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Biomedical subjects

M O'Donovan

Publications and source records attributed to M O'Donovan.

At least 19 recordsLinked to original sources
PubMed2006

Elastic scattering spectroscopy accurately detects high grade dysplasia and cancer in Barrett's oesophagus.

BACKGROUND AND AIMS: Endoscopic surveillance of Barrett's oesophagus currently relies on multiple random biopsies. This approach is time consuming, has a poor diagnostic yield, and significant interobserver variability. Elastic scattering spectroscopy is a real time in vivo optical technique which detects changes in the physical properties of cells. The aim of this study was to assess the potential for elastic scattering to detect high grade dysplasia or cancer within Barrett's oesophagus. METHODS: Elastic scattering spectroscopy measurements collected in vivo were matched with histological specimens taken from identical sites within Barrett's oesophagus. All biopsies were reviewed by three gastrointestinal pathologists and defined as either "low risk" (non-dysplastic or low grade dysplasia) or "high risk" (high grade dysplasia or cancer). Two different statistical approaches (leave one out and block validation) were used to validate the model. RESULTS: A total of 181 matched biopsy sites from 81 patients, where histopathological consensus was reached, were analysed. There was good pathologist agreement in differentiating high grade dysplasia and cancer from other pathology (kappa = 0.72). Elastic scattering spectroscopy detected high risk sites with 92% sensitivity and 60% specificity and differentiated high risk sites from inflammation with a sensitivity and specificity of 79%. If used to target biopsies during endoscopy, the number of low risk biopsies taken would decrease by 60% with minimal loss of accuracy. A negative spectroscopy result would exclude high grade dysplasia or cancer with an accuracy of >99.5%. CONCLUSIONS: These preliminary results show that elastic scattering spectroscopy has the potential to target conventional biopsies in Barrett's surveillance saving significant endoscopist and pathologist time with consequent financial savings. This technique now requires validation in prospective studies.

Adenocarcinoma↗
PubMed2006

Is vaginal breech delivery outdated for all singletons and twins? The current kaleidoscope of obstetric thinking.

The best practice for the delivery of a term breech in singleton and twin pregnancies is still controversial. We sought the opinions of obstetricians working in Ireland. A questionnaire was used to address the management of the obstetrician's "own hypothetical pregnancy" in three different scenarios. We also inquired about factors which might influence the decision on mode of delivery. The response rate was 104/174 (60%). In the scenario of a singleton fetus presenting by the breech in a nulliparous woman, 15/84 (18%) of obstetricians would chose a spontaneous vaginal delivery compared to 40/80 (50%) for a multiparous woman (p < 0.01). In the scenario of a second twin in breech presentation (nulliparous and multiparous), 75/93 (81%) would choose a spontaneous vaginal delivery. When asked about a singleton cephalic presentation, 85/91 (93%) would choose a spontaneous vaginal delivery. These decisions were influenced by concerns about perinatal morbidity [91/100 (91%)], published evidence [73/98 (75%)], the delivery doctor's inexperience [56/94 (60%)], but not by gender. Our study indicates that obstetricians in Ireland consider that there is a role for vaginal breech delivery in selected scenarios.

Attitude of Health Personnel↗
PubMed2005

An audit of the use of magnesium sulphate in severe pre-eclampsia and eclampsia.

Over the last decade there has been an increase in the use of MgSO4 for the prevention of seizures in women with severe pre-eclampsia or eclampsia. At the Rotunda Hospital it is regularly used for this purpose. The aim of this study was to audit the use of MgSO4 at the hospital, to determine whether the drug was being used according to the hospital's protocol and to observe its effectiveness in the prevention of eclampsia in our population. A retrospective chart review over the two years from 1/1/2000 to 31/12/2001 was undertaken. Outcome measures assessed were; Patient selection, Administration of the drug - whether recommended protocols were adhered, Effectiveness of therapy for seizure prophylaxis, Maternal and neonatal outcomes. There were 12,910 deliveries at the Rotunda hospital over this period of time. Fifty of these women were treated with MgSO4 (0.4%). Patient selection was appropriate in all cases. The correct loading dose of MgSO4 was administered in all cases, however MgSO4 levels were recorded in only 30 (60%) of women. There were no seizures in the treated group. Two women presented with seizures (one was antenatal the other post-natal period), both were treated with MgSO4. There were no maternal or neonatal mortality. Seventy two percent (36) of these women were delivered by lower segment caesarean section. The mean gestation at delivery was 36 weeks (range 28-41 weeks). Thirty eight percent (13) of babies required admission to the neonatal intensive care unit. The mean birth weight at delivery was 2.54 kg (range 1.11-3.68 kg). MgSO4 use in the Rotunda hospital appears to be safe and effective for the prevention of seizures in women with severe pre-eclampsia or eclampsia. Serum MgSO4 levels were only recorded in 60% of patients and the hospital's protocol was not adhered to regarding monitoring of patients on treatment. This needs to be addressed.

