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J A Franklyn

Publications and source records attributed to J A Franklyn.

At least 19 recordsLinked to original sources
PubMed2000

Expression of thyroid receptor isoforms in the human fetal central nervous system and the effects of intrauterine growth restriction.

BACKGROUND: Congenital hypothyroidism is known to be associated with mental retardation which, if recognized promptly, is largely prevented by thyroid hormone replacement. Intrauterine growth restriction (IUGR) is a major cause of perinatal mortality and morbidity, and is also associated with neurodevelopmental delay. Fetuses with IUGR have reduced circulating concentrations of free thyroxine (T4) and free triiodothyronine (T3), leading to the hypothesis that a reduction in the tissue effects of thyroid hormones in the central nervous system (CNS) may contribute to neurodevelopmental morbidity. Since thyroid hormone effects are mediated through binding to specific nuclear thyroid hormone receptors (TRs), we have defined the pattern of TR isoform expression in the CNS throughout normal human development and have compared TR expression in the CNS of normal fetuses with those affected by IUGR. METHODS: Samples of normal human fetal brain from first and second trimesters were obtained at surgical termination of pregnancy. Appropriately grown and third trimester fetuses affected by Intrauterine growth restriction (IUGR) were also investigated after unexplained stillbirth at post mortem examination. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to examine the expression of TR isoform mRNAs in frozen cerebral cortex from 10 to 16 weeks gestation. TR protein expression in human fetal brains (both cerebral hemispheres and cerebellum) was also examined in formalin fixed sections and expression of TR alpha1, alpha2, beta1 and beta2 isoforms being defined using semiquantitative immunocytochemistry. RESULTS: RT-PCR revealed the presence of mRNAs encoding TR alpha1, beta1 and beta2 isoforms and the nonfunctional TRalpha2 variant in the fetal cerebral cortex from week 10 of human pregnancy. Immunostaining of the fetal brain revealed TR alpha1 and alpha2 protein from week 11 of human gestation. Expression of all TR isoform proteins was largely confined to the pyramidal neurones of the cerebral cortex and the Purkinje cells of the cerebellum with increasing receptor expression evident with gestational age. Semiquantitative observer scoring showed that by the second trimester, there was a marked increase in the proportion of pyramidal and Purkinje cells expressing TR isoforms, while by the third trimester, all these cells immunostained. Comparison of TR immunostaining in the cerebral cortex and cerebellum from IUGR fetuses (n = 18) matched for gestational age to normal fetuses revealed a lower intensity of expression of all the TR isoforms confirmed by observer scoring and quantification using TR protein immunofluoresence (P<0.01). CONCLUSIONS: Our findings indicate both pre- and post-translational expression of TR alpha and beta isoforms in the cerebral cortex of first trimester fetuses. These findings support the view that the transplacental passage of thyroid hormone in early gestation may be critical to neurological development. Our finding that in severe IUGR the expression of TR isoforms in the human fetal cerebral cortex and cerebellum was significantly reduced, in association with reduced circulating thyroid hormone concentrations indicate that changes in free ligand and receptors may affect CNS development. These findings should prompt further investigation of the potential therapeutic role of peripartum thyroid hormone treatment.

Case-Control Studies↗
PubMed2000

Age and gender predict the outcome of treatment for Graves' hyperthyroidism.

The response to treatment in Graves' hyperthyroidism is unpredictable, and factors postulated to predict outcome have not generally proved clinically useful or been widely adopted in clinical practice. We audited outcome in 536 patients with Graves' hyperthyroidism presenting consecutively to determine whether simple clinical features predict disease presentation and response to treatment. At presentation males had slightly more severe biochemical hyperthyroidism [free T4: males, 64.3 +/- 3.0 pmol/L (mean +/- SE); females, 61.3 +/- 1.7 (P = 0.45); free T3: males, 24.3 +/- 1.5 pmol/L; females, 21.0 +/- 0.6, (P = 0.04)]. Patients less than 40 yr at diagnosis had more severe hyperthyroidism than patients more than 40 yr old [free T4: <40 yr, 64.3 +/- 2.0; >40 yr, 56.7 +/- 2.3 (P = 0.02); free T3: <40 yr, 22.8 +/- 0.8; >40 yr, 19.0 +/- 0.9 (P = 0.003)]. Males had a lower remission rate than females after a course of antithyroid medication [19.6% vs. 40%; odds ratio, 0.37; 95% confidence interval (CI), 0.17-0.79; P < 0.01]. Similarly, patients aged less than 40 yr had a lower remission rate than older patients (32.6% vs. 47.8%; odds ratio, 0.53; 95% CI, 0.32-0.87; P = 0.01). One dose of radioiodine cured hyperthyroidism in fewer males than females (47% vs. 74%; P < 0.0001). Logistic regression analysis demonstrated male sex (odds ratio, 2.80; 95% CI, 1.31-5.98; P = 0.008), serum free T4 concentration at diagnosis (odds ratio, 1.02; 95% CI, 1.0-1.04; P = 0.01), and dose of radioiodine administered (odds ratio, 0.99; 95% CI, 0.99-1.00; P = 0.001) were contributing factors associated with failure to respond to a single dose of radioiodine. As males and younger patients are more likely to fail to respond to medical treatment, and male patients are likewise less likely to respond to a single dose of radioiodine, we suggest that those groups with low remission rates should be offered definitive treatment with radioiodine or surgery soon after presentation and that the value of higher initial doses of radioiodine in males be evaluated.

