVE: Recommendations from the Diabetes Control and Complications Trial (DCCT) indicate that adolescents with type 1 diabetes should be treated with intensive therapy involving multiple daily injections (MDI) of insulin or insulin pump therapy (continuous subcutaneous insulin infusion [CSII] to help obtain better metabolic control and prevent later complications. Interest has thus focused on insulin pump therapy to help adolescents meet this challenge. The purpose of this study was to examine responses to CSII and MDI in a large group of adolescents with established type 1 diabetes during a 12-month period and to determine whether either treatment regimen more favorably affected clinical and psychosocial outcomes. RESEARCH DESIGN AND METHODS: One-third of 75 youths aged 12-20 years who were candidates for intensive therapy chose CSII as their mode of treatment. Patients received intensive treatment and education as described by the DCCT investigators. Psychosocial data (e.g., quality of life, depression, self-efficacy, and coping) were collected at baseline and at 6-month intervals, and clinical data (e.g., HbA1c levels, adverse events) were collected every 4-6 weeks. RESULTS: Although both MDI- and CSII-treated adolescents initially exhibited improved metabolic control, this level of control was more difficult to sustain for 12 months in the MDI group (at 6 months HbA1c = 8.1, at 12 months HbA1c = 8.3), whereas average HbA1c levels in the CSII group continued to decrease during the 12 months of treatment (at 6 months HbA1c = 7.7, at 12 months HbA1c = 7.5). Despite lower HbA1c levels in CSII-versus MDI-treated patients, the rate of severe hypoglycemic events was reduced by almost 50% in the CSII group (P = 0.01). Self-reported questionnaires demonstrated that there was improvement in self-efficacy, depression, and quality of life in both MDI- and CSII-treated patients. Finally, adolescents using CSII found coping with diabetes to be less difficult than adolescents using MDI did. CONCLUSIONS: CSII is an alternative means to lower HbA1c levels and reduce the risk of hypoglycemia without adversely affecting psychosocial outcomes in adolescents with type 1 diabetes.

Adaptation, Psychological↗
PubMed1998

Low glutathione pools in the original pso3 mutant of Saccharomyces cerevisiae are responsible for its pleiotropic sensitivity phenotype.

The original pso3-1 mutant isolate of the yeast Saccharomyces cerevisiae exhibits a pleiotropic mutagen-sensitivity phenotype that includes sensitivity to UVA-activated 3-carbethoxypsoralen, to UVC-light, to mono- and bi-functional nitrogen mustard, to paraquat, and to cadmium; on the other hand, it shows hyper-resistance (HYR) to nitrosoguanidine when compared to established wild-type strains. Also, the original pso3-1 mutant exhibits a low UVC-induced mutability and mitotic gene conversion and a high rate of spontaneous and UVC-induced petite mutations. Since the HYR to the nitrosoguanidine (MNNG) phenotype resembles that of low glutathione-containing yeast cells, the original pso3-1 mutant was crossed to a gsh1 knock-out mutant that lacks the enzyme for the first step in glutathione biosynthesis and the resulting diploid was tested for complementation. While there was none for HYR to nitrosoguanidine, and other low glutathione-related phenotypes, some other phenotypic characteristics of pso3-1, e.g. UVC sensitivity and UVC-induced mutability were restored to a wild-type level. Tetrad analysis of a diploid derived from a cross of the original haploid pso3-1 isolate with a repair-proficient, normal glutathione-containing, PSO3 GSH1 wild-type led to the separation of a leaky gsh1 mutation phenotype from that of the repair-deficient pso3-1 phenotype. Linkage studies by tetrad and random spore analyses indicated no linkage of the two genes. This shows that the low glutathione content in the original pso3-1 isolate is due to a second, additional, mutation in the GSH1 locus and is unrelated to the pso3-1 mutation. Thus, the original pso3-1 isolate is a pso3-1 gsh1 double mutant with most of the particular characteristics of the pleiotropic sensitivity phenotype contributed by either the pso3-1 or the gsh1-leaky mutant allele. The expression of a few phenotypic characteristics of pso3, however, were most pronounced in pso3-1 mutants with a low glutathione pool.

Fungal Proteins↗
PubMed1998

Menadione toxicity in Saccharomyces cerevisiae cells: activation by conjugation with glutathione.

Menadione (2-methyl-1,4-naphthoquinone) has been used extensively as an oxidant stressor at the cellular level. However, the mechanism of cytotoxicity of this compound still remains controversial. This study deals with the role of intracellular glutathione in the resistance of the yeast Saccharomyces cerevisiae to menadione. Incubation with 0.5 mM menadione resulted in a decrease of total glutathione concentration in yeast cells, intracellular formation of menadione S-glutathione conjugate and export of the conjugate from cells. GSH-deficient mutants showed lower stimulation of superoxide and hydrogen peroxide production upon exposure to menadione and were more resistant to menadione than wild-type isogenic strains. These results indicate that in yeast cells the formation of S-glutathione conjugate is a major pathway of menadione metabolism and that this reaction leads to redox activation of menadione but permits its removal from the cells.

