bluuebunny/crossref_metadata_2025 huggingface dataset:
Chromosome copy number analysis in screening for prognosis‐related genomic regions in colorectal carcinoma
Authors: Kurashina Kentaro , Yamashita Yoshihiro , Ueno Toshihide , Koinuma Koji , Ohashi Jun , Horie Hisanaga , Miyakura Yasuyuki , Hamada Toru , Haruta Hidenori , Hatanaka Hisashi , Soda Manabu , Choi Young Lim , Takada Shuji , Yasuda Yoshikazu , Nagai Hideo , Mano Hiroyuki
Published: June 2008

Colorectal carcinoma (CRC) remains the major cause of cancer death in humans. Although chromosomal structural anomaly is presumed to play an important role in the carcinogenesis of CRC, chromosomal copy number alterations (CNA) and loss of heterozygosity (LOH) have not yet been analyzed extensively at high resolution in CRC. Here we aim to identify recurrent CNA and LOH in human CRC with the use of single nucleotide polymorphism‐typing microarrays, and to reveal their relevance to clinical outcome. Surgically resected CRC specimens and paired normal mucosa were obtained from a consecutive series of 94 patients with CRC, and both of them were subjected to genotyping with Affymetrix Mapping 50K arrays. CNA and LOH were inferred computationally on every single nucleotide polymorphism site by integrating the array data for paired specimens. Our large dataset reveals recurrent CNA in CRC at chromosomes 7, 8, 13, 18, and 20, and recurrent LOH at chromosomes 1p, 4q, 5q, 8p, 11q, 14q, 15q, 17p, 18, and 22. Frequent uniparental disomy was also identified in chromosomes 8p, 17p, and 18q. Very common CNA and LOH were present at narrow loci of <1 Mbp containing only a few genes. In addition, we revealed a number of novel CNA and LOH that were linked statistically to the prognosis of the patients. The precise and large‐scale measurement of CNA and LOH in the CRC genome is efficient for pinpointing prognosis‐related genome regions as well as providing a list of unknown genes that are likely to be involved in CRC development. (Cancer Sci2008; 99: 1835–1840)
Impact of the hyaluronan‐rich tumor microenvironment on cancer initiation and progression
Authors: Itano Naoki , Zhuo Lisheng , Kimata Koji
Published: June 2008

Hyaluronan acts as a microenvironmental stimulus that can influence the malignant phenotype of cancer cells. During cancer progression, hyaluronan assembles an extracellular matrix that is favorable for both the motility and proliferation of cancer cells and the recruitment of inflammatory and bone marrow‐derived progenitor cells. The varied roles of this polysaccharide are regulated via multiple mechanisms involving biosynthesis, degradation, binding with other extracellular molecules, and activation of signaling pathways. Recent animal studies have provided evidence that aberrant biosynthesis of hyaluronan accelerates tumor growth through a diverse repertoire of host–tumor interactions, such as stromal cell recruitment, angiogenesis, lymphangiogenesis, and inflammation. Hyaluronan in the tumor microenvironment thus significantly impacts cancer initiation and progression via stroma–cancer cell interactions. (Cancer Sci 2008; 99: 1720–1725)
I‐gel insertion by novices in manikins and patients*
Authors: Wharton N. M. , Gibbison B. , Gabbott D. A. , Haslam G. M. , Muchatuta N. , Cook T. M.
Published: June 2008

The i‐gel, a novel supraglottic airway, has been proposed for use during cardiopulmonary resuscitation. We evaluated the performance of this device in manikins and anaesthetised patients when used by novices: medical students, non‐anaesthetist physicians and allied health professionals all unfamiliar with the i‐gel. Fifty i‐gels were placed in manikins. Eighty‐eight percent (44/50) were placed on the first attempt with a median insertion time of 14 s (range 7–45). I‐gels were placed in 40 healthy anaesthetised patients. Success on the first attempt was 82.5% (33/40) and on the second attempt 15% (6/40). After three attempts there were no failures. Median insertion time was 17.5 s (range 7–197). Median airway seal was 20 cmH2O (range 13–40). One case of regurgitation and partial aspiration occurred. Our results suggest the i‐gel is rapidly inserted in both manikins and patients by novice users and compares favourably to other supraglottic airways available. Further work determining safety and efficacy during cardiopulmonary resuscitation is required.
The optimum bolus dose of remifentanil to facilitate laryngeal mask airway insertion with a single standard dose of propofol at induction in children
Authors: Kwak H. J. , Kim J. Y. , Kim Y. B. , Chae Y. J. , Kim J. Y.
Published: June 2008

The purpose of this study was to determine the optimal bolus dose of remifentanil required for the successful insertion of the laryngeal mask airway during propofol induction in children without a neuromuscular blocking agent. Twenty‐six paediatric patients, aged 3–10 years, requiring anaesthesia for short ambulatory surgery were recruited. A predetermined bolus dose of remifentanil was injected over 30 s, followed by propofol 2.5 mg.kg−1over 10 s. The bolus dose of remifentanil was determined by a modified Dixon’s up‐and‐down method, starting from 0.5 μg.kg−1(0.1 μg.kg−1as a step size). Laryngeal mask insertion was attempted 90 s after the end of remifentanil injection and the response of patients was classified as either ‘movement’ or ‘no movement’. The bolus dose of remifentanil at which there was a 50% probability of successful laryngeal mask insertion (ED50) during induction with 2.5 mg.kg−1propofol was 0.56 (0.07) μg.kg−1in children without a neuromuscular blocking agent. From probit analysis, the ED50and ED95of remifentanil were 0.52 μg.kg−1(95% confidence limits, 0.42–0.62 μg.kg−1) and 0.71 μg.kg−1(95% confidence limits, 0.61–1.40 μg.kg−1), respectively.
Seamounts, knolls and petit‐spot monogenetic volcanoes on the subducting Pacific Plate
Authors: Hirano Naoto , Koppers Anthony A. P. , Takahashi Ayu , Fujiwara Toshiya , Nakanishi Masao
Published: June 2008

