bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns of ferroelectric domains in LiNbO3crystals characterized by X-ray topography
Authors: González-Mañas M. , Vallejo B. , Caballero M. A.
Published: November 2005

A complex pattern of opposite and antiparallel periodic poled domains in LiNbO3single crystals has been studied by X-ray topography. The antiparallel periodic poled domains appear directly at the growth interface during the growth in alternating crescent-shaped (CS) domains. The measured Li/Nb ratio is higher in the CS domains than in other zones. A model of the electric fields responsible for the observed configuration is proposed, connected to the role of the Li atom. Diffraction contrast associated with the different domain walls is examined and different kinds of dislocations associated with the ferroelectric domains are also studied, determining their geometrical characters.
Conceptual design of a macromolecular neutron diffractometer (MaNDi) for the SNS
Authors: Schultz Arthur J. , Thiyagarajan P. , Hodges Jason P. , Rehm Christine , Myles Dean A. A. , Langan Paul , Mesecar Andrew D.
Published: November 2005

This paper describes the design criteria, calculations and simulations for a high-resolution macromolecular neutron diffractometer (MaNDi) for the Spallation Neutron Source (SNS). MaNDi is optimized to achieve 1.5 Å resolution from crystals of 0.1–1 mm3with lattice repeats in the range of 150 Å. It was determined that locating MaNDi on a decoupled hydrogen moderator beamline with a curved guide will provide data of higher resolution and higher signal-to-noise than a coupled hydrogen moderator at the SNS. In addition, for an instrument with an initial flight path of 24 m at the 60 Hz source and a wavelength bandwidth of Δλ≃ 2.7 Å, bandwidth selection disk choppers can shift the wavelength range higher or lower for different experiments. With a wavelength range of 1.5–4.2 Å anddmin= 2.0 Å, simulations predict experiment duration times of 1–7 d, which is expected to revolutionize neutron macromolecular crystallography (NMC) for applications in the fields of structural biology, enzymology and computational chemistry.
Screening and optimization of protein crystallization conditions through gradual evaporation using a novel crystallization platform
Authors: Talreja Sameer , Kim David Y. , Mirarefi Amir Y. , Zukoski Charles F. , Kenis Paul J. A.
Published: November 2005

High-throughput screening of a wide range of different conditions is typically required to obtain X-ray quality crystals of proteins for structure–function studies. The outcomes of individual experiments,i.e.the formation of gels, precipitates, microcrystals, or crystals, guide the search for and optimization of conditions resulting in X-ray diffraction quality crystals. Unfortunately, the protein will remain soluble in a large fraction of the experiments. In this paper, an evaporation-based crystallization platform is reported in which droplets containing protein and precipitant are gradually concentrated through evaporation of solvent until the solvent is completely evaporated. A phase transition is thus ensured for each individual crystallization compartment; hence the number of experiments and the amount of precious protein needed to identify suitable crystallization conditions is reduced. The evaporation-based method also allows for rapid screening of different rates of supersaturation, a parameter known to be important for optimization of crystal growth and quality. The successful implementation of this evaporation-based crystallization platform for identification and especially optimization of crystallization conditions is demonstrated using the model proteins of lysozyme and thaumatin.
Design and performance of a thermal-neutron double-crystal diffractometer for USANS at NIST
Authors: Barker J. G. , Glinka C. J. , Moyer J. J. , Kim M. H. , Drews A. R. , Agamalian M.
Published: November 2005

An ultra-high-resolution small-angle neutron scattering (USANS) double-crystal diffractometer (DCD) is now in operation at the NIST Center for Neutron Research (NCNR). The instrument uses multiple reflections from large silicon (220) perfect single crystals, before and after the sample, to produce both high beam intensity and a low instrument background suitable for small-angle scattering measurements. The minimum detector background to beam intensity ratio (noise-to-signal, N/S) forq≥ 5 × 10−4 Å−1is 4 × 10−7. The instrument uses 2.38 Å wavelength neutrons on a dedicated thermal neutron beam port, producing a peak flux on the sample of 17300 cm−2 s−1. The typical measurement range of the instrument extends from 3 × 10−5 Å−1to 5 × 10−3 Å−1in scattering wavevector (q), providing information on material structure over the size range from 0.1 µm to 20 µm. This paper describes the design and characteristics of the instrument, the mode of operation, and presents data that demonstrate the instrument's performance.
The spatial structure of dendritic macromolecules
Authors: Ozerin A. N. , Svergun D. I. , Volkov V. V. , Kuklin A. I. , Gordelyi V. I. , Islamov A. Kh. , Ozerina L. A. , Zavorotnyuk D. S.
Published: November 2005

