Biomedical subjects

M Reilly

Publications and source records attributed to M Reilly.

At least 19 recordsLinked to original sources

PubMed2006

Estimation of genetic and environmental factors for melanoma onset using population-based family data.

Estimation of genetic and environmental contributions to cancers falls in the framework of generalized linear mixed modelling with several random effect components. Computational challenges remain, however, in dealing with binary or survival phenotypes. In this paper, we consider the analysis of melanoma onset in a population of 2.6 million nuclear families in Sweden, for which none of the current survival-based methodologies is feasible. We treat the disease outcome as a binary phenotype, so that the standard proportional hazard model leads to a generalized linear model with the complementary-log link function. For rare diseases this link is very close to the probit link, and thus allows the use of marginal likelihood for the estimation of the variance components. We correct for the survival length bias by censoring the parent generation within each family at the time they attain the same cumulative hazard as the child generation, thus improving the validity of the estimates. Our finding that childhood shared environment in addition to genetic factors had a considerable effect on the development of melanoma is consistent with epidemiological studies.

Adolescent↗

PubMed2006

A population-based binational register for monitoring long-term outcome and possible disease concordance among blood donors and recipients.

BACKGROUND AND OBJECTIVES: Even with appropriate donor deferrals and advanced screening tests, the risk of disease transmission through blood transfusion cannot be completely disregarded. Efficient monitoring of possible disease transmission between blood donors and recipients should be an important component of a comprehensive haemovigilance system. MATERIALS AND METHODS: We assembled the Scandinavian Donations and Transfusions (SCANDAT) database, with data on virtually all blood donors and recipients who have been registered at least once in any of the computerized local blood bank databases in Sweden and Denmark since the start of computerized registration in 1966. The records of these individuals, with their entire computerized donation and/or transfusion histories and all donor-component-recipient connections, were linked to nationwide population and health registers to attain essentially complete follow-up for up to 36 years regarding reproduction, hospital morbidity, cancer, and death. RESULTS: After data cleaning, the database contained 1,134,290 blood donors who contributed 15,091,280 records of donations and 1,311,079 recipients who received 11,693,844 transfusions. The data quality in the existing data sources was satisfactory. From the data obtained from local blood banks, 4.6%, 1.6%, and 6.4% of the person, donation, and transfusion records, respectively, had to be discarded after review of the legitimacy of recorded values, and comparisons with independent, external databases. CONCLUSION: It is possible to use existing computerized data, collected in routine health care, in haemovigilance systems for monitoring long-term outcome and disease concordance in blood donors and transfusion recipients.

Blood Donors↗

PubMed2005

Reliability and validity of the CMT neuropathy score as a measure of disability.

OBJECTIVE: To determine the validity and reliability of the Charcot-Marie-Tooth disease (CMT) neuropathy score (CMTNS) in patients with inherited neuropathy. BACKGROUND: Natural history studies and potential treatment trials for patients with various forms of CMT are limited by the lack of quantitative methodologies to monitor disease progression. Most cases of CMT can be considered length-dependent axonal neuropathies because disability for even the demyelinating forms correlates with length-dependent axonal degeneration. The total neuropathy score (TNS) is a validated composite measure of disability in length-dependent axonal neuropathies but is weighted toward predominantly sensory neuropathies. Thus, the authors have devised a CMTNS, modified from the TNS, to provide a single measure to quantify CMT disability. METHODS: The authors measured inter- and intrainvestigator reliability of the CMTNS and performed a validation of the score with the Neuropathy Impairment Score (NIS), patient self-assessment scores, an ambulation index, and other measures of disability. RESULTS: Inter- and intrainvestigator reliability was more than 95% in the 60 patients evaluated. Patients could be divided into mild (CMTNS, < or =10), moderate (CMTNS, 11 to 20), and severe (CMTNS, > or =21) categories and demonstrated excellent correlations among all measures of disability. CONCLUSION: The Charcot-Marie-Tooth disease (CMT) neuropathy score is a validated measure of length-dependent axonal and demyelinating CMT disability and can be investigated as an end point for longitudinal studies and clinical trials of CMT.

