Search PubMed⌕ Search

Biomedical subjects

M O'Driscoll

Publications and source records attributed to M O'Driscoll.

At least 19 recordsLinked to original sources
PubMed2006

New roles to support practice learning - can they facilitate expansion of placement capacity?

The National Health Service (NHS) Plan [Department of Health, 2000. The NHS Plan: A Plan for Investment, a Plan for Reform, The Stationery Office, London] set out an ambitious programme of growth for the number of students undertaking health professional education programmes. To meet this demand there is a growing and widely acknowledged need to increase the number of clinical placements needed by these students. This paper outlines the findings from a regional project that aimed to map the current pattern and availability of clinical placements for healthcare students by the collection of quantitative placement data (such as location, specialty, and number of mentors) as well as in-depth interviews with Clinical Placement Managers (CPMs). This article will focus on the findings from interviews with CPMs and their views and experiences of what role they can play in increasing placement capacity. The study revealed that the introduction of this role had facilitated the development and expansion of placement capacity, as the CPMs filled a gap in the form of up-to-date local knowledge about the clinical areas. The CPMs provided a much needed 'bridge' between the Higher Education Institution (HEI), the student and the clinical area. Recommendations are made in relation to future introduction of similar roles that aim to support student learning in practice. Furthermore, useful insights for ongoing policy implementation and development are highlighted.

Attitude of Health Personnel↗
PubMed2006

Self-reported benefits from successive bilateral cochlear implantation in post-lingually deafened adults: randomised controlled trial.

Adult users of unilateral Nucleus CI24 cochlear implants with the SPEAK processing strategy were randomised either to receive a second identical implant in the contralateral ear immediately, or to wait 12 months while they acted as controls for late-emerging benefits of the first implant. Twenty four subjects, twelve from each group, completed the study. Receipt of a second implant led to improvements in self-reported abilities in spatial hearing, quality of hearing, and hearing for speech, but to generally non-significant changes in measures of quality of life. Multivariate analyses showed that positive changes in quality of life were associated with improvements in hearing, but were offset by negative changes associated with worsening tinnitus. Even in a best-case scenario, in which no worsening of tinnitus was assumed to occur, the gain in quality of life was too small to achieve an acceptable cost-effectiveness ratio. The most promising strategies for improving the cost-effectiveness of bilateral implantation are to increase effectiveness through enhanced signal processing in binaural processors, and to reduce the cost of implant hardware.

Adult↗
PubMed2006

Rapidly changing pulmonary infiltrates.

Pulmonary eosinophilia responds very quickly to steroid treatment. Chronic pulmonary eosinophilia is common in middle aged females. We report on a patient who presented with subacute onset of shortness of breath, severe weight loss associated with a rise in the peripheral eosinophil count. She was treated successfully with steroids resulting in complete resolution of the pulmonary infiltrates.

Aged↗
PubMed2004

The clinical and biological overlap between Nijmegen Breakage Syndrome and Fanconi anemia.

Fanconi anemia (FA), an autosomal recessive chromosomal instability syndrome, is characterized clinically by developmental abnormalities, growth retardation, progressive bone marrow failure, pancytopenia, and pronounced cancer predisposition. Nijmegen Breakage Syndrome (NBS) is a related disorder that shares overlapping clinical features, principally, developmental delay, microcephaly, and cancer predisposition. The diagnosis has relied on chromosomal instability following exposure to DNA cross-linking agents in FA and to ionizing radiation (IR) in NBS. We describe two patients who clinically had FA, but showed sensitivity to both DNA cross-linking agents and ionizing radiation, and who were found to have a rare mutation in the NBS gene. The importance of genetic diagnosis with respect to treatment and prognosis is discussed.

Abnormalities, Multiple↗
PubMed2002

Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination.

