bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two mutations causing vitamin D resistant rickets: modelling on the basis of steroid hormone receptor DNA‐binding domain crystal structures
Authors: Rut A. R. , Hewlson Y. , Kristjansson K. , Luisl B. , Hughes M. R. , O'Riordan J. L. H. 
Published: March 2008

SummaryOBJECTIVE Hereditary vitamin D resistant rickets (HVDRR) has been shown to be due to mutations in the gene encoding the vitamin D receptor (VDR). In two patients with the characteristic phenotype we have investigated the functional defect and sequenced the VDR cDNA. We report two new mutations in the DNA binding domain of the VDR gene and we have used the crystal‐lographic structure of the glucocorticold and oeltrogen receptors (GR and ER respectively) as models to explain the stereochemical consequences of these mutations.DESIGN Patient and control cell lines prepared from skin fibroblasts were used to measure binding of 1,25dlhydroxyvltamln D3 (1,25(OH)2D3) and functional responses to this hormone. These cells were also used to Isolate VDR mRNA from which cDNA was prepared and sequenced. VDR cDNA from affected and control patlents was also transfected into receptor defective cells to analyse further functional responses to 1,25(OH)2D3. Computer analysis of mutations in the VDR gene was carried out using the glucocorticold and oestrogen receptors as model systems.PATIENTS Two patients with HVDRR from unrelated families.MEASUREMENTS Cytosollc binding and nuclear association of 1,25(OH)2D3 were determined in control and affected patients, and functional response to 1,25(OH)2D3 was assessed by measurement of 2bhydroxyvltamln D‐24‐hydroxylase activity (24‐hydroxylase). VDR cDNA was sequenced and transfected into VDR‐deficient CV‐1 cells for further analysis of functional response to 1,25(OH)2D3 following cotransfection with a chloramphenicol acetyltransferase (CAT) reporter plasmid.RESULTS Cells from HVDRR patients I and II showed detectable numbers of VDR with normal hormone binding. However, unlike controls, the HVDRR cells did not show induction of 24‐hydroxylase activity following treatment with 1,25(OH)2D3. Sequencing of cDNA revealed single mutations, in patient I (Phe44 → IIe) and in patient II (Lys42 → Glu). Both these residues are conserved in the steroid/thyroid hormone receptor superfamily and stereochemical analysis has been used to deduce the importance of these amino acids and the deleterious effect of these and other mutations in the DNA‐binding domain of the VDR.CONCLUSIONS Two new mutations in the vitamin D receptor which cause hereditary vitamin D resistant rickets have been described and using molecular modelling we have been able to analyse the genesis of this inherited disease at the level of stereochemistry.
IGF‐I treatment of adult patients with Laron syndrome: preliminary results
Authors: Laron Zvi , Klinger Beatrice 
Published: March 2008

