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Biomedical subjects

E Sweeney

Publications and source records attributed to E Sweeney.

At least 19 recordsLinked to original sources
PubMed2007

Functional characterization of a novel insulin receptor mutation contributing to Rabson-Mendenhall syndrome.

OBJECTIVE/PATIENTS: Rabson-Mendenhall syndrome (RMS) is a rare, recessively inherited disorder of extreme insulin resistance due to mutations in the insulin receptor gene. We have identified a pair of siblings with RMS attributable to compound heterozygosity for two insulin receptor mutations, one previously unreported, and have characterized the novel receptor mutation functionally. MEASUREMENTS: Insulin receptor sequencing was performed to identify the mutations. Expression levels of the mature receptor were determined in lymphoblastoid cells from the affected subjects. Further studies of immortalized cell lines transfected with mutant and wild type (WT) receptors were undertaken to characterize the effects of the novel mutation on [(125)I]-labelled insulin binding, proreceptor processing and insulin-stimulated receptor autophosphorylation. RESULTS: Sequencing of the insulin proreceptor coding sequence revealed both siblings to be compound heterozygotes for the missense mutations Arg209His and Gly359Ser in the mature insulin receptor. The former mutation has been described in homozygous form in Donohue syndrome, while the latter is novel. Insulin receptor expression in lymphoblastoid cell lines was present at only 10-30% of that in control cells; studies of immortalized cells transfected with mutant and WT receptors confirmed the reduced expression of the mutant. The degree of impairment of insulin binding and insulin-stimulated receptor autophosphorylation were commensurate with the decrease in expression of the mature receptor. CONCLUSIONS: Loss of function of the novel insulin receptor (INSR) G359S variant is largely accounted for by aberrant proreceptor processing rather than intrinsically impaired signal transduction by the mutant receptor.

Animals↗
PubMed2005

Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients.

MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p<0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.

Adolescent↗
PubMed2005

Nail patella syndrome revisited: 50 years after linkage.

Nail Patella Syndrome (NPS; OMIM #161200) is a pleiotropic condition, with a classical clinical tetrad of involvement of the nails, knees, elbows and the presence of iliac horns. Kidney disease and glaucoma are now recognised as part of the syndrome. Fifty years ago, James Renwick chose NPS to develop methods of linkage analysis in humans and revealed the third linkage group identified in man--that between NPS and the ABO blood group loci. After a fallow period of some forty years, the gene mutated in NPS has been identified (LMX1B) and the condition serves as a model for understanding the complex relationships between disease loci, modifier genes and the resultant clinical phenotype.

ABO Blood-Group System↗
PubMed2003

Nail patella syndrome: a review of the phenotype aided by developmental biology.

Nail patella syndrome (NPS) is an autosomal dominant condition affecting the nails, skeletal system, kidneys, and eyes. Skeletal features include absent or hypoplastic patellae, patella dislocations, elbow abnormalities, talipes, and iliac horns on x ray. Kidney involvement may lead to renal failure and there is also a risk of glaucoma. There is marked inter- and intrafamilial variability. The results of a British study involving 123 NPS patients are compared with previously published studies and it is suggested that neurological and vasomotor symptoms are also part of the NPS phenotype. In addition, the first data on the incidence of glaucoma and gastrointestinal (GI) symptoms in NPS are presented. NPS is caused by loss of function mutations in the transcription factor LMX1B at 9q34. The expansion of the clinical phenotype is supported by the role of LMX1B during development.

Adolescent↗
PubMed2002

Nasomaxillary hypoplasia and severe orofacial clefting in a child of a mother with phenylketonuria.

The offspring of mothers with untreated or poorly controlled phenylketonuria (PKU) (McKusick 261600) are at risk of having congenital anomalies including microcephaly, congenital heart defects and developmental delay (Rouse et al 1997). We report a child born to a mother with poorly controlled PKU and suggest that the facial abnormalities seen in this child could be part of the specturn of maternal PKU embryopathy.

Cleft Lip↗
PubMed2001

Spontaneous and inducible apoptosis in oesophageal adenocarcinoma.