A low-resolutionab initioshape determination was performed from small-angle neutron and X-ray scattering (SANS and SAXS) curves from solutions of polycarbosilane dendrimers with the three-functional and the four-functional branching centre of the fourth, fifth, sixth, seventh and eighth generations. In all cases, anisometric dendrimer shapes were obtained. The overall shapes of the dendrimers with the three- and four-functional branching centres were oblate ellipsoids of revolution and triaxial ellipsoids, respectively. The restored bead models revealed a pronounced heterogeneity within the dendrimer structure. The density deficit was observed in the central part and close to the periphery of the dendrimers. The fraction of the overall volume of the dendrimers available for solvent penetration was about 0.2–0.3. These results may help in the design of new practical applications of dendrimer macromolecules.
Hb Woodville, a rare α‐globin variant, caused by codon 6 mutation of the α1 gene
Authors: Viprakasit Vip , Chinchang Worrawut , Chotimarat Pipat
Published: November 2005

Abstract:  Since 1995, the national programme for the prevention and control of severe thalassaemia has been implemented in Thailand. This programme is composed of the population screening in pregnant women and couples by osmotic fragility, HbE screening and the confirmation test using haemoglobin analyses by electrophoresis or chromatography. Thereafter, several hitherto unidentified haemoglobins (Hbs) with structural defects are increasingly described and these variants are now easily studied using DNA technology. In this study, the authors describe the haematology and molecular analyses in a 28‐yr‐old healthy female who was identified as having an exceptionally ‘high HbA2’ from haemoglobin analysis. Subsequent analyses demonstrated that observed atypical ‘HbA2’ was, in fact, a rare innocuous α‐globin variant, called Hb Woodville [alpha 2 6(A4); Asp → Tyr]. For the first time, this abnormal Hb species is characterised at the molecular level.
Social control and coercion in addiction treatment: towards evidence‐based policy and practice
Authors: Wild T. Cameron
Published: November 2005

Background  Social pressures are often an integral part of the process of seeking addiction treatment. However, scientists have not developed conclusive evidence on the processes, benefits and limitations of using legal, formal and informal social control tactics to inform policy makers, service providers and the public. This paper characterizes barriers to a robust interdisciplinary analysis of social control and coercion in addiction treatment and provides directions for future research.

Approach  Conceptual analysis and review of key studies and trends in the area are used to describe eight implicit assumptions underlying policy, practice and scholarship on this topic.

Findings  Many policies, programmes and researchers are guided by a simplistic behaviourist and health‐service perspective on social controls that (a) overemphasizes the use of criminal justice systems to compel individuals into treatment and (b) fails to take into account provider, patient and public views.

Conclusions  Policies and programmes that expand addiction treatment options deserve support. However, drawing a firm distinction between social controls (objective use of social pressure) and coercion (client perceptions and decision‐making processes) supports a parallel position that rejects treatment policies, programmes, and associated practices that create client perceptions of coercion.
Family structure and substance use problems in adolescence and early adulthood: examining explanations for the relationship
Authors: Barrett Anne E. , Turner R. Jay
Published: November 2005

Aims Our study has two goals: to evaluate variation in symptoms of substance abuse/dependence by family structure and to examine several potential explanations for this association, including differences in socio‐economic status, social support, social stress and perceived approval and use of substances by family and friends.

Design Ordinary least squares (OLS) regression is used to examine the association between family type and problematic substance use and to assess the hypothesized mediators.

Setting Data were collected between 1998 and 2000 as part of a study of the prevalence and social distributions of psychiatric and substance use disorders. The study involved face‐to‐face interviews with a representative sample of young adults in a South Florida community.

Participants Respondents (n = 1760) were between 18 and 23 years of age. Approximately 25% were of Cuban origin, 25% other Caribbean basin Hispanic, 25% African American and 25% non‐Hispanic white.

