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M Reilly

Publications and source records attributed to M Reilly.

At least 55 records · Page 3Linked to original sources
PubMed1996

Multigeneration maternal transmission in Italian families with neural tube defects.

Periconceptional vitamin supplementation with folate prevents about three-quarters of expected cases of neural tube defects (NTDs) in clinical trials. However, vitamin action may be regulated at the level of the gene, and individual susceptibility to environmental agents, including dietary components, also may be under genetic control. We investigated the presence of familial factors in a retrospective case control study of neural tube defects in Genoa, Italy. Cases included all patients treated at a single pediatric neurosurgical service. Controls matched on age and sex came from the same hospital. We found strong evidence for the contribution of genetic factors in this study. There was an excess risk of 14 for the occurrence of NTDs in first-degree relatives compared to controls (P < .0005). There was no difference in sex ratio in any group of relatives, but maternal grandparents of children with a high spinal lesion had 14% fewer off-spring than paternal grandparents (P < .005), possibly because of excess miscarriages. Our study is the first to show complex patterns of inheritance in spina bifida families affecting three generation in one clinical subgroup and preferentially on the mother's side. These results support a role for genomic imprinting and highlight the value of multidisciplinary epidemiologic and clinical studies that include multiple generations. New studies incorporating dietary and genetic approaches will help clarify and extend these findings.

Adolescent↗
PubMed1996

Modulation of oxidant stress in vivo in chronic cigarette smokers.

BACKGROUND: Free radical-induced oxidative damage is thought to be involved in the pathogenesis of diseases associated with cigarette smoking. We examined the production of 8-epi-prostaglandin (PG) F2 alpha, a stable product of lipid peroxidation in vivo, and its modulation by aspirin and antioxidant vitamins in chronic cigarette smokers. METHODS AND RESULTS: We performed the following studies: (1) a cross-sectional comparison of smokers and control subjects, (2) an examination of the dose-response relationship, (3) an exploration of the effect of smoking cessation (3 weeks) and nicotine patch supplementation, (4) the effect of aspirin consumption, and (5) the effects of 5 days' dosing with vitamin E (100 and 800 U), vitamin C (2 g), and their combination. 8-epi-PGF2 alpha excretion (in pmol/mmol, mean +/- SEM) was 176.5+/-30.6 in heavy smokers, 92.7+/-4.8 (P<.05) in moderate smokers, and 54.1+/-2.7 (P<.005) in nonsmokers. Urinary levels fell from 145.5+/-24.9 to 114.6+/-27.1 (week 2, P<.05) and 112.6+/-24.9 (week 3, P<.05) on cessation of smoking. Aspirin treatment failed to suppress urinary levels of 8-epi-PGF2 alpha despite a significant reduction in urinary 11-dehydro-TxB2 production and suppression of 8-epi-PGF2 alpha and TxB2 in serum. Vitamin C (pre, 194.6+/-40.9; post, 137.2+/-34.1; P<.05) and a combination of vitamin C and E (pre, 171.0+/-39.8; post, 133.5+/-29.6 P<.05) suppressed urinary 8-epi-PGF2 alpha, whereas vitamin E alone had no effect. CONCLUSIONS: Urinary 8-epi-PGF2 alpha may represent a noninvasive, quantitative index of oxidant stress in vivo. Elevated levels of 8-epi-PGF2 alpha in smokers may be modulated by quitting cigarettes and switching to nicotine patches or by antioxidant vitamin therapy.

Administration, Cutaneous↗
PubMed1996

Optimal sampling strategies for two-stage studies.

The optimal allocation of available resources is the concern of every investigator in choosing a study design. The recent development of statistical methods for the analysis of two-stage data makes these study designs attractive for their economy and efficiency. However, little work has been done on deriving two-stage designs that are optimal under the kinds of constraints encountered in practice. The methods presented in this paper provide a means of deriving designs that will maximize precision for a fixed total budget or minimize the study cost necessary to achieve a desired precision. These optimal designs depend on the relative information content and the relative cost of gathering the first- and second-stage data. In place of the usual sample size calculations, the investigator can use pilot data to estimate the study size and second-stage sampling fractions. The gains in efficiency that can result from such carefully designed studies are illustrated here by deriving and implementing optimal designs using data from the Coronary Artery Surgery Study.