Adolescent↗
PubMed2000

A heterozygous deletion of the autoimmune regulator (AIRE1) gene, autoimmune thyroid disease, and type 1 diabetes: no evidence for association.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic autoimmune disease with endocrine components including type 1 diabetes, adrenal failure, and thyroid dysfunction, with major autoantibodies directed against adrenal, pancreas, and thyroid tissue. A 13-bp deletion in exon 8 of the autoimmune regulator (AIRE1) gene on chromosome 21q22.3 accounts for more than 70% of mutant alleles in United Kingdom subjects with APECED. To determine whether this polymorphism contributes to disease susceptibility in subjects with autoimmune disease in general, we screened 302 patients with Graves' disease, 154 patients with autoimmune hypothyroidism, 235 patients with type 1 diabetes, and 318 control subjects for the 13-bp deletion of the AIRE1 gene. The mutation was present in only 1 (0.33%) patient with Graves' disease, 1 patient with autoimmune hypothyroidism (0.6%), and 1 (0.315) of the control subjects. No patients with type 1 diabetes were found to carry the mutation. We conclude, therefore, that the 13-bp deletion of the AIRE1 gene is not a susceptibility locus for the more common autoimmune endocrinopathies in the United Kingdom.

Chromosomes, Human, Pair 21↗
PubMed2000

Tissue-specific regulation of thyroid hormone receptor mRNA isoforms and target gene proteins in domestic ducks.

Skeletal muscles are important target tissues for thyroid hormone action. The present study examines the influence of thyroid status on muscle growth and tissue-specific expression of thyroid receptor (TR) mRNA isoforms in a commercial strain of the domestic duck (Anas platyrhynchos). Four groups (n=5) of 1-week-old ducklings were rendered either hypothyroid by treatment with methimazole (6 mg 100 g(-1) body mass or 12 mg 100 g(-1) body mass), or hyperthyroid by treatment with methimazole (6 mg 100 g(-1) body mass) in combination with thyroid hormones (5 microg thyroxine (T(4)) and tri-iodothyronine (T(3)) 100 g(-1) body mass or 10 microg T(4) and T(3) 100 g(-1) body mass). Serum and tissue samples (cardiac, pectoralis and semimembranosus leg muscle, liver, pituitary and cerebral cortex) were collected from these four groups, and from a group of untreated controls, at 8 weeks of age. Development of duckling morphology was retarded in methimazole-treated birds compared with that in euthyroid controls, as evidenced by differences in skeletal dimensions, primary feather length, and body and muscle masses. Body mass was lower by 18%, and relative masses of cardiac and pectoralis muscles were lower by 28% and 32% respectively. Heterologous oligonucleotides for TR alpha, TR beta 0, TR beta2 and the housekeeping gene beta-actin were derived from chicken sequences. RT-PCR showed that TR alpha mRNA was expressed in all tissues but was not significantly affected by any of the experimental treatments. TR beta 0 mRNA expression was significantly lower in the leg muscles of ducklings treated with 12 mg methimazole 100 g(-1) body mass (0.109+/-0.047 TR:beta-actin ratio, P<0.05) compared with that in euthyroid controls (0.380+/-0.202), but was unaltered in the pectoralis and cardiac muscles. Expression of TR beta 0 mRNA was significantly higher in pectoralis (by 3.5-fold, P<0. 05), cardiac (by 4.2-fold, P=0.003) and leg (by 4.0-fold, P<0.001) muscles of ducklings treated with thyroid hormones compared with those in euthyroid controls (0.098+/-0.019, 0.822+/-0.297 and 0. 38+/-0.202 TR:beta-actin respectively). Only the pituitary gland expressed significant levels of TR beta 2 mRNA.

