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R Coffey

Publications and source records attributed to R Coffey.

At least 19 recordsLinked to original sources
PubMed2001

A phase I study of vitamin E, 5-fluorouracil and leucovorin for advanced malignancies.

Six patients with incurable malignancies were originally treated with vitamin E, 3200 IU/day for fourteen days, followed by the same dose of vitamin E daily plus LCV (20 mg/m2 i.v. bolus daily x 5) with 5FU (425 mg/m2 i.v. bolus immediately following LCV). The same schedule of LCV and 5FU was repeated 4 weeks later, then every 5 weeks indefinitely. When 3 of the first 6 had grade 3/4 toxicity, six more patients were treated on the identical drugs and schedule. Seven of twelve total patients had one or more grade 3/4 toxicities. Neutropenia, abdominal pain, and diarrhea were most common. No patient had a documented response, though seven patients did have stable disease. Though the combination of vitamin E and chemotherapy was toxic, this trial demonstrated maximal therapeutic doses of vitamin E can be combined with standard 5FU and LCV, without significantly increasing the side effects of the chemotherapy itself.

Abdominal Pain↗
PubMed2000

The lactoperoxidase system functions in bacterial clearance of airways.

Airway mucus is a complex mixture of secretory products that provides a multifaceted defense against pulmonary infection. Mucus contains antimicrobial peptides (e.g., defensins) and enzymes (e.g., lysozyme) although the contribution of these to airway sterility has not been tested in vivo. We have previously shown that an enzymatically active, heme-containing peroxidase comprises 1% of the soluble protein in sheep airway secretions, and it has been hypothesized that this airway peroxidase may function as a biocidal system. In this study, we show that sheep airway peroxidase is identical to milk lactoperoxidase (LPO) and that sheep airway secretions contain thiocyanate (SCN(-)) at concentrations necessary and sufficient for a functional peroxidase system that can protect against infection. We also show that airway LPO, like milk LPO, produces the biocidal compound hypothiocyanite (OSCN(-)) in vitro. Finally, we show that in vivo inhibition of airway LPO in sheep leads to a significant decrease in bacterial clearance from the airways. The data suggest that the LPO system is a major contributor to airway defenses. This discovery may have significant implications for chronic airway colonization seen in respiratory diseases such as cystic fibrosis.

Amino Acid Sequence↗
PubMed1999

Regulation of Fas antibody induced neutrophil apoptosis is both caspase and mitochondrial dependent.

Resolution of neutrophil mediated inflammation is achieved, in part, through induction of neutrophil apoptosis. This constitutively expressed programme can be delayed by inflammatory mediators and induced by ligation of the Fas receptor. However, functional activation of the neutrophil results in resistance to Fas signalled death. We evaluated the effects of Fas antibody engagement on caspase activation and mitochondrial permeability, and the impact of co-stimulation by lipopolysaccharide (LPS) or granulocyte macrophage-colony stimulating factor (GM-CSF) on these events. Fas engagement by an agonistic anti-Fas antibody resulted in enhanced caspase 3 and 8 activity and increased mitochondrial permeability. Studies with pharmacological inhibitors of caspase activity showed that activation of caspase 8 occurred before, and activation of caspase 3 occurred after mitochondrial disruption. The mitochondrial stabilising agent bongkrekic acid also inhibited caspase activation and apoptosis. LPS, GM-CSF and increased glutathione stabilised the mitochondria and inhibited caspase 3. Caspase 8 activity was also inhibited by co-stimulation through a mechanism independent of mitochondrial stabilisation. Glutathione directly inhibited caspase 3 and 8 activity. We conclude inhibition of Fas antibody induced apoptosis by inflammatory proteins is associated with augmented mitochondrial stability and reduced caspase 3 activity that may be glutathione mediated.

Acetylcysteine↗
PubMed1999

Concurrence of Pendred syndrome, autoimmune thyroiditis, and simple goiter in one family.