Aged↗
PubMed1996

8-Epi PGF2 alpha: specific analysis of an isoeicosanoid as an index of oxidant stress in vivo.

1. Excessive free radical generation is thought to contribute to tissue injury in a broad spectrum of diseases. A particular constraint in addressing this hypothesis has been the inability to assess free radical generation in vivo and the lack of information on drugs or vitamins which act as effective antioxidants in vivo. 2. Traditional approaches have relied upon measures of substrate oxidizability or spin trapping of free radical adducts ex vivo. It is unknown how these measurements might relate, in a quantitative fashion, to the generation of reactive oxygen species in vivo. Isoeicosanoids are free radical catalyzed products of arachidonic acid. One of these compounds, 8-epi prostaglandin F2 alpha (8-epi PGF2 alpha) exhibits biological activity and may function as an autacoid. Specific analysis of this 8-epi PGF2 alpha isomer indicates that it is elevated in certain syndromes thought to be associated with oxidant stress. These include vascular reperfusion, paracetamol poisoning and liver cirrhosis. Apparently healthy individuals who smoke cigarettes or consume alcohol exhibit dose dependent increments in excretion of 8-epi PGF2 alpha. Excretion is depressed by antioxidant vitamins, although not by the nonspecific cyclooxygenase (COX) inhibitor, aspirin, even though 8-epi PGF2 alpha may be formed by either COX-1 or COX-2. 3. Specific analysis of this and other isoeicosanoids may afford an opportunity to evaluate the effects of antioxidant interventions in human diseases characterized by excessive lipid peroxidation in vivo.

Animals↗
PubMed1996

Changes in the amplitude of the nasal cycle associated with symptoms of acute upper respiratory tract infection.

Nasal airflow is normally asymmetrical and subject to spontaneous reciprocal changes which are often referred to as the 'nasal cycle'. The nature of these spontaneous changes in nasal resistance is poorly understood and little information is available about how they are affected by nasal disease. In order to understand the changes in nasal resistance in health and disease it is important to record unilateral resistance rather than express results as total nasal resistance. Unilateral resistance is subject to continuous reciprocal changes and therefore new measurements were developed in this study in order to quantify the nasal resistance of each nasal passage. Twelve human subjects (age 19-38) with symptoms of acute respiratory tract infection (URTI) were recruited for the study which involved serial measurements of unilateral nasal airway resistance using the technique of posterior rhinomanometry over a period of six hours. Measurements were made on one day when subjects had symptoms of URTI and then repeated 6-8 weeks later when subjects were healthy. The results of this study show that all of the subjects exhibited spontaneous reciprocal changes in nasal airway resistance on both study days but that there was a significant increase in the amplitude of the changes in resistance when the subjects had symptoms of URTI with one nasal passage often becoming severely congested. In order to quantify the amplitude of the reciprocal changes in nasal resistance two new measures were used. The minimum and maximum nasal airway resistance recorded for each nasal passage during the six hour recording period (MIN NAR and MAX NAR). Mean MIN NAR with URTI was 0.4 Pa cm3s +/- 0.07 which was not significantly different from mean MIN NAR in health which was 0.36 Pa cm3s +/- 0.05 (p = 0.22, n = 20). The mean MAX NAR during URTI was 2.44 Pa cm3s +/- 0.38 and this decreased significantly to 1.36 +/- 0.17 when recorded during healthy conditions (p = 0.01, n = 20). The increased amplitude of spontaneous reciprocal changes in nasal airway resistance associated with symptoms of URTI is proposed to be due to an increased filling pressure to the nasal venous sinusoids associated with a nasal inflammatory response. A model is proposed to explain the role of the nasal sympathetic vasoconstrictor tone and nasal venous filling pressure in the control of nasal airway resistance and to help explain the periods of unilateral nasal obstruction often associated with allergic and infective rhinitis.

Acute Disease↗
PubMed1995

Expression of SPARC during development of the chicken chorioallantoic membrane: evidence for regulated proteolysis in vivo.