Measurements Four family types are examined: mother–father families, single‐parent families, single‐parent families that include other adult relative(s) and stepfamilies. Problematic substance use is measured by a set of 22 substance abuse/dependence symptoms.

Findings Controlling for race–ethnicity and gender, respondents from single‐parent families report a significantly higher level of problematic substance use than those from mother–father families. Although nearly all explanations receive support, we find the strongest evidence for differential association with deviant peers and exposure to stress.

Conclusions Our findings suggest that—rather than representing a unique and independent predictor of substance use problems—family structure can be viewed as a marker of the unequal distribution of factors influencing the risk of problematic substance use.
Prognostic value of inhibitory anti‐ADAMTS13 antibodies in adult‐acquired thrombotic thrombocytopenic purpura
Authors: Coppo P. , Wolf M. , Veyradier A. , Bussel A. , Malot S. , Millot G. A. , Daubin C. , Bordessoule D. , Pène F. , Mira J. P. , Heshmati F. , Maury E. , Guidet B. , Boulanger E. , Galicier L. , Parquet N. , Vernant J. P. , Rondeau E. , Azoulay E. , Schlemmer B. ,   the Réseau d'Etude des Microangiopathies Thrombotiques de l'Adulte
Published: November 2005

In order to assess the prognostic value of inhibitory anti‐ADAMTS13 antibodies in thrombotic thrombocytopenic purpura (TTP), we performed a multicentre prospective study of 33 adult patients with idiopathic acquired TTP. Patients were treated with high‐dose plasma infusion and therapeutic plasma exchange. Patients without (group 1, n = 12) and with (group 2, n = 21) detectable inhibitory anti‐ADAMTS13 antibodies were compared for clinical presentation, treatment and outcome. Both groups were comparable for clinical presentation. All patients in group 1 achieved a sustained complete remission within a median of 7 d [95% confidence interval (CI), 4–18], which required a median plasma volume of 235 ml/kg (range, 131–1251). In group 2, 17 patients achieved a durable complete remission within a median of 23 d (95% CI, 11–32) (P = 0·001). Median plasma volume was 718 ml/kg (range, 219–3107) (P = 0·02). In group 2, there was a trend for more episodes of flare‐up than in group 1 (13 vs. 3, respectively, P = 0·07). Four patients, all from group 2, died (P = not significant). The relapse rate was comparable between both groups. We suggest that TTP with detectable inhibitory anti‐ADAMTS13 antibodies displays a worse prognosis, relative to a delayed platelet count recovery, a higher plasma volume requirement to achieve complete remission, and a trend for more frequent episodes of flare‐up.
Novel roles of osteopontin and CXC chemokine ligand 7 in the defence against mycobacterial infection
Authors: Khajoee V , Saito M , Takada H , Nomura A , Kusuhara K , Yoshida S-I , Yoshikai Y , Hara T
Published: November 2005

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced human monocyte-derived macrophage (GM-Mφ) or macrophage CSF (M-CSF)-induced human monocyte-derived Mφ (M-Mφ) are distinct in terms of the resistance to Mycobacterium tuberculosis. To elucidate the role of molecules involved in the functional differences between these Mφs, we investigated the gene expression profiles using microarray. After culture of CD14+ monocytes with CSFs, Mφs were cultured with or without bacillus Calmette–Guérin (BCG) (GM-Mφ-BCG and M-Mφ-BCG). The gene expression profiles from these cells were compared. Chemokines highly expressed in M-Mφs were selected and evaluated for anti-mycobacterial activity and superoxide production.  FN1 and  FCGR2B were the most up-regulated genes in GM-Mφ and M-Mφ, respectively. After stimulation with BCG, three chemokine genes (Osteopontin (SPP1), CXC chemokine ligand 7 (CXCL7) and CC chemokine ligand 11 (CCL11)) were highly expressed in M-Mφ-BCG when compared to those in GM-Mφ-BCG. A significantly increased resistance to M. tuberculosis H37Ra was observed after the stimulation of GM-Mφ with SPP1 or CXCL7. Superoxide production levels of SPP1- or CXCL7-stimulated GM-Mφs were higher than those of GM-Mφs without stimulation. These results indicate that both SPP1 and CXCL7 might have a role in the resistance against mycobacteria, at least in part, through augmenting reactive oxygen intermediate production in Mφs.
Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations
Authors: Learoyd Diana L. , Gosnell Jessica , Elston Marianne S. , Saurine Tricia J. , Richardson Anne‐Louise , Delbridge Leigh W. , Con Aglen John V. , Robinson Bruce G.
Published: November 2005

