bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation, management and therapeutic outcome in 12 cases of childhood and adolescent Cushing's syndrome
Authors: Weber A. , Trainer P. J. , Grossman A. B. , Afshar F. , Medbak S. , Perry L. A. , Plowman P. N. , Rees L. H. , Besser G. M. , Savage M. O. 
Published: March 2008

SummaryOBJECTIVE Cushing's syndrome In childhood and adolescence Is rare. We analysed the clinical presentation, Investigation, management and therapeutic outcome In 12 paediatric patients with Cushing's syndrome.DESIGN Retrospective review of case notes.PATIENTS Twelve patients, 7 males and 5 females, aged 7.6‐17.8 years with Cushing's syndrome who were admitted to St Bartholomew's Hospital between 1978 and 1993, were studied. Aetiologies of the Cushing's syndrome patients were: Cushing's disease (9), adrenal adenoma (1), nodular adrenocortical dysplasia (1) and ectopic ACTH syndrome (1). One further male patient, aged 17.8 years who presented with Nelson's syndrome after bilateral adrenalectomy for Cushing's disease In 1978, Is described.MEASUREMENTS Presenting symptoms, endocrine tests for hypercortlsolism, Imaging studies, simultaneous bilateral Inferior petrosal sinus sampling and therapeutic strategies are discussed.RESULTS The dominant clinical features were obesity, short stature, virillzation, headaches, fatigue and emotional lability. Investigations confirmed Cushing's syndrome by demonstrating absent Cortisol clrcadlan rhythm and Impaired suppression on low dose dexa‐methasone test and differentiated Cushing's disease from other aetiologies by high dose dexamethasone and hCRH tests. In Cushing's disease, pituitary CT scan Identified a microadenoma In 4 out of 9 subjects. In 5 of the 9 patients (3 with a normal pituitary CT, 2 with a suggested microadenoma), a pituitary MRI scan was performed and confirmed the CT findings. Inferior petrosal sinus catheterization for ACTH In 4 patients confirmed excess pituitary ACTH secretion, correctly lateralizing the tumour In all cases. Cushing's disease was treated by transsphenoidal surgery alone In 6 patients and combined with pituitary Irradiation In 3 patients. Of these 9 patients, 7 are cured and 2 are in remission. The patient with Nelson's syndrome Is cured after total hypophysectomy.CONCLUSIONS This series describes the clinical features, aetiologies and management of juvenile Cushing's syndrome. Investigation with low and high‐dose dexamethasone suppression tests and hCRH test identified the aetiology In each case. Collaboration between paediatric and adult endocrine units together with an experienced neurosurgeon and a radiotherapist contributed to the successful therapeutic outcome of these patients
Low frequency of germline mutations in the RET proto‐oncogene in patients with apparently sporadic medullary thyroid carcinoma
Authors: Eng Charls , Mulligan Lois M. , Smith Darrin P. , Healey Catherine S. , Frilling Andrea , Raue Friedhelm , Neumann Hartmut P.H. , Ponder Margaret A. , Ponder Bruce A.J. 
Published: March 2008

SummaryBACKGROUND AND OBJECTIVES Medullary thyroid carcinoma (MTC) occurs both sporadically and In the autosomal domlnantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical managment of both the patient and family. The susceptibility gene for MEN 2 is theRET proto‐oncogene. Systematic analysis for germ‐line mutations of theRET proto‐oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases.DESIGN AND PATIENTS Sixty‐seven unselected patients with sporadic MTC were randomly ascertained from clinic patients from four centres. The diagnosis of MTC was confirmed by hlstopathology. Germline DNA was extracted from peripheral blood leucocytes or from paraffin‐embedded tissue and subsequently used for polymerase chain reaction amplification.MEASUREMENTS Polymerase chain reaction basedRET mutation analysis was performed by direct double‐stranded cycle sequencing of axons 10, 11, 13 and 16, within which the majority ofMEN2 mutations have been shown to occur.RESULTS In this series, there was one proven case of germline mutation InRET codon 620, which previously has been shown to be responsible for MEN 2, thus Indicating heritable disease. No germline mutation in codon 918, typical of MEN 2B, was found.CONCLUSIONS A figure of 1.5% germline mutations In 67 apparently sporadic MTC Is lower than the incidence of familial disease reported in previous series Involving clinical and biochemical screening. The presence of a germline mutation in theRET proto‐oncogene in a patient with MTC indicates heritable disease. The absence of germlineRET exon 10,11,13 or 16 mutation appears to rule out MEN 2A to a high probability, although the presence of a familial form of MTC other than classical MEN 2A cannot be excluded conclusively.
Growth stimulating antibodies in endemic goitre: a reappraisal
Authors: Davies R. , Lawry J. , Bhatia V. , Weetman A. P. 
Published: March 2008