The DNA double stranded break (DSB) repair mechanism, non-homologous end joining (NHEJ) represents an essential step in antigen receptor gene rearrangement mechanisms, processes believed to be intimately involved in the aetiology of lymphoproliferative disease. We investigated the potential impact that previously undescribed polymorphisms identified within NHEJ DNA ligase IV (LIG4) have upon predisposition to several lymphoproliferative disorders, including leukaemia, lymphoma, and multiple myeloma. Two LIG4 polymorphisms were examined, both C>T transitions, which result in the amino acid substitutions A3V and T9I. Inheritance of the LIG4 A3V CT genotype was found to be significantly associated with a two-fold reduction in risk of developing multiple myeloma (OR 0.49, 95% CI 0.27 to 0.89). Similarly, inheritance of the LIG4 T9I CT and the T9I TT genotypes were found to associate with a 1.5-fold reduction (OR 0.77, 95% CI 0.51 to 1.17) and a four-fold reduction (OR 0.22, 95% CI 0.07 to 0.70) in risk of developing multiple myeloma respectively, suggesting a gene dosage effect for this polymorphism. The LIG4 A3V and T9I variant alleles are in linkage disequilibrium (D'=0.95, p<0.0001), and the protective effect associated with these polymorphisms was found to be the result of inheritance of the A3V-T9I CT and A3V-T9I TT haplotypes. These data suggest that genetic variants of NHEJ LIG4 may modulate predisposition to multiple myeloma, a tumour characterised by aberrant immunoglobulin (Ig) class switch recombination.

Base Sequence↗
PubMed2001

DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency.

DNA ligase IV functions in DNA nonhomologous end-joining and V(D)J recombination. Four patients with features including immunodeficiency and developmental and growth delay were found to have mutations in the gene encoding DNA ligase IV (LIG4). Their clinical phenotype closely resembles the DNA damage response disorder, Nijmegen breakage syndrome (NBS). Some of the mutations identified in the patients directly disrupt the ligase domain while others impair the interaction between DNA ligase IV and Xrcc-4. Cell lines from the patients show pronounced radiosensitivity. Unlike NBS cell lines, they show normal cell cycle checkpoint responses but impaired DNA double-strand break rejoining. An unexpected V(D)J recombination phenotype is observed involving a small decrease in rejoining frequency coupled with elevated imprecision at signal junctions.

Cell Cycle↗
PubMed2000

A Ku80 fragment with dominant negative activity imparts a radiosensitive phenotype to CHO-K1 cells.

DNA non-homologous end joining, the major mechanism for the repair of DNA double-strands breaks (DSB) in mammalian cells requires the DNA-dependent protein kinase (DNA-PK), a complex composed of a large catalytic subunit of 460 kDa (DNA-PKcs) and the heterodimer Ku70-Ku80 that binds to double-stranded DNA ends. Mutations in any of the three subunits of DNA-PK lead to extreme radiosensitivity and DSB repair deficiency. Here we show that the 283 C-terminal amino acids of Ku80 introduced into the Chinese hamster ovary cell line CHO-K1 have a dominant negative effect. Expression of Ku(449-732) in CHO cells was verified by northern blot analysis and resulted in decreased Ku-dependent DNA end-binding activity, a diminished capacity to repair DSBs as determined by pulsed field gel electrophoresis and decreased radioresistance determined by clonogenic survival. The stable modifications observed at the molecular and cellular level suggest that this fragment of Ku80 confers a dominant negative effect providing an important mechanism to sensitise radioresistant cells.

Animals↗
PubMed2000

Unmasking a killer: DNA O(6)-methylguanine and the cytotoxicity of methylating agents.

Methylating agents are potent carcinogens that are mutagenic and cytotoxic towards bacteria and mammalian cells. Their effects can be ascribed to an ability to modify DNA covalently. Pioneering studies of the chemical reactivity of methylating agents towards DNA components and their effectiveness as animal carcinogens identified O(6)-methylguanine (O(6)meG) as a potentially important DNA lesion. Subsequent analysis of the effects of methylating carcinogens in bacteria and cultured mammalian cells - including the discovery of the inducible adaptive response to alkylating agents in Escherichia coli - have defined the contributions of O(6)meG and other methylated DNA bases to the biological effects of these chemicals. More recently, the role of O(6)meG in killing mammalian cells has been revealed by the lethal interaction between persistent DNA O(6)meG and the mismatch repair pathway. Here, we briefly review the results which led to the identification of the biological consequences of persistent DNA O(6)meG. We consider the possible consequences for a human cell of chronic exposure to low levels of a methylating agent. Such exposure may increase the probability that the cell's mismatch repair pathway becomes inactive. Loss of mismatch repair predisposes the cell to mutation induction, not only through uncorrected replication errors but also by methylating agents and other mutagens.

