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Biomedical subjects

M Godfrey

Publications and source records attributed to M Godfrey.

At least 19 recordsLinked to original sources
PubMed2006

The molecular genetics of Marfan syndrome and related disorders.

Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of MFS and related disorders has changed our understanding of this disorder by demonstrating changes in growth factor signalling and in matrix-cell interactions. The purpose of this review is to provide a comprehensive overview of recent advances in the molecular biology of fibrillin and fibrillin-rich microfibrils. Mutations in FBN1 and other genes found in MFS and related disorders will be discussed, and novel concepts concerning the complex and multiple mechanisms of the pathogenesis of MFS will be explained.

Activin Receptors, Type I↗
PubMed2003

In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome.

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.

Abnormalities, Multiple↗
PubMed2001

Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24-40.

Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, an autosomal dominant disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. There is a remarkable degree of clinical variability both within and between families with Marfan syndrome as well as in individuals with related disorders of connective tissue caused by FBN1 mutations and collectively termed type-1 fibrillinopathies. The so-called neonatal region in FBN1 exons 24-32 comprises one of the few generally accepted genotype-phenotype correlations described to date. In this work, we report 12 FBN1 mutations identified by temperature-gradient gel electrophoresis screening of exons 24-40 in 127 individuals with Marfan syndrome or related disorders. The data reported here, together with other published reports, document a significant clustering of mutations in exons 24-32. Although all reported mutations associated with neonatal Marfan syndrome and the majority of point mutations associated with atypically severe presentations have been found in exons 24-32, mutations associated with classic Marfan syndrome occur in this region as well. It is not possible to predict whether a given mutation in exons 24-32 will be associated with classic, atypically severe, or neonatal Marfan syndrome.

Adolescent↗
PubMed2001

Prevention: developing a framework for conceptualizing and evaluating outcomes of preventive services for older people.

There is growing preoccupation among policy makers and commissioners in developing preventive strategies and services. There is simultaneous concern with evidence-based purchasing and provision, within health and social care. In social care the evidence base regarding prevention is neither extensive nor robust. As the review of recent policy documents indicates, the concept of prevention is extremely slippery. What preventive services are and whether they are effective depends on the specific policy context, the overall service objectives and the perspective on outcomes adopted (user, carer, professional, service). Focusing on older people, the paper seeks a way through the confusion, locating prevention within a theoretical model of successful ageing. This conceptualizes ageing as involving adaptation to the changing balance between gains and losses over the life course. Successful ageing is perceived as the attainment of valued goals, the minimisation of losses and maximization of gains through the linked processes of selective compensation and optimisation. The paper then identifies necessary elaborations of the model to take into account the wider cultural and socio-economic context. This shapes and constrains the goals pursued and the resources available in adopting particular adaptation strategies. Within this model, preventive services may be conceived as resources to be drawn upon to support compensatory strategies. Similarly, outcomes and effectiveness of services may be evaluated in terms of whether they facilitate/allow older people to achieve valued goals. In developing and evaluating preventive services in social care the question of interest is reformulated: what contribution do specific services make in optimising gains and compensating for the losses that accompany ageing? This framework is explored in respect of two substantive areas ripe for secondary prevention services and strategies - bereavement and instrumental support in the home.

Adaptation, Psychological↗
PubMed2000

Two novel fibrillin-2 mutations in congenital contractural arachnodactyly.

Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder, comprising marfanoid habitus, flexion contractures, severe kyphoscoliosis, abnormal pinnae, and muscular hypoplasia. It is now known that mutations in the gene encoding fibrillin-2 cause CCA. Interestingly, mutations described to date cluster in the fibrillin-2 region homologous to the so-called neonatal Marfan syndrome region of fibrillin-1. Thus, it has been hypothesized that the relative infrequency of CCA compared with the Marfan syndrome is due to the limited region of the gene targeted for mutations. In support of the above hypothesis, we report here the finding of two additional FBN2 mutations in CCA, C1141F (exon 26) and C1252W (exon 29). In addition, a new 3' UTR polymorphism is also described.