SummaryOBJECTIVE Previous studies, using a variety of methods, have reported growth‐promoting Immunoglobulins (IGs) In a large proportion of patients with endemic goitre. We sought to determine whether thyroid growth‐promoting Immunoglobulins (TGI) are present in the serum of Indian patients with endemic goitre.DESIGN IgG was prepared by protein G‐Sepharose affinity purification and added to FRTL‐5 thyroid cells In the presence of suboptimal concentrations of TSH.PATIENTS We studied 30 sequential patients with endemic goitre and 16 euthyroid controls without a goitre from the same areaMEASUREMENTS Two assays for thyroid cell growth were used: 3H‐thymldine Incorporation, and flow cytometric measurement of the proportion of cells in the S phase and G2/M phase of the cell cycle.RESULTS Both assays were shown to detect growth produced by TSH and by thyroid stimulating antibodies in IgG preparations from 3 patients with Graves' disease. There was no significant Increase In either 3H‐thymldine Incorporation or the distribution of cells In S or G2/M phase with IgGs from endemic goitre patients, and no difference between the effects of these IgGs and those from the normal subjects.CONCLUSIONS Thyroid growth‐promoting immunoglobulins cannot be detected In Indian patients with endemic goitre.
Temperature‐induced down‐regulation of the glucocorticoid receptor in peripheral blood mononuclear leucocyte in patients with sepsis or septic shock
Authors: Molijn G. J. , Koper J. W. , van Uffelen C. J. C. , de Jong F. H. , Brinkmann A. O. , Bruinlng H. A. , Lamberts S. W. J. 
Published: March 2008

SummaryOBJECTIVE Activation of the hypothalamic‐pituitary‐adrenal axis is of vital importance during critical Illness. We have studied the adaptive mechanisms which occur at the level of the glucocorticoid receptor in glucocorticoid target tissues in patients with sepsis or septic shock.DESIGN The effects of hypercortlsolaemia, hyperthermia and cellular composition on number of glucocorticoid receptors per cell and their affinity were evaluated, both In vitro and In vivo, In peripheral blood mononuclear leucocytes of control subjects and In patients with sepsis or septic shock.SUBJECTS Fifteen patients (age 25‐79) with sepsis or septic shock who were admitted to an Intensive care unit were studied. The control group consisted of 24 healthy laboratory employees.MEASUREMENTS The binding capacity and affinity of the glucocorticoid receptors were measured and compared to clinical data and the plasma Cortisol concentrations.RESULTS Hypercortlsolaemia, in vitro, resulted in a decreased affinity and a decreased binding capacity of the glucocorticoid receptor. In vitro, hyperthermia as well as variations In the cellular composition did not Influence the glucocorticoid receptor. In vivo, there was no change In the number of receptors per cell In patients with sepsis or septic shock as compared to healthy controls. However, a decreased affinity of the glucocorticoid receptor was observed. There was a weak but significant negative correlation between body temperature and the number of glucocorticoid receptors In the patient group. There was no relation between circulating Cortisol concentrations and glucocorticoid receptor affinity and number.CONCLUSIONS There Is no obvious regulation of the number of glucocorticoid receptors by plasma Cortisol concentrations In vivo.The decreased affinity of the glucocorticoid receptor together with the negative correlation between hyperthermia and the number of glucocorticoid receptors In patients with sepsis or septic shock suggest that hypo‐thalamlc‐pitultary‐adrenal axis activation during critical illness Is accompanied by peripheral adaptation in glucocorticoid receptor number and affinity.
MELAS syndrome associated with diabetes mellitus and hyperthyroidism: a case report from Taiwan
Authors: Yang Chwen‐Yi , Lam Hing‐Chung , Lee Hsin‐Chen , Wei Yau‐Huel , Lu Chlh‐Chen , Han Tlan‐Mu , Tsalt Jin‐Llan , Chuang Yen‐Hwang , Lee Jenn‐Kuen 
Published: March 2008