Action Potentials↗

PubMed2005

Mixed modelling to characterize genotype-phenotype associations.

We propose using mixed effects models to characterize the association between multiple gene polymorphisms, environmental factors and measures of disease progression. Characterizing high-order gene-gene and gene-environment interactions presents an analytic challenge due to the large number of candidate genes and the complex, undescribed interactions among them. Several approaches have been proposed recently to reduce the number of candidate genes and post hoc approaches to identify gene-gene interactions are described. However, these approaches may be inadequate for identifying high-order interactions in the absence of main effects and generally do not permit us to control for potential confounders. We describe how mixed effects models and related testing procedures overcome these limitations and apply this approach to data from a cohort of subjects at risk for cardiovascular disease. Four (4) genetic polymorphisms in three genes of the same gene family are considered. The proposed modelling approach allows us first to test whether there is a significant genetic contribution to the variability observed in our disease outcome. This contribution may be through main effects of multi-locus genotypes or through an interaction between genotype and environmental factors. This approach also enables us to identify specific multi-locus genotypes that interact with environmental factors in predicting the outcome. Mixed effects models provide a flexible statistical framework for controlling for potential confounders and identifying interactions among multiple genes and environmental factors that explain the variability in measures of disease progression.

Adult↗

PubMed2005

Helicobacter pylori status in family members as risk factors for infection in children.

This study aimed to disentangle the independent contributions of Helicobacter pylori infections in mothers, fathers and siblings to the risk for the infection in the 11-13 years age group. Index children from a cross-sectional Stockholm school survey and their family members completed questionnaires and contributed blood samples. H. pylori serostatus was determined with an enzyme-linked immunosorbent assay and immunoblot. Fifty-four seropositive and 108 seronegative index children were included and 480 out of 548 family members contributed blood. In multivariate logistic regression modelling, having an infected mother (OR 11.6, 95% CI 2.0-67.9) or at least one infected sibling (OR 8.1, 95% CI 1.8-37.3) were risk factors for index child infection, whilst the influence of infected fathers was non-significant. Birth in high-prevalence countries was an independent risk factor (OR 10.4, 95% CI 3.4-31.3). H. pylori infections in mothers and siblings and birth in high-prevalence countries stand out as strong markers of infection risk amongst children in Sweden.

Adult↗

PubMed2004

Estimation of genetic and environmental factors for binary traits using family data.

While the family-based analysis of genetic and environmental contributions to continuous or Gaussian traits is now straightforward using the linear mixed models approach, the corresponding analysis of complex binary traits is still rather limited. In the latter we usually rely on twin studies or pairs of relatives, but these studies often have limited sample size or have difficulties in dealing with the dependence between the pairs. Direct analysis of extended family data can potentially overcome these limitations. In this paper, we will describe various genetic models that can be analysed using an extended family structure. We use the generalized linear mixed model to deal with the family structure and likelihood-based methodology for parameter inference. The method is completely general, accommodating arbitrary family structures and incomplete data. We illustrate the methodology in great detail using the Swedish birth registry data on pre-eclampsia, a hypertensive condition induced by pregnancy. The statistical challenges include the specification of sensible models that contain a relatively large number of variance components compared to standard mixed models. In our illustration the models will account for maternal or foetal genetic effects, environmental effects, or a combination of these and we show how these effects can be readily estimated using family data.

Cluster Analysis↗

PubMed2004

Ultrasound dating at 12-14 or 15-20 weeks of gestation? A prospective cross-validation of established dating formulae in a population of in-vitro fertilized pregnancies randomized to early or late dating scan.