On the western part of the Pacific Plate most seamounts formed during the Cretaceous period in the so‐called West Pacific Seamount Province (WPSP). On the northwestern part of the same plate, the Joban and Japanese Seamount Trail (JJST) are also composed of Early Cretaceous seamounts. However, two new groups of knolls were recently discovered during multibeam surveys on the Pacific Plate along the Japan Trench. One group consists of circular knolls that are flat‐topped in shape and correspond to eruptive ages of approximately 75 Ma. The other group consists of irregularly shaped knolls, also called petit‐spot volcanoes, that are found on the outer‐rise systems of the subducting Pacific Plate. These petit‐spots seem much younger and available age data suggest that they only formed in the last few million years. Acoustic reflective data, which are simultaneously obtained with bathymetrical data, are a most powerful tool to distinguish the petit‐spots from the Cretaceous edifices in the WPSP and JJST. In this paper, we present the results of an exploratory search for these new kind of petit‐spot volcanoes along the trenches in the Pacific Ocean, with an emphasis on the Japan and Tonga trenches. The sizes of these irregularly shaped petit‐spot volcanoes are several orders of magnitude less than the Cretaceous seamounts and circular knolls, yet they appear to be ubiquitous on the ocean floor, in particular, where incipient melts in the asthenosphere can be squeezed out by tectonic forces.
Hormesis and medicine
Authors: Calabrese Edward J.
Published: June 2008

Evidence is presented which supports the conclusion that the hormetic dose–response model is the most common and fundamental in the biological and biomedical sciences, being highly generalizable across biological model, endpoint measured and chemical class and physical agent. The paper provides a broad spectrum of applications of the hormesis concept for clinical medicine including anxiety, seizure, memory, stroke, cancer chemotherapy, dermatological processes such as hair growth, osteoporosis, ocular diseases, including retinal detachment, statin effects on cardiovascular function and tumour development, benign prostate enlargement, male sexual behaviours/dysfunctions, and prion diseases.
Insulin, adiponectin, IGFBP‐1 levels and body composition in small for gestational age born non‐obese children during prepubertal ages
Authors: Sancakli Ozlem , Darendeliler Feyza , Bas Firdevs , Gokcay Gulbin , Disci Rian , Aki Semih , Eskiyurt Nurten
Published: June 2008

Background  Being small for gestational age (SGA) at birth and postnatal growth pattern may have an impact on insulin resistance and body composition in later life. Adiponectin is a strong determinant of insulin sensitivity.

Objective  The aim of this study was to evaluate insulin resistance and adiponectin levels in SGA born children with catch‐up growth (CUG) in the absence of obesity in prepubertal ages and relations with body composition and insulin‐like growth factor binding protein (IGFBP)‐1.

Methods  Twenty‐four (15F, 9M) SGA born children with CUG but without obesity were evaluated at age 6·3 ± 0·5 years with respect to glucose, insulin, IGFBP‐1, leptin and adiponectin levels, and body composition by dual‐energy X‐ray absorptiometry (DEXA). Their data were compared to that of 62 (27F, 35M) appropriate for gestational age (AGA) children.

Results  SGA and AGA children had similar height standard deviation score (SDS) corrected for parental height and body mass index (BMI) SDS. Homeostasis model for insulin resistance (HOMA‐IR) was significantly high in SGA (0·7 ± 0·6) than in AGA children (0·4 ± 0·2) (P = 0·029). There were no significant differences in leptin, IGFBP‐1, adiponectin, and total and truncal fat between SGA and AGA children. However, being born SGA and having higher BMI in the upper half for the distribution in the sample, although within normal ranges, was associated with lower adiponectin levels (estimated means of log adiponectin levels 3·8 ± 0·3 vs. 4·4 ± 0·1 µg/ml, P = 0·040).

Conclusions  SGA children with CUG and with no obesity have higher insulin levels compared to AGA children. Both SGA birth and recent size seem to have an effect on serum adiponectin levels in childhood.
The G/G genotype of a single nucleotide polymorphism at –1066 of c‐Jun N‐terminal kinase 1 gene (MAPK8) does not affect type 2 diabetes susceptibility despite the specific binding of AP2α
Authors: Osawa Haruhiko , Yamada Kazuya , Tabara Yasuharu , Ochi Masaaki , Onuma Hiroshi , Nishida Wataru , Shimizu Ikki , Kawamoto Ryuichi , Fujii Yasuhisa , Miki Tetsuro , Ohashi Jun , Makino Hideichi
Published: June 2008

Objective  The c‐Jun N‐terminal kinase 1 (JNK1, mitogen‐activated kinase 8; MAPK8) phosphorylates insulin receptor substrate‐1 (IRS‐1) at serine 307, which induces insulin resistance. MAPK8 activity is increased in obese insulin‐resistant mice, whereas mapk8 (–/–) mice show decreased adiposity and improved insulin sensitivity. The aim of this study was to determine the relationship between single nucleotide polymorphisms (SNPs) of MAPK8 and type 2 diabetes (T2DM).

Design, patients and measurements  Approximately 2 kb of 5′ flanking and the coding regions were initially sequenced in 24 Japanese T2DM subjects. Identified SNPs were genotyped in 204 T2DM cases and 201 nondiabetic controls. The function of promoter SNP–1066 (g.–1066G > A, rs10857561) was analysed by electrophoretic mobility shift assay (EMSA) and luciferase assay. SNP–1066 was further genotyped in a total of 498 cases and 407 controls, and in 2075 subjects in the general population.