Biotransformation↗
PubMed1998

Short-term effects of coping skills training as adjunct to intensive therapy in adolescents.

OBJECTIVE: Given the urgent need to develop effective programs that improve the ability for adolescents to achieve metabolic control equivalent to programs studied in the Diabetes. Control and Complications Trial, we have undertaken a clinical trial to determine if a behavioral intervention (coping skills training [CST]) combined with intensive diabetes management can improve metabolic control and quality of life in adolescents implementing intensive therapy regimens. RESEARCH DESIGN AND METHODS: A total of 65 youths between the ages of 13 and 20 years, who elected to initiate intensive insulin therapy, were randomly assigned to one of two groups: the intensive management with CST group and the intensive management without CST group. CST consists of a series of small group efforts designed to teach adolescents the coping skills of social problem-solving, social skills training, cognitive behavior modification, and conflict resolution. Data were collected at pre-intervention and at 3 months following the use of the Self-Efficacy for Diabetes scale, Children's Depression Inventory, Issues in Coping with IDDM scale, and the Diabetes Quality of Life: Youth scale. Clinical data (HbA1c, adverse effects) were collected monthly. RESULTS: The experimental and control groups were comparable on all measures at baseline. Results show that adolescents who received CST had lower HbA1c and better diabetes self-efficacy and were less upset about coping with diabetes than adolescents receiving intensive management alone. In addition, adolescents who received the CST found it easier to cope with diabetes and experienced less of a negative impact of diabetes on quality of life than those who did not receive CST. CONCLUSIONS: CST is useful in improving not only an adolescent's metabolic control, but also their quality of life. As more pediatric providers aim for improved control, in adolescents with diabetes, the addition of this behavioral intervention may be helpful in achieving metabolic and life goals.

Adaptation, Psychological↗
PubMed1998

Personal and family factors associated with quality of life in adolescents with diabetes.

OBJECTIVE: Quality of life is an important criterion for assessing outcomes of treatment in chronic illness related to psychosocial well-being. The purpose of this study was to evaluate the factors that influence quality of life in adolescents with IDDM. RESEARCH DESIGN AND METHODS: Self-reports were obtained from 52 adolescents (age 13-20 years, mean 16.1 +/- 1.9 [mean +/- SD], diabetes duration 8.2 +/- 3.4 years, 49% female) using the following scales: Diabetes Quality of Life for Youths, Children's Depression Inventory, Issues in Coping with Diabetes, Diabetes Family Behavior Scale, Family Adaptability and Cohesion, Self-Efficacy for Diabetes, and the Adolescent Coping Orientation. Metabolic control was measured by HbA1c. RESULTS: Teenagers whose diabetes had the greater impact (R2 = 0.48) and were less satisfied (R2 = 0.45) felt that management was more difficult (r = 0.56) and that diabetes was more upsetting (r = 0.63). They also used fewer rebellion strategies for coping (r = -0.44), had lower diabetes self-efficacy (r = -0.36), and had more depressive symptoms (r = 0.61). Higher impact was also associated with higher family warmth and caring (r = -0.54) and lower family adaptability (r = -0.42). Teenagers who were more worried (R2 = 0.37) about their diabetes felt that management was more difficult (r = 0.40) and that diabetes was more upsetting (r = 0.58), and they used less rebellion (r = -0.49) and more ventilation (r = 0.42) to cope, had lower diabetes (r = -0.40) and medical (r = -0.30) self-efficacy, were more depressed (r = 0.55), and their families were less warm and caring (r = -0.33). HbA1c levels were not associated with quality of life or any other psychosocial factors except in teenagers who perceived their families as providing more guidance and control. These teenagers had lower HbA1c values than those whose families were less involved. CONCLUSIONS: Even teenagers who are successfully achieving HbA1c goals of therapy may perceive diabetes as having a negative impact on their lives, be depressed, and find diabetes difficult to manage. Diabetes treatment teams need to pay equal attention to the psychosocial needs to the quiet, nonrebellious teen with well-controlled diabetes from a supportive family as they do to the rebellious adolescent with poorly controlled diabetes.

Adolescent↗
PubMed1997

Effect on cell kill of addition of multidrug resistance modifiers cyclosporin A and PSC 833 to cytotoxic agents in acute myeloid leukaemia.