SummaryMELAS syndrome Is a form of mitochondrial myopathy with manifestations of seizure, stroke‐like syndrome, lactic acidosis, ragged red muscle fibres and mitochondrial encephalopathy. The syndrome has been reported in association with a variety of endocrine and metabolic disorders Including diabetes mellitus (DM), hypothalamo‐pituitary hypofunction, hypothalamic growth hormone deficiency and delayed puberty. Mitochondrial DNA (mtDNA) point mutation may be the major pathological defect. However, association of MELAS syndrome with hyperthyroidism has not previously been reported. A case Is reported from Taiwan of a 32‐year‐old woman suffering from MELAS syndrome with associated DM and hyperthyroidism. When the latter was diagnosed In April 1988, the patient underwent subtotal thyroidectomy. There was no family history of thyroid disease. Because of repeated seizures, she had computed tomography (CT) and magnetic resonance Imaging (MRI) of the brain which showed focal, low‐density lesions over the cerebral hemispheres. Both serum and cerebral spinal fluid lactic acid levels were elevated. Mild elevations of serum T4 and T3 and a high titre of TSH receptor antibody were still present. Hyperglycaemla was noted during hospitalization and DM confirmed by oral glucose tolerance test. Muscle biopsy showed ragged red fibres. DNA analysis showed an A‐to‐G transition at the 3243rd nucleotide position of the tRNALeu(uur)gene of the mtDNA from the patient. Quantitative polymerase chain reaction (PCR) and restriction analysis revealed that about 60% of the blood mtDNA was of mutant type. The patient received antithyroid drugs for hyperthyroidism, diet control for DM and anti‐epileptic drugs for seizure.
Mineralocorticoid hypertension and congenital deficiency of 11β‐hydroxysteroid dehydrogenase in a family with the syndrome of‘apparent’mineralocorticoid excess
Authors: Mllford David V. , Shackleton Cedrlc H. L. , Stewart Paul M. 
Published: March 2008

SummaryThe so‐called syndrome of‘apparent mineralocorticoid excess’(AME) Is a rare cause of endocrine hypertension thought to result from a defect In the peripheral conversion of Cortisol to cortisone. Less than 30 cases have been described. From a consanguineous marriage we present a family comprising 2 and probably 3 affected cases of AME. The index case is a 4‐year‐old boy with mineralocorticoid hypertension, short stature, failure to thrive, hypokalemic nephropathy and osteopenia. The ratio of the urinary excretion of tetrahydrocortisone/tetrahydro‐cortisols was reduced at 0‐05 (reference range 1.77‐2.11), and the plasma half‐life of 3H‐11α‐cortisol elevated at 152 minutes (reference range 30‐50) indicative of severe 11β‐hydroxysterold dehydrogenase deficiency. Plasma Cortisol concentrations were normal and dally secretion rate reduced. Dexamethasone administration induced a natriuresis in keeping with the observation that Cortisol itself is the implicated mineralocorticoid. Treatment with amiloride lowered blood pressure, increased potassium levels, and resulted in an Increase In growth rate.The boy's twin brother died at the age of 3‐5 years following a trivial diarrhoeal illness and was almost certainly affected. AME was also diagnosed in a younger brother (age 17 months), but both parents are normal.Congenital deficiency of 11β‐hydroxysterold dehydrogenase should be considered in any child with mineralocorticoid hypertension and failure to thrive. As Cortisol is the‘offending’mineralocorticoid in this condition, the term‘apparent’mineralocorticoid excess Is perhaps obsolete. The cloning of renal isoforms of 11β‐HSD should facilitate the description of the molecular basis of this condition.
Menstrual disturbance and hypersecretion of progesterone in women with congenital adrenal hyperplasia due to 21‐hydroxylase deficiency
Authors: Hoimes‐Walker D. J. , Conway G. S. , Honour J. W. , Rumsby G. , Jacobs H. S. 
Published: March 2008