Results  In 204 cases and 201 controls, 11 identified SNPs were not associated with T2DM. These SNPs were in the same linkage disequilibrium (LD) block. The tag SNP–1066 was not associated with T2DM in a total of 498 cases and 407 controls with the power > 80% when the relative risk is > 1·31. Functionally, transcription factor AP2α specifically recognized G but not A at –1066. MAPK8 promoter activity was unchanged between G and A. In 2075 subjects, neither body mass index (BMI), fasting plasma glucose (FPG), homeostasis model assessment insulin resistance index (HOMA‐IR), nor β cell function index (HOMA‐β) was associated with SNP–1066.

Conclusions  The G/G genotype of MAPK8 SNP–1066 did not affect T2DM susceptibility despite specific binding of AP2α.
Variation in Niemann–Pick C1‐like 1 gene as a determinant of apolipoprotein B‐100 kinetics and response to statin therapy in centrally obese men
Authors: Chan Dick C. , Watts Gerald F. , Wang Jian , Hegele Robert A. , Van Bockxmeer Frank M. , Barrett P. Hugh R.
Published: June 2008

Objective  Niemann–Pick C1‐like 1 protein (NPC1L1) plays a key role in lipoprotein metabolism. We examined the association of common genetic polymorphisms in NPC1L1 on apolipoprotein (apo) B‐100 metabolism and the response to statin treatment in 37 men with central obesity.

Research methods and procedure  Very‐low density lipoprotein (VLDL) and low‐density lipoprotein (LDL)–apoB kinetics were determined using stable isotope method. NPC1L1 genotypes (1735G > C, 25432A > C and 27677T > C) were determined by allele‐specific methods. These three polymorphisms are defined as haplotype, namely 1735C‐25432A‐27677T, and was designated as ‘haplotype 2’.

Results  Relative to non‐2/2 haplotype (n = 23), subjects with the 2/2 haplotype (n = 14) had significantly increased plasma concentrations of total, LDL‐cholesterol, and total apoB (P < 0·05). The fractional catabolic rate (FCR) of LDL‐apoB was significantly lower in 2/2 subjects compared with non‐2/2 subjects (P < 0·05), with an associated increase in LDL‐apoB pool size in the former group. Sixteen subjects were then treated with 40 mg atorvastatin (6 weeks): 2/2 subjects (n = 8) had a significantly greater reduction in plasma concentrations of cholesterol and total apoB and in LDL‐apoB pool size, as well as a greater increase in LDL‐apoB FCR compared with non‐2/2 subjects. There were no significant treatment‐related between‐haplotype differences in VLDL‐apoB kinetics or in plasma concentrations of lathosterol and campesterol.

Conclusion  Our data demonstrate that NPC1L1 2/2 haplotype was associated with variation in LDL‐apoB metabolism and its response to statin therapy in centrally obese men, by a mechanism that did not involve changes in VLDL‐apoB kinetics, nor cholesterol synthesis or absorption.
The evaluation of metabolic parameters and insulin sensitivity for a more robust diagnosis of the polycystic ovary syndrome
Authors: Amato Marco Calogero , Galluzzo Aldo , Finocchiaro Sara , Criscimanna Angela , Giordano Carla
Published: June 2008

Background  Polycystic ovary syndrome (PCOS) is considered predominantly as a hyperandrogenetic syndrome and the evaluation of metabolic parameters and insulin sensitivity is not mandatory.

Context  PCOS diagnostic criteria [National Institute of Health (NIH), Rotterdam Consensus (ROT), Androgen Excess Society (AES)] are unanimous recognized. We aimed to assess in women with suspected PCOS whether the application of the three diagnostic criteria differently characterizes the metabolic profile and insulin sensitivity.

Design  Retrospective study in a cohort of women admitted to our Outpatient Clinic for suspected PCOS.

Patients  Two hundred and four women with suspected PCOS in comparison to a group of normal, age‐matched Sicilian women (N = 34) without signs of metabolic syndrome.

Measurements  We evaluated hyperandrogenaemia and clinical hyperandrogenism, ovarian morphology, hypothalamo–hypophyseal axis and metabolic syndrome parameters. An oral glucose tolerance test (OGTT; 75 g glucose) measured areas under the curve (AUC) for insulin, C peptide and homeostasis model assessment of insulin‐resistance (HOMA‐IR) were performed.

Results  The prevalence of PCOS was 51% according to NIH, 83% to ROT and 70·6% to AES, and only 100 patients were qualified simultaneously under these three criteria. The prevalence of the metabolic syndrome in PCOS women was 26·92% (NIH), 21·77% (ROT) and 23·61% (AES), respectively. In comparison to healthy women, PCOS women showed increased fasting insulinaemia (PCOS/ROT: P = 0·028; PCOS/NIH: P = 0·007; PCOS/EAS: P = 0·023), 120 min insulin after OGTT insulinaemia (for the three criteria: P < 0·001), AUC2h insulin (for the three criteria: P < 0·001) and AUC2h C peptide (for the three criteria: P < 0·001).

Conclusions  Our study highlights the fact that regardless of the diagnostic criteria used, evaluation of the metabolic parameters and insulin sensitivity is important for a correct diagnosis of PCOS and a therapeutic approach.
A novel phenotypic expression associated with a new mutation in LMNA gene, characterized by partial lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy
Authors: Araújo‐Vilar David , Lado‐Abeal Joaquin , Palos‐Paz Fernando , Lattanzi Giovanna , Bandín Manuel A. , Bellido Diego , Domínguez‐Gerpe Lourdes , Calvo Carlos , Pérez Oscar , Ramazanova Alia , Martínez‐Sánchez Noelia , Victoria Berta , Costa‐Freitas Ana Teresa
Published: June 2008

Background  Lipodystrophies are a heterogeneous group of diseases characterized by abnormal fat distribution. Familial partial lipodystrophy 2 (FPLD2) is due to mutations in the LMNA gene. Previous studies have suggested that LMNA mutations 5′ to the nuclear localization signal (NLS) are more likely to underlie laminopathies with cardiac or skeletal muscle involvement, while mutations 3′ to the NLS are more likely to underlie lipodystrophy and progeroid syndromes.