Alkylating Agents↗
PubMed2000

A phase II study of biochemotherapy for the treatment of metastatic malignant melanoma.

The use of interleukin-2 (IL-2) and interferon-alpha (IFNalpha) in combination with chemotherapy for the treatment of advanced malignant melanoma has generated considerable interest. In particular, the relatively high number of durable complete responses has suggested this may be a significant advance in the treatment of malignant melanoma. We report our experience at the University of Colorado in 43 patients, including many with poor prognostic factors. Patients received cisplatin 20 mg/m2 on days 1-4, vinblastine 1.6 mg/m2 on days 1-4, dacarbazine 800 mg/m2 on day 1, IL-2 9 x 10(6) IU/m2 per day intravenously over 24h on days 1-4 and IFNalpha 5 x 10(6) IU/m2 per day subcutaneously on days 1-5 every 3 weeks. The median follow-up for all patients was 34 months. Responses were seen in 20 patients (47%, 95% confidence interval 31-62%) and comprised five complete responses (CRs) (12%) and 15 partial responses (PRs) (35%). Two patients achieving a CR remain disease free at 45 and 47 months follow-up. In addition three patients who obtained a surgical CR and another with only minor residual changes on computed tomography scan have not progressed at 27, 30, 40 and 27 months, respectively. Toxicity was manageable, but all patients had at least one grade 3 or 4 toxicity, predominantly hypotension and neutropenia. There were no treatment-related deaths. In conclusion, the response rate and duration is within the range previously reported for biochemotherapy. The results of ongoing randomized studies are awaited to better define the value of biochemotherapy in the treatment of advanced melanoma.

Abdominal Neoplasms↗
PubMed1999

The experience of breathlessness in lung cancer.

Breathlessness is a common problem in advanced cancer ranked amongst the 10 most common symptoms in patients admitted to palliative care units. Alongside coughing, it is the most commonly reported symptom in lung cancer. Despite the prevalence of breathlessness, little research has been undertaken on the experience of the symptom, or on the restrictions it imposes on daily life. The data reported in this paper were collected as part of a study piloting new non-pharmacological intervention for patients with breathlessness as a result of lung cancer. Data on the experience of breathlessness from assessment notes recorded by nurses during conversations with 52 patients with lung cancer, were analysed using content analysis. Both physical and emotional sensations were associated with descriptions of breathlessness, such as the feeling of being unable to get enough breath, or of panic or impending death. Breathlessness was only continuous in eight patients, the remainder (85%) had an intermittent pattern of the symptom, usually triggered by exertion or, less commonly, emotion. Numerous restrictions on activity were reported as a result of breathlessness, on functioning inside and outside the home, to social life, and its implications for feelings about oneself. Most patients had attempted to find ways of managing the problems for themselves since, prior to receiving nursing intervention, little or no help had been forthcoming from health professionals.

Activities of Daily Living↗
PubMed1999

Combined mismatch and nucleotide excision repair defects in a human cell line: mismatch repair processes methylation but not UV- or ionizing radiation-induced DNA damage.