Adolescent↗
PubMed2005

An evaluation of chromatin condensation and DNA integrity in the spermatozoa of men with cancer before and after therapy.

Cancer has been known for a long time to have a depressive effect on sperm number and quality. Cytotoxic agents and radiotherapy have also been shown to impair spermatogenesis. The aim of this study was to assess DNA integrity and chromatin condensation in the spermatozoa of men with cancer before and after treatment. Chromatin condensation was evaluated using flowcytometric assessment with propidium iodide, DNA integrity was determined using the comet assay. Thirty-three men with cancer (testicular cancer, lymphoma and leukaemia) and 14 men with proven fertility took part in the study. The study found that in men with cancer, the percentage of spermatozoa with highly condensed DNA was less than that of controls. DNA integrity when assessed using the comet assay was also reduced by cancer. Percentage head DNA intact and percentage of condensed chromatin in the spermatozoa of men with cancer after treatment were less than those in fertile men. This study, although small, does demonstrate a detrimental effect on chromatin condensation and DNA integrity of cancer and its treatment. These findings are important because of the potential effects impaired chromatin and DNA integrity could have on fertilization, blastocyst and embryo development.

Chromatin↗
PubMed2005

Preservation of fertility in women affected by cancer. An audit of the cryopreservation services provided for women at Human Assisted Reproduction Ireland.

There has been a remarkable improvement in survival rates for adult and childhood cancers, due to progress in cancer treatments. However multiagent chemotherapy and radiotherapy are associated with gonadal failure. Whereas sperm banking is commonly performed, female gametes are not so amenable to cryopreservation. Options available to women for fertility preservation include, embryo and oocyte cryopreservation. Our unit established an oocyte/embryo cryopreservation service for women affected by cancer in October 2003. Ninteen women have been referred and five (26%) women have had oocytes cryopreserved. The mean age of women in the group cryopreserved was 34 years (range 21-41). Their mean day 3 FSH was 6.2 IU (range 5.5-6.8). The mean dose of rFSH used was 1870 units (range 1500-2600). The mean number of oocytes cryopreserved was 8 (range 3-16). Preservation of fertility is of major concern to women affected by cancer. This service offers them hope for their future fertility.

Adult↗
PubMed2004

Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD.

Attention deficit hyperactivity disorder (ADHD) is a childhood onset disorder, for which there is good evidence that genetic factors contribute to the aetiology. Recently reported linkage findings suggested evidence of a susceptibility locus on chromosome 16p13 (maximum LOD score of 4.2, P=5 x 10(-6)). The GRIN2A (glutamate receptor, ionotropic, N-methyl D-aspartate 2A) gene that encodes the N-methyl D-aspartate receptor subunit 2A (NMDA2A) maps to this region of linkage. As this is also a good functional candidate gene for ADHD, we undertook family-based association analysis in a sample of 238 families. We found significant evidence of association with a GRIN2A exon 5 polymorphism (chi(2)=5.7, P=0.01). Our data suggest that genetic variation in GRIN2A may confer increased risk for ADHD and that this, at least in part, might be responsible for the linkage result on 16p reported by Smalley et al. We conclude that replication is required and that further work examining for association of GRIN2A polymorphisms with ADHD is warranted.

Adolescent↗
PubMed2004

Antibiotic prescribing policy and Clostridium difficile diarrhoea.