Objective  To study the clinical and molecular features of a subject with FPLD.

Subjects and methods  We carried out mutational analysis of LMNA gene in a woman with FPLD phenotype and in her relatives. Insulin resistance was evaluated by minimal model. Body composition was evaluated by dual‐energy X‐ray absorptiometry (DEXA). Echocardiography was done in affected subjects. 3T3‐L1 preadipocytes were transfected with wild‐type or mutant prelamin A constructs. In transfected cells, lamin A was detected using a Cy3‐conjugated monoclonal anti‐FLAG antibody.

Results  The patient showed atypical fat distribution, insulin resistance, severe aortic stenosis and hypertrophic cardiomyopathy. She has an affected 11‐year‐old son, not yet lipodystrophic but with an incipient aortic disease. LMNA sequencing showed that mother and son were both heterozygous for a novel c.1772G > T missense mutation in exon 11, which causes the substitution of the cysteine at residue 591 by a phenylalanine (C591F). In mouse preadipocytes transfected with the mutant human LMNA gene, the mutant lamin A isoform was mislocated in the nucleus.

Conclusions  This patient shows a novel clinical form of FPLD2, due to a mutation affecting lamin A only, with cardiac involvement.
Serum levels of the adipokine visfatin are increased in pre‐eclampsia
Authors: Fasshauer Mathias , Waldeyer Theresa , Seeger Jeannette , Schrey Susanne , Ebert Thomas , Kratzsch Jurgen , Lossner Ulrike , Bluher Matthias , Stumvoll Michael , Faber Renaldo , Stepan Holger
Published: June 2008

Objective  Pre‐eclampsia (PE) is a serious cardiovascular complication in pregnancy which shares risk factors with the metabolic syndrome including insulin resistance and obesity. Recently, visfatin was introduced as a novel insulin‐mimetic adipokine which is up‐regulated when weight is gained. In the current study, we investigated visfatin serum levels in pre‐eclamptic patients as compared to healthy gestational age‐matched controls.

Patients and measurements  Visfatin was quantified by ELISA in control (n = 20) and PE (n = 15) patients. Furthermore, visfatin was correlated to clinical and biochemical measures of renal function, glucose and lipid metabolism, as well as inflammation.

Results  Mean maternal visfatin serum levels adjusted for maternal age were about twofold up‐regulated in PE (31·1 ± 23·4 µg/l) as compared to controls (15·7 ± 23·1 µg/l). Furthermore, visfatin concentrations correlated positively with age, blood pressure, creatinine, free fatty acids (FFA), IL‐6 and C reactive protein (CRP), whereas a negative correlation was found with fasting insulin and the HOMA‐insulin resistance index (HOMA‐IR). In multivariate analyses, HOMA‐IR and CRP remained independently associated with visfatin serum levels and explained 58% of the variation in visfatin concentrations.

Conclusions  We show that maternal visfatin levels are significantly increased in PE patients. Furthermore, insulin sensitivity and inflammatory status independently predict serum visfatin levels.
Sizes of abdominal organs in adults with severe short stature due to severe, untreated, congenital GH deficiency caused by a homozygous mutation in the GHRH receptor gene
Authors: Oliveira Carla R. P. , Salvatori Roberto , Nóbrega Luciana M. A. , Carvalho Erick O. M. , Menezes Menilson , Farias Catarine T. , Britto Allan V. O. , Pereira Rossana M. C. , Aguiar‐Oliveira Manuel H.
Published: June 2008

Objective  To assess the sizes of intra‐abdominal organs of adult subjects with untreated severe congenital isolated GH deficiency (IGHD) due to lack of functional GHRH receptor (GHRH‐R), and to verify whether there is proportionality between size of organ and adult stature and body surface area (BSA).

Subjects and methods  By using ultrasound, we studied the sizes (absolute and corrected by height, weight and BSA) of the intra‐abdominal organs of 18 adult subjects with IGHD (eight females, IGHD group) who have never received GH replacement therapy. They were all homozygous for the same null mutation (IVS1 + 1G → A) in the GHRH receptor gene (GHRH‐R). They were compared with normal controls from the same region.

Results  After correction for BSA, subjects lacking a functional GHRH‐R have normal prostate and ovaries size, small spleen and uterus, and large liver, pancreas and kidney.

Conclusions  Size of individual abdominal organs is influenced in different ways by severe and congenital lack of GH due to a GHRH‐R mutation.
Assessment of the efficacy and safety of intravenous conivaptan in patients with euvolaemic hyponatraemia: subgroup analysis of a randomized, controlled study
Authors: Verbalis Joseph G. , Zeltser David , Smith Neila , Barve Abhijit , Andoh Masakazu
Published: June 2008

Objective and design Most cases of euvolaemic hyponatraemia are associated with elevated plasma levels of AVP. Conivaptan is a high‐affinity, nonpeptide vasopressin V1A/V2‐receptor antagonist. We performed a subgroup analysis of a multicentre, randomized, placebo‐controlled, double‐blind, parallel‐group study to evaluate the efficacy and safety of intravenous (i.v.) conivaptan for the treatment of euvolaemic hyponatraemia.

Patients Fifty‐six euvolaemic patients with serum [Na+] of 115 to < 130 mmol/l received conivaptan 40 or 80 mg/day or placebo via continuous i.v. infusion for 4 days. A 20‐mg loading dose was administered intravenously over 30 min in the conivaptan groups; the placebo group received a placebo loading dose.

Measurements Change in serum [Na+], measured by the baseline‐adjusted area under the serum [Na+]–time curve (AUC), was the primary efficacy parameter. Secondary efficacy measures included the time from the first dose to a confirmed ≥ 4 mmol/l increase in serum [Na+], total time with serum [Na+] ≥ 4 mmol/l above baseline, change in serum [Na+] from baseline, and number of patients with a confirmed ≥ 6 mmol/l increase in serum [Na+] or normal [Na+]. Safety assessments included adverse events (AE), incidence of overly rapid correction of serum [Na+], and changes in vital signs and electrocardiographic and clinical laboratory parameters.