OBJECTIVES: To determine the accuracy of established ultrasound dating formulae when used at 12-14 and 15-20 gestational weeks. METHODS: A total of 363 singleton pregnancies conceived after in-vitro fertilization (IVF) and randomized to a dating scan at 12-14 or 15-20 gestational weeks were studied. 'True' gestational age was calculated on the basis of the day of oocyte retrieval and was compared to gestational age calculated on the basis of seven dating formulae including the fetal biparietal diameter (BPD) and three dating formulae including BPD and fetal femur length (FL). The mean of the differences between estimated and true gestational age (systematic measurement error) and their SD (random measurement error) were calculated for each formula. RESULTS: Three formulae showed systematic errors of less than -0.7 days at both early and late scanning. Two formulae overestimated gestational age at both early and late scanning by 5.7 and 3.1 vs. 2.3 and 2.8 days, respectively, while five formulae manifested very different systematic errors at early and late scanning. The formulae used for clinical management underestimated gestational age by a mean of 3 days when dating was performed at 12-14 weeks, and by a mean of 0.8 days when dating was done at 15-20 weeks. The random error was on average 1 day less when the scan was carried out early (2 vs. 3 days; P < 0.0005). Mean true gestational age at delivery in IVF pregnancies with spontaneous start of labor was 279 days (SD 12.9); excluding preterm deliveries it was 281 days (SD 8.1). CONCLUSIONS: Ultrasound dating formulae originally intended for use in the middle of the second trimester do not necessarily perform well when used for dating earlier in gestation. The systematic and random error of any dating formula must be assessed for the gestational age interval in which the formula is intended to be used.

Chi-Square Distribution↗

PubMed2004

MDR and PRP: a comparison of methods for high-order genotype-phenotype associations.

Complex diseases such as cardiovascular disease are likely due to the effects of high-order interactions among multiple genes and demographic factors. Therefore, in order to understand their underlying biological mechanisms, we need to consider simultaneously the effects of genotypes across multiple loci. Statistical methods such as multifactor dimensionality reduction (MDR), the combinatorial partitioning method (CPM), recursive partitioning (RP), and patterning and recursive partitioning (PRP) are designed to uncover complex relationships without relying on a specific model for the interaction, and are therefore well-suited to this data setting. However, the theoretical overlap among these methods and their relative merits have not been well characterized. In this paper we demonstrate mathematically that MDR is a special case of RP in which (1) patterns are used as predictors (PRP), (2) tree growth is restricted to a single split, and (3) misclassification error is used as the measure of impurity. Both approaches are applied to a case-control study assessing the effect of eleven single nucleotide polymorphisms on coronary artery calcification in people at risk for cardiovascular disease.

Cardiovascular Diseases↗

PubMed2002

Peripheral blood stem cell transplantation for POEMS syndrome.

In common with other plasma cell dyscrasias in which a small tumour burden is associated with severe clinical symptoms (notably systemic AL amyloidosis) the possible benefits of dose intensification are yet to be fully explored in POEMS syndrome. One important issue is whether the toxicity of the procedure is significantly increased in this group. We report two cases of POEMS syndrome with solitary asymptomatic bone lesions treated with high-dose melphalan (200 mg/m(2)) and peripheral blood stem cell (PBSC) rescue. In both cases there was minimal peri-transplant morbidity and a subsequent substantial and maintained improvement in the peripheral neuropathy.

Adult↗

PubMed2001

Morbidity and mortality in breastfed and formula-fed infants of HIV-1-infected women: A randomized clinical trial.