SPARC is a secreted glycoprotein that has been shown to disrupt focal adhesions and to regulate the proliferation of endothelial cells in vitro. Moreover, peptides resulting from the proteolysis of SPARC exhibit angiogenic activity. Here we describe the temporal synthesis, turnover, and angiogenic potential of SPARC in the chicken chorioallantoic membrane. Confocal immunofluorescence microscopy revealed specific expression of SPARC protein in endothelial cells, and significantly higher levels of SPARC were observed in smaller newly formed blood vessels in comparison to larger, developmentally older vessels. SPARC mRNA was detected at the earliest stages of chorioallantoic membrane morphogenesis and reached maximal levels at day 13 of embryonic development. Interestingly, steady-state levels of SPARC mRNA did not correlate directly with protein accumulation; moreover, the protein appeared to undergo limited degradation during days 10-15. Incubation of [125I]-SPARC with chorioallantoic membranes of different developmental ages confirmed that extracellular proteolysis occurred during days 9-15, but not at later stages (e.g., days 17-21). Comparison of peptides produced by incubation with chorioallantoic membranes with those generated by plasmin showed an identical pattern of proteolysis. Plasmin activity was present throughout development, and in situ zymography identified sites of plasminogen activator activity that corresponded to areas exhibiting high levels of SPARC expression. Synthetic peptides from a plasmin-sensitive region of SPARC, between amino acids 113-130, stimulated angiogenesis in the chorioallantoic membrane in a dose-dependent manner; in contrast, intact SPARC was inactive in similar assays. We have shown that SPARC is expressed in endothelial cells of newly formed blood vessels in a manner that is both temporally and spatially restricted. Between days 9 and 15 of chorioallantoic membrane development, the protein undergoes proteolytic cleavage that is mediated, in part, by plasmin. SPARC peptides released specifically by plasmin induce angiogenesis in vivo. We therefore propose that SPARC acts as an intrinsic regulator of angiogenesis in vivo.

Allantois↗
PubMed1995

Human immunodeficiency virus DNA in urethral secretions in men: association with gonococcal urethritis and CD4 cell depletion.

To evaluate the prevalence and correlates of human immunodeficiency virus (HIV)-infected cells in urethral secretions, samples were collected from 106 HIV-seropositive men with and without urethritis. HIV DNA was detected by polymerase chain reaction in 27% of 184 urethral specimens and was associated with CD4 cell depletion (P for trend, .03) and with urethritis (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.2-4.6) or gonorrhea (OR, 2.9; 95% CI, 1.5-5.8). Two multivariate models were constructed that included age, CD4 cell count < 200/mm3, and either urethritis or gonococcal infection. Detection of HIV-infected cells in urethral secretions was independently associated with < 200 CD4 cells/mm3 (OR, 2.2; 95% CI, 0.9-5.2; P = .05) and urethritis (OR, 2.7; 95% CI, 1.3-5.3; P = .003) in the first model and with gonococcal infection (OR, 3.2; 95% CI, 1.6-6.4; P < .001) in the second model. Successful treatment of gonococcal urethritis was associated with a 2-fold reduction in urethral HIV DNA (44% vs. 21%; P = .02). Thus, treatment of gonococcal urethritis may be an effective strategy for reducing HIV transmission.

Adult↗
PubMed1995

Participation of glomerular endothelial cells in the capillary repair of glomerulonephritis.

In many glomerular diseases severe injury to the mesangium may occur, leading to matrix dissolution and damage to the glomerular capillaries. Although the destruction of glomerular architecture may lead to permanent injury, in some cases spontaneous recovery occurs. The mechanisms that mediate this recovery are unknown. In this study we provide evidence for glomerular capillary repair (angiogenesis) in the adult injured glomerulus. Injection of anti-Thy 1 antibody into rats results in severe mesangiolysis with capillary ballooning, microaneurysm formation, and loss of endothelial cells in addition to mesangial cells. Although mesangial proliferation is a major response to injury, proliferation of endothelial cells also can be documented from days 2 to 14 in association with repair of the capillaries. The endothelial cell proliferation peaks on days 2 and 7, when it is seven- to ninefold greater than normal. Many of the endothelial cells display morphological features of angiogenesis. The initial wave of endothelial cell proliferation can be reduced by 40% with neutralizing anti-basic fibroblast growth factor antibodies (P < 0.001). The later glomerular endothelial cell proliferation is associated with upregulated expression of vascular permeability factor/endothelial cell growth factor (VPF/VEGF) and an increase of flk, a VPF/VEGF receptor. Although PDGF is expressed in this model, anti-PDGF antibody treatment did not affect the endothelial cell proliferative response. In summary, glomerular endothelial cells have an active role in the glomerular response to injury. Glomeruli are capable of healing microaneurysms, and the mechanism involves basic fibroblast growth factor- and VPF/VEGF-mediated endothelial proliferative responses.

