bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired trafficking of mutated AVP prohormone in cells expressing rare disease genes causing autosomal dominant familial neurohypophyseal diabetes insipidus
Authors: Christensen Jane H. , Siggaard Charlotte , Corydon Thomas J. , Robertson Gary L. , Gregersen Niels , Bolund Lars , Rittig Søren 
Published: December 2004

Summaryobjective and study design  Two different mutations in the arginine vasopressin (AVP) gene associated with autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) predict Y21H (AVP2) and V67A (NP36) amino acid substitutions of the AVP prohormone. They are unique in that they change, respectively, the AVP moiety and a region of the neurophysin II domain not so far affected by any mutations. To test whether they affect the cellular handling of the AVP prohormone in a similar manner to previously investigated mutations, they were examined by heterologous expression in cell lines.results  Both mutations resulted in significantly reduced amounts of immunoreactive AVP in the cell culture medium as determined by radioimmunoassay analysis. Metabolic labelling combined with immunoprecipitation demonstrated that processing and secretion of the mutant prohormones was reduced but not prevented. Finally, confocal laser scanning microscopy showed that normal AVP prohormone and/or its processed products were localized in the tips of the cellular processes, whereas both mutant prohormones were accumulated in the endoplasmic reticulum (ER) and in the case of the V67A prohormone, also in perinuclear structures outside the ER.conclusion  Both mutations result in reduced AVP prohormone processing and secretion probably due to retention in the ER. This supports, at least partly, the hypothesis that the mutations lead to the production of a mutant hormone precursor that fails to fold and/or dimerize properly and, as a consequence, is retained by the ER protein quality control machinery. Perinuclear accumulation of the V67A prohormone outside the ER indicates that additional mechanisms could be involved.
Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor
Authors: Park S.‐M. , Clifton‐Bligh R. J. , Betts P. , Chatterjee V. K. K. 
Published: December 2004

Summaryobjective  We wished to ascertain whether mutations in the TSH receptor (TSHR) gene were present in two siblings with congenital hypothyroidism with no parental consanguinity.design  The pituitary–thyroid axis and thyroid gland morphology were investigated in both affected siblings and their parents. The TSHR gene was analysed in each subject.measurements  Basal thyroid function together with circulating thyroglobulin levels were measured in each subject. In addition, a TRH stimulation test was undertaken in each parent. All family members underwent thyroid ultrasonography. The TSHR gene was amplified from genomic DNA using the polymerase chain reaction and receptor mutations were identified by sequence analysis.results  Two siblings were diagnosed with severe congenital hypothyroidism (total T4 19–21 nmol/l, TSH 160–230 mU/l on neonatal screening). Although radioiodine scanning showed no tracer uptake and ultrasound imaging in both individuals failed to demonstrate thyroid tissue, suggesting complete athyreosis, circulating thyroglobulin levels were measurable. The thyroid status of the parents was discordant: in the father, baseline thyroid function (FT4 13 pmol/l, TSH 4 mU/l), the peak TSH level after TRH stimulation (30 mU/l) were normal and he exhibited an appropriate rise in circulating thyroid hormones in response to the elevated TSH; in contrast, in the mother, baseline thyroid function was abnormal (FT4 10 pmol/l, TSH 15 mU/l), the TSH response to TRH was exaggerated (110 mU/l), with no subsequent rise in circulating thyroid hormones. An eutopic, slightly hypoplastic thyroid gland was visualized on ultrasonography in the mother and her thyroid antibody status was negative. Both children were compound heterozygotes for missense (alanine to threonine at codon 553, A553T) and premature stop (tryptophan at codon 546, W546X) mutations in the fourth transmembrane domain of the TSH receptor. The mother and father were heterozygous for W546X and A553T mutations, respectively. Each mutation is known to abolish the function or cellular surface expression of the TSH receptor.conclusions  Inactivating mutations in the TSH receptor can be associated with severe TSH resistance presenting as congenital hypothyroidism with apparent athyreosis. Our observations also suggest that heterozygosity for an inactivating TSHR mutation may be associated with compensated hypothyroidism and thyroid hypoplasia.
Aggregation of thyroid autoantibodies in first‐degree relatives of patients with autoimmune thyroid disease is mainly due to genes: a twin study
Authors: Heiberg Brix Thomas , Skov Hansen Pia , Ohm Kyvik Kirsten , Hegedüs Laszlo 
Published: December 2004