Pendred syndrome is the autosomal recessively transmitted association of familial goiter and congenital deafness. There is no specific biochemical marker of this disease, and the diagnosis depends upon the demonstration of the triad of congenital sensorineural hearing loss, goiter, and abnormal perchlorate discharge test. Pendred syndrome is caused by mutations within the putative ion transporter gene (PDS gene), located on chromosome 7q. A wide variation in the clinical presentation of this condition, and its well documented phenotypic overlap with other thyroid disorders (such as Hashimoto's thyroiditis), can lead to diagnostic difficulties. The potential for misdiagnosis increases when these disorders occur coincidentally in the same family. We describe a kindred in which Pendred syndrome, autoimmune thyroiditis, and simple goiter coexisted, to highlight these diagnostic pitfalls and to illustrate the use of mutational analysis in resolving diagnostic confusion.

Adult↗
PubMed1999

Prevalence, age of onset, and natural history of thyroid disease in Pendred syndrome.

BACKGROUND: We have sought to establish the prevalence of goitre within a Pendred syndrome (PS) cohort and to document the course of thyroid disease in this patient group. As part of a genetic study of PS we have assessed 57 subjects by perchlorate discharge test and in 52 (M 21, F 31, age range 9-54 years) a discharge of radioiodide of >10% was observed. RESULTS: Goitre was present in 43 (83%) of the cohort (28 F, 15 M), generally developing after the age of 10 years, 56% remained euthyroid (age range 9-37 years), and 19 patients (44%) had objective evidence of hypothyroidism, all of whom had goitre. CONCLUSIONS: In summary, thyroid dysfunction in PS is variable and inclusion of goitre as a diagnostic requirement will maintain significant underascertainment. The recent identification of the genetic defect underlying PS is likely to provide an important diagnostic aid in the identification of this disorder and this communication should assist clinicians in identifying deaf patients who ought to be considered for this investigation.

Adolescent↗
PubMed1998

Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study.

BACKGROUND: Congenital heart defects are generally assumed to have a multifactorial aetiology. We have tested this hypothesis by studying adults with heart defects and their families. METHODS: We identified 1094 patients who survived surgery for major cardiac defects before 1970. We chose individuals with disturbance of situs or segmental connection, with atrioventricular septal defect or with tetralogy of Fallot. After exclusion and non-participation, 727 individuals were traced. Each was visited by an investigator and completed a detailed questionnaire. If possible, all "normal" offspring were examined by a paediatric cardiologist. FINDINGS: The 727 individuals had 393 live offspring. There were 71 miscarriages and five terminated pregnancies. Overall, we found recurrent heart defects in 16 liveborn offspring--a recurrence risk of 4.1%. This result differed significantly from sibling risk (2.1%; p=0.021). More congenital heart defects occurred in the offspring of affected women than in those of affected men (p=0.047); when all malformations (cardiac and non-cardiac) in the offspring were taken into account the excess was more significant (p=0.032). We found an excess of miscarriages in the offspring of affected women (p=0.001). In tetralogy of Fallot, heart defects occurred in seven (3.1%) of 223 offspring, 12 (2.2%) of 539 siblings, five (0.3%) of 1575 second-degree relatives, and eight (0.3%) of 2728 third-degree relatives. INTERPRETATION: Our findings do not support a polygenic basis for all heart defects. Atrioventricular septal defect seems to be a single-gene defect and tetralogy of Fallot a polygenic disorder with a small number of interacting genes. Our data suggest that isolated transposition of the great arteries is a sporadic defect.

Adult↗
PubMed1998

Alström syndrome. Report of 22 cases and literature review.