SummaryOBJECTIVE While menstrual disturbance is often quoted as a feature of congenital adrenal hyperplasia (CAH), little is known about the mechanism of this symptom. We set out to determine the relationship between menstrual pattern and biochemical characteristics of women with CAH due to 21‐hydroxylase deficiency.PATIENTS AND DESIGN All 21 female patients with classic CAH attending the adult endocrinology clinics at The Middlesex Hospital were reviewed. Their ages at menarche and menstrual pattern were recorded and blood samples were taken in the follicular phase of the menstrual cycle when on their usual maintenance therapy.MEASUREMENTS Measurements Of serum LH, FSH, progesterone, 17α‐hydroxyprogesterone, testosterone, androstenedione and plasma renin activity were recorded. Urinary steroid profiles were obtained by gas chromatography and mass spectrometry. Molecular genetic analysis of the 21‐hydroxylase gene was performed on leucocyte DNA.RESULTS In the 18 patients who had spontaneous menarche the degree of menstrual disturbance and progesterone excess was related to the effectiveness of adrenal suppressive therapy. Three out of 21 patients, however, failed to experience menarche on standard medical therapy. These patients with primary amenorrhoea were characterized by reduced endometrial thickening, by non‐suppressible serum progesterone concentrations despite suppression of 17α‐hydroxyprogesterone levels and by the presence of progesterone metabolites in urinary steroid profiles. Molecular genetic analysis did not differentiate between patients with raised progesterone concentrations and those without.CONCLUSION A subgroup of women with congenital adrenal hyperplasia have the triad of non‐suppressible serum progesterone of adrenal origin, primary amenorrhoea and Infertility due to failure of endometrial thickening. The characteristic urinary steroid profile best distinguishes this subgroup of women from others with Congenital adrenal hyperplasia and menstrual disturbance due to inadequate adrenal suppression.
Prevalence of an immunological LH β‐subunit variant in a UK population of healthy women and women with polycystic ovary syndrome
Authors: Rajkhowa M. , Taibot J. A. , Jones P. W. , Pettersson K. , Haavisto A. M. , Huhtaniemi I. , Clayton R. N. 
Published: March 2008

SummaryOBJECTIVE An Immunological LH β‐subunit variant has been described, which is undetectable using monoclonal antibodies directed to the intact LH molecule alone. Subjects have been found homozygous or heterozygous for nucleotide mutations within codons 8 and 15 in the LH β‐subunit gene. The prevalence of the variant LH β‐subunit has been estimated in a healthy UK population of women of reproductive age and in women with polycystic ovary syndrome (PCOS). The relationship of the variant molecule to the clinical and hormonal parameters of the subjects has been evaluated.DESIGN The control and PCOS subjects were screened for the presence of the mutation by using a ratio of two immunofluorometric assays using monoclonal antibodies (Mab). One assay, not detecting the LH variant, uses a Mab directed to the intact LH molecule and a β‐specific Mab. The other assay, detecting both the variant and wildtype LH, uses two β‐subunit specific Mabs. The mutations in the LH β‐subunit gene were confirmed by restriction fragment length polymorphism. The relationship of the presence of the variant to the clinical and hormonal parameters was assessed by ANOVA.PATIENTS Two hundred and twelve normal ovulatory women, of whom 86 (31%) were obese (body mass Index >25) and 146 (69%) non‐obese, and 153 women with PCOS, 115 (75%) obese and 38 (25%) non‐obese participated in the study.RESULTS The variant LH was detected In 31 (15%) controls and 32 (21%) PCOS subjects (P=0.124) using specific Mab. Obese PCOS had a higher incidence of the heterozygous LH variant compared to obese controls (odds ratio 2.5, P=0.03), and compared to non‐obese PCOS (odds ratio 6.3, P= 0.01). The previously described two mutations in codon 8 and codon 15 were present in all subjects detected to be mutant hetero or homo‐zygous by RFLP. There was no relationship between the presence of the variant LH and the clinical and hormonal parameters In the PCOS subjects; however, in the controls the presence of the variant LH was associated with a higher serum total testosterone (P=0.046), oestradiol (P=0.03) and SHBG (P=0.002).CONCLUSIONS The results of this study show that the variant LH β‐subunit is a common polymorphism occurring in 15% of a healthy UK population of women. The prevalence was not higher in women with PCOS, though it was over represented in obese women with PCOS. The presence of the variant did not alter the clinical or hormonal expression of the disorder in women with PCOS. Its presence in the controls was however associated with higher serum oestradiol and probably secondary elevation of SHBG and testosterone, suggesting that the variant form of LH may be associated with subtle changes in the function of the hypothalamic‐pituitary‐gonadal axis.
Nifedipine, but not verapamil, acutely elevates parathyroid hormone levels in premenopausal women
Authors: Wynne Alan O. , Romanskl Susan A. , Klee George G. , Ory Steven J. , O'Fallon William M. , Fitzpatrick Lorraine A. 
Published: March 2008