Interaction between long patch mismatch repair (MMR) and persistent DNA O6-methylguanine or 6-thioguanine (6-TG) is implicated in the cytotoxicity of methylating agents and 6-TG, respectively. Human cells with defective MMR tolerate DNA methylation damage and are cross-resistant to 6-TG. To determine whether MMR contributes to the lethal effects of persistent UV-induced DNA lesions, MMR deficiency was introduced into nucleotide excision repair (NER)-defective XP12RO cells. The doubly repair-defective cells, designated XP12ROB4, did not express detectable hMSH2 protein. They had the mutator phenotype, N-methyl-N-nitrosourea and 6-TG resistance typical of MMR-defective cells. Active MMR was not required for the cytotoxicity of UV light, and the hMSH2 defect did not detectably alter the survival of XP12ROB4. The level of spontaneous or UV-induced SCE was also similar in XP12RO and XP12ROB4, indicating that hMSH2 is not required for this recombination process. The combined deficiency in MMR and NER did not confer a significant degree of tolerance to ionizing radiation, and the survival of XP12RO and XP12ROB4 after gamma-radiation was similar. Although it recognizes and processes some persistent damaged or modified DNA base pairs, MMR is unlikely to serve as a general sensor of DNA damage.

Cell Line↗
PubMed1999

The cytotoxicity of DNA carboxymethylation and methylation by the model carboxymethylating agent azaserine in human cells.

Carboxymethylating agents are potential sources of endogenous DNA damage that have been proposed as possible contributors to gastrointestinal carcinogenesis. The cytotoxicity of the model DNA carboxymethylating agent azaserine was investigated in human cells. Expression of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) did not affect sensitivity to the drug in two related Raji Burkitt's lymphoma cell lines. DNA mismatch repair-defective variants of Raji cells which display increased tolerance to DNA methylation damage were not selectively resistant to azaserine. Complementary results were obtained with a second carboxymethylating agent, potassium diazoacetate. In contrast, lymphoblastoid cell lines representative of each of the xeroderma pigmentosum complementation groups, including the variant, were all significantly more sensitive to azaserine than nucleotide excision repair-proficient cells. The hypersensitivity of XP cells was not due to systematic differences in the concentrations of intracellular thiol compounds or related thiol metabolizing enzymes. The data indicate that of the two types of potentially lethal DNA damage which azaserine introduces, carboxymethylated bases and O(6)-methylguanine, the former are repaired by nucleotide excision repair and are a more significant contributor to azaserine lethality in human cells.

Adenine↗
PubMed1999

Development of a breathlessness assessment guide for use in palliative care.

The complex nature of breathlessness in advanced cancer makes it a difficult symptom to understand and control. Measurement instruments applied to breathlessness have thus far failed to consider the multivariant components of this symptom. This study developed a breathlessness assessment guide for use in the clinical practice setting, that may be completed by any member of the health care team. The guide aims to encourage breathlessness to be addressed as a multidimensional problem, in which the emotional experience of breathlessness is inseparable from the sensory experience and the causative biological mechanisms. This guide provides the foundation for understanding the symptom of breathlessness in advanced cancer, and in turn promotes the development of management strategies to deal with this complex symptom.

Activities of Daily Living↗
PubMed1999

Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: phase I/II experience.

PURPOSE: We have completed a phase I study, followed by three phase I/II studies, in patients with metastatic melanoma, renal cell carcinoma (RCC), and sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containing a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1, 2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleyl-phosphatidyl-ethanolamine (DMRIE/DOPE) and administered intratumorally. PATIENTS AND METHODS: Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 microg, 30 microg, or 300 microg weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melanoma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 microg twice a week for 3 weeks, 750 microg weekly for 6 weeks, and 1,500 microg weekly for 6 weeks. RESULTS: There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority of patients experienced mild constitutional symptoms after treatment. In the phase I/II studies, 45 patients were assessable for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two patients with RCC and one with melanoma have achieved partial responses lasting from 16 to 19 months and continuing. In addition, two RCC, three melanoma, and six sarcoma patients had stable disease lasting from 3 to 18 months and continuing. The plasmid was detected by polymerase chain reaction assay in the posttreatment samples of 29 of 46 evaluated patients. Immunohistochemistry studies on serial biopsy specimens showed increased IL-2 expression and CD8(+) infiltration after treatment in the tumor samples of several patients (12 and 16, respectively). CONCLUSION: Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.

Adult↗