SummaryOBJECTIVE Laron syndrome is a genetic disease due to a defect in the GH receptor or in the pod‐receptor mechanism which leads to an inability to generate IGF‐I. Biosynthetic IGF‐I treatment given to dwarfed children with this syndrome, produced a significant acceleration of growth velocity and reduction in obesity. In view of the known metabolic disturbances in untreated adult patients, the present clinical trial was performed to define the usefulness of IGF‐I treatment in LS adults.PATIENTS AND DESIGN Five patients (1 male, 4 females) aged 28‐40 years were treated during 9 months by daily administration of IGF‐I (120 μg/kg), and followed for 6 months after its discontinuation.METHODS At each visit, a complete physical examination was performed and blood was drawn for biochemical and hormone determinations. Twenty‐four‐hour urinary samples were collected at various Intervals during treatment. Bone densitometry was performed before and after 6‐9 months of therapy.RESULTS The main findings were a reduction in subscapular skinfold thickness (from 27·5 ± 1·4 (mean ± SEM) to 19·5 ± 1·0 mm; P < 0·002), a decrease in total cholesterol (from 6·78 ± 0·28 (mean ± SEM) to 5·80 ± 0·36 mmol/l) and in LDL cholesterol (from 4·86 ± 0·23 to 3·76 ± 0·35 mmol/l), an increase in creatlnlne clearance (from 71·2 ± 8·4 to 86·8 ± 4·3 ml/min/l·73m2, P < 0·04), an increase in phosphate reabsorption (from 0·89 ± 0·06 to 1·14 ± 0·06 mmol%; P < 0·02) leading to an increase in serum phosphate (from 1·08 ± 0·06 to 1·27 ± 0·03 mmol/l; P < 0·03), a rise in alkaline phosphatase (from 80·8 ± 5·0 to 100·7 ± 7·0 U/I) and in procollagen I‐PICP (from 44·2 ± 4·0 to 171·0 ± 19·2 μg/l; P < 0·0001) and in procoilagen III‐PIIINP (from 2·68 ± 0·45 to 10·10 ± 1·4μg/l; P < 0.005). There was a transient retention of water, sodium and chloride. Pretreatment serum IGFBP‐3 levels were low, but increased progressively during treatment. This permitted a reduction in the IGF‐I dose. There were no adverse effects other than pain and slight erythema at the injection site during the first weeks of treatment. All the anthropometric and metabolic changes reversed upon discontinuation of IGF‐I.CONCLUSIONS IGF‐I treatment is beneficial in adults, as well as in children, with resistance to GH.
An audit of selected patients with non‐functioning pituitary adenoma treated by transsphenoidal surgery without irradiation
Authors: Bradley K. M. , Adams C. B. T. , Potter C. P. S. , Wheeler D. W. , Anslow P. J. , Burke C. W. 
Published: March 2008

SummaryOBJECTIVE To determine whether the rate of tumour regrowth in patients with non‐functioning pituitary tumour treated by transsphenoidal surgery and selected for observation without post‐operative irradiation is acceptably low, and to identify a group of patients who could appropriately avoid pituitary irradiation.SUBJECTS One hundred and thirty‐two patients treated by transsphenoidal surgery, of whom 98 did not undergo post‐operative irradiation. These 98 were selected as having had apparently complete surgical removal, and as lacking features of tumour invasion or rapid growth; 73 of them are being followed by serial pituitary imaging to detect tumour regrowth.RESULTS Forty‐two patients who have been imaged on two or more occasions or more than two years after operation have shown no sign of tumour regrowth; 25 of them have been imaged at 3 or more years after operation, 13 at more than 5 years, and 4 at more than 10 years. Eight patients have shown regrowth as judged by imaging, although only one had pressure symptoms at the time; 5 out of 6 of these recurrences were found within 5 years of operation (two cannot be timed). The unirradiated group of 73 patients showed 90% recurrence‐free survival at 5 years (95% confidence limits 80‐100%).CONCLUSIONS Provided that careful surgery and meticulous recall mechanisms for imaging can be ensured, patients so selected may be given the information contained in these results and offered the choice of follow‐up by imaging alone, without pre‐emptive irradiation. We recommend that they should be imaged 6‐8 weeks post‐operatively, then at either 6 or 12 months depending on the appearance, and then every 3‐5 years for at least 15 years. By this means, many patient‐years of good health and relative medical independence can be gained, together with some financial saving.
Evidence for the effect of antibodies to TSH receptors on the thyroid ultrasonographic volume in patients with Graves' disease
Authors: Rieu Max , Raynaud Agathe , Richard Alain , Lapianche Sophie , Sambor Boris , Berrod Jean‐Louis 
Published: March 2008