Animals↗
PubMed1999

Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study.

BACKGROUND: Radioiodine is used increasingly as first-line treatment for hyperthyroidism, but concerns remain about subsequent risk of cancer, especially in those treated at a young age. We investigated cancer incidence and mortality in patients treated with radioiodine for hyperthyroidism. METHODS: We did a population-based study in 7417 patients treated in Birmingham, UK, between 1950 and 1991. We compared details of all cancer diagnoses and deaths in 1971-91 from the UK Office for National Statistics with data on cancer incidence and mortality for England and Wales specific for age, sex, and period. FINDINGS: During 72,073 person-years of follow-up, 634 cancer diagnoses were made, compared with an expected number of 761 (standardised incidence ratio [SIR] 0.83 [95% CI 0.77-0.90]). The relative risk of cancer mortality was also decreased (observed cancer deaths 448, expected 499; standardised mortality ratio [SMR] 0.90 [0.82-0.98]). Incidence of cancers of the pancreas, bronchus, trachea, bladder, and lymphatic and haemopoietic systems was lowered. Mortality from cancers at all these sites was also reduced but findings were significant only for bronchus and trachea. There were significant increases in incidence and mortality for cancers of the small bowel (SIR 4.81 [2.16-10.72], SMR 7.03 [3.16-15.66]) and thyroid (SIR 3.25 [1.69-6.25], SMR 2.78 [1.16-6.67]), although absolute risk of these cancers was small. INTERPRETATION: The decrease in overall cancer incidence and mortality in those treated for hyperthyroidism with radioiodine is reassuring. The absolute risk of cancers of the small bowel and thyroid remain low, but the increased relative risk shows the need for long-term vigilance in those receiving radioiodine.

Aged↗
PubMed1999

Estrogen receptor beta mRNA expression in normal and adenomatous pituitaries.

Estrogen (E2), acting via its nuclear receptors, has been implicated in tumor development and growth, particularly in the pathogenesis of breast cancer. E2 also modulates anterior pituitary hormone production and is a potent cell mitogen. Until recently, the actions of E2 were thought to be mediated by a single estrogen receptor (ER) isoform (ER alpha), and currently little is known of the pathophysiological relevance of the ER beta isoform. The presence of ER beta mRNA has been demonstrated by RT-PCR in the normal human pituitary, although expression of ER beta mRNA in human pituitary tumors has now been described. We have used semiquantitative RT-PCR to determine the relative levels of expression of ER beta mRNA in normal human pituitaries, non-functioning pituitary adenomas and GH-secreting tumors. ER beta mRNA was detected in normal pituitaries and all pituitary tumors examined. The ratio of ER beta mRNA to beta-actin mRNA expression was significantly reduced in non-functioning pituitary tumors (NFTs; 0.92 +/- 0.09; mean +/- SE; n = 23) compared with findings in normal pituitaries (1.56 +/- 0.21; mean +/- SE; n = 5; p < 0.05 Student's t-test). Studies of ER beta protein expression are required to determine the functional significance of reduced ER beta mRNA expression in NFTs.

Adenoma↗
PubMed1999

Increased MEN1 mRNA expression in sporadic pituitary tumours.