Objective and design  Genetic screening in multiple endocrine neoplasia type 2 (MEN 2) has led to specific management guidelines based on genotype–phenotype analysis. However, there is controversy regarding the appropriate age for prophylactic thyroidectomy in families with mutations in codon 804 in exon 14 of the RET proto‐oncogene, where medullary thyroid cancer (MTC) may not develop until adulthood. We prospectively studied two MEN 2A families, one with the V804L and the other with the V804M RET mutation, to report our experience of genetic and biochemical screening and prophylactic thyroidectomy. Family 1 is one of the largest MEN 2A families in the literature, where 22 prophylactic thyroidectomies have been performed.

Patients and results  C‐cell hyperplasia (CCH) was found in 23 out of 25 thyroidectomy specimens from family members of ages 5 years and upwards. MTC was found in 10 out of 18 adults of age 25 years upwards, including the family 2 proband, who was found to have MTC with lymph node metastases at age 28. Phaeochromocytoma was only observed in one patient, but six cases of histologically confirmed hyperparathyroidism were seen in family 1.

Conclusion  We suggest that prophylactic thyroidectomy should not be delayed until adulthood in MEN 2A families carrying codon 804 RET mutations, but should be performed when there is CCH, before the development of MTC, as close as possible to age 6 years, which is the age of the youngest reported case of MTC in ‘804’ families.
Does pravastatin increase chylomicron remnant catabolism in postmenopausal women with type 2 diabetes mellitus?
Authors: Ng T. W. K. , Watts G. F. , Stuckey B. G. A. , Ching H. L. , Chan D. C. F. , Uchida Y. , Sakai N. , Yamashita S. , Martins I. J. , Redgrave T. G. , Barrett P. H. R.
Published: November 2005

Objective  We investigated the effects of pravastatin on chylomicron remnant catabolism measured with a 13C stable isotope breath test and plasma apolipoprotein (apo) B‐48 and remnant‐like particle (RLP)‐cholesterol in postmenopausal women with type 2 diabetes mellitus.

Patients and measurements  Nineteen postmenopausal women with type 2 diabetes were randomized to receive 40 mg/day pravastatin or no treatment for 6 weeks followed by a 2‐week washout period, and crossed over for a further 6 weeks. Fractional catabolic rate (FCR) of a chylomicron remnant‐like emulsion was determined from 13CO2 enrichment in the breath and plasma using isotope‐ratio mass spectrometry and multicompartmental modelling. Plasma apo B‐48 and RLP‐cholesterol concentrations were also measured as static markers of chylomicron remnant metabolism.

Results  Pravastatin significantly reduced plasma concentrations of cholesterol (5·9 ± 0·3 vs. 4·8 ± 0·2 mmol/l; P < 0·001), low density lipoprotein (LDL)‐cholesterol (3·5 ± 0·2 vs. 2·6 ± 0·2 mmol/l; P < 0·001), triglyceride (2·1 ± 0·3 vs. 1·7 ± 0·2 mmol/l; P = 0·017), non‐high density lipoprotein (HDL)‐cholesterol (4·4 ± 0·3 vs. 3·3 ± 0·2 mmol/l; P < 0·001), lathosterol/total cholesterol ratio (2·6 ± 0·2 vs. 2·0 ± 0·3, P = 0·035), apo B‐100 (1·1 ± 0·1 vs. 0·8 ± 0·1 g/l; P = 0·001), apo B‐48 (4·8 ± 0·9 vs. 3·3 ± 0·6 mg/l; P = 0·016), and RLP‐cholesterol (31·4 ± 8·2 vs. 18·6 ± 4·6 mg/dl; P = 0·024). Pravastatin was also associated with an increase in sitosterol/total cholesterol ratio (2·8 ± 0·3 vs. 3·1 ± 0·3, P = 0·029). Chylomicron remnant‐like emulsion catabolism was not, however, significantly altered by pravastatin estimated by either breath or plasma clearance measurements.