SummaryBACKGROUND Calcium channel antagonist therapy in humans has been associated with changes In anterior pitultary, thyroid and adrenal hormone secretion. Human studies assessing effects of calcium channel antagonists on calclotropic hormones have been few and typically involved small numbers of subjects studied for short periods of time. Few of these previously published studies have included women. The endocrine effects of calcium channel antagonists in women have become increasingly important as more women are taking these agents for diseases such as hypertension, angina, Raynaud's phenomenon and migraine.OBJECTIVE To assess both acute and chronic effects of calcium channel antagonists on calclotropic hormones in women.DESIGN A four‐week prospective, randomized trial.SUBJECTS Twenty‐nine premenopausal women, randomly assigned to receive either 240 mg of sustained release verapamil or 30 mg of sustained release nifedipine daily.LABORATORY END‐POINTS Total and ionized serum calcium, phosphate, creatinine, parathyrold hormone (PTH), parathyroid hormone‐related protein (PTHrP) and calcitonin, measured at baseline, after 24 hours, and 28 days of treatment.RESULTS Total and ionized calcium, phosphate, creatinine, PTHrP and calcitonin levels were not altered significantly after 24 hours or 28 days in any of the subjects, when compared to baseline. There were no significant differences in PTH levels after 24 hours or 28 days of verapamil treatment. There was a significant increase in serum PTH levels after 24 hours of nifedipine therapy; however, these differences were not evident after 28 days of therapy.CONCLUSIONS The short‐term administration of nifedipine results in increased release of parathyroid hormone; however, long‐term administration has no significant effect on the concentrations of calclotropic hormones.
Absence of mutations in the MEN2A region of the ret proto‐oncogene in non‐MEN 2A phaeochromocytomas
Authors: Chew S. L. , Lavender P. , Jain A. , Weber A. , Ross R. J. M. , Wass J. A. H. , Besser O. M. , Clark A. J. L. 
Published: March 2008

SummaryOBJECTIVE To determine the presence of abnormalities of the MENZA region of the ret proto‐oncogene in phaeochromocytomas/paragangllomas (PHAEO) of different aetiologies.DESIGN Total RNA was extracted from tumours and used as templates for reverse transcriptase polymerase chain reactions. A ret primer pair, which encompasses the region which is mutated in the germ‐line of patients with MEN 2A, was used. The resulting 262‐bp product was sequenced.PATIENTS Ten PHAEOs were examined. Four tumours were from von Hippel‐Lindau disease patients; five were sporadic, Isolated tumours; one from a patient with multiple endocrine neoplasia type 2A (MEN 2A). The medullary thyroid cancer from the single MEN 2A patient was also examined.RESULTS A heterozygous TGC to CGC mutation of codon 634 (cysteine to arginine) was found In the PHAEO and medullary thyroid cancer from the MEN 2A patient. The 262‐bp ret fragment was not found in two tumours (one malignant PHAEO and one secretory paraganglloma), although the Intra‐cellular ret tyrosine kinaw domain was detected in these tumours. The cysteine codons were normal in all other non‐MEN 2A PHAEOs.CONCLUSION Mutations of key cysteine codons of the ret proto‐oncogene may be specific to MEN 2A.
Natural history of thyroid associated ophthalmopathy
Authors: Perros Petros , Cromble Alex L. , Kendall‐Taylor Pat 
Published: March 2008

SummaryBACKGROUND The natural history of thyroid associated ophthalmopathy is poorly documented, although It is widely thought that many cases Improve spontaneously with time. This has Important Implications in the management of patients and is also a critical factor when assessing the effects of different treatments.OBJECTIVE To document the natural history of thyroid associated ophthalmopathy, 59 patients were studied longitudinally and the severity of eye disease documented at regular Intervals.METHODS Fifty‐nine patients with thyroid associated ophthalmopathy who had not received Immunosuppressive or surgical treatment for their eye disease, were recruited from a combined thyroid‐eye clinic. They were assessed at presentation and at 3–6‐monthly Intervals for a median of 12 months. The eyes were assessed by separate and objective measurements relating to the status of the eyelids, cornea, extraocular muscles, proptosis and optic nerve function. In addition, a scoring system based on the above measurements was used to grade the overall severity of eye disease.RESULTS Thirteen patients (22%) Improved substantially, 25 patients (42·4%) showed minor Improvement, 13 patients (22%) did not change, and 8 patients (13·5%) deteriorated progressively, to the extent that Immunosuppressive treatment was considered to be necessary.CONCLUSIONS A significant proportion of patients with thyroid associated ophthalmopathy (64·4% in the present series) Improve spontaneously so serial assessment plays an Important part in deciding which patients require Immunosuppressive treatment. These findings also support the view that clinical trials designed to test the efficacy of new treatments in thyroid associated ophthalmopathy should be scrupulously controlled to allow for the natural tendency towards remission.