BACKGROUND: Broad-spectrum antibiotics, particularly intravenous cephalosporins, are associated with Clostridium difficile diarrhoea. Diarrhoea due to C. difficile is a growing problem in hospitals, especially among elderly patients. AIM: To establish whether changing an antibiotic policy with the aim of reducing the use of injectable cephalosporins leads to a reduction in the incidence of C. difficile diarrhoea in elderly patients. DESIGN: Retrospective analysis. METHODS: A group of patients who were subject to the new antibiotic policy from the period following July 2000, were compared with patients who were admitted prior to July 2000 and were not subject to the new policy. Infections, antibiotic prescriptions and mortality rates were determined from case notes, and C. difficle diarrhoea rates from microbiological data. RESULTS: Intravenous cephalosporin use fell from 210 to 28 defined daily doses (p < 0.001) following the change in antibiotic policy, with a corresponding increase in piperacillin-tazobactam (p < 0.001) and moxifloxacin (p < 0.001) use. The new policy led to a significant reduction in C. difficile diarrhoea cases. The relative risk of developing C. difficile infection with the old policy compared to the new policy was 3.24 (95%CI 1.07-9.84, p = 0.03). DISCUSSION: The antibiotic policy was successfully introduced into an elderly care service. It reduced both intravenous cephalosporin use and C. difficile diarrhoea.

Aged↗
PubMed2003

p16INK4A as a marker for cervical dyskaryosis: CIN and cGIN in cervical biopsies and ThinPrep smears.

AIM: To examine the potential of p16(INK4A) as a biomarker for dysplastic squamous and glandular cells of the cervix in tissue sections and ThinPrep smears. METHODS: Immunocytochemical analysis of p16(INK4A) expression was performed on 22 normal cervical tissue samples, five cervical glandular intraepithelial neoplasia (cGIN), 38 cervical intraepithelial neoplasia 1 (CIN1), 33 CIN2, 46 CIN3, and 10 invasive cancer cases (eight squamous and two adenocarcinomas). All samples were formalin fixed and paraffin wax embedded, and immunohistochemical analysis was carried out using a mouse monoclonal anti-p16(INK4A) antibody after antigen unmasking. The staining intensity was assessed using a 0 to 3 scoring system. In addition, the expression status of p16(INK4A) was examined in 12 normal ThinPrep smears, one smear exhibiting cGIN, and a total of 20 smears exhibiting mild, moderate, and severe dyskaryosis. Human papillomavirus (HPV) detection was carried out using a modified SYBR green assay system. Fluorogenic polymerase chain reaction (PCR) and solution phase PCR were used for specific HPV typing. RESULTS: p16(INK4A) immunoreactivity was absent in all normal cervical tissues examined. Dysplastic squamous and glandular cells were positive for p16(INK4A) expression in all cases included in this study, except for one CIN3 case. p16(INK4A) expression was mainly nuclear in CIN1 cases, and both nuclear and cytoplasmic in CIN2, CIN3, cGIN, and invasive cases. All cases positive for HPV expressed the p16(INK4A) protein, although not all cases found positive for p16(INK4A) were HPV positive. In general, the p16(INK4A) staining intensity was lower in cases negative for HPV or those containing a low risk HPV type. CONCLUSION: This pattern of overexpression demonstrates the potential use of p16(INK4A) as a diagnostic marker for cervical squamous and also glandular neoplastic lesions. In addition, the technique can be used to identify individual dyskaryotic cells in ThinPrep smears. Thus, p16(INK4A) is a useful marker of cervical dyskaryosis.

Biomarkers↗
PubMed2002

Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable and heterogeneous disorder, which usually becomes apparent during the first few years of childhood. Imbalance in dopamine neurotransmission has been suggested as a factor predisposing to ADHD. However, evidence has suggested an interaction between dopamine and serotonin systems in the pathophysiology of the disorder. Studies using selective agonists of the different 5-HT receptors microinjected into selected brain structures have shown a positive modulating effect on the functional activities of the mesotelencephalic dopaminergic system. This suggests that some of the genetic predisposition to ADHD might be due to DNA variation at serotonin system genes. In this study, we investigated polymorphisms in HTR(1B) and HTR(2A) (which encode the serotonin receptors 5-HT(1B) and 5-HT(2A) respectively) in a European ADHD sample. Using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) analyses, we observed significant preferential transmission of the allele 861G of the HTR(1B) in the total sample (for HHRR; chi(2) = 7.4, P = 0.0065 and TDT; (chi(2) = 6.4, P = 0.014). Analysis of HTR(2A) failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone (chi(2) = 4.9, P = 0.026). These preliminary data suggest an important role for the serotonin system in the development of ADHD. Further studies, preferentially including different ethnic groups are required to substantiate these findings.