Conclusions  In postmenopausal women, pravastatin decreases plasma concentrations of remnant lipoproteins by a mechanism that may relate chiefly to inhibition of remnant production, but this requires further evaluation.
The significance of thyroid blood flow at the inferior thyroid artery as a predictor for early Graves’ disease relapse
Authors: Ueda Misako , Inaba Masaaki , Kumeda Yasuro , Nagasaki Toshiki , Hiura Yoshikazu , Tahara Hideki , Onoda Naoyoshi , Ishikawa Tetsuro , Nishizawa Yoshiki
Published: November 2005

Objective  We investigated the clinical usefulness of thyroid blood‐flow measurement in predicting relapse of Graves’ disease (GD) in comparison with known risk factors for GD relapse.

Measurement  Thyroid blood flow was measured in pulsed Doppler mode at the inferior thyroid artery (ITA), and the peak systolic velocity (PSV) calculated.

Patients  ITA‐PSV was measured in euthyroid GD patients (n = 79) immediately before withdrawal of anti‐thyroid drug (ATD) and in healthy subjects (n = 17).

Results  In the 79 euthyroid GD patients, the values of free triiodothyronine (FT3), TSH receptor autoantibody (TRAb), ITA‐PSV and thyroid volume were significantly higher in the relapse group (n = 40) than in the nonrelapse group (n = 39) and the Youden index of ITA‐PSV was significantly higher than that of FT3, TSH, TRAb and vascular endothelial growth factor (VEGF).

Conclusion  ITA‐PSV may assist in the prediction of early GD relapse after ATD withdrawal.
Effects of Tai Chi and resistance training on cardiovascular risk factors in elderly Chinese subjects: a 12‐month longitudinal, randomized, controlled intervention study
Authors: Thomas G. Neil , Hong Athena W. L. , Tomlinson Brian , Lau Edith , Lam Chris W. K. , Sanderson John E. , Woo Jean
Published: November 2005

Background   Tai Chi is rapidly gaining in popularity, worldwide. This study was performed to assess its impact on cardiovascular risk factors in comparison with resistance training exercises in elderly Chinese subjects.

Methods  A total of 207 healthy elderly participants (65–74 years, 113/207 (55%) men) were randomly assigned to one of three intervention groups: (1) Tai Chi, three times/week for 1 h/session (n = 64); (2) resistance training exercise, three times/week for 1 h/session (n = 65); (3) usual level of physical activity control group (n = 78). Anthropometric measures, dual X‐ray densitometry body composition, blood pressure, lipids, glycaemic and insulin sensitivity indices were measured at baseline and 12 months. Repeated‐measures analysis of variance (anova) was used to assess the between‐group changes using a last‐observation‐carried‐forward intention‐to‐treat approach.

Results  A total of 180 (87·0%) subjects completed the study. No significant changes were identified in the Tai Chi group compared to the resistance training or control group. Of the primary outcomes, only the improvement in the insulin sensitivity index differed, being significantly greater in the resistance training than in the control group [mean difference 0·018 (95% confidence interval ( CI) 0·000–0·037) mmol glucose/min, P = 0·02), and tending to be greater than in the Tai Chi group (mean difference 0·019 (95% CI 0·000–0·038) mmol glucose/min, P < 0·06).

Conclusion  Tai Chi had no significant effect on any measure compared to the controls, whereas resistance training improved the insulin sensitivity index in this 12‐month study.
Thyroid dysfunction and serum lipids: a community‐based study
Authors: Walsh John P. , Bremner Alexandra P. , Bulsara Max K. , O'Leary Peter , Leedman Peter J. , Feddema Peter , Michelangeli Valdo
Published: November 2005

Objective  It is uncertain whether subclinical hypothyroidism (SCH) is associated with hypercholesterolaemia, particularly in subjects with SCH and serum TSH ≤ 10 mU/l.

Design, patients and measurements  Cross‐sectional study of 2108 participants in a 1981 community health survey in Busselton, Western Australia. Serum total cholesterol and triglycerides were measured in all subjects and high density lipoprotein cholesterol (HDL‐C) measured (and low density lipoprotein cholesterol (LDL‐C) calculated) in a subgroup of 631 subjects at the time of the survey. In 2001, TSH and free T4 concentrations were measured on archived sera stored at −70 °C. Serum lipid concentrations in subjects with thyroid dysfunction and euthyroid subjects were compared using linear regression models.