BACKGROUND: The MEN1 gene on chromosome 11q13 encodes a tumour suppressor gene, mutations in which cause multiple endocrine neoplasia (MEN) type 1 syndrome. Loss of heterozygosity (LOH) at this locus is a common finding amongst sporadic pituitary tumours. We have therefore screened the MEN1 gene for mutations in sporadic pituitary tumours and, as the gene is a putative tumour suppressor, have quantified mRNA expression in tumorous and normal pituitaries to assess the role of MEN1 in pituitary tumorigenesis. SUBJECTS AND DESIGN: Thirty-one nonfunctioning pituitary tumours, 8 GH secreting, 2 TSH-secreting tumours and 1 corticotrophinoma have been assessed for the presence of MEN1 mutations, to examine the hypothesis that MEN1 mutations may contribute to the pathogenesis of sporadic pituitary neoplasms. In addition, quantitative changes in the pretranslational expression of the tumour suppressor gene MEN1 have been determined in 42 pituitary tumours and 6 normal pituitaries using semiquantitative reverse transcriptase PCR. RESULTS: No novel or previously published mutations were apparent in the MEN1 coding regions of any tumours studied, although several polymorphisms were identified. Transcriptional changes of the gene, assessed by semiquantitative RT-PCR, indicated that nonfunctioning and GH-secreting pituitary tumours are associated with significantly increased pretranslational expression of the MEN1 gene. In addition, the single corticotrophinoma showed increased expression compared to normal, as did one of the two TSH-omas. CONCLUSION: Coding mutations of the putative tumour suppressor gene MEN1 are unlikely to contribute to pituitary tumorigenesis in sporadic nonfunctioning, GH-secreting and TSH-secreting adenomas. Changes in pretranslational expression of MEN1 were observed in pituitary tumours, suggesting that changes in the level of MEN1 expression, rather than coding changes, may be of functional importance in influencing sporadic pituitary tumorigenesis.

Adenoma↗
PubMed1999

Association of the large multifunctional proteasome (LMP2) gene with Graves' disease is a result of linkage disequilibrium with the HLA haplotype DRB1*0304-DQB1*02-DQA1*0501.

OBJECTIVE: The large multifunctional proteasome (LMP) molecules are over expressed in thyrocytes, the target cells of Graves' disease, and the LMP genes are found within the MHC class II region. The LMP genes may therefore play a role in susceptibility to Graves' disease. The aim of this this study was to determine whether polymorphisms of the LMP genes, LMP 2 and LMP 7 are in linkage disequilibrium with Graves' disease. DESIGN: Target DNA was amplified using the polymerase chain reaction. The distribution of an Arg-His polymorphism in the LMP 2 gene and a G/T polymorphism in the LMP 7 gene, both of which lead to the presence of an HhaI restriction site, were investigated in a population based case control and family based study in patients with Graves' disease. PATIENTS: We obtained DNA from 306 patients with Graves' disease and 364 control subjects for the population based case-control study. In an independent family based study, DNA was obtained from 129 families including both parents, an affected sibling with Graves' disease and an unaffected sibling. All families, patients and control subjects were white caucasians. MEASUREMENTS: Frequencies of the alleles and genotypes of the LMP 2 and LMP 7 genes were compared between patients and control subjects using the chi2 test. Transmission of alleles from heterozygous parents to affected and unaffected offspring was assessed using the transmission disequilibrium test (TDT). RESULTS: In the case control study, no difference in allele or genotype frequency was seen between patients and control subjects at the LMP7 locus. At the LMP2 locus the R allele and the RH genotype were increased in subjects with Graves' disease when compared with control subjects (R allele: 36.3% vs. 29.5%, pc = 0. 0164; RH genotype: 56.5% vs. 45%, pc = 0.0102). However, the R allele was in linkage disequilibrium with the associated HLA DRB1*0304-DQB1*02-DQA1*0501 haplotype, delta = 0.102. Within the family based study, no preferential allelic transmission was seen from heterozygote parents to offspring at either loci. CONCLUSION: These results show that association of the LMP 2 locus with Graves' disease is due to linkage disequilibrium with the associated HLA haplotype DRB1*0304-DQB1*02-DQA1*0501.

Case-Control Studies↗
PubMed1999

Gender, clinical findings, and serum thyrotropin measurements in the prediction of thyroid neoplasia in 1005 patients presenting with thyroid enlargement and investigated by fine-needle aspiration cytology.

One thousand five euthyroid patients (870 females and 135 males, mean age 47 years), who presented with thyroid enlargement were evaluated by fine-needle aspiration cytology (FNAC) of the thyroid as the first-line investigation. The final cytological or histological diagnosis was determined after surgery (n = 312) or clinical follow-up for a minimum period of 2 years (range 2-14 years, mean 6.7 years). Goiter type was assessed clinically and was classified as diffuse in 147, multinodular in 247, or solitary nodule in 611. The overall sensitivity and specificity of the procedure in the detection of thyroid neoplasia was 88% and 89%, respectively. Males who presented with thyroid enlargement had significantly higher rates of malignancy (p = 0.007) and neoplasia (benign + malignant) (p = 0.002) than females, as did subjects with solitary nodule compared with diffuse or multinodular goiters (malignancy p = 0.001, neoplasia p < 0.001). Subjects with normal thyrotropin (TSH) (>0.4 mU/L) at presentation had a nonsignificantly increased risk of thyroid neoplasia (p = 0.07) and malignancy, in contrast to those with low TSH (<0.4 mU/L). We confirmed FNAC of the thyroid to be an accurate test in the detection of thyroid neoplasia. Gender and goiter type at presentation both contribute significantly to the prediction of the diagnosis of thyroid neoplasia.

