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Biomedical subjects

M Boyd

Publications and source records attributed to M Boyd.

At least 55 records · Page 3Linked to original sources
PubMed1995

Synthesis, DNA interactions and biological activity of DNA minor groove targeted polybenzamide-linked nitrogen mustards.

A series of polybenzamide DNA minor groove binding ligands bearing either one or two monofunctional mustards have been synthesised, and their cytotoxicities and interactions with DNA have been studied. Analogues with two alkylating functions (e.g. compounds 7 and 14) are the most cytotoxic, with 7 being 1000-fold more potent than the clinical mustard chlorambucil against P388 leukemia in culture, as well as being more potent in vivo. Monofunctional analogues were also significantly more cytotoxic than chlorambucil, despite bearing much less reactive mustard species. These results support the concept that targeting nitrogen mustard alkylating agents to DNA by attachment to DNA-affinic carriers can greatly enhance cytotoxicity due to alkylation, and that even for such DNA-targeted mustards, crosslinking is a more toxic event than monoalkylation. Close analogues of 7 differing only in their radius of curvature, appear to alkylate and crosslink DNA in similar fashion, yet have widely differing cytotoxicities. The most cytotoxic compound (7) possesses a geometry most complementary to that of duplex DNA, suggesting that the most toxic lesions are those which result in least DNA distortion, thus being less easily recognised by DNA repair systems.

Alkylation↗
PubMed1995

Radiographic imaging requirements following ventriculoperitoneal shunt procedures.

The requirements for radiographic imaging of the ventricles after a ventricular shunt procedure are not well defined. At British Columbia's Children's Hospital, the standard protocol included an ultrasound examination or CT scan at 6-8 weeks postoperatively, and a delayed CT scan at 6 months to 2 years, with additional scans only if the patient had symptoms of shunt malfunction. This study was performed to determine if the delayed scan could be omitted without compromising patient care. The study comprised 86 children with ventriculoperitoneal shunt operations, who had early CT scans or ultrasound examinations less than 20 weeks postoperatively, delayed postoperative CT scans between 20 weeks and 2 years, and who were asymptomatic at the time of these radiographic studies. In 39 of the 86 patients a change in ventricular size occurred between the early and delayed imaging studies, and in these patients the delayed scan was felt to be required. In patients in whom the early imaging study was done at more than 12 weeks postoperatively, and probably in patients with small ventricles preoperatively, there was no added information gained by doing a delayed scan. It is concluded that a radiographic examination of ventricular size at 12 weeks after a shunt operation may provide an adequate baseline study. If the early postoperative radiographic study is done less than 12 weeks after surgery, we would advise that in asymptomatic patients, with the exception of patients with very small ventricles preoperatively, a CT scan be repeated at a later date to obtain an appropriate baseline assessment of ventricular size for the future.

Adolescent↗
PubMed1994

Cloning and expression of functional cDNA genes of a mouse/human chimeric antibody rcM4.

AIM: The purpose of this study was to clone and express cDNA genes of heavy and light chains of the mouse/human chimeric antibody rcM4, which recognize the sialosyl-Tn epitope of the TAG72 antigen. METHODS: The cDNA genes of chimeric heavy-chain M4H2 and light-chain M4K4 were cloned from the cDNA library of the ccM4 transfectoma. The M4H2 and M4K4 genes were modified in polymerase chain reaction and ligated into mpSV2neo-EP-PA and mpSVgpt-EP-PA to form the heavy- and the light-chain expression vectors mpSV2neo-EP-M4H2-PA and mpSV2gpt-EP-M4K4-PA, respectively. These two expression vectors were then co-transfected into the myeloma cell line SP2/0Ag14. Transfectants were selected in media containing G418 and mycophenolic acid. The rcM4 antibody was purified from transfectant culture supernates by protein A affinity chromatography. RESULTS: The yield of the recombinant chimeric antibody rcM4 from its culture supernates was 6 micrograms/ml. We demonstrated that the rcM4 antibody retained its binding reactivity for sialosyl-Tn and that it was able to mediate effective antibody-dependent cellular cytotoxicity to the human ovarian cancer cell line OVCAR 3 in a manner comparable to the original ccM4 antibody. CONCLUSION: The cDNA genes of chimeric heavy-chains (M4H2) and light-chains (M4K4) could be functionally expressed in the SP2/0Ag14 myeloma cell line. They thus have potential utility in the construction of some novel hybrid proteins such as those containing both antitumor immunoglobulins and cytokine molecules for use in cancer immunotherapy.