OBJECTIVE: The authors report 22 cases of Alström syndrome (AS), which is the largest series to date. Only 37 cases have been reported in the world literature since 1959. The authors review the clinical features and compare these with the overlapping condition of Bardet-Biedl syndrome. Their aim is to clarify the AS phenotype and to increase awareness of the early features. DESIGN: A retrospective case series. PARTICIPANTS: All patients (22) with a diagnosis of AS admitted to the authors' hospital in the past 10 years were included in this review. INTERVENTION: This is principally a review of ocular features, but other features are recorded and discussed. MAIN OUTCOME MEASURES: Features noted included age at onset of visual symptoms, presence of photophobia, visual acuity, and electroretinogram findings. Nonocular features recorded included cardiac status, weight and height, hearing, and presence of diabetes mellitus. RESULTS: Cardiomyopathy presenting in infancy has only been recognized recently to be a feature of AS. Of the authors' cases, 18 of 22 had infantile cardiomyopathy. In the authors' tertiary referral institution, there is an ascertainment bias toward younger patients and especially those with pathology that is other than ocular pathology. In addition, AS is difficult to recognize in childhood without the development of infantile cardiomyopathy. Alström syndrome often is not recognized until diabetes mellitus develops in the second or third decade. Initially, a diagnosis of cone-rod dystrophy, achromatopsia, Leber's congenital amaurosis, or Bardet-Biedl syndrome may be made. In AS, there is a severe infantile retinal dystrophy. The electroretinogram is absent or attenuated with better preserved rod than cone function. The retinal dystrophy is progressive with the patient's visual acuity of 6/60 or less by 10 years of age and no light perception by 20 years of age. CONCLUSIONS: A diagnosis of AS should be considered in infantile cone and rod retinal dystrophy, particularly if the weight is above the 90th percentile (16 of 18 cases) or if there is an infantile cardiomyopathy (18 of 22 cases).

Abnormalities, Multiple↗
PubMed1998

Molecular analysis of the PDS gene in Pendred syndrome.

Pendred syndrome is an autosomal recessive disorder characterized by the association between sensorineural hearing loss and thyroid swelling or goitre and is likely to be the most common form of syndromic deafness. Within the thyroid gland of affected individuals, iodide is incompletely organified with variable effects upon thyroid hormone biosynthesis, whilst the molecular basis of the hearing loss is unknown. The PDS gene has been identified by positional cloning of chromosome 7q31, within the Pendred syndrome critical linkage interval and encodes for a putative ion transporter called pendrin. We have investigated a cohort of 56 kindreds, all with features suggestive of a diagnosis of Pendred syndrome. Molecular analysis of the PDS gene identified 47 of the 60 (78%) mutant alleles in 31 families (includes three homozygous consanguineous kindreds and one extended family segregating three mutant alleles). Moreover, four recurrent mutations accounted for 35 (74%) of PDS disease chromosomes detected and haplotype analysis would favour common founders rather than mutational hotspots within the PDS gene. Whilst these findings demonstrate molecular heterogeneity for PDS mutations associated with Pendred syndrome, this study would support the use of molecular analysis of the PDS gene in the assessment of families with congenital hearing loss.

DNA Mutational Analysis↗
PubMed1997

Pendred syndrome--100 years of underascertainment?

Pendred syndrome is an autosomal recessive condition classically characterized by deafness and goitre. Since both cochlear and thyroid pathology are required to secure the diagnosis, it is unclear whether the condition might present without the classical features. The perchlorate discharge test, the gold-standard investigation for Pendred syndrome, is non-specific, and in the absence of alternative means of confirming the diagnosis, its sensitivity is unknown. We used the recent mapping of the gene to chromosome 7q to identify pedigrees with a likely diagnosis of Pendred syndrome, and assessed the prevalence of clinical parameters of disease in affected patients. Thirty-six familial cases showed co-segregation between disease and the Pendred syndrome locus on chromosome 7q. Clinical and investigative findings were compared in index cases (n = 18) vs. affected siblings (n = 18). The overall prevalence of goitre was 73%, higher in index cases (94%) than in siblings (56%), many of whom had not previously been considered to have the condition. One perchlorate discharge test was false-negative (2.9%). Radiological malformations of the cochlea were identified in 86% of cases. Securing a diagnosis of Pendred syndrome may be difficult, especially in the single case. The perchlorate discharge test, although valuable, is difficult to undertake in the younger patient, and radiology may assist in diagnosing such patients.