SummaryOBJECTIVE it has been demonstrated that antibodies (Ab) to thyroid‐stimulating hormone receptors (R), which stimulate the thyroid gland, induce hyperthyroidism in patients with Graves' disease. Furthermore, it has been shown in thyroid cells in culture that thyroid‐stimulating hormone receptor Ab acts through the adenosine 3′, 5′‐monophosphate pathway which stimulates both thyroid hormonogenesis and growth. We investigated the relations between thyroid autoimmunlty expression and thyroid ultrasonographic parameters or thyroid hormonal status in patients with Graves' disease.PATIENTS A prospective study of 53 consecutive patients referred with untreated Graves' disease.MEASUREMENTS Measurements were made of serum TSH‐R, peroxidase (TPO) and thyroglobulin (Tg) Ab and basal plasma free T4 (FT4), free T3 (FT3) and TSH. Thyroid morphological characteristics (number and total volume of nodule(s), total volume of lobes and total thyroid volume) were determined by ultrasonography.RESULTS There were significant correlations (P < 0·001) between TSH‐RAb levels and FT4 values (r= 0·48) or FT3 levels (r= 0·46). Likewise, significant correlations were found between TSH‐RAb levels and total lobe volume values (r= 0·56, P < 0·001), total nodular volume values (r= 0·59, P < 0·01) or total thyroid volume values (r= 0·63, P< 0·001). By contrast, no correlation was found between TSH‐RAb levels and the number of nodules or between any of the ultrasonographic parameters and TPOAb levels or TgAB values.CONCLUSIONS This study demonstrates, in vivo, that TSH receptor antibodies modulate the thyroid ultrasonographic edranodular and nodular volumes in patients with Graves' disease.
Corticotrophin‐releasing factor immunostaining is present in placenta and fetal membranes from the first trimester onwards and is not affected by labour or administration of mifepristone
Authors: Cooper E. S. , Brooks A. N. , Miller M. R. , Greer I. A. 
Published: March 2008

SummaryBACKGROUND AND OBJECTIVES Corticotrophin releasing factor (CRF) is present in the human placenta and fetal membranes. Placental CRF content and plasma CRF concentrations rise throughout gestation and fail rapidly after delivery. The regulation of CRF production from the placenta is poorly understood. The objective of this study was to use the antiprogestin, mifepristone, to determine whether progesterone has a regulatory effect on CRF production in the first trimester of pregnancy.PATIENTS Women undergoing first trimester (gestation 5‐12 weeks) therapeutic abortion (by suction curettage with and without the synthetic PGE, analogue, gemeprost (16,16‐dimethyl‐trans‐ Δ2‐PGE1 methyl ester) vaginally 2‐4 hours prior to the procedure; or with 600 mg mifepristone 48 hours prior to receiving 1 mg gemeprost vaginally), second trimester therapeutic abortion (600 mg mifepristone, 1 mg gemeprost), In association with pre‐term delivery (gestation 25‐34 weeks) and at term (gestation 35‐42 weeks) by spontaneous delivery, induced labour or elective Caesarean section.MEASUREMENTS immunohistochemical localization Of CRF and quantification of CRF content by radioimmunoassay of tissue extracts, in human placenta and fetal membranes.RESULTS CRF was Immunolocalized to the syncytlo‐trophoblast cells of the placenta at ail stages of gestation from 5 to 42 weeks. In the fetal membranes CRF immunoreactlvity was localized in the epithelial and subepithelial cells of the amnion, some cells of the reticular and cellular layers of the chorion, and in decidual stroma. This pattern was seen in all tissues studied. Pretreatment with prostaglandins, mifepristone or both during the first trimester did not alter the distribution or the intensity of the CRF Immunostaining. Placental CRF content rose throughout gestation but, consistent with the Lmmunostaining results, was unaffected by the administration of mifepristone or by labour.CONCLUSIONS CRF is localized in the syncitlotropho‐blast cells of the placenta and is clearly present early in the first trimester of pregnancy. The lack of an effect of mifepristone or mode of delivery suggests that syncytlo‐trophoblast produces CRF constitutively throughout pregnancy.
Growth hormone deficiency coupled with hypogonadism in AIDS
Authors: Ng Tony T. C. , O'Connell Ian P. M. , Wilkins Edmund O. L. 
Published: March 2008