Summarybackground Family studies have repeatedly shown aggregation of thyroid autoantibodies to thyroid peroxidase (TPOab) and thyroglobulin (Tgab) in first‐degree relatives of patients with autoimmune thyroid disease (AITD). This phenomenon has generally been interpreted as evidence of a genetic component in the development of thyroid autoantibodies. However, family studies cannot determine whether the observed familial aggregation of these antibodies is due to shared genes or shared environment.aim To test the hypothesis that the familial aggregation of thyroid autoantibodies is mainly genetically determined.design A cross‐sectional study of healthy twin siblings to twins with AITD.participants Thirty‐eight healthy twin siblings to twins with AITD and a control group of 76 healthy twins, matched for age, sex and zygosity, but without AITD among their first‐degree relatives.main outcome measures Prevalence of TPOab, Tgab and TSH‐receptor antibodies (TSHRab).methods All antibodies were measured by routine commercial kits. TPOab, Tgab and TSHRab were regarded as positive if > 60 U/ml, > 60 U/ml and > 1·0 U/l, respectively. Zygosity was established by DNA fingerprinting.results The prevalence of TPOab, Tgab and TSHRab in the 38 healthy twin siblings was 34% (13/38), 26% (10/38) and 13% (5/38), respectively, which was higher than the corresponding prevalences in the control population, 9% (7/76;P = 0·002), 7% (5/76;P = 0·006) and 1·3% (1/76;P = 0·015), respectively. Combination of two or more thyroid autoantibodies was also significantly more common among index subjects (10/38 or 26%) than in the control group (2/76 or 3%),P = 0·0001. Among the healthy monozygotic twin siblings, 53%, 47% and 20% had TPOab, Tgab and TSHRab, respectively, compared with 22% (P = 0·045), 13% (P = 0·02) and 9% (P = 0·36), respectively, in the dizygotic twin siblings. Significantly more monozygotic twin siblings were positive for two or more autoantibodies than dizygotic twin siblings (8/15vs.2/23;P = 0·006).conclusion Healthy first‐degree relatives to patients with AITD show significant clustering of thyroid autoantibodies. Moreover, healthy monozygotic and dizygotic twin siblings to twins with AITD differ in prevalence of thyroid autoantibodies. These observations strongly support the hypothesis that the familial aggregation of thyroid autoantibodies is mainly genetically determined.
Marked and sustained increase in bone mineral density after parathyroidectomy in patients with primary hyperparathyroidism; a six‐year longitudinal study with or without parathyroidectomy in a Japanese population
Authors: Nomura Rikako , Sugimoto Toshitsugu , Tsukamoto Tatsuo , Yamauchi Mika , Sowa Hideaki , Chen Qingxiang , Yamaguchi Toru , Kobayashi Akira , Chihara Kazuo 
Published: December 2004

Summaryobjective  Although many reports have demonstrated the sustained increase in bone mineral density (BMD) at trabecular sites in primary hyperparathyroidism (pHPT) after parathyroidectomy (PTX), there have been no data available on BMD changes over the long‐term in pHPT patients with and without PTX in Japanese population. The present study was designed to investigate long‐term BMD changes at both trabecular and cortical sites in Japanese pHPT patients with or without PTX.methods  The subjects were 97 patients who had been followed up in Kobe University Hospital for at least 1 year up to 6 years with or without PTX. PTX was recommended to all patients whose pathological parathyroid gland(s) could be determined by image diagnosis. BMD was measured at the lumbar spine (L2–L4) and at distal one‐third of the radius (R1/3) by dual energy X‐ray absorptiometry (QDR2000). Serum levels of calcium, alkaline phosphatase and parathyroid hormone (PTH) were determined at the time of the BMD measurement.results  Significant increases in any of the indices of BMD from the baseline values were observed within three months after PTX, followed by sustained increases over 6 years at L2–L4 even in postmenopausal women. Radial BMD also showed a marked increase six years after PTX. L2–L4 eventually reached the normal BMD but R1/3 did not. The percentage changes in L2–L4 were positively and significantly correlated with the preoperative PTH levels over the study period. However, the percentage changes in R1/3 showed a significant correlation with the preoperative PTH levels only 5 and 6 years after PTX. In the patients without PTX, no obvious changes in biochemical indices and BMD were observed over the six years.conclusion  We demonstrated that PTX led to marked and sustained increases in BMD not only at L2–L4 but also at R1/3 in Japanese pHPT patients, including postmenopausal women. The preoperative PTH level could be a clinically useful index for predicting long‐term BMD changes after PTX.
Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy
Authors: Lanfranco Fabio , Zitzmann Michael , Simoni Manuela , Nieschlag Eberhard 
Published: December 2004