Adolescent↗
PubMed1997

Pendred syndrome: evidence for genetic homogeneity and further refinement of linkage.

Pendred syndrome is the association between congenital sensorineural deafness and goitre. The disorder is characterised by the incomplete discharge of radioiodide from a primed thyroid following perchlorate challenge. However, the molecular basis of the association between hearing loss and a defect in organification of iodide remains unclear. Pendred syndrome is inherited as an autosomal recessive trait and has recently been mapped to 7q31 coincident with the non-syndromic deafness locus DFNB4. To define the critical linkage interval for Pendred syndrome we have studied five kindreds, each with members affected by Pendred syndrome. All families support linkage to the chromosome 7 region, defined by the microsatellite markers D7S501-D7S523. Detailed haplotype analysis refines the Pendred syndrome linkage interval to a region flanked by the marker loci D7S501 and D7S525, separated by a genetic distance estimated to be 2.5 cM. As potential candidate genes have as yet not been mapped to this interval, these data will contribute to a positional cloning approach for the identification of the Pendred syndrome gene.

Adolescent↗
PubMed1997

Abnormal audiograms and elevated acoustic reflex thresholds in obligate carriers of autosomal recessive non-syndromic hearing loss.

Pure-tone audiograms and acoustic reflex thresholds were obtained in 24 presumed obligate carriers of autosomal recessive non-syndromic hearing loss and 30 sex and age appropriate control subjects, with a view to evaluating the prevalence of abnormalities on these tests in the two groups, and a possible link between the findings on the two tests, which may help to localize threshold deficits and/or abnormal configurations to different sections of the reflex arc. Six (25%) of the carriers and one control subject had abnormal audiograms, inferred to be of genetic aetiology through careful exclusion of environmental risk factors. Four additional carriers had acoustic reflex threshold abnormalities. None of the carriers had an abnormality on both tests. The audiometric configurations and acoustic reflex patterns of abnormality were diverse, and may be a reflection of the genetic heterogeneity in ARNSHL.

Adult↗
PubMed1996

Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4.

Inherited causes account for about 50% of individuals presenting with childhood (prelingual) hearing loss, of which 70% are due to mutation in numerous single genes which impair auditory function alone (non-syndromic). The remainder are associated with other developmental anomalies termed syndromic deafness. Genes responsible for syndromic forms of hearing loss include the COL4A5 gene in Alport syndrome and the PAX3 and MITF genes in Waardenburg syndrome. Pendred syndrome is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensorineural hearing loss and diffuse thyroid enlargement (goitre). Pendred syndrome is the most common syndromal form of deafness, yet the primary defect remains unknown. We have established a panel of 12 families with two or more affected individuals and used them to search for the location of the Pendred gene by linkage analysis. We excluded localization to four previously mapped nonsyndromic deafness loci but obtained conclusive evidence for linkage of the Pendred syndrome gene to microsatellite markers on chromosome 7q31 (D7S495 Zmax 7.32, Qmax = 0). This region contains a gene, DFNBL, for autosomal recessive non-syndromic sensorineural hearing loss. Multipoint analysis indicates that DFNB4 and Pendred syndrome co-localize to the same 5.5 centiMorgan (cM) interval flanked by D7S501 and D7S523. These data raise the possibility that Pendred syndrome is either allelic with DFNB4 or may represent an inherited contiguous gene disorder, not clinically manifest in the heterozygote.

Chromosome Mapping↗
PubMed1996

Thyroid peroxidase: evidence for disease gene exclusion in Pendred's syndrome.