CONTEXT: Breastfeeding among women infected with human immunodeficiency virus type 1 (HIV-1) is associated with substantial risk of HIV-1 transmission, but little is known about the morbidity risks associated with formula feeding in infants of HIV-1-infected women in resource-poor settings. OBJECTIVE: To compare morbidity, nutritional status, mortality adjusted for HIV-1 status, and cause of death among formula-fed and breastfed infants of HIV-1-infected women. DESIGN: Randomized clinical trial conducted between 1992 and 1998. SETTING: Four antenatal clinics in Nairobi, Kenya. PARTICIPANTS: Of 401 live-born, singleton, or first-born twin infants of randomized HIV-1-seropositive mothers, 371 were included in the analysis of morbidity and mortality. INTERVENTIONS: Mothers were randomly assigned either to use formula (n = 186) or to breastfeed (n = 185) their infants. MAIN OUTCOME MEASURES: Mortality rates, adjusted for HIV-1 infection status; morbidity; and nutritional status during the first 2 years of life. RESULTS: Two-year estimated mortality rates among infants were similar in the formula-feeding and breastfeeding arms (20.0% vs 24.4%; hazard ratio [HR], 0.8; 95% confidence interval [CI], 0.5-1.3), even after adjusting for HIV-1 infection status (HR, 1.1; 95% CI, 0.7-1.7). Infection with HIV-1 was associated with a 9.0-fold increased mortality risk (95% CI, 5.3-15.3). The incidence of diarrhea during the 2 years of follow-up was similar in formula and breastfeeding arms (155 vs 149 per 100 person-years, respectively). The incidence of pneumonia was identical in the 2 groups (62 per 100 person-years), and there were no significant differences in incidence of other recorded illnesses. Infants in the breastfeeding arm tended to have better nutritional status, significantly so during the first 6 months of life. CONCLUSIONS: In this randomized clinical trial, infants assigned to be formula fed or breastfed had similar mortality rates and incidence of diarrhea and pneumonia during the first 2 years of life. However, HIV-1-free survival at 2 years was significantly higher in the formula arm. With appropriate education and access to clean water, formula feeding can be a safe alternative to breastfeeding for infants of HIV-1-infected mothers in a resource-poor setting.

Adult↗

PubMed2001

Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14.

Distal hereditary motor neuronopathy type VII (dHMN-VII) is an autosomal dominant disorder characterized by distal muscular atrophy and vocal cord paralysis. We performed a genomewide linkage search in a large Welsh pedigree with dHMN-VII and established linkage to chromosome 2q14. Analyses of a second family with dHMN-VII confirmed the location of the gene and provided evidence for a founder mutation segregating in both pedigrees. The maximum three-point LOD score in the combined pedigree was 7.49 at D2S274. Expansion of a polyalanine tract in Engrailed-1, a transcription factor strongly expressed in the spinal cord, was excluded as the cause of dHMN-VII.

Chromosome Mapping↗

PubMed2001

The effect of treatment of vaginal infections on shedding of human immunodeficiency virus type 1.

To assess the effect of treatment of vaginal infections on vaginal shedding of cell-free human immunodeficiency virus type 1 (HIV-1) and HIV-1-infected cells, HIV-1-seropositive women were examined before and after treatment of Candida vulvovaginitis, Trichomonas vaginitis, and bacterial vaginosis. For Candida (n=98), vaginal HIV-1 RNA decreased from 3.36 to 2.86 log(10) copies/swab (P<.001), as did the prevalence of HIV-1 DNA (36% to 17%; odds ratio [OR], 2.8; 95% confidence interval [CI], 1.3-6.5). For Trichomonas vaginitis (n=55), HIV-1 RNA decreased from 3.67 to 3.05 log(10) copies/swab (P<.001), but the prevalence of HIV-1 DNA remained unchanged (22%-25%; OR, 0.8; 95% CI, 0.3-2.2). For bacterial vaginosis (n=73), neither the shedding of HIV-1 RNA (from 3.11 to 2.90 log(10) copies/swab; P=.14) nor the prevalence of DNA (from 21% to 23%; OR, 0.8; 95% CI, 0.3-2.0) changed. Vaginal HIV-1 decreased 3.2- and 4.2-fold after treating Candida and Trichomonas, respectively. These data suggest that HIV-1 transmission intervention strategies that incorporate diagnosis and treatment of these prevalent infections warrant evaluation.

Adult↗

PubMed2001

Outer membrane protein-specific monoclonal antibodies protect SCID mice from fatal infection by the obligate intracellular bacterial pathogen Ehrlichia chaffeensis.