Amino Acid Sequence↗
PubMed1994

In vitro assessment of compounds for anti-HIV activity.

Human immunodeficiency virus types 1 and 2 (HIV-1, -2), the etiological agents of AIDS, are retroviruses that replicate in CD4+ T lymphocytes, monocytes, and macrophages. Early anti-HIV therapies were directed at the step in the virus life cycle that was considered the most readily blocked: the transcription of viral RNA into its DNA copy by the viral enzyme reverse transcriptase (RT). Unfortunately, to date, patient therapies have been relatively unsuccessful and hampered by toxicological problems. This has promoted further research into inhibitors of HIV replication, which may act at alternative stages in the viral replicative cycle as well as more effective RT inhibitors. In order to facilitate such research, simple and accurate in vitro assays are highly desirable. Here we describe such assays that measure components of the HIV replicative cycle and are suitable for use within antiviral experiments.

Amino Acid Sequence↗
PubMed1994

Health visiting: a new model for a deprived area.

Discusses Nottingham's approach to developing a public health role explicitly alongside traditional health visiting. Argues that their approach makes significant improvements to the health status of a selected deprived area.

Accident Prevention↗
PubMed1994

In vitro antiviral activity of penciclovir, a novel purine nucleoside, against duck hepatitis B virus.

The in vitro antihepadnavirus activities of the purine nucleoside analogs ganciclovir (9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine) and penciclovir [9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; BRL 39123] were compared in primary duck hepatocyte cultures congenitally infected with the duck hepatitis B virus (DHBV). Both compounds inhibited DHBV DNA replication to a comparable extent during continuous short-term treatment of the cultures. However penciclovir was more active both during longer-term continuous treatment (50% inhibitory concentrations: penciclovir, 0.7 +/- 0.1 microM; ganciclovir, 4.0 +/- 0.2 microM) and in washout experiments (50% inhibitory concentrations: penciclovir, 3.0 +/- 0.4 microM; ganciclovir, 46 +/- 1.5 microM) designed to compare the persistence of inhibitory activity after removal of the extracellular compound. The effects on viral protein synthesis were similar to the effects on viral DNA replication. These data suggest that penciclovir or its oral form, famciclovir, may have clinical utility in the treatment of chronic hepatitis B virus infection.

Acyclovir↗
PubMed1994

The detailed characterisation of a 400 kb cosmid walk in the BRCA1 region: identification and localisation of 10 genes including a dual-specificity phosphatase.

We have produced a detailed physical and transcriptional map of a 400 kb region within the narrowest flanking markers known to contain the hereditary breast and ovarian susceptibility gene, BRCA1. The approach described here has avoided the problems of chimaerism, instability and rearrangements commonly observed in yeast artificial chromosomes by converting the YAC clones into ordered chromosome 17-specific cosmid contigs and joining these contigs by cosmid end-walking. A detailed long-range restriction map provided a framework for the cosmid contig assembly and further refines existing physical mapping data. We have used a combined approach towards the isolation of the genes housed within these cosmids. This has resulted in the isolation and precise localisation of eight novel genes, including a novel G protein and an endogenous retrovirus related to the HERV-K family, and the previously described dual-specificity VHR phosphatase and MOX1 homeobox genes.

Animals↗
PubMed1993

Screening for molecular pathologies in Lesch-Nyhan syndrome.

Heteroduplex detection by hydrolink gel electrophoresis was performed to screen for small mutations in 12 Lesch-Nyhan syndrome families with characterised molecular pathology which included nine point mutations, two small deletions, and a 1-bp insertion. This modified protocol for heteroduplex detection by hydrolink gel electrophoresis detected all 12 of these mutations and was utilised to rapidly determine the carrier status of females from affected families. On the basis of these results this approach appears to be a rapid and reliable screening method for point mutations in addition to small length mutations and for carrier detection in Lesch-Nyhan syndrome.