Results During the first 2 days of treatment, and over the entire 4‐day treatment period, both conivaptan doses significantly increased the serum [Na+] AUC more than placebo (P < 0·01). Conivaptan 40 and 80 mg/day significantly improved all secondary efficacy measures. Conivaptan was generally well tolerated; infusion‐site reaction was the most common AE.

Conclusions In hospitalized patients with euvolaemic hyponatraemia, i.v. conivaptan significantly increased serum [Na+] promptly and was well tolerated.
Influence of iodine on the reference interval of TSH and the optimal interval of TSH: results of a follow‐up study in areas with different iodine intakes
Authors: Guan Haixia , Shan Zhongyan , Teng Xiaochun , Li Yushu , Teng Di , Jin Ying , Yu Xiaohui , Fan Chenling , Chong Wei , Yang Fan , Dai Hong , Yu Yang , Li Jia , Chen Yanyan , Zhao Dong , Shi Xiaoguang , Hu Fengnan , Mao Jinyuan , Gu Xiaolan , Yang Rong , Chen Wei , Tong Yajie , Wang Weibo , Gao Tianshu , Li Chenyang , Teng Weiping
Published: June 2008

Objective  The aim of the present study was to evaluate whether the status of iodine nutrition influences the TSH concentration in a selected Chinese reference population according to the criteria proposed by National Academy of Clinical Biochemistry (NACB) and regular thyroid ultrasonography, to establish a new reference interval of TSH based on the wide variation of iodine nutrition in populations, and to identify an optimal interval of TSH by following up the cohort with normal TSH concentrations at baseline.

Design  The study was conducted in Panshan, Zhangwu and Huanghua, the regions with mildly deficient, more than adequate and excessive iodine intake, respectively. Of the 3761 unselected subjects who were enrolled at baseline, 2237 met the criteria for a reference population. Of 3048 subjects with normal serum TSH at baseline, 2727 (80·0%) participated in the 5‐year follow‐up study. TSH and thyroid autoantibodies in serum and iodine in urine were measured, and B‐mode ultrasonography of the thyroid was performed.

Results  In the reference population, there was a urinary iodine‐related increment of serum TSH levels (r = 0·21, P = 0·000), and the mean levels of TSH in Panshan, Zhangwu and Huanghua were 1·15, 1·28 and 1·93 mIU/l, respectively (P = 0·000), corresponding to the rising regional iodine intake. Based on the overall data, we obtained a reference interval of 0·3–4·8 mIU/l. TSH concentrations obtained in the follow‐up study correlated well with those at baseline (r = 0·58, P = 0·000). A baseline serum TSH > 1·9 mIU/l was associated with an increased incidence of development of supranormal TSH and a baseline serum TSH < 1·0 mIU/l was associated with an increased incidence of subnormal TSH development.

Conclusions  Iodine nutrition is an important factor associated with TSH concentration even in the rigorously selected reference population. Baseline TSH of 1·0–1·9 mIU/l is an optimal interval with the lowest incidence of abnormal TSH in 5 years.
Familial prevalence and age of RET germline mutations: implications for screening
Authors: Machens Andreas , Dralle Henning
Published: June 2008

Objective  No comprehensive information exists nationwide about the familial prevalence and age of rearranged during transfection (RET) germline mutations. The current investigation was undertaken to provide such natural history data which are urgently needed to enable factual decision‐making about DNA‐based screening programmes for RET germline mutations.

Design  Descriptive study drawn on countrywide referrals to a specialist surgical centre.

Patients  Included were 452 patients from 141 German RET families: 277 carriers referred for pre‐emptive or therapeutic surgery, and 175 additional carriers or relatives with endocrine tumours associated with multiple endocrine neoplasia type 2 (MEN2).

Measurements  Key variables included familial prevalence, phenotype and latest year of birth of RET germline mutations.

Results  A total of 26 different RET germline mutations were identified among the 141 RET families: C634R (21%); M918T (15%); C634Y (9%); L790F/TTG→TTT (8%), Y791F (7%), V804M (6%); C620R and C634F (5% each); L790F/TTG→TTC and C634S/TGC→TCC (4% each); C618S/TGC→AGC, C634G and S891A (2% each); C618F and E768D (1% each); and in < 1% each: C609G, C611F, C611Y, C618G, C618Y, C620S/TGC→AGC, C620S/TGC→TCC, C620Y, C630R, D631Y and V804L. Most of these differences in prevalence rates, seemingly, were caused by recent spontaneous mutations in the germline. With rare exceptions, longstanding transmission was noted in at least one RET family per affected codon. Many germline mutations were traceable back to the early 20th, and a few even to the 19th century.

Conclusions  These data reveal the potential of DNA‐based screening of all relevant RET exons, especially for index patients with solitary, seemingly sporadic disease.
Serum resistin is positively correlated with the accumulation of metabolic syndrome factors in type 2 diabetes
Authors: Osawa Haruhiko , Ochi Masaaki , Tabara Yasuharu , Kato Kenichi , Yamauchi Junko , Takata Yasunori , Nishida Wataru , Onuma Hiroshi , Shimizu Ikki , Fujii Yasuhisa , Miki Tetsuro , Ohashi Jun , Makino Hideichi
Published: June 2008

Objective  Resistin, secreted from adipocytes, causes insulin resistance in rodents. We reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at −420 increases type 2 diabetes (T2DM) susceptibility by enhancing promoter activity. We also showed that serum resistin was positively correlated with G at SNP‐420, the duration of T2DM, and HbA1c in T2DM. The aim of this study was to determine the relation between serum resistin and factors related to the metabolic syndrome (MetS) in T2DM.