Attention Deficit Disorder with Hyperactivity↗
PubMed2002

Evidence to suggest biased phenotypes in children with Attention Deficit Hyperactivity Disorder from completely ascertained trios.

The transmission disequilibrium test (TDT) is widely used as a robust statistical method to test for genetic association due to linkage based upon analysis of parent-proband trios. The TDT and other family-based tests (eg haplotype relative risk method) are commonly used in association studies including those of ADHD because of concerns that the case-control design has a strong tendency for false positives due to poor matching between cases and controls. Unfortunately, it is not always possible to obtain DNA from both parents in studies of this design, even where the onset of disorder is in childhood, and usually the missing parent is the father. Despite the fact that methods exist for analysis where one parent is missing, many family-based studies are based on the collection or analysis of complete trios only. However this selection process might potentially introduce bias, particularly for studies of behavioural phenotypes like ADHD because the phenotype of proband or parents might influence family stability and therefore complete parental ascertainment. We set out to examine whether children with ADHD and for whom DNA samples from fathers were missing ('duos') differed phenotypically from children for whom genotype information was available from both parents ('trios'). Children from duos showed a significantly higher frequency of DMS-IV ADHD-combined type, significantly more co-morbid conduct disorder and conduct disorder symptoms, and a trend for higher total ADHD symptom scores. Excluding duos from sample collection and analysis may result in systematic bias. If comorbid conduct disorder and ADHD-combined type index increased genetic liability, exclusion of duos could further reduce the power of the TDT (and similar tests) to detect susceptibility genes for ADHD, or replicate effects detected by case-control analysis.

Adolescent↗
PubMed2002

Perinatal outcome in unbooked women at the Rotunda Hospital.

To determine the incidence and outcome of unbooked pregnancies in women at the Rotunda Hospital Retrospective case control study. All unbooked deliveries in the Rotunda Hospital over a two year period were identified and matched with a control. Control patients were selected as the next delivery after each case and were regular antenatal attenders. Demographic and obstetric data was collected from each case and control and compared using the Chi-square test. There were 101 unbooked women in the study, during this time there were 11522 deliveries giving an incidence of unbooked pregnancies of 0.88%. Unbooked women were found to be young, multiparous, unemployed and unmarried. They were more likely to deliver by spontaneous vaginal delivery to preterm, low birth weight infants and were at greater risk of a stillbirth and neonatal death. Unbooked pregnancies account for a small proportion of our antenatal population. However, perinatal outcome is significantly worse in unbooked patients compared to those who are regular antenatal attenders.

Adult↗
PubMed2001

Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease.

Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including beta-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5'-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5' flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK ( P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.

Age of Onset↗
PubMed2001

Examining for association between candidate gene polymorphisms in the dopamine pathway and attention-deficit hyperactivity disorder: a family-based study.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable childhood-onset psychiatric condition characterized by developmentally inappropriate inattention, hyperactivity, and impulsiveness. The pathophysiology of ADHD is currently unknown. However, the therapeutic effects of stimulant medication together with findings from animal and neuroimaging studies as well as from several molecular genetic studies of the dopamine receptor D4 gene and dopamine transporter gene have implicated involvement of the dopaminergic system. To test the dopaminergic hypothesis further, we have looked for association between ADHD and alleles of seven dopamine-related candidate genes using a family-based association approach in a sample of 150 children diagnosed with ADHD. We tested polymorphisms in genes encoding three dopamine receptors (DRD3, DRD4, and DRD5) and four dopamine-relevant enzymes: tyrosine hydroxylase [tyrosine hydroxylase (TH)], dopamine beta hydroxylase (DbetaH), catechol-O-methyltransferase (COMT), and monoamine oxidase A (MAOA). We were unable to detect a significant association with any of the polymorphisms genotyped, although there was a trend for preferential transmission of the DRD5 148 bp marker allele and the MAOA 122 bp marker allele. We conclude that none of the alleles we have tested makes a major contribution to ADHD, although much larger samples are required to exclude small effects.