Adolescent↗
PubMed2000

The molecular genetics of Marfan syndrome and related microfibrillopathies.

Mutations in the gene for fibrillin-1 (FBN1) have been shown to cause Marfan syndrome, an autosomal dominant disorder of connective tissue characterised by pleiotropic manifestations involving primarily the ocular, skeletal, and cardiovascular systems. Fibrillin-1 is a major component of the 10-12 nm microfibrils, which are thought to play a role in tropoelastin deposition and elastic fibre formation in addition to possessing an anchoring function in some tissues. Fibrillin-1 mutations have also been found in patients who do not fulfil clinical criteria for the diagnosis of Marfan syndrome, but have related disorders of connective tissue, such as isolated ectopia lentis, familial aortic aneurysm, and Marfan-like skeletal abnormalities, so that Marfan syndrome may be regarded as one of a range of type 1 fibrillinopathies. There appear to be no particular hot spots since mutations are found throughout the entire fibrillin-1 gene. However, a clustering of mutations associated with the most severe form of Marfan syndrome, neonatal Marfan syndrome, has been noted in a region encompassing exons 24 to 32. The gene for fibrillin-2 (FBN2) is highly homologous to FBN1, and mutations in FBN2 have been shown to cause a phenotypically related disorder termed congenital contractural arachnodactyly. Since mutations in the fibrillin genes are likely to affect the global function of the microfibrils, the term microfibrillopathy may be the most appropriate to designate the spectrum of disease associated with dysfunction of these molecules. The understanding of the global and the molecular functions of the fibrillin containing microfibrils is still incomplete and, correspondingly, no comprehensive theory of the pathogenesis of Marfan syndrome has emerged to date. Many, but not all, fibrillin-1 gene mutations are expected to exert a dominant negative effect, whereby mutant fibrillin monomers impair the global function of the microfibrils. In this paper we review the molecular physiology and pathophysiology of Marfan syndrome and related microfibrillopathies.

Abnormalities, Multiple↗
PubMed2000

Partial cloning and sequencing of chick fibrillin-1 cDNA.

The recent identification of numerous matrix genes and gene products has allowed a detailed examination of their roles in development. Two of these extracellular matrix proteins, fibrillin-1 and fibrillin-2, are components of the elastin-associated microfibrils. Given what is known about the distribution of the fibrillins in normal tissues and the abnormalities that result when mutations occur, a basic hypothesis has emerged: fibrillin-1 is primarily responsible for load bearing and providing structural integrity, whereas fibrillin-2 may be a director of elastogenesis. Nevertheless, examination of phenotypes in disorders caused by mutations in fibrillin-1 or fibrillin-2 suggests some common functions. To better understand these similar and diverse roles, it would be helpful to examine these proteins during chick development. To accomplish this goal, it is first necessary to characterize the chick homologs of the known fibrillins. In this study, the partial chick FBN1 cDNA was identified by polymerase chain reaction-aided cloning as a first step toward elucidating these goals. Sequence analysis indicated that there is striking conservation between chick and mammalian fibrillin-1 at the DNA and protein levels. Antisense and sense riboprobes were synthesized and used in in situ hybridization in stage 14 chick embryos and high levels of FBN1 transcripts were observed in the heart.

Amino Acid Sequence↗
PubMed1999

Repeated antenatal corticosteroids: size at birth and subsequent development.

OBJECTIVE: The objective was to study the effects of repeated antenatal corticosteroids on birth size, growth, and development in preterm infants. STUDY DESIGN: This observational study followed up for 3 years a prospective geographic cohort in the state of Western Australia of 477 singleton infants born at <33 weeks' gestation. RESULTS: Birth weight ratio decreased with increasing number of corticosteroid courses (P =.001), and multivariate analyses confirmed a reduction in birth weight of as much as 9% (P =.014) and a reduction in head circumference of as much as 4% (P =.0024). There were no additional benefits in mortality or respiratory outcomes, and there was a trend toward more severe chronic lung disease. At age 3 years growth and severe disability outcomes did not appear to be related to increasing number of corticosteroid courses. CONCLUSIONS: In this cohort study repeated corticosteroid courses were associated with adverse effects on size at birth without apparent benefits. These changes have the potential to affect later development.