Design, patients and measurements  We analysed 238 Japanese T2DM subjects (124 males and 114 females, age 60·2 ± 11·3 years, body mass index (BMI) 24·1 ± 3·9) whose overnight fasting sera were available. Serum resistin was measured using ELISA.

Results  Serum resistin was higher in subjects with either obesity (P = 0·041), low HDL (P = 0·004), high triglycerides (TG) (P = 0·019), hypertension (HT) (P = 0·001) or atherosclerosis (P = 0·012). Simple regression analysis revealed that serum resistin was correlated with lower HDL, TG and high‐sensitivity C‐reactive protein (hsCRP). Multiple regression analysis (or logistic regression analysis for HT), adjusted for age, gender, BMI and the duration of T2DM, revealed that serum resistin was correlated with lower HDL (P = 0·008), TG (P = 0·041), HT (P = 0·031) and hsCRP (P = 0·004). Serum resistin was positively correlated with the number of MetS factors, independent of age, gender and the duration of T2DM (P < 0·001). Adjustment by either thiazolidinedione (TZD) treatment or hsCRP had no effects on these findings.

Conclusions  Serum resistin was positively correlated with the accumulation of MetS factors in T2DM.
Gonadotrophic status in adolescents with pituitary stalk interruption syndrome
Authors: Rottembourg Diane , Linglart Agnès , Adamsbaum Catherine , Lahlou Najiba , Teinturier Cécile , Bougnères Pierre , Carel Jean‐Claude
Published: June 2008

Objective  Pituitary stalk interruption syndrome (PSIS) is a frequent cause of GH deficiency (GHD) and is commonly associated with other PH deficiencies (PHDs). Although previous reports have correlated multiple PHDs with severe anatomical lesions, the status of the gonadotrophic axis has not yet been thoroughly analysed.

Methods  We retrospectively reviewed the medical records of 27 patients (15 males, 12 females) with GHD and PSIS defined by MRI findings. The status of the gonadotrophic axis was evaluated in children who were at least 14·5 years (boys) or 13 years (girls).

Results  Out of 27 patients, five displayed spontaneous full pubertal development with normal hormonal values at the final evaluation, whereas 22 of 27 patients (81%) had complete (n = 18) or partial pubertal deficiency. Three girls had primary amenorrhoea with normal gonadotrophin values, raising the possibility of subtle disturbances of gonadotrophin pulsatility. Of the 21 patients with TSH or ACTH deficiency, 17 (81%) had complete gonadotrophin deficiency. Two of our six patients with apparently isolated GHD during childhood had gonadotrophin deficiency. Cryptorchidism was present at birth in six boys (40%). Of these six boys, one had normal pubertal development. Ten of 11 boys with micropenis at birth had gonadotrophin deficiency.

Conclusions  Gonadotrophin deficiency is a common finding in adolescents with PSIS and is frequently associated with other PHDs. However its severity is variable, ranging from complete gonadotrophin deficiency to normogonadotrophic amenorrhoea. The occurrence of gonadotrophin deficiency in 33% of children with apparently isolated GHD and PSIS has important implications for the counselling and follow‐up of these patients.
Long‐term treatment of familial male‐limited precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole
Authors: Almeida Madson Queiroz , Brito Vinicius Nahime , Lins Thereza Selma S. , Guerra‐Junior Gil , De Castro Margaret , Antonini Sonir Roberto , Arnhold Ivo Jorge Prado , Mendonca Berenice Bilharinho , Latronico Ana Claudia
Published: June 2008

Background Familial male‐limited precocious puberty (FMPP) or testotoxicosis is a rare gonadotrophin‐independent form of sexual precocity caused by constitutively activating mutations of the LH receptor. Several clinical therapeutic approaches have been reported for this disorder, but with a paucity of long‐term outcome data.

Objective To evaluate the long‐term treatment of testotoxicosis with cyproterone acetate or ketoconazole.

Design A multicentric retrospective clinical study.

Patients Ten boys from eight unrelated Brazilian families who carried known LH‐receptor activating mutations were treated with 70 mg/m2cyproterone acetate (n = 5) or 10 mg/kg ketoconazole (n = 5) for a mean period of 5 and 8 years, respectively.

Measurements Chronological and bone ages, bone age/chronological age ratio, target height (TH) range, adult height, basal and GnRH‐stimulated gonadotrophin levels and basal testosterone levels were assessed.

Results Growth velocity decreased significantly during treatment with cyproterone acetate or ketoconazole when compared to pretreatment value in each group (P < 0·05). Bone age/chronological age ratio decreased significantly after cyproterone acetate or ketoconazole therapy. Basal testosterone levels were significantly lower in patients undergoing ketoconazole compared to cyproterone acetate treatment [0·6 ± 0·3 nmol/l (42 ± 21 ng/dl)vs.5·6 ± 4·0 nmol/l (392 ± 280 ng/dl);P < 0·05], as expected. Secondary gonadotrophin‐dependent precocious puberty occurred at a similar frequency (40%) in both groups. Five patients have attained adult height and two patients have already reached 90% of their adult height. Two of them achieved their TH range and one patient, for whom TH was not available, had an adult height of 0·3 SDS. Four boys (two in each group) did not attain their TH range.

Conclusion Long‐term treatment with cyproterone acetate or ketoconazole resulted in similar outcomes without important side‐effects in boys with testotoxicosis. However, both therapies showed limited efficacy in attaining normal adult height.
Previous radiotherapy negatively influences quality of life during 4 years of follow‐up in patients cured from acromegaly
Authors: Van Der Klaauw Agatha A. , Biermasz Nienke R. , Hoftijzer Hendrieke C. , Pereira Alberto M. , Romijn Johannes A.
Published: June 2008

Objective  Cross‐sectional studies have shown impaired quality of life (QoL) in patients in biochemical control of acromegaly. The aim of this study was to assess longitudinal changes in QoL in a homogenous cohort of patients with sustained biochemical control of acromegaly.