Multidrug resistance (MDR) mediated by the drug efflux pump P-glycoprotein (Pgp), may cause remission failure and relapse in patients with acute myeloid leukaemia (AML) by extruding cytotoxic agents such as anthracyclines from leukaemic cells thus allowing them to survive. Cell line data suggest that reversal of MDR is possible using modifying drugs such as cyclosporin A (CSA) and its analogue PSC 833. We have investigated the effects on cell kill of the addition of CSA and PSC 833 to daunorubicin, idarubicin, mitozantrone, etoposide and cytarabine in 52 fresh cell samples from AML patients using an MTT assay. Pgp status was determined by using monoclonal antibodies JSB-1 and MRK-16 and by assessment of rhodamine efflux. Although overall each cytotoxic-modifier combination produced significant improvements in cell kill compared to cytotoxic alone (P values ranged from P < 0.001 to P = 0.017), modifiers also produced significant cytotoxicity in their own right, and no consistent difference was seen between responses in Pgp-positive and negative groups. Up to one in three Pgp-positive samples failed to show any improvement in cell kill with the addition of CSA or PSC 833, possibly owing to co-expression of alternative resistance mechanisms not affected by the MDR modifiers. The best responses were seen when PSC 833 was added to idarubicin, with 7 out of 22 Pgp-positive cases (32%) showing five-fold improvements in cell kill or better compared to idarubicin alone. Comparison of equimolar concentrations of the two modifiers in the Pgp positive group failed to show a significant difference in cell kill, though PSC 833 was markedly superior to CSA in a minority of highly responsive samples which demonstrated clear evidence of MDR reversal. Our in vitro data suggest that MDR modifiers such as CSA and PSC 833 could play an important role in the therapy of AML and indicate the need for prospective randomised trials to assess their clinical efficacy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Genetic engineering of baker's and wine yeasts using formaldehyde hyperresistance-mediating plasmids.

Yeast multi-copy vectors carrying the formaldehyde-resistance marker gene SFA have proved to be a valuable tool for research on industrially used strains of Saccharomyces cerevisiae. The genetics of these strains is often poorly understood, and for various reasons it is not possible to simply subject these strains to protocols of genetic engineering that have been established for laboratory strains of S. cerevisiae. We tested our vectors and protocols using 10 randomly picked baker's and wine yeasts all of which could be transformed by a simple protocol with vectors conferring hyperresistance to formaldehyde. The application of formaldehyde as a selecting agent also offers the advantage of its biodegradation to CO2 during fermentation, i.e., the selecting agent will be consumed and therefore its removal during down-stream processing is not necessary. Thus, this vector provides an expression system which is simple to apply and inexpensive to use.

Drug Resistance, Microbial↗
PubMed1996

Allelism of PSO4 and PRP19 links pre-mRNA processing with recombination and error-prone DNA repair in Saccharomyces cerevisiae.

The radiation-sensitive mutant pso4-1 of Saccharomyces cerevisiae shows a pleiotropic phenotype, including sensitivity to DNA cross-linking agents, nearly blocked sporulation and reduced mutability. We have cloned the putative yeast DNA repair gene PSO4 from a genomic library by complementation of the blocked UV-induced mutagenesis and of sporulation in diploids homozygous for pso4-1. Sequence analysis revealed that gene PSO4 consists of 1512 bp located upstream of UBI4 on chromosome XII and encodes a putative protein of 56.7 kDa. PSO4 is allelic to PRP19, a gene encoding a spliceosome-associated protein, but shares no significant homology with other yeast genes. Gene disruption with a destroyed reading frame of our PSO4 clone resulted in death of haploid cells, confirming the finding that PSO4/PRP19 is an essential gene. Thus, PSO4 is the third essential DNA repair gene found in the yeast S.cerevisiae.

Alleles↗
PubMed1996

A microbiological assay for the quantitative determination of glutathione.

Based on the requirement of a glutathione-deficient mutant strain of Saccharomyces cerevisiae to take up external glutathione for growth on synthetic media, a simple agar diffusion test for quantitative detection of total glutathione from various sources was established. Glutathione concentrations can be reliably detected in a less expensive way, requiring less technical effort compared to enzymatic or biochemical detection methods.

Glutathione↗
PubMed1996

Overexpression of ADH1 confers hyper-resistance to formaldehyde in Saccharomyces cerevisiae.

In an attempt to clone genes involved in resistance to formaldehyde we have screened a genomic library based on the episomal plasmid YEp24 for the ability to increase resistance to formaldehyde in a wild-type strain. In addition to SFA, the gene encoding the formaldehyde dehydrogenase Adh5, an enzyme most potent in formaldehyde de-toxification, we isolated a second plasmid that conferred a less pronounced but significant hyper-resistance to formaldehyde. Its passenger DNA contained the gene ADH1, encoding alcohol dehydrogenase 1 (EC 1.1.1.1), which could be shown to be responsible for the observed hyper-resistance phenotype. Construction of an adh1-0 mutant revealed that yeast lacking a functional ADH1 gene is sensitive to formaldehyde. While glutathione is essential for Adh5-mediated formaldehyde de-toxification, Adh1 reduced formaldehyde best in the absence of this thiol compound. Evidence is presented that formaldehyde is a substrate for Adh1 in vivo and in vitro and that its cellular de-toxification employs a reductive step that may yield methanol.