Summaryobjective  Adiponectin is an adipocyte‐specific secretory protein which exhibits antiatherogenic, anti‐inflammatory and antidiabetic properties. We hypothesized that testosterone plays an important role in the regulation of its secretion in humans, as adiponectin concentrations are higher in women than in men and as testosterone administration is accompanied by a reduction in serum adiponectin in animals and by reduced protein secretion in cultured adipocytes. This study aimed to evaluate adiponectin levels in hypogonadal men prior to and during testosterone replacement therapy.subjects and methods  In a retrospective study, adiponectin, total and free testosterone, oestradiol, SHBG, total cholesterol and triglyceride levels were evaluated in 31 hypogonadal men [HM; age, mean ± SEM: 36·5 ± 2·4 years; body mass index (BMI) 24·6 ± 0·8 kg/m2] and 29 weight‐matched eugonadal men (EM; age 30·8 ± 1·5 years; BMI 23·4 ± 0·6 kg/m2). In 13 HM (age 33·9 ± 3·2 years; BMI 24·2 ± 0·9 kg/m2) the same parameters were also evaluated after 6 months of testosterone replacement therapy. Correlation analysis between adiponectin and hormonal, biochemical and anthropometric parameters was performed in all subjects.results  Testosterone, free testosterone and oestradiol concentrations were significantly lower in HM than in EM (4·4 ± 0·4 nmol/l, 78·4 ± 10·9 pmol/l and 36·1 ± 3·0 pmol/l, respectively, in HM vs. 21·9 ± 0·7 nmol/l, 507·9 ± 13·8 pmol/l and 65·2 ± 1·8 pmol/l, respectively, in EM, P < 0·0001), while SHBG levels in HM were higher than in EM (54·4 ± 7·5 vs. 30·9 ± 2·2 nmol/l, P < 0·005). Serum adiponectin levels in HM were significantly higher than in EM (9·53 ± 0·73 vs. 6·80 ± 0·55 µg/ml, P < 0·01). Calculation of the Pearson coefficient showed that adiponectin levels in HM were not correlated with any of the anthropometric and hormonal parameters examined, but showed a significant negative correlation with serum triglycerides (r = −0·38, P < 0·05). Serum adiponectin levels were negatively correlated with body weight (r = −0·41, P < 0·05) in EM but not with other anthropometric, hormonal or biochemical parameters. Six months after initiation of testosterone replacement therapy, which increased testosterone and free testosterone levels to the normal range, adiponectin levels were significantly reduced in HM (6·37 ± 0·93 vs. 9·26 ± 1·01 µg/ml, P < 0·01) and similar to those recorded in EM.conclusions  Compared to eugonadal subjects, hypogonadal men show higher adiponectin levels which are reduced by testosterone replacement therapy. This study indicates that testosterone exerts a regulatory role on adiponectin secretion in humans.
Effects of low and high dose oestradiol and dydrogesterone therapy on insulin and lipoprotein metabolism in healthy postmenopausal women
Authors: Godsland I. F. , Manassiev N. A. , Felton C. V. , Proudler A. J. , Crook D. , Whitehead M. I. , Stevenson J. C. 
Published: December 2004

Summaryobjective  Menopause diminishes insulin secretion and elimination, increases risk of diabetes and adversely affects lipoprotein metabolism. This study was undertaken to establish whether oral oestradiol plus dydrogesterone postmenopausal hormone therapy can modify these changes.design  Randomized prospective trial of postmenopausal women taking low dose therapy (1 mg/day oestradiol‐17 beta with 5 or 10 mg/day dydrogesterone for days 17–28 of each cycle, n = 15) or high dose therapy (2 mg/day oestradiol‐17 beta with 10 or 20 mg/day orally administered dydrogesterone, n = 9).measurements  Patients underwent measurement of glucose, insulin and C‐peptide in the fasting state and during an intravenous glucose tolerance test (IVGTT) at baseline and after 12 and 24 cycles of treatment. Modelling analysis was used to derive measures of insulin secretion, elimination and sensitivity. Fasting serum lipids, lipoproteins and apolipoproteins were also measured.results  In both groups there were significant reductions in fasting glucose, insulin and C‐peptide. Pancreatic insulin secretion during the IVGTT was increased by treatment (ranging from 45% to 92%, P < 0·01). Insulin elimination was increased at both the peripheral (16% to 43%, P < 0·05) and hepatic (18% to 31%, P < 0·05) levels. Insulin sensitivity was unaffected. Low density lipoprotein (LDL) cholesterol was reduced and high density lipoprotein (HDL) cholesterol increased with treatment.conclusions  Postmenopausal hormone therapy with oestradiol plus dydrogesterone can favourably affect lipoprotein concentrations and can reverse menopause‐associated changes in insulin secretion and elimination.
Baseline characteristics and the effects of two years of growth hormone replacement therapy in adults with growth hormone deficiency previously treated for Cushing's disease
Authors: Johannsson Gudmundur , Sunnerhagen Katharina Stibrant , Svensson Johan 
Published: December 2004