Animals↗
PubMed1995

Formation of 8-iso-prostaglandin F2 alpha by human platelets.

F2-isoprostanes are free radical catalyzed prostaglandin F2 isomers formed from arachidonic acid in an enzyme independent manner (1). Analogous families of other prostaglandin isomers have also been described. Detection of these compounds in vivo has been postulated to represent an approach to the quantitative assessment of free radical generation in humans (2). Additionally, the 8-iso analogues of PGF2 alpha and PGE2 have been shown to induce vasoconstriction, a response which is prevented by pharmacological antagonists of the thromboxane receptor (3). Consequently, it is conceivable that these particular isomers might exhibit an autacoidal function. We chose to explore the factors which regulate the biosynthesis of one of these compounds, 8-iso-PGF2 alpha, in vivo and by human platelets in vitro, to understand more clearly how the discovery of these compounds might be exploited to further our understanding of free radical catalyzed processes in vivo.

Adult↗
PubMed1994

Inherited neuropathies.

Charcot-Marie-Tooth neuropathy (CMT) type 1 is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B), the X chromosome (CMTX), and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-Mb duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0) gene. The molecular defect in CMT1C is unknown. CMTX is associated with mutations in the connexin 32 gene. CMT2 is an axonal neuropathy of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A). Dejerine-Sottas disease is a severe, infantile-onset demyelinating polyneuropathy that may be associated with point mutations in either the PMP22 gene or the P0 gene. Hereditary neuropathy with liability to pressure palsies (HNPP) is a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and may result from reduced expression of the PMP22 gene. Most examples of CMT1A and HNPP are reciprocal duplication or deletion syndromes originating from unequal crossover during germ cell meiosis. Familial amyloid polyneuropathy (FAP) is an autosomal dominant disorder that classically presents with a sensory peripheral neuropathy and early autonomic involvement. Transthyretin (TTR) is the most common constituent amyloid fibril protein deposited in FAP, and there are now 28 point mutations in the TTR gene described in TTR-related FAP. Liver transplantation looks promising as a treatment for TTR-related FAP.

Amyloid Neuropathies↗
PubMed1994

Lipoprotein(a) in restenosis after percutaneous transluminal coronary angioplasty and coronary artery disease.

BACKGROUND: The purpose of the study was to investigate the relation of lipoprotein(a) and serum lipid parameters to restenosis after percutaneous transluminal coronary angioplasty (PTCA) and to assess the association of these same biochemical markers to coronary artery disease (CAD) in individuals with angiographically defined normal and diseased coronary arteries. METHODS AND RESULTS: Sixty-two patients with successful PTCA had follow-up angiography at 35 +/- 10 weeks. Restenosis occurred in 21 male patients (46%) and 6 female patients (38%). Elevated apolipoprotein B (P < .01) and decreased high-density lipoprotein-2 cholesterol (P < .02) were found to be independently associated with restenosis after angioplasty, whereas lipoprotein(a) was not. Eighty-five patients undergoing PTCA were compared with 46 subjects who had no evidence of CAD on angiography. Elevated lipoprotein(a) (P < .001) and reduced apolipoprotein A1 to B ratio (P < .001) were found to be strong independent risk factors for the presence of CAD when adjustment was made for age (P < .005), male sex (P < .01), smoking (P < .005), and hypertension (P = .06). CONCLUSIONS: Serum lipoprotein(a) levels are not associated with restenosis after PTCA, but elevated levels are strongly associated with CAD. Low-serum, high-density lipoprotein-2 cholesterol concentration and elevated apolipoprotein B concentration were found to be associated with restenosis after PTCA.

Angioplasty, Balloon, Coronary↗
PubMed1993

An epidemiological study of Wilson's disease in the Republic of Ireland.