1-Propanol↗
PubMed1995

Gene PSO5 of Saccharomyces cerevisiae, involved in repair of oxidative DNA damage, is allelic to RAD16.

The pos5-1 mutation renders Saccharomyces cerevisiae cells sensitive to DNA-damaging agents. We have isolated plasmids from a S. cerevisiae genomic library capable of restoring wild-type levels of 254-nm ultraviolet light sensitivity of the pso5-1 mutant. DNA sequence analysis revealed that the complementing activity resides in RAD16, a gene involved in excision repair. Tetrad analysis showed that PSO5, like RAD16, is tightly linked to LYS2 on chromosome II. Moreover, allelism between the pso5-1 and rad16 mutants was demonstrated by the comparison of mutagen sensitivity phenotypes, complementation tests, and by meiotic analysis. The cloned RAD16 gene was capable of restoring wild-type resistance of the pso5-1 mutant to H2O2 and photoactivated 3-carbethoxypsoralen, both treatments generating oxidative stress-related DNA damage. This indicates that RAD16/PSO5 might also participate in the repair of oxidative base damage.

Alleles↗
PubMed1995

SNG1--a new gene involved in nitrosoguanidine resistance in Saccharomyces cerevisiae.

We have molecularly characterized the SNG1 gene that confers hyper-resistance to the mutagen N-methyl-N'nitro-N-nitrosoguanidine (MNNG) in Saccharomyces cerevisiae when overexpressed on a multi-copy plasmid. This hyper-resistance to MNNG is not due to depletion of glutathione pools since multi-copy SNG1 containing yeast transformants contain at least wild type levels of glutathione; DNA repair seems unaffected in these transformants as the multi-copy SNG1-mediated MNNG hyper-resistance is also seen in DNA repair mutants belonging to each of the three epistasis groups of yeast repair mutants. It could be shown that SNG1 is not under control of the YAP1 encoded transcription activator that controls expression of at least two genes involved in MNNG metabolism in yeast. sng1 null mutants are viable but exhibit only slight sensitivity to MNNG, indicating that SNG1 does not encode a protein involved in a major detoxification step of this mutagen. Sequencing of the HYR-mediating passenger DNA revealed that SNG1 encodes a 547 a polypeptide containing seven transmembrane-spanning regions that may be membrane-bound. Comparison of the DNA sequence with established gene databanks revealed that SNG1 is a novel yeast gene.

Amino Acid Sequence↗
PubMed1995

Psychosocial status of children with diabetes in the first 2 years after diagnosis.

OBJECTIVE: The purpose of this study was to determine the pattern of adjustment over time of a cohort of children with newly diagnosed diabetes compared with a cohort of peer-selected children without diabetes over the first 2 years after the diagnosis of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: Children (n = 89 with IDDM, n = 53 without IDDM) ages 8-14 years were studied with the Children's Depression Inventory, State-Trait Anxiety Inventory for Children, Child and Adolescent Adjustment Profile, Self-Perception Profile for Children, and a general health scale. Initial data were collected within 6 weeks of the diagnosis of IDDM and at 3, 6, 12, and 24 months thereafter. RESULTS: There were no demographic differences between the two groups. Initially, children with diabetes were more depressed, more dependent, and more withdrawn than their peers. By 1 year postdiagnosis, there were no significant differences in psychosocial status between the two groups. By 2 years postdiagnosis, depression, dependency, and withdrawal were significantly higher in children with diabetes than in their peers without IDDM. Self-perceived competence remained similar between the two groups at all time points. CONCLUSIONS: After an initial period of adjustment, children with IDDM have equivalent psychosocial status to children without IDDM, but by 2 years after diagnosis, they have experienced twice the amount of depression and adjustment problems as their peers. Interventions should be aimed at this critical period between 1 and 2 years postdiagnosis.

Adolescent↗
PubMed1994

Overexpression of the SNQ3/YAP1 gene confers hyper-resistance to nitrosoguanidine in Saccharomyces cerevisiae via a glutathione-independent mechanism.

The MNNG hyper-resistance of yeast transformants containing multiple copies of the SNQ3/YAP1 yeast gene is not caused by lowered MNNG activation due to depleted pools of glutathione. On the contrary, the SNQ3/YAP1-encoded protein stimulates production of GSH, apparently by promoter activation due to the AP-1 recognition element. Expression of at least one further gene, encoding a protein with a strong detoxifying activity, must also be stimulated to explain the MNNG hyper-resistance phenotype.

Base Sequence↗