The use of neoadjuvant chemoradiotherapy prior to surgery in the treatment of oesophageal adenocarcinoma has increased in recent years, and up to 25% of patients will have a complete pathological response to the neoadjuvant therapy. Many patients will not respond, however, and the knowledge of molecular factors predicting response or resistance to chemoradiotherapy is required to enhance treatment results. An understanding of apoptosis and cell proliferation may be relevant and this study focused on apoptotic indices and cell-cycle related (Ki-67, p53 and bcl-2) protein expression in a cohort of 42 patients with primary oesophageal adenocarcinoma. We documented that apoptosis occurs among viable (proliferating) tumour cells in all adenocarcinoma cases examined in this study. Pre-operative chemoradiotherapy significantly increased apoptosis and significantly decreased cell proliferation (estimated by Ki-67 expression). Immunohistochemically detected p53 and bcl-2 gene products had no regulatory role in the apoptotic process. The cumulative expression of p53 protein is significantly associated with increasing proliferation activity. Evaluation of apoptosis in pre-treatment specimens may have potential utility in predicting the efficacy of treatment. Assessment of the tumours proliferation activity by Ki-67 expression might identify patients who are at risk of developing metastatic disease.

Adenocarcinoma↗
PubMed2001

Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation.

To elucidate further the role, in normal development and in disease pathogenesis, of TFAP2B, a transcription factor expressed in neuroectoderm, we studied eight patients with Char syndrome and their families. Four novel mutations were identified, three residing in the basic domain, which is responsible for DNA binding, and a fourth affecting a conserved PY motif in the transactivation domain. Functional analyses of the four mutants disclosed that two, R225C and R225S, failed to bind target sequence in vitro and that all four had dominant negative effects when expressed in eukaryotic cells. Our present findings, combined with data about two previously identified TFAP2B mutations, show that dominant negative effects consistently appear to be involved in the etiology of Char syndrome. Affected individuals in the family with the PY motif mutation, P62R, had a high prevalence of patent ductus arteriosus but had only mild abnormalities of facial features and no apparent hand anomalies, a phenotype different from that associated with the five basic domain mutations. This genotype-phenotype correlation supports the existence of TFAP2 coactivators that have tissue specificity and are important for ductal development but less critical for craniofacial and limb development.

3T3 Cells↗
PubMed2001

An evaluation of a caffeinated taurine drink on mood, memory and information processing in healthy volunteers without caffeine abstinence.

RATIONALE: Caffeine is present in a wide variety of beverages, often together with a number of other ingredients, such as sugars, taurine, glucuronolactone and vitamins. However, the majority of psychopharmacological studies have used pure caffeine tablets or drinks with doses in excess of those normally consumed in daily life. In addition, all the participants are usually deprived of caffeine for 10 h or more before the study. Consequently, it has been argued that any improvement in performance is only due to a reversal of caffeine withdrawal. OBJECTIVE: The present two studies tested participants who had minimal deprivation from caffeine (an hour or less) with an 80-mg caffeinated (80 mg/250 ml), taurine-containing beverage (commercially available) verum, which also contained sugars, glucuronolactone and vitamins. The placebos in the two studies were a sugar-free and a sugar-containing drink, in order to examine the effects of the sugar. METHODS: In total, 42 participants were tested with a rapid visual information test, a verbal reasoning test, a verbal and non-verbal memory test and a set of mood measures. Prior to testing, they were allowed ad libitum caffeinated beverages until 1 h before testing (study 1) and unrestricted caffeine use before testing (study 2). RESULTS: In both studies, the caffeinated, taurine-containing beverage produced improved attention and verbal reasoning, in comparison with a sugar-free and the sugar-containing drinks. The improvement with the verum drink was manifested in terms of both the mean number correct and the reaction times. Another important finding was the reduction in the variability of attentional performance between participants. No effects on memory were found. There were no differences in performance between the glucose and sugar-free drinks. CONCLUSIONS: Moderate doses of caffeine and taurine can improve information processing in individuals who could not have been in caffeine withdrawal.

Adolescent↗
PubMed2000

Char syndrome: a new family and review of the literature emphasising the presence of symphalangism and the variable phenotype.

We report a family of three affected individuals with the facial features of Char syndrome. The family also demonstrates symphalangism of the distal interphalangeal joints of the fifth fingers, extending the digital phenotype seen in this condition. We review the features of previously reported patients and emphasise the variability in the phenotype of Char syndrome.

Adult↗
PubMed1999

Primary cutaneous B-cell lymphoma: an association of chronic hepatitis C infection.

Primary cutaneous B-cell lymphoma is a low-grade malignancy, distinct from other lymphomas in terms of biological activity and response to treatment. We describe a 77-year-old woman with a five-year history of chronic hepatitis C infection who developed a lower-limb lesion over a period of 3 months which was diagnosed as a high-grade cutaneous B-cell lymphoma. Despite a lack of definitive evidence implicating hepatitis C virus (HCV) in the aetiology of lymphomas, there is considerable research which establishes a strong association between these two diseases. On the basis of published research and the demonstration of HCV RNA in the lymphomatous tissue, we consider this to be a rare case of primary cutaneous lymphoma in association with hepatitis C.