Design  Prospective follow‐up study.

Patients and methods  QoL was assessed using four health‐related QoL questionnaires (HADS, Hospital Anxiety and Depression Scale; MFI‐20, Multidimensional Fatigue Index; NHP, Nottingham Health Profile; and SF‐36, Short Form‐36) and one disease‐specific acromegaly quality of life (ACRO‐QOL) questionnaire in 82 patients (43 men) with strict biochemical control of acromegaly, aged 56 years (range 29–84 years) at baseline and after 4 years of follow‐up. The mean duration of controlled disease was 12 years (range 1–26 years).

Results  During follow‐up, scores in 5 of 26 QoL subscales significantly worsened: physical and social functioning (SF‐36), physical fatigue (MFI‐20), and psychological well‐being and personal relations (ACRO‐QOL). Using linear regression analysis, baseline item scores predicted the follow‐up scores, indicating individual stability over time. Previous radiotherapy (n = 27, 33%) negatively influenced several QoL subscales at follow‐up: energy, pain and social isolation (NHP), physical fatigue and reduction in activity and motivation (MFI‐20), depression and total anxiety and depression scores (HADS) and physical performance (ACRO‐QOL).

Conclusion  During 4 years of follow‐up in patients with long‐term biochemical control of ACRO‐QOL is subtly, but progressively impaired. Radiotherapy was the predominant indicator of progressive impairment in QoL.
Polymorphisms of the ghrelin/obestatin gene and ghrelin levels in Chinese children with short stature
Authors: Zou Chao Chun , Huang Ke , Liang Li , Zhao Zheng Yan
Published: June 2008

Objective  To investigate the role of ghrelin and polymorphisms of ghrelin/obestatin gene in children with short stature.

Methods  A total of 117 GH deficient (GHD) and 81 idiopathic short stature (ISS) children were studied. The controls consisted of 125 age and gender‐matched healthy children. The Arg51Gln, Leu72Met and Gln90Leu polymorphisms were genotyped using MassArray and total plasma ghrelin was measured by radioimmunoassay.

Results  In this study, the frequency of the Arg51Gln polymorphism was very low (0% in controls and 1·0% in patients). The frequency of the Gln90Leu polymorphism was 1·6% in controls and 0·5% in patients, respectively. Higher frequencies of Leu72Met (34·4% in controls and 39·9% in patients) and Met72Met genotypes (4·0% in controls and 2·0% in patients) were found. The differences in the Arg51Gln, Leu72Met or Gln90Leu genotypes and allele frequencies between patients and controls were not significant. Also, there were no significant differences in the Leu72Met genotypes and allele frequencies between GHD and ISS subgroups. There were no significant differences in clinical characteristics and biochemistry markers (including ghrelin levels) among the different genotypes of Leu72Met. However, plasma ghrelin levels in the GHD group were significantly lower than those of controls (P = 0·001).

Conclusion  These results suggest that ghrelin may have a role in GH secretion and controlling growth. Lower ghrelin levels, but not ghrelin/obestatin polymorphism, might contribute to GHD.
A novel therapeutic paradigm to treat congenital hypothyroidism
Authors: Mathai Sarah , Cutfield Wayne S. , Gunn Alistair J. , Webster Dianne , Jefferies Craig , Robinson Elizabeth , Hofman Paul
Published: June 2008

Objective  To determine the effectiveness of a novel therapeutic paradigm to treat congenital hypothyroidism (CH) incorporating variable initial doses of L‐T4 based on the underlying aetiology and frequent monitoring, up to 2 years of age.

Design  Retrospective cohort study.

Patients  Infants with primary CH diagnosed by newborn screening.

Measurements  Treatment with L‐T4 suspension initiated at 10, 12 and 15 µg/kg/day for dyshormonogenesis, ectopia and athyreosis, respectively. Serum TSH and free T4 (FT4) levels monitored weekly during the first 4 weeks, at 6 weeks, thereafter monthly during the first 2 years. Dose changes were made to keep FT4 level in upper half of the normal range.

Results  Sixty‐nine infants; 17 had dyshormonogenesis, 35 ectopia and 17 athyreosis. Seventy‐eight percent of subjects normalized FT4 levels within 7 days of treatment and 100% within 14 days. TSH levels normalized in 26% of infants within 7 days and in 92% by 21 days. Supraphysiological levels of FT4 were noted in 28% of infants, for a maximum of 2 weeks. 48% infants needed one dose adjustment and 30% needed at least two in the first month. In 52 infants over the first 2 years, mean FT4 levels were consistently in the upper half of the normal range. Two or more dose adjustments every 3 months were made 57 times in the first year as compared to 19 times in the second year.

Conclusions  A variable initial dose paradigm based on aetiology with frequent testing and using T4 suspension rapidly normalizes FT4 levels without producing persistent hyperthyroxinaemia.
Heritability of blood concentrations of sex‐steroids in relation to body composition in young adult male siblings
Authors: Bogaert Veerle , Taes Youri , Konings Peter , Van Steen Kristel , De Bacquer Dirk , Goemaere Stefan , Zmierczak Hans , Crabbe Patricia , Kaufman Jean‐Marc
Published: June 2008

Objective  Sex steroid concentrations in men are related to body composition and both are determined by genetic and environmental factors. This study investigates heritability estimates of sex steroid serum concentrations and body composition as well as the genetic and environmental components of their interrelation.

Patients  Six hundred and seventy‐four men (25–45 years) were included in this study with 274 independent pairs of brothers.

Measurements  Body composition and regional fat mass estimates were determined using dual‐energy X‐ray absorptiometry. Serum testosterone (T), SHBG, oestradiol (E2) and LH levels were determined by immunoassay; free T and E2 levels were calculated.