Summaryobjective  To determine baseline characteristics and the effects of 2 years of GH replacement therapy on body composition, muscle strength, bone mass, and metabolic indices in GH‐deficient (GHD) adults previously treated for pituitary‐dependent Cushing's disease.design  A single‐centre, open‐labelled, prospective study.patients  Fifteen consecutive GHD adults previously treated for pituitary‐dependent Cushing's disease (CD group) and 15 closely matched GHD adults with previous nonfunctioning hypopituitary disease (NF group) were included. All patients had adult‐onset GH deficiency.results  The mean dose of GH was similar in both study groups during the 2‐year treatment. At baseline, diastolic blood pressure was higher, and lumbar (L2–L4) bone mineral density (BMD) was lower, in the CD group than in the NF group. The increase in lean mass in response to GH therapy, as measured by dual‐energy X‐ray absorptiometry (DEXA), was less marked in the CD group. GH replacement therapy reduced diastolic blood pressure only in the CD group. The patients in the CD group had greater treatment response in lumbar (L2–L4) spine BMD and in isometric and isokinetic knee extension strength than the patients in the NF group. At study end, no difference remained between the two study groups.conclusions  This study revealed differences in the baseline characteristics between GHD patients previously treated for Cushing's disease as compared with closely matched GHD patients with previous nonfunctioning hypopituitary disease. The 2‐year GH replacement therapy eliminated all the differences between the two study groups.
Left ventricular mass and function in children with GH deficiency before and during 12 months GH replacement therapy
Authors: Salerno Mariacarolina , Esposito Valentina , Spinelli Letizia , Di Somma Carolina , Farina Vincenzo , Muzzica Stefania , De Horatio Laura Tanturri , Lombardi Gaetano , Colao Annamaria 
Published: December 2004

Summaryobjective  This open, prospective study was designed to evaluate the effect of GH deficiency (GHD) on left ventricular (LV) mass (LVM) and performance, by echocardiography, and on lipid profile during childhood.subjects  Twelve prepubertal children with GHD (eight boys and four girls) aged 8·1 ± 1·7 years were studied before and after 6 and 12 months of GH replacement therapy at a dose of GH of 30 µg/kg/day. Twelve healthy children sex‐, height‐, weight‐ and body surface area‐matched with the patients, served as controls.methods  Echocardiography was performed at study entry and after 12 months both in GHD children and in controls. Only in GHD children, echocardiography was repeated also after 6 months of GH replacement. In all subjects, we measured LV posterior wall thickness (LVPWT), LV end‐diastolic diameter (LVEDD), LVM index (LVMi), LV systolic and diastolic function.results  At study entry, LVPWT (5·3 ± 0·8 vs. 6·2 ± 1·1 mm, P < 0·05), LVEDD (34·0 ± 2·4 vs. 36·7 ± 2·1 mm, P < 0·007) and LVMi (47·0 ± 6·9 vs. 59·6 ± 9·5 g/m2, P < 0·005) were significantly lower in GHD children than in controls. Lipid profile, heart rate, blood pressure, LV systolic function and indeces of ventricular filling were similar in patients and controls. After 12 months of GH replacement therapy, LVPWT (6·1 ± 0·7 mm, P < 0·0005), LVEDD (38·8 ± 4·3 mm, P < 0·002) and LVMi (71·5 ± 12·7 g/m2, P < 0·0005) significantly increased in GHD children compared to pretreatment values. In particular, after 12 months of therapy GHD children achieved a normal LVMi when compared to controls (60·7 ± 8·6, P = ns). LVMi increase was significantly correlated with the increase in IGF‐I level (r = 0·49; P < 0·004). LV systolic performance, diastolic filling and blood pressure did not change significantly during GH therapy. After 12 months of treatment, the atherogenic index, measured as total/high‐density lipoprotein‐cholesterol ratio (2·7 ± 0·8) was significantly lower than both pretreatment (3·4 ± 0·3, P < 0·03) and control values (3·8 ± 1·1, P < 0·04).conclusions  GH deficiency in children affects heart morphology, by inducing a significant decrease in cardiac size, but does not modify cardiac function and lipid profile. Twelve months of GH replacement treatment normalizes cardiac mass, and reduces the atherogenic index.
Exopolysaccharide biosynthesis genes required for social motility in Myxococcus xanthus
Authors: Lu Ann , Cho Kyunyung , Black Wesley P. , Duan Xue‐yan , Lux Renate , Yang Zhaomin , Kaplan Heidi B. , Zusman David R. , Shi Wenyuan 
Published: December 2004