OBJECTIVE: Pendred's syndrome is an association between congenital neurosensory deafness and goitre with abnormal discharge of iodide following perchlorate challenge, indicating a defect of iodide organification. Although Pendred's syndrome may cause up to 7.5% of all cases of congenital deafness, the molecular basis of the association between the hearing loss and the thyroid organification defect remains unknown. We chose to investigate the role of the thyroid peroxidase (TPO) gene as the genetic defect in Pendred's syndrome. DESIGN: A highly informative variable number tandem repeat (VNTR), located 1.5 kb downstream of exon 10 of the TPO gene, was used to search for genetic linkage in multiple sibships affected by Pendred's syndrome. PATIENTS: Seven kindreds were recruited from the UK, each with at least two affected members. We have also examined a large inbred Israeli family with two affected offspring and five unaffected children. MEASUREMENTS: Individuals were assigned affected status based on the characteristic clinical features of Pendred's syndrome, namely the presence of congenital sensorineural hearing loss and the appearance in early life of a goitre. Additionally, at least one affected member from each sibship had a characteristic positive perchlorate discharge test (Morgans & Trotter, 1958). PCR amplification of genomic DNA at the TPO VNTR allowed assignment of genotypes to each individual and the calculation of a two-point LOD score. RESULTS: In six of the nine sibships analysed we found obligatory recombination between TPO and Pendred's syndrome. Non-complementation observed in affected parents with an affected offspring excluded TPO in an affected sibship with genotype sharing and supports a hypothesis of genetic homogeneity for Pendred's syndrome. In two sibships, mutation of the TPO gene as the cause of Pendred's syndrome could not be excluded. CONCLUSIONS: These data suggest that defects at the thyroid peroxidase locus on chromosome 2 are not the major cause of Pendred's syndrome.

Base Sequence↗
PubMed1996

Dips on Békésy or audioscan fail to identify carriers of autosomal recessive non-syndromic hearing loss.

Békésy and audioscan sweep audiometry tests were carried out in 24 presumed obligate carriers of autosomal recessive non-syndromic hearing loss and 30 sex and age appropriate controls, with a view to defining the most expedient criteria for dips on either test in respect of possible carrier detection. On Békésy, dips with a minimum depth of 22.5 dB generated the greatest difference between carriers and non-carriers, while on audioscan, the criterion of a minimum dip depth of 15 dB provided the best discriminant. Using these criteria, the prevalence of dips was also evaluated in 8 unaffected siblings and 24 age appropriate control subjects. The findings both in the adult and the paediatric groups do not support the hypothesis that the presence of dips, either on Békésy or audioscan, is linked to the carrier state in ARNSHL.

Acoustic Impedance Tests↗
PubMed1993

Concordance and recessive inheritance of Leber congenital amaurosis.

Pedigrees were obtained on 43 patients with confirmed Leber congenital amaurosis, a rare form of blindness caused by congenital dysfunction of the retina. All of the pedigrees were consistent with autosomal recessive inheritance and the segregation frequency using classical segregation analysis was 0.24 +/- 0.07. Six of the 7 affected sib pairs were concordant in regards to systemic abnormalities. Despite previous reports that Leber congenital amaurosis can be inherited either as an autosomal dominant or recessive condition, our findings support only an autosomal recessive inheritance of this disorder.

Adolescent↗
PubMed1993

Linkage analysis of infantile pyloric stenosis and markers from chromosome 9q11-q33: no evidence for a major gene in this candidate region.

A genetic component in the aetiology of infantile pyloric stenosis (PS) is well established. Segregation analysis is compatible with a multifactorial sex modified threshold model of inheritance but a major gene of low penetrance has not been excluded. PS has been reported to occur in 57% (four of seven) of cases with duplication of chromosome 9q11-q33. Twenty families with PS were studied using genetic markers at loci D9S55, D9S111, D9S15, D9S12, D9S56, D9S59, and ASS from this region of chromosome 9. Pairwise lod scores of -2 were obtained with all these markers at recombination fractions greater or equal to 0.04 under both autosomal dominant and autosomal recessive models of inheritance. This provides evidence against the existence of a major locus predisposing to PS within chromosome 9q11-q33.

Chromosomes, Human, Pair 9↗