Results  Both sex steroid hormone concentrations and indices of body composition exhibited significant heritability estimates. Among sex steroid hormones, T had the highest heritability (h2 = 0·65), followed by free T (h2 = 0·54). A heritability of 0·73 was observed for SHBG; a heritability estimate of 0·83 was obtained for body weight. Significant genetic correlations were found between whole body fat mass and serum T (ρG = –0·46), free T (ρG = –0·27) and SHBG (ρG = –0·48) concentrations. No genetic relationship was observed between total (F) E2 or LH concentrations, respectively, and body composition.

Conclusion  Both sex steroid serum levels and body composition are under strong genetic control. Their interrelation is in part underlied by a genetic correlation, indicative of the action of shared genes.
Primary cell cultures from anaplastic thyroid cancer obtained by fine‐needle aspiration used for chemosensitivity tests
Authors: Antonelli Alessandro , Ferrari Silvia Martina , Fallahi Poupak , Berti Piero , Materazzi Gabriele , Barani Lucio , Marchetti Ivo , Ferrannini Ele , Miccoli Paolo
Published: June 2008

Objective  Anaplastic thyroid cancer (ATC) is often inoperable and chemotherapy and radiotherapy are the main treatments. Until now, ‘primary ATC cell cultures’ (ANA) have been developed from surgical biopsies. We investigated the possibility of obtaining ANA from fine‐needle aspiration (FNA‐ANA) and testing their sensitivity to chemotherapeutic agents, which could enable treatments to be more effective and avoid unnecessary surgical procedures.

Design and patients  The aim of this study was to obtain FNA‐ANA from three ATC patients and to evaluate the chemosensitivity of FNA‐ANA to chemotherapeutic agents.

Measurements and results  FNA‐ANA from ATC patients were cultured in RPMI 1640 and propagated in Dulbecco's modified Eagle's medium (DMEM). Chemosensitivity was evaluated by inhibiting the proliferation (analysing the number of viable cells by the cleavage of tetrazolium salts), by increasing the concentration of four different chemotherapeutic agents: bleomycin, cisplatin, gemcitabine and etoposide. The chemotherapeutic agents significantly inhibited (> 50%) FNA‐ANA proliferation. Another ANA for each patient was obtained from a surgical biopsy specimen; the results for the chemosensitivity tests were similar to those obtained using FNA‐ANA.

Conclusions  Our study demonstrates the possibility of obtaining FNA‐ANA, and opens the way to the use of FNA‐ANA as a means of testing the chemosensitivity to different chemotherapeutic agents (and possibly the radiosensitivity) in each patient, avoiding unnecessary surgical procedures and the administration of inactive chemotherapeutics.
The role of cervical cytology and colposcopy in detecting cervical glandular neoplasia
Authors: Ullal A. , Roberts M. , Bulmer J. N. , Mathers M. E. , Wadehra V.
Published: June 2008

Objective:  To determine the role of cervical cytology and colposcopy in the management of endocervical neoplasia.

Setting:  Colposcopy unit and cytology laboratory in a teaching hospital.

Sample:  Group 1 included 184 smears showing endocervical glandular neoplasia from 129 patients and group 2 included 101 patients with histology showing endocervical abnormalities in a 6‐year period (1993–1998). Follow‐up of 6–11 years to 2004 was available.

Methods:  Group 1 were identified from the cytology computer records. Group 2 were identified from histology records on the cytology database and a record of histology cases kept for audit purposes. The clinical records were examined retrospectively.

Results:  The positive predictive value (PPV) of abnormal endocervical cells in smears was 81.1% for significant glandular/squamous [cervical glandular intraepithelial neoplasia (CGIN)/cervical intraepithelial neoplasia grade2 (CIN2 or worse)] lesions. The PPV of colposcopy was 93.5% for significant glandular/squamous lesions of the cervix. The postcolposcopy probability of a significant lesion when colposcopy was normal was 87.5%. The sensitivity of colposcopy in detecting endocervical lesions was 9.8%. The sensitivity of cervical smears in detecting a significant endocervical abnormality (CGIN or worse) was 66.3%. The false negative rate for cytology of endocervical glandular lesions was 4.0%.

Conclusions:  Endocervical glandular neoplasia detected on cytology is predictive of significant cervical pathology even when colposcopy is normal, which supports excisional biopsy in the primary assessment of these smears. The high concomitant squamous abnormality rate justifies the use of colposcopy to direct biopsies from the ectocervix. Cervical cytology is the only current screening method for cervical glandular abnormalities but sensitivity is poor.
Diagnosis, clinical features and molecular assessment of the dysfibrinogenaemias
Authors: HILL M. , DOLAN G.
Published: June 2008

Summary.  Hereditary dysfibrinogenaemia is characterized by the presence of functionally abnormal plasma fibrinogen. Dysfibrinogenaemia is a heterogeneous disorder associated with different mutations throughout the three genes that code for the fibrinogen sub‐units, affecting many different aspects of fibrinogen/fibrin activity. Dysfibrinogenaemia may be discovered during the investigation of individuals who present with bleeding or thombosis, or may be found in individuals during routine coagulation screening. More specialized coagulation tests may confirm the diagnosis of dysfibrinogenaemia but do not reliably distinguish between the different fibrinogen variants and are not usually useful in predicting bleeding or thrombotic risk. Advances in molecular diagnostics have facilitated the investigation of the molecular causes of fibrinogen disorders. Several ‘hot spot’ areas have been identified where mutations causing a high proportion of cases of dysfibrinogenaemia are found (AαArg16 and γArg275). Molecular diagnostics have also shown that many fibrinogen variants share the same causative mutation. There is a discrepancy between the quality of the molecular and functional data available for each mutation and the clinical information on individuals and their family members. However, there are accumulating data that the ‘hot spot’ mutations accounting for 60–80% of cases of dysfibringenaemia are not associated with a significant bleeding or thrombosis in the absence of other risk factors. Rapid screening for these mutations may provide reassurance for patients in the presurgical setting.