DNA Mutational Analysis↗
PubMed1993

Psychosocial rehabilitation in schizophrenia: beginnings in acute hospitalization.

Schizophrenic patients discharged from acute inpatient settings are often unprepared to function outside the hospital, leading to recidivism and frequent rehospitalization. Social skills training programs addressing this need have hitherto only been developed for use in outpatient or long-term inpatient settings. We describe the development of a social skills training program for application in a short-term acute inpatient unit. Nursing coordinates the program, which is designed for a 3 to 4 week hospitalization and is delivered in an open group setting. The training program emphasizes communication skills, problem solving, affect identification, needs recognition, and social relatedness. The program uses group discussions, writing tasks, physical activity, education, role-play, feed-back, and assignments. Goals include assessment of individual deficits, inculcation of awareness that life-objectives can be identified and achieved, assistance with transition to postdischarge living situation or outpatient treatment program, and development of awareness of one's roles and responsibilities. The evolution and present structure of the program are described and four representative lessons are detailed.

Activities of Daily Living↗
PubMed1993

Biography as therapy.

The feeling that life has had no meaning is an impediment to a peaceful death. Life review enables a person to identify events that have been of worth and so enhances self-esteem. This approach has been extended and formalized by establishing a biographer service to compile oral and written biographies of patients who may be expected to benefit from such a re-examination of their lives. The service is now also being offered to patients whose disability precludes most other forms of activity. The value of biography as therapy is considered and it is concluded that it has much to offer in the circumstances described.

Aged↗
PubMed1992

Hypoxia-selective antitumor agents. 6. 4-(Alkylamino)nitroquinolines: a new class of hypoxia-selective cytotoxins.

A series of isomeric 4-[[3-(dimethylamino)propyl]amino]nitroquinolines has been synthesized and evaluated as hypoxia-selective cytotoxins and as radiosensitizers of hypoxic cells. The compounds showed widely-differing hypersensitivity factors (ratios of cytotoxicity against wild-type and repair-deficient mammalian cells). Many compounds showed oxygen-sensitive bioreduction resulting in DNA alkylation, while others show oxygen-insensitive modes of action. Of the nitro isomers studied, the 5-nitro showed the greatest hypoxic selectivity. A series of ring-substituted analogues were then prepared, in an effort to lower its reduction potential of -286 mV. Structure-activity studies showed that the effects of substitution on reduction potential were complex, being mediated by electronic and steric effects on the nitro group, as well as by effects on quinoline pKa. Two compounds of lower reduction potential, the 3- and 8-methyl analogues, showed improved selectivity (47- and 60-fold in a clonogenic assay). These two compounds also showed the highest "in vitro therapeutic indices" of the series as hypoxic cell radiosensitizers. Despite these favorable in vitro properties, neither compound had activity against hypoxic cells in SCCVII tumors when administered at 60% of the MTD.

Animals↗
PubMed1992

Potential antitumor agents. 64. Synthesis and antitumor evaluation of dibenzo[1,4]dioxin-1-carboxamides: a new class of weakly binding DNA-intercalating agents.

A series of substituted dibenzo[1,4]dioxin-1-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. The required substituted dibenzo[1,4]dioxin-1-carboxylic acids were prepared by a variety of methods. No regiospecific syntheses were available for many of these, and separation of the mixtures of regioisomers obtained was sometimes difficult. The dibenzo[1,4]dioxin-1-carboxamides are active against wild-type P388 leukemia in vitro and in vivo, with structure-activity relationships resembling those for both the acridine-4-carboxamide and phenazine-1-carboxamide series of DNA-intercalating antitumor agents. In all three series, substituents placed peri to the carboxamide sidechain (the 5-position in the acridines, and the 9-position in the phenazines and dibenzo[1,4]dioxins) enhance activity and potency. The 9-chlorodibenzodioxin-1-carboxamide was also curative against the remotely sited Lewis lung carcinoma. Several of the compounds showed much lower levels of cross-resistance to the P388/AMSA line than classical DNA-intercalating agents, which suggests that their primary mechanism of action may not be via interference with topoisomerase II alpha. This is of interest with regard to the development of drugs to combat resistance mechanisms which arise by the expression of the topo II beta isozyme.