Previous studies of Ehrlichia chaffeensis infection in the mouse have demonstrated that passive transfer of polyclonal Abs from resistant immunocompetent mice to susceptible SCID mice ameliorated infection and disease, even when Abs were administered during established infection. To identify particular Abs that could mediate bacterial clearance in vivo, E. chaffeensis-specific mAbs were generated and administered to infected SCID mice. Bacterial infection in the livers was significantly lowered after administration of either of two Abs of different isotypes (IgG2a and IgG3). Moreover, repeated administration of one Ab (Ec56.5; IgG2a) rescued mice from an otherwise lethal infection for at least 5 wk. Both protective Abs recognized the E. chaffeensis major outer membrane protein (OMP)-1g. Further studies revealed that both Abs recognized closely related epitopes within the amino terminus of the first hypervariable region of OMP-1g. Analyses of human sera showed that E. chaffeensis-infected patients also generated serological responses to OMP-1g hypervariable region 1, indicating that humans and mice recognize identical or closely related epitopes. These studies demonstrate that OMP-specific mAbs can mediate bacterial elimination in SCID mice, and indicate that Abs, in the absence of cell-mediated immunity, can play a significant role in host defense during infection by this obligate intracellular bacterium.

Amino Acid Sequence↗

PubMed2001

Hepatocyte growth factor is secreted by osteoblasts and cooperatively permits the survival of haematopoietic progenitors.

Human osteoblasts (HOBs) support the growth of human haematopoietic progenitor cells, and support the survival and limited expansion of long-term culture-initiating cells. Using human CD34+ cells and the murine myelomonocytic cell line NFS-60 as targets, we previously found that one component of HOB-derived haematopoietic activity is cell-associated granulocyte colony-stimulating factor (G-CSF). However, antibody failed to neutralize all the activity, suggesting that more than one factor supports haematopoietic cells. In the present investigations, we asked whether the HOB-derived, non-G-CSF secreted activity was as a result of other known growth factors. We found that, among the cytokines expressed by HOBs, only hepatocyte growth factor (HGF) and G-CSF stimulated NFS-60 cell proliferation. HOB cells and osteosarcoma cells secreted biologically active HGF, although the levels varied considerably. Moreover, addition of neutralizing HGF antibody to CD34+ cell/HOB co-cultures resulted in a significant reduction ( approximately 50%) in the ability of the HOBs to support haematopoietic progenitor cells. These results suggest that a major component of osteoblast-derived haematopoietic activity is HGF. Secretion of HGF, in concert with cell-associated cytokines such as G-CSF, may account for the stem cell-stimulating activities of osteogenic cells and, thereby, the unique stem cell-supporting role of the osteoblasts within the bone marrow microenvironment.

Antibodies, Monoclonal↗

PubMed2001

A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V.

A boy with recurrent pyrexial episodes from early life sustained a painless ankle injury and was found to have a calcaneus fracture and, later, neuropathic joint degeneration of the tarsus. Examination revealed distal loss of pain and temperature sensation and widespread anhidrosis. Sural nerve biopsy demonstrated severe reduction in small-caliber myelinated fiber density but only modest reduction in unmyelinated axons, the pattern of type V hereditary sensory and autonomic neuropathy (HSAN V). DNA analysis showed that he was homozygous for a mutation in the NTRK1/high-affinity nerve growth factor (TrkA) gene, his parents being heterozygous. Mutations in this gene are known to be responsible for HSAN IV (congenital insensitivity to pain with anhidrosis). The two disorders are therefore likely to be allelic.

Biopsy↗

PubMed2001

Effects of coexpression of the LDL receptor and apoE on cholesterol metabolism and atherosclerosis in LDL receptor-deficient mice.