SummarySocial (S)‐motility in Myxococcus xanthus is a flagellum‐independent gliding motility system that allows bacteria to move in groups on solid surfaces. S‐motility has been shown to require type IV pili (TFP), exopolysaccharide (EPS; a component of fibrils) and lipopolysaccharide (LPS). Previously, information concerning EPS biogenesis in M. xanthus was lacking. In this study, we screened 5000 randomly mutagenized colonies for defects in S‐motility and EPS and identified two genetic regions essential for EPS biogenesis: the EPS synthesis (eps) region and the EPS‐associated (eas) region. Mutants with insertions in the eps and eas regions were defective in S‐motility and fruiting body formation. These mutants failed to bind the dye calcofluor white, indicating that they lacked EPS; however, they retained normal TFP and LPS. Analysis of the eps locus showed several open reading frames (ORFs) that encode homologues to glycosyltransferases, glucanases and EPS transporters as well as regulatory proteins; the eas locus contains two ORFs: one exhibits homology to hypothetical proteins with a conserved domain of unknown function and the other displays no apparent homology to other proteins in the database. Further genetic mutagenesis analysis indicates that the whole eps region is involved in the biosynthesis of fibrils and fibril EPS. The operon at the proximal end of the eps region was analysed by generating in‐frame deletion mutations. These mutants showed varying degrees of defects in the bacterium's ability to produce EPS or perform EPS‐related functions, confirming the involvement of these genes in M. xanthus EPS biogenesis.
BotR/A and TetR are alternative RNA polymerase sigma factors controlling the expression of the neurotoxin and associated protein genes in Clostridium botulinum type A and Clostridium tetani
Authors: Raffestin Stéphanie , Dupuy Bruno , Marvaud Jean Christophe , Popoff Michel R. 
Published: December 2004

Summary Clostridium botulinum and Clostridium tetani, respectively, produce potent toxins, botulinum neurotoxin (BoNT) and tetanus neurotoxin (TeTx), which are responsible for severe diseases, botulism and tetanus. Neurotoxin synthesis is a regulated process in Clostridium. The genes botR/A in C. botulinum A and tetR in C. tetani positively regulate expression of BoNT/A and associated non‐toxic proteins (ANTPs), as well as TeTx respectively. The botR/A gene lies in close vicinity of the two operons which contain bont/A and antps genes in C. botulinum A, and tetR immediately precedes the tetX gene in C. tetani. We show that BotR/A and TetR function as specific alternative sigma factors rather than positive regulators based on the following results: (i) BotR/A and TetR associated with target DNAs only in the presence of the RNA polymerase core enzyme (Core), (ii) BotR/A and TetR directly bound with the core enzyme, (iii) BotR/A‐Core recognized −35 and −10 regions of ntnh‐bont/A promoter and (iv) BotR/A and TetR triggered in vitro transcription from the target promoters. In C. botulinum A, bont/A and antps genes are transcribed as bi‐ and tricistronic operons controlled by BotR/A. BotR/A and TetR are seemingly related to a new subgroup of the σ70 family that includes TcdR and UviA, which, respectively, regulate production of toxins A and B in C. difficile and bacteriocin in C. perfringens. Sequences of −35 region are highly conserved in the promoter of target toxin genes in C. botulinum, C. tetani, C. difficile and C. perfringens. Overall, a common regulation mechanism probably controls toxin gene expression in these four toxigenic clostridial species.