SummaryBoth growth hormone and sex steroid deficiencies are known to affect quality of life adversely. Hypogonadism is not infrequent in patients with AIDS and due mostly to hypothalamic or end‐organ failure. The prevalence of GH deficiency is unknown. We report two cases of GH deficiency in AIDS, one of which war associated with gonadotroph failure. The significance of GH deficiency in HIV infection in terms of its potential effects on disease progression is discussed. Further studies are required to assess the prevalence of OH deficiency and to clarify its role in the immunopathogenesis of AIDS.
Pyridostigmine induced growth hormone release in mania: focus on the cholinergic/somatostatin system
Authors: Dinan Timothy G. , O'Keane Veronica , Thakore Jogin 
Published: March 2008

SummaryOBJECTIVE The release of growth hormone (GH) from the anterior pituitary is partly under cholinergic control. Pyridostigmine, the acetylcholinesterase inhibitor, releases GH by this mechanism. Pyridostigmine/GH responses have been reported as enhanced in depression. The aim of the current study was to examine such responses during a manic episode.DESIGN A between subjects design was employed.SUBJECTS Seven male manic patients and seven male healthy controls were studied. They were matched in terms of age and body mass index.MEASUREMENTS GH response to pyridostigmine (120 mg) challenge was measured as the net increase above baseline. Cortisol levels were also measured.RESULTS Release of GH in the manic patients was significantly enhanced and their baseline Cortisol levels were elevated.CONCLUSIONS These results demonstrate enhanced pyridostigmine/GH responsiveness in mania which may be due to enhanced somatostin tone or increased cholinergic receptor responsivity.
Influence of sodium valproate on medium‐late luteal phase pulsatile LH secretion in normal women
Authors: Abeal J. Lado , Losada C. Rey , Agricola J. M. Cabezas , Cabezas‐Cerrato J. 
Published: March 2008

SummaryOBJECTIVE It is not known whether gamma‐aminobutyric acid (GABA) is involved in control of pulsatile LH secretion in human beings. Previous work by our group has shown that manipulation of the GABAergic system with sodium valproate does not affect pulsatile LH secretion in normal women in the late follicular phase. However, it has been suggested that steroid levels are critical for the influence of GABA upon hormone secretion; in particular, progesterone has been said to enhance inhibition by GABA. In this work we studied the effect of sodium valproate on pulsatile LH secretion in medium‐late luteal phase of normal women.DESIGN Six normal young women were studied over an 8‐hour period in two successive menstrual cycles. On each occasion blood samples were taken every 10 minutes between 1000 and 1800 h. We administered 400 mg of sodium valproate every 8 hours on the 7 days preceding their second cycle and additional 400 mg at 0900 and 1400 h on the day of the study. Ovulation day was estimated by means of serial ovarian ultrasound examinations and confirmed by serum progesterone concentrations.MEASUREMENTS In each cycle, LH, oestradiol and progesterone were determined by radioimmunoassay and sodium valproate by repolarization fluorescence spectrophotometry. The series of LH levels was smoothed for 1‐minute sampling periods by means of a spline function and analysed by means of a program developed in our laboratory and written in Fortran 77. The program deconvolved the signal and calculated the pulse area, pulse duration, interpulse interval and number of pulses. LH pulse identification on the deconvolved signals was performed using our own method based on Friedman's non‐parametric statistic. The statistical significance of differences between parameters was estimated using the Mann‐Whitney test and Wilcoxon signed rank test.RESULTS There were no significant differences in LH pulse area, pulse duration, interpulse interval or number of pulses with the administration of sodium valproate.CONCLUSIONS Activation of the GABAergic system with sodium valproate had no biologically significant effect on the mid‐late luteal phase pulsatile LH secretion in normal women.
Acute suppurative thyroiditis in an asymptomatic woman: an atypical presentation simulating thyroid carcinoma
Authors: Yamashita Jun‐ichi , Ogawa Michio , Yamashita Shin‐ichi , Saishoji Telsushi , Nomura Koichi , Tsuruta Jun‐ji 
Published: March 2008