Adolescent↗
PubMed1999

The A-G polymorphism in exon 1 of the CTLA-4 gene is not associated with systemic lupus erythematosus.

OBJECTIVES: Factors contributing to the development of systemic lupus erythematosus (SLE) remain largely unknown although are likely to include both environmental and genetic components. Studies on murine lupus have indicated a role for an antibody that blocks binding of cytotoxic T lymphocyte associated-4 (CTLA-4) to B7 on antigen presenting cells in the treatment of disease, suggesting that CTLA-4 may play an important part in the disease process. This study, therefore, investigated the frequency of a previously described A-G polymorphism in exon 1 of the CTLA-4 gene, the G allele of which has shown to be associated with both Graves' disease and type I diabetes, to determine whether this polymorphism was playing a part in the development of SLE. METHODS: One hundred and twenty six SLE patients and 363 control subjects were genotyped for the A-G polymorphism in exon 1 of the CTLA-4 gene. Target DNA was amplified using the polymerase chain reaction and the resulting product was digested using the BbvI restriction enzyme. RESULTS: No differences in allele or genotype frequencies were observed between patients with SLE and control subjects. CONCLUSION: These data suggest that the A-G polymorphism in exon 1 of the CTLA-4 gene does not play a part in the genetic susceptibility to the development of SLE.

Abatacept↗
PubMed1999

Thyroid receptor alpha1 and alpha2 mutations in nonfunctioning pituitary tumors.

We previously reported that nonfunctioning tumors of the anterior pituitary exhibit reduced expression of thyroid receptor (TR) alpha and beta isoforms, an observation that may account for abnormalities of T3-mediated negative regulation of the glycoprotein hormone common alpha-subunit. Reduced TR protein was associated with a parallel reduction in TRbeta messenger RNA (mRNA), although TRalpha1 and alpha2 mRNA levels were similar in nonfunctioning tumors and normal pituitaries. Because TRalpha shows aberrant posttranscriptional processing, and TRbeta is under ligand-dependent autoregulation, we hypothesized that aberrant TR expression in nonfunctioning tumors may reflect mutation in receptor coding and regulatory sequences, and therefore screened TRalpha mRNA and TRbeta T3 response elements and ligand binding domains for sequence anomalies. Screening TRalpha mRNA in 23 tumors and subsequently sequencing candidate fragments identified one silent change from published sequences and three novel missense mutations, two in the common TRalpha region (ser45ile and lys370asn) and one that was alpha2 specific (ser377leu). TRbeta response elements failed to show any differences from published sequences in 14 nonfunctioning tumors. Sequencing of TRbeta ligand binding domains were also identical to wild type in 23 nonfunctioning tumors. The functional significance of the novel TRalpha mutations is unknown; definition of mutant TR action may provide insight into the role of TRs in the growth control of pituitary cells.

Adult↗
PubMed1999

The development of Graves' disease and the CTLA-4 gene on chromosome 2q33.

Case-control studies suggest that the CTLA-4 gene may be a susceptibility locus for Graves' disease. The previously reported A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene was, therefore, investigated in a case-control (n = 743) and family-based (n = 179) dataset of white Caucasian subjects with Graves' disease. The relationship between CTLA-4 genotype and severity of thyroid dysfunction at diagnosis was also investigated. An increase in frequency of the G (alanine) allele was seen in Graves' patients compared with control subjects (42% vs. 31.5%, respectively; corrected P<0.0002; odds ratio = 1.58), and a significant difference in the distribution of GG, GA, and AA genotypes was observed between the groups (chi2 = 21.7; corrected P<0.00003). Increased transmission of the G allele was seen from heterozygous parents to affected offspring compared to unaffected offspring (chi2 = 5.7; P = 0.025). Circulating free T4 concentrations at diagnosis were significantly associated with CTLA-4 genotype (F = 3.26; P = 0.04). These results support the hypothesis that CTLA-4 may play a role in regulating self-tolerance by the immune system and in the pathogenesis of autoimmune disorders such as Graves' disease.

Abatacept↗