Adolescent↗
PubMed2001

Expression profile of human herpesvirus 8 (HHV-8) in pyothorax associated lymphoma and in effusion lymphoma.

AIMS: Pyothorax associated lymphoma (PAL) occurs in a clinical setting of longstanding pyothorax or chronic inflammation of the pleura. Like primary effusion lymphoma, it has an association with Epstein-Barr virus (EBV), and is confined to the pleural cavity, but has differing morphological and phenotypic features. Human herpesvirus 8 (HHV-8) has been consistently reported in primary effusion lymphoma. This study examines the immunophenotype of two European cases of PAL, investigates the presence of HHV-8 and its expression profile, and assesses whether PAL is similar to other effusion lymphomas. METHODS: Material was obtained from two European cases of PAL. Immunocytochemical analysis was performed using antibodies against CD45, CD20, CD79a, CD45RAA, CD3, CD43, CD45RO (UCHL1), CD30, BCL-2, CD68, epithelial membrane antigen (EMA), BCL-6, p53, Ki-67, kappa light chain, lambda light chain, and the EBV antigens latent membrane protein 1 (LMP-1) and EBV encoded nuclear antigen 2 (EBNA-2). The cases were examined for HHV-8 by means of polymerase chain reaction in situ hybridisation (PCR-ISH), solution phase PCR, in situ hybridisation (ISH), and real time quantitative TaqMan PCR to HHV-8 open reading frame 26 (ORF-26) and viral (v) cyclin encoding regions. The expression profile of HHV-8 in PAL and in BC-1 and BC-3 cells was assessed by RNA TaqMan PCR to the HHV-8 genes encoding v-cyclin, v-IL-6, and G protein coupled receptor (GPCR). RESULTS: Both cases expressed CD24, CD20, CD79a, BCL-2, light chain restriction, and high Ki-67 staining. EBV was identified by EBER-ISH in one case. HHV-8 was not identified by solution phase PCR, but was detected by PCR-ISH (sensitivity of 1 viral genome copy/cell) in 35% of the cells and by TaqMan PCR, which showed 50-100 HHV-8 copies/2,000 cell genome equivalents (sensitivity of 1 viral genome in 10(6) contaminating sequences). HHV-8 v-IL-6, v-cyclin, and GPCR encoded transcripts were identified using RNA TaqMan PCR. v-IL-6 was high in PAL and in BC-1 and BC-3 cells. CONCLUSION: The presence of HHV-8 in one of two patients with PAL raises interesting questions in relation to the pathobiology of the condition. Clearly, the results indicate that HHV-8 is not an obligate pathogen, necessary for the effusion phenotype, but might contribute to it by its secretion of specific cytokines.

Aged↗
PubMed2000

Mouse lymphoma thymidine kinase locus gene mutation assay: International Workshop on Genotoxicity Test Procedures Workgroup Report.

The Mouse Lymphoma Assay (MLA) Workgroup addressed and reached consensus on a number of issues. Discussion focused on five areas: (1) acceptable assay versions; (2) cytotoxicity measure; (3) 24-hr treatment; (4) microwell colony counting and sizing; and (5) data acceptability/statistical analysis. Although the International Conference on Harmonisation (ICH) indicated a preference for the microwell over the soft agar method, all of the workgroup members agreed that both versions of the MLA are equally acceptable. The workgroup agreed that it is desirable for both assay versions to use the same measure of cytotoxicity to define the acceptable and required concentration range. Currently, laboratories using the microwell version use the relative survival (RS) determined by cloning immediately after the treatment. Laboratories using the soft agar method do not obtain an RS but use the relative total growth (RTG), a combination of the relative suspension growth (RSG) during the expression period and the relative cloning efficiency determined at the time of mutant selection. The workgroup agreed to investigate the RSG, the RS, and the RTG and to develop further guidance. In the interim, the workgroup reached consensus that the RTG be used as the standard measure of cytotoxicity. The ICH recommended a 24-hr treatment in the absence of S9 when negative results are obtained with short (3-4 hr) treatments. The workgroup agreed to retain this requirement but acknowledged that more data are needed prior to making final recommendations concerning the need for and the specific protocol for the 24-hr treatment. Environ. Mol. Mutagen. 35:185-190, 2000 Published 2000 Wiley-Liss, Inc.

Animals↗