SummaryPatients with acute suppurative thyroiditis usually have pain or tenderness in the anterior part of the neck associated with erythema and dysphagia. A 26‐year‐old Japanese woman with none of these symptoms presented with a left anterior cervical mass. Since physical examination and laboratory studies showed a firm and irregular tumour located in the left lobe of the thyroid without any inflammatory signs, we made a diagnosis of thyroid carcinoma. After surgery, histological examination of the thyroid specimen revealed various changes of severe inflammation, and a barium swallow demonstrated a left pyriform sinus fistula. We describe here a unique case of acute suppurative thyroiditis in an asymptomatic woman.
Acute effects of a single administration of dexamethasone on basal and growth hormone‐releasing hormone stimulated GH secretion in acromegaly
Authors: Losa Marco , Arosio Maura , Cusin Alberto , Biella Orietta , Palmieri Eva , Faglia Giovanni , Giovanelli Massimo 
Published: March 2008

SummaryA single administration of dexamethasone causes both an early stimulatory and a late inhibitory effect on GH secretion in normal subjects.OBJECTIVE We investigated the effects of a single administration of dexamethasone on basal and GH‐releasing hormone‐stimulated GH secretion in eight patients with active acromegaly.DESIGN On three different days the patients received 4 mg i.v. dexamethasone, 1 μg/kg body weight GH‐releasing hormone 1‐29, or matched placebos in different order.PATIENTS Eight subjects with active acromegaly, five of whom had not been treated previously, while the other three had received octreotide therapy which was stopped at least 7 days before testing.MEASUREMENTS Serum GH levels were measured in duplicate by a commercially available RIA kit.RESULTS Dexamethasone administration caused a significant decline of mean ± SE GH levels from 51.8 ± 13.8 to 30.0 ± 9.2 mU/l at 180 minutes, that was not influenced by placebo administration at 180 minutes. On the contrary, when GH‐releasing hormone substituted placebo administration, GH levels increased from 34.0 ± 9.8 mU/l at 180 minutes to 56.0 ± 15.6 mU/l at 195 minutes. The GH increase was higher when GH‐releasing hormone was given without dexamethasone pretreatment (from 52.4 ± 13.0 mU/l at 180 minutes to 86.4 ± 25.4 mU/l at 195 minutes). Analysis of the GH area under the curve confirmed the significant inhibition of GH secretion after dexamethasone administration and the significant reduction of the GH response to GH‐releasing hormone in the study with dexamethasone pretreatment.CONCLUSIONS At variance with data in normal subjects, acute i.v. administration of dexamethasone inhibits basal GH secretion and partially suppresses the GH response to GH‐releasing hormone in acromegaly. Both alterations in the regulatory mechanism of adenomatous cells and perturbations of hypothalamic regulatory influences, induced by the state of chronic GH hypersecretion, are likely explanations of the different response to dexamethasone.
In‐vitro evidence for the regulation of 17,20‐lyase activity by cytochrome b5 in adrenocortical adenomas from patients with Cushing's syndrome
Authors: Sakai Yoshiyuki , Yanase Toshihiko , Hara Takayuki , Takayanagi Ryoichi , Haji Masafumi , Nawata Hajime 
Published: March 2008