Adrenal Cortex Hormones↗
PubMed1999

Novel exon skipping mutation in the fibrillin-1 gene: two 'hot spots' for the neonatal Marfan syndrome.

The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue that involves principally the skeletal, ocular, and cardiovascular systems. The most severe end of the phenotypic spectrum, the neonatal Marfan syndrome (nMFS), is characterized by pronounced atrioventricular valve dysfunction, and death often occurs within the first year of life due to congestive heart failure. Mutations in the gene coding for fibrillin-1, FBN1, are known to cause Marfan syndrome, and have been identified in almost all exons of FBN1. Here, we describe a novel mutation affecting the invariant + 1 position of the splice donor site in intron 31, associated with skipping of exon 31, in a patient with nMFS. Published reports of nMFS are reviewed and a strict definition for nMFS is suggested. If this definition is used, all nMFS mutations reported to date lie in one of two hot spots, comprising mainly missense mutations in FBN1 exons 24-27 and mutations causing skipping of exon 31 or 32.

Exons↗
PubMed1998

Renal handling of circulating nitrates in anesthetized dogs.

Nitric oxide (NO) is rapidly oxidized to nitrite (NO-2) and then to nitrate (NO-3) in biological tissues. Although urinary excretion rates of NO-3 are often used as an index of NO production in the body, very little is known regarding the kidney's ability to excrete circulating NO-3. We have evaluated the renal responses to systemic administration of sodium nitrate (NaNO3) in eight anesthetized dogs treated with the NO synthase inhibitor, nitro-L-arginine (NLA; 50 microg . kg-1 . min-1), intrarenally to minimize renal production of NO. Urinary and plasma concentrations of NO-3/NO-2 (NOX) were determined by the Greiss reaction after enzymatic reduction of NO-3 to NO-2. NLA treatment alone resulted in reductions in urinary NOX excretion rates (UNOXV, 1.13 +/- 0.2 to 0.53 +/- 0.1 nmol . min-1 . g-1) and an increase in fractional reabsorption of NOX (FRNOX, 93.8 +/- 0.6 to 97 +/- 0.6%) without changes in arterial plasma concentrations (ANOX, 18.7 +/- 1.4 to 21.2 +/- 3.7 microM). Administration of NaNO3 (10, 20, 30, and 40 microg . kg-1 . min-1) resulted in dose-dependent increases in ANOX (34.5 +/- 8.0, 46.4 +/- 7.3, 60.7 +/- 6.3, and 78.1 +/- 6.3 microM), UNOXV (1.8 +/- 0.7, 4.2 +/- 1.8, 7.0 +/- 2.0, and 11.4 +/- 3.3 nmol . min-1 . g-1), and decreases in FRNOX (93.8 +/- 2.3, 90.3 +/- 3.5, 88.6 +/- 3.2, and 84.6 +/- 3.5%). Absolute net tubular reabsorption of NO-3 showed a linear relationship with filtered loads, with no evidence of a transport maximum. These data show that, in the absence of additions from intrarenal sources, urinary excretion rates of nitrate increases progressively in response to increases in its circulating levels without exhibiting a transport maximum but with progressive decreases in fractional reabsorption.

Absorption↗
PubMed1998

Heritable connective tissue disorders in cervical artery dissections: a prospective study.

We prospectively evaluated 15 consecutive patients with spontaneous cervical artery dissections. Three patients (20%) had a heritable connective tissue disorder, each with a unique phenotype. None of these patients met the criteria of any of the named syndromes, and collagen and fibrillin analyses were normal. Heritable connective tissue disorders are common among patients with spontaneous cervical artery dissections, but, despite intensive investigations, the type of disorder usually cannot be identified. The underlying arteriopathy in cervical artery dissections is likely to be heterogeneous.

Adult↗
PubMed1997

Marfan Database (second edition): software and database for the analysis of mutations in the human FBN1 gene.