Animals↗
PubMed1992

The region of the envelope gene of human immunodeficiency virus type 1 responsible for determination of cell tropism.

Different isolates of human immunodeficiency virus type 1 (HIV-1) vary in the cell tropisms they display, i.e., the range of cell types in which they are able to establish a productive infection. Here, we report on the phenotypes of recombinants between two molecularly cloned strains of HIV-1. Our results prove that the envelope glycoprotein gp120 is solely responsible for the difference in cell tropism between the two parental isolates and that no other genes or sequences are involved in determining the cell tropism of these strains. The region of the envelope involved in the determination of cell tropism includes sequences which encode the V3 loop of gp120. Control of cell tropism by this region of the virus env gene is a general phenomenon which applies to many different HIV-1 isolates.

Amino Acid Sequence↗
PubMed1992

Education in the elderly. Adapting and evaluating teaching tools.

1. The patient's Bill of Rights documents the rights of patients to be informed of their illness, health, and treatment. 2. The use of appropriate teaching tools can significantly increase learning, especially if the tools are modified to accommodate normal aging changes. 3. An appropriate teaching tool is a critical component to the learning success of the elderly. 4. With aging changes that result in loss of short-term memory, a teaching tool may make the difference between short-term learning and long-term success.

Aged↗
PubMed1992

Emergency room resuscitative thoracotomy: when is it indicated?

This study was designed to examine the results of emergency room resuscitative thoracotomy (ERRT) and to formulate cost-effective indications for this procedure. A retrospective study was performed of 28 patients who had ERRT at St. Elizabeth Hospital Medical Center, Youngstown, Ohio, during the 4 years from July 1985 through June 1989. The prognostic factors analyzed included mechanism and site of injury, signs of life (SOL), vital signs (VS), age, gender, and prehospital care. The overall survival rate of ERRT was 7% (2 of 28 patients). The survival rate was 18% (2 of 11 patients) with penetrating trauma, and 0% (none of 17 patients) with blunt trauma. The best survival rate was 66% in the subgroup of patients with penetrating trauma and SOL present at the scene and in the emergency room (ER), (two of three patients). Our observations were combined with those of 23 studies from the literature involving 2294 trauma patients who had ERRT. Using meta-analysis, the survival rate was 11% overall. Improved survival was noted for patients with penetrating trauma compared with patients with blunt trauma (14% vs. 2%, p < 0.01). There were no survivors in the group of patients with no SOL at the scene, and there were no neurologically intact survivors among blunt trauma patients with no SOL upon arrival at the ER. An algorithm based on mechanism of injury and presence or absence of SOL at the scene and in the ER is proposed. This algorithm would decrease the number of ERRTs performed by 41% without decreasing the number of neurologically intact survivors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Potential antitumor agents. 63. Structure-activity relationships for side-chain analogues of the colon 38 active agent 9-oxo-9H-xanthene-4-acetic acid.

A series of 16 analogues of the solid tumor active compound 9-oxo-9H-xanthene-4-acetic acid (XAA), with variations in the acetic acid side chain, have been prepared and evaluated for their ability to cause early haemorrhagic necrosis of colon 38 tumors in mice. The results extend the previous SAR for this class and confirm the necessity for a carboxylic acid group in a fixed disposition with respect to the xanthenone chromophore. None of the compounds showed superior potency to XAA itself, with virtually all alterations in the nature of the anionic center or its geometry with respect to the chromophore greatly reducing or abolishing activity. However, alpha-methylation of the side chain was permissible, and the two enantiomers of 5-methyl-alpha-methyl-XAA were separated and tested. Both were active, but the S-(+) enantiomer was much more dose-potent than the R-(-) enantiomer, in both the in vivo tumor necrosis assay and an in vitro assay measuring the stimulation of nitric oxide production by macrophages. This suggests that the enantiomers have different intrinsic activities, rather than differing in their vivo metabolism.

Animals↗