SummaryOBJECTIVE The electron transfer system molecules, NADPH‐cytochrome P450 reductase (Red) and cytochrome b5 (bS) are known to increase the relative activity of 17,20‐lyase to 17α‐hydroxylase in vitro. Consistent with this hypothesis, we have reported recently that adrenocortical adenomas from patients with Cushing's syndrome that produced exceptionally high concentrations of androgens also contained more b5 mRNA as well as greater 17,20‐lyase activity than adenomas that produced low concentrations of androgens. This finding was suggestive but inconclusive in linking b5 functionally to this difference in adenoma 17,20‐lyase activity. In the present study, we have extended this finding by examining the effect of bS on microsomal 17,20‐lyase activity using an antibody against cytochrome b5.DESIGN Biochemical quantitation of the content of b5 and Red activity in the microsomal fraction of the tumours and determination of 17,20‐lyase activity In the microsomes in the presence or absence of an antibody against b5.PATIENTS Seven patients with a clinical diagnosis of Cushing's syndrome secondary to benign adrenocortical adenoma were studied.MEASUREMENTS The microsomal activities of 17α‐hydroxylase, 17,20‐lyase and 3β‐hydroxysterold dehydrogenase were measured by in‐vitro enzyme assay with thin layer chromatography. Microsomal Red activity was assayed by measuring NADPH‐dependent cytochrome c reduction reaction. Cytochrome b5 concentration was determined by spectrophotometric analysis.RESULTS An in‐vitro enzyme assay of microsomal fractions from the adenoma showed that the 17,20‐lyase activities of two adenomas that produced high concentrations of adrenal androgen were threefold greater than those of five other adenomas that produced low concentrations of androgens. Cytochrome b5 concentrations were greater in the two adenomas with high 17,20‐lyase activity than in the other adenomas, while no significant difference in Red activity was observed among all the adenomas. The increased 17,20‐lyase activity in the two adenomas was partially but significantly antagonized by an antibody against b5.CONCLUSIONS These results suggest that differences in tissue b5 are functionally associated with differences in 17,20‐lyase activity in adrenocortical adenomas In Cushing's syndrome, resulting in a dissociated secretion of Cortisol and androgens in some patients.
Doppler echocardiographic evaluation of left ventricular diastolic function in acute hypothyroidism
Authors: Grossmann Georg , Wieshammer Siegfried , Keck Fritz S. , Göller Veit , Giesler Martin , Hombach Vinzenz 
Published: March 2008

SummaryOBJECTIVE Left ventricular diastolic dysfunction Is an important cause of symptomatic heart failure. Previous studies suggest that thyroid dysfunction affects left ventricular diastolic function but the underlying mechanisms remain controversial. The study was undertaken to assess the influence of acute hypothyroidism on left ventricular diastolic function and to elucidate possible underlying mechanisms by means of Doppler echocardiography in a group of athyreotic patients, whose thyroid state depended only on external thyroid hormone supply and could therefore easily be controlled.PATIENTS Eleven patients (5 men, 6 women, aged 20‐55 years), who had had total thyroidectomy, were investigated during mild hyperthyroidism and during acute hypothyroidism. Additionally, 11 healthy control subjects aged 25‐51 years were included in the study.DESIGN M‐mode echocardiography of the left ventricle and pulsed‐wave Doppler echocardiography of the trans‐mitral flow velocity pattern were carried out.RESULTS Acute hypothyroidism produced a decrease of left ventricular end‐diastolic diameter from 48 ± 5 to 46 ± 5 mm (mean ± SD P < 0.05), of peak velocity of early diastolic filling from 0.52 ± 0.10 to 0.42 ± 0.05 m/s (P < 0.05), of peak velocity of late diastolic filling from 0.42 ± 0.10 to 0.36 ± 0.09 m/s (P < 0.05), and a decreased time‐velocity integral of early diastolic filling (6 2 ± 1 8 vs 5.1 ± 0.7 cm, P < 0.05). The other M‐mode and Doppler echocardiographic parameters did not differ between the hyperthyroid and the hypothyroid states.CONCLUSIONS The observed changes of the transmitral flow velocity pattern during acute hypothyroidism can be attributed to a reduction of pre‐load. There is no direct evidence that acute hypothyroidism affects the intrinsic diastolic properties of the left ventricle.