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were described at first in the heritable connective tissue disorder, Marfan syndrome (MFS). More recently, FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS. These mutations are private, essentially missense, generally non-recurrent and widely distributed throughout the gene. To date no clear genotype/phenotype relationship has been observed excepted for the localization of neonatal mutations in a cluster between exons 24 and 32. The second version of the computerized Marfan database contains 89 entries. The software has been modified to accomodate new functions and routines.

Animals↗
PubMed1997

A validation study of home uterine activity monitoring technology in Western Australia.

Home uterine activity monitoring has been developed as an 'early warning' device to detect premature uterine activity, thereby encouraging earlier referral and tocolysis of women at risk of preterm delivery. This ambulatory monitoring system, utilizing a ring-guard tocodynamometer, was piloted in Western Australia to determine if it can reliably record and transmit antenatal uterine activity data in an Australian environment. Pregnant women were readily able to correctly apply and use the ambulatory monitoring device. The information collected was able to be transmitted using standard Australian telecommunications systems within our hospital environment. Validation studies with the ambulatory monitor and current external tocodynamometry hardware were performed. The ring-guard tocodynamometer detected more uterine activity at gestations less than 32 weeks compared with conventional external tocodynamometers. As term approached, however, the sensitivity of the ring-guard tocodynamometer decreased. A cross-sectional profile of antenatal uterine activity was developed for women at low risk of delivering preterm. A gradual increase in the number, duration and amplitude of uterine contractions as pregnancy advanced was observed.

Female↗
PubMed1997

Antenatal patterns of uterine activity in low-risk women: a longitudinal study.

There is a surprising lack of information on antenatal patterns of uterine activity in the normal obstetric population, with the majority of research having focussed on women at high-risk for preterm birth. We conducted a prospective longitudinal study to investigate patterns of uterine activity in women with singleton gestations at low-risk for preterm birth. Twenty pregnant women were recruited and their uterine activity was recorded using ambulatory tocodynamometry twice weekly throughout the latter half of pregnancy. The collected data were transmitted to a central receiving station for analysis. As gestation advanced there was a progressive increase in the median number of contractions detected per hour, peaking and stablizing at 37-40 weeks (median of 0 contractions/hour at 20-24 weeks rising to 5.4 contractions/hour at 37-40 weeks). In those women with uterine activity, contraction duration and amplitude of deflection significantly increased as gestation advanced. There was a progressive increase in the number of higher amplitude contractions throughout the third trimester. Increasing parity was not associated with increasing antenatal uterine contraction frequency. No association between normal daily physical activity and uterine contraction frequency was evident throughout gestation. In normal human pregnancy there is a steady, progressive increase in the frequency, duration and amplitude of antenatal uterine activity throughout the latter half of gestation. The uterine contractile profile alters from one of a low amplitude, low frequency pattern in the second trimester to a higher amplitude, higher frequency pattern at term.

Adult↗
PubMed1997

Factors influencing the selection of analgesia in spontaneously labouring nulliparous women at term.

We investigated the maternal characteristics, labour performance and delivery mode of 497 nulliparas entering labour spontaneously at term to identify the obstetric factors which influenced their choice of analgesia; 51.7% of these women used epidural analgesia. They were shorter (163 versus 165 cm, p = 0.002) and the mean gestation was 3 days greater than those not using epidural analgesia (40.2 versus 39.6 weeks, p = 0.0007). Median birth-weight in the epidural group was greater by 155 g (3,450 versus 3,295 gs, p = 0.0001). Analysis of the labour characteristics showed a lesser cervical dilatation on admission, significantly longer latent and active phases of labour and second stage length in the epidural cohort. The need for oxytocin augmentation was significantly greater in the epidural group, both prior to and after insertion. Oxytocin augmentation was strongly associated with an increased risk of operative intervention regardless of analgesia. Selection of intrapartum analgesia is not a random event and epidural analgesia appears to be an indicator of abnormal labour patterns. To further investigate the impact of analgesic methods on nulliparous labour we are currently conducting a prospective randomized controlled trial.

Adult↗