In a population based study of the prevalence of Wilson's disease in the Republic of Ireland from 1970-89, 26 definite and probable cases were ascertained. The adjusted birth incidence rate was 17.0 per million live births (95% (confidence interval 9.9 to 27.2)) for the 20 year period 1950-69. The gene frequency was 0.41% (95% (confidence interval 0.31% to 0.52%) indicating that one in 122 of the population was a gene carrier. Allowing for a maximal degree of consanguinity, the gene frequency is reduced to 0.36% and the proportion of heterozygotes to one in 139 of the population. The consistency of the adjusted birth incidence rates over the decades 1950-59 and 1960-69 suggests a high degree of ascertainment of diagnosed cases of Wilson's disease.

Adolescent↗
PubMed1993

Transthyretin gene mutations in British and French patients with amyloid neuropathy.

Five patients, two British and three French, with late onset amyloid neuropathy were found to have mutations of the transthyretin (TTR) gene associated with the Portuguese and German types of familial amyloid polyneuropathy. Familial amyloid polyneuropathy is rare in the United Kingdom and has not previously been defined at a molecular genetic level. None of the patients had a history of affected antecedents; the role of TTR gene analysis in diagnosing known or suspected amyloid neuropathy, regardless of family history or ethnic background, is emphasised.

Aged↗
PubMed1993

Early detection of de novo hepatitis C infection in patients after liver transplantation by reverse transcriptase polymerase chain reaction.

BACKGROUND: Reverse transcriptase polymerase chain reaction (RT-PCR) can detect the viral genome and show hepatitis C recurrence in patients who undergo transplantation for chronic hepatitis C viral (HCV) infection. We investigated the utility of an RT-PCR-based HCV assay for early detection of viral RNA in de novo HCV infection after liver transplantation. METHODS: Pretransplantation antibodies and explanation HCV viral RNA status were obtained from 117 patients. Follow-up liver biopsy specimens were examined for evidence of hepatitis activity. Plasma samples during the period of time of the biopsy were assayed for HCV antibody and viral RNA. RNA was extracted from samples and reverse transcribed to cDNA. cDNA was amplified by PCR, and products were detected by liquid hybridization. RESULTS: Clinical hepatitis developed in seventeen of 117 patients who, before transplantation, were HCV antibody negative and explant viral RNA negative. Ten patients were plasma PCR negative and had known non-hepatitis C causes for the biopsy findings. Of the remaining seven patients, five (70%) were plasma RT-PCR positive before seroconversion in matched plasma samples. CONCLUSIONS: In liver transplant patients, the incidence of de novo clinical hepatitis is low, and HCV viral RNA in de novo clinical hepatitis C infection can be detected in the absence of HCV antibodies.

Base Sequence↗
PubMed1993

Cellular activation by thromboxane A2 and other eicosanoids.

Thromboxane A2 (TXA2), the major cyclooxygenase (COX) product of arachidonic acid (AA), activates platelets and is a potent vasoconstrictor. The functional importance of this eicosanoid has been demonstrated in syndromes of acute coronary ischaemia. The cellular response to this agonist is tightly regulated. The liberation of AA from membrane phospholipids is conventionally thought to be the rate limiting step in TXA2 biosynthesis. However, the discovery of a second, highly regulated COX gene (COX-2) and the demonstration of product-based inactivation of COX and thromboxane synthase suggest a more complex regulation of TXA2 formation. TXA2 signalling is mediated by a G-protein linked receptor (PGH2/TXA2 receptor) which activates phospholipase C (PLC). Pharmacological studies suggest two distinct binding sites on platelets, but receptor heterogeneity has yet to be documented at a molecular level. The PGH2/TXA2 receptors are linked via a pertussis and cholera toxin-insensitive G-protein which has not been fully characterized, but is thought to belong to the Gq class of G-proteins. The diversity of G-protein alpha subunits, and growing evidence suggesting functional roles for the beta-gamma subunit, support a possible dual signalling mechanism of cellular activation. This may be of particular importance in regulating the response to eicosanoids with contrasting actions. A receptor for prostacyclin (PGI2) has not yet been cloned but biochemical studies suggest that it is linked to the activation of adenylate cyclase via Gs. At least three distinct prostaglandin E receptors have been identified. Desensitization of the cellular responses to the activation of TXA2, PGI2 and PGE receptors have been demonstrated and potential phosphorylation sites in their COOH terminal ends may be important in mediating this effect.

Coronary Disease↗