The low density lipoprotein receptor (LDLR) plays a major role in regulation of plasma cholesterol levels as a ligand for apolipoprotein B-100 and apolipoprotein E (apoE). Consequently, LDLR-deficient mice fed a Western-type diet develop significant hypercholesterolemia and atherosclerosis. ApoE not only mediates uptake of atherogenic lipoproteins via the LDLR and other cell-surface receptors, but also directly inhibits atherosclerosis. In this study, we examined the hypothesis that coexpression of the LDLR and apoE would have greater effects than either one alone on plasma cholesterol levels and the development of atherosclerosis in LDLR-deficient mice. LDLR-deficient mice fed a Western-type diet for 10 weeks were injected with recombinant adenoviral vectors encoding the genes for human LDLR, human apoE3, both LDLR and apoE3, or lacZ (control). Plasma lipids were analyzed at several time points after vector injection. Six weeks after injection, mice were analyzed for extent of atherosclerosis by two independent methods. As expected, LDLR expression alone induced a significant reduction in plasma cholesterol due to reduced VLDL and LDL cholesterol levels, whereas overexpression of apoE alone did not reduce plasma cholesterol levels. When the LDLR and apoE were coexpressed in this model, the effects on plasma cholesterol levels were no greater than with expression of the LDLR alone. However, coexpression did result in a substantial increase in large apoE-rich HDL particles. In addition, although the combination of cholesterol reduction and apoE expression significantly reduced atherosclerosis, its effects were no greater than with expression of the LDLR or apoE alone. In summary, in this LDLR-deficient mouse model fed a Western-type diet, there was no evidence of an additive effect of expression of the LDLR and apoE on cholesterol reduction or atherosclerosis.

Animals↗

PubMed2000

Pharmacology of the receptors for the phorbol ester tumor promoters: multiple receptors with different biochemical properties.

The phorbol ester tumor promoters and related analogs are widely used as potent activators of protein kinase C (PKC). The phorbol esters mimic the action of the lipid second messenger diacylglycerol (DAG). The aim of this commentary is to highlight a series of important and controversial concepts in the pharmacology and regulation of phorbol ester receptors. First, phorbol ester analogs have marked differences in their biological properties. This may be related to a differential regulation of PKC isozymes by distinct analogs. Moreover, it seems that marked differences exist in the ligand recognition properties of the C1 domains, the phorbol ester/DAG binding sites in PKC isozymes. Second, an emerging theme that we discuss here is that phorbol esters also target receptors unrelated to PKC isozymes, a concept that has been largely ignored. These novel receptors lacking kinase activity include chimaerins (a family of Rac-GTPase-activating proteins), RasGRP (a Ras exchange factor), and Unc-13/Munc-13 (a family of proteins involved in exocytosis). Unlike the classical and novel PKCs, these "non-kinase" phorbol ester receptors possess a single copy of the C1 domain. Interestingly, each receptor class has unique pharmacological properties and biochemical regulation. Lastly, it is well established that phorbol esters and related analogs can translocate each receptor to different intracellular compartments. The differential pharmacological properties of the phorbol ester receptors can be exploited to generate specific agonists and antagonists that will be helpful tools to dissect their cellular function.

Animals↗

PubMed2000

Comparison of patient self-reports and urinalysis results obtained under naturalistic methadone treatment conditions.

This study examined under naturalistic assessment conditions the validity of self-reported opiate and cocaine use among 175 veterans enrolled in methadone treatment, and factors related to self-report validity, such as stage in treatment and drug of abuse. Veterans were interviewed by clinical staff about past 30-day drug use with the addiction severity index (ASI), and urinalysis results were obtained for the same 30-day interval assessed with the ASI. Analysis revealed that urinalysis generally produced higher rates of substance use than patient self-report, and with the exception of reported opiate use among new patients presenting for treatment, validity of patient self-reported drug use generally was poor with patients under-reporting both opiate and cocaine use. The findings are in marked contrast to those obtained in other studies in which participants are ensured confidentiality regarding their self-reports. Further, the results raise questions about the utility of self-report measures of substance use to assess patient progress or methadone program performance.

Adult↗