Aged↗
PubMed1997

Disulfide bond assignment in human interleukin-7 by matrix-assisted laser desorption/ionization mass spectroscopy and site-directed cysteine to serine mutational analysis.

Interleukin-7 (IL-7) is a proteinaceous biological response modifier that has a bioactive tertiary structure dependent on disulfide bond formation. Disulfide bond assignments in human (h)IL-7 are based upon the results of matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy and Cys to Ser mutational analyses. A gene encoding the hIL-7 was synthesized incorporating Escherichia coli codon usage bias and was used to express biologically active protein as determined by stimulation of precursor B-cell proliferation. MALDI mass spectroscopic analysis of trypsin-digested hIL-7 was performed and compared with the anticipated results of a simulated tryptic digestion. Many of the anticipated hIL-7 tryptic fragments were detected including one with a molecular mass equivalent to the sum of two polypeptides linked through a disulfide bond formed from Cys residues (Cys3 and Cys142). Subsequently, Cys to Ser substitution mutational analyses were performed. A hIL-7 variant with all six Cys substituted with Ser was found to be biologically inactive (EC50 > 1 x 10(-7) M). In contrast, a family of single disulfide bond-forming variants of hIL-7 were constructed by reintroducing Cys pairs (Cys3-Cys142, Cys35-Cys130, and Cys48-Cys93), and each could stimulate cell proliferation with an EC50 of 4 x 10(-9), 2 x 10(-8), and 2 x 10(-9) M, respectively. In single disulfide bond-forming mutants of hIL-7, the ability to stimulate cell proliferation was abolished in the presence of 2 mM dithiothreitol. The results presented strongly suggest that only a single disulfide bond is required for hIL-7 to form a tertiary structure capable of stimulating precursor B-cell proliferation.

Amino Acid Sequence↗
PubMed1996

Somatostatin and somatostatin analogues in medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumour characterized by the production and secretion of calcitonin. MTC tumours may express functional somatostatin receptors (hSSTR). A significant proportion of hSSTR receptor-positive MTC tumours, including metastatic disease, may be visualized in vivo through 111In-pentetreotide scintigraphy. Four patients with recurrent/metastatic disease, who had previously been assessed with 111In-anti-CEA monoclonal antibody fragment [F(ab')2] imaging, were evaluated. 111In-pentetreotide scintigraphy localized all known disease sites. Furthermore, mediastinal disease was detected in one patient with negative conventional, and 111In-anti-CEA F(ab')2 imaging studies. The detection of somatostatin within the tumour (2 patients), or negative octreotide challenges (2 patients), did not affect the outcome of 111In-pentetreotide scintigraphy. In conclusion, 111In-pentetreotide scintigraphy appears at least as effective as 111In-anti-CEA F(ab')2 imaging and should be considered in the diagnostic evaluation of MTC, particularly in the setting of recurrent/metastatic disease not detected by conventional means.

Adult↗
PubMed1995

Early ultrastructural changes of antral mucosa with aspirin in the absence of Helicobacter pylori.

AIMS: To describe the ultrastructural changes that occur in human antral mucosa following direct application of aspirin in volunteers without Helicobacter pylori infection. METHODS: Ten healthy male volunteers without H pylori infection underwent three consecutive endoscopies (at zero, one and five hours). At the first endoscopy, two biopsy specimens were obtained (one for histology and the other for electron microscopy (EM)). At subsequent endoscopies, a single biopsy specimen was obtained for EM. A 50 ml solution of aspirin (concentration 3 mg/ml) was applied to the antral mucosa at the first endoscopy in five subjects; the other five subjects received 50 ml distilled water (placebo). RESULTS: The ultrastructural appearance of the first biopsy specimen in all subjects and subsequent biopsy specimens in the placebo treated subjects was normal. The aspirin treated group had evidence of intercellular oedema, widening of capillary fenestrae, rupturing of apical membranes, and dilatation of endoplasmic reticulum and mitochondria after one hour; these changes were more marked at five hours. Tight junctions were maintained. CONCLUSION: This is the first study to describe the early ultrastructural changes in antral mucosa induced by aspirin in subjects without H pylori infection.

Adult↗