Results  In the group as a whole, serum total cholesterol was higher in subjects with SCH (N = 119) than in euthyroid subjects (N = 1906) (mean ± SD 6·3 ± 1·3 mmol/l vs. 5·8 ± 1·2 mmol/l, P < 0·001 unadjusted, P = 0·061 adjusted for age, age2 and sex). Serum total cholesterol was similarly elevated in subjects with SCH and TSH ≤ 10 mU/l (N = 89) (6·3 ± 1·3 mmol/l, P < 0·001 unadjusted, P = 0·055 adjusted for age, age2 and sex). In the subgroup analysis, LDL‐C was higher in subjects with SCH (N = 30) than in euthyroid subjects (N = 580) (4·1 ± 1·2 mmol/l vs. 3·5 ± 1·0 mmol/l, P < 0·01 unadjusted, P = 0·024 adjusted for age, age2 and sex). LDL‐C was significantly increased in subjects with SCH and TSH ≤ 10 mU/l (N = 23) (4·3 ± 1·3 mmol/l, P < 0·001 unadjusted, P = 0·002 adjusted for age, age2 and sex).

Conclusion  SCH is associated with increased serum LDL‐C concentrations, which is significant after adjustment for age, age2 and sex.
Multiple endocrine neoplasia 2A due to a unique C609S RET mutation presents with pheochromocytoma and reduced penetrance of medullary thyroid carcinoma
Authors: Kinlaw William B. , Scott Sarah M. , Maue Robert A. , Memoli Vincent A. , Harris Robert D. , Daniels Gilbert H. , Porter Donna M. , Belloni Dorothy R. , Spooner Edward T. , Ernesti Manfred M. , Noll Walter W.
Published: November 2005

Objective   We have identified a large kindred with multiple endocrine neoplasia 2A (MEN 2A) due to a mutation at RET codon 609 that results in a cysteine to serine substitution, a mutation previously identified in only one case in the literature. We characterized the clinical phenotype of the kindred and the biochemical mechanism of this new mutation.

Patients and design   The index case, a 42‐year‐old woman, presented with pheochromocytoma. We screened 29 family members for the presence of the mutation. Of the 15 mutation‐positive family members, 11 agreed to undergo further evaluation by physical examination, calcium and pentagastrin‐stimulated calcitonin levels, measurement of urinary metanephrines, adrenal imaging and serum calcium levels. Biochemical characterization of the mutation was by transient transfection of human neuroblastoma cells and Western blot analysis.

Results   This kindred demonstrated an inheritance pattern consistent with autosomal dominant pheochromocytoma. Strikingly, no clinically evident case of medullary thyroid cancer (MTC) was observed among mutation‐positive family members. Thyroidectomy in six cases revealed C‐cell hyperplasia in all and microscopic MTC in two cases. Transfection experiments using human neuroblastoma cells showed that the mutant RET, unlike the wild‐type receptor, is constitutively phosphorylated in the absence of ligand, and thus resembles other previously characterized MEN 2A mutations.

Conclusions   The identification of a new mutation causing a MEN 2A phenotype that features pheochromocytoma and the surprising absence of clinically apparent MTC has significant implications for carriers of this mutation and provides further insights into the genotype–phenotype correlation in MEN 2A.
Genotyping of an Italian papillary thyroid carcinoma cohort revealed high prevalence of BRAF mutations, absence of RAS mutations and allowed the detection of a new mutation of BRAF oncoprotein (BRAFV599Ins)
Authors: Carta Claudio , Moretti Sonia , Passeri Lucia , Barbi Flavia , Avenia Nicola , Cavaliere Antonio , Monacelli Massimo , Macchiarulo Antonio , Santeusanio Fausto , Tartaglia Marco , Puxeddu Efisio
Published: November 2005

Objectives  The genes RET and RAS, and more recently BRAF, have been shown to be frequently mutated in human papillary thyroid carcinomas (PTC). The aim of this study was to genotype for these mutations a cohort of thyroid tumours collected at our institutions.

Design and patients  Thyroid tumours removed from 51 subjects were analysed, including 43 PTC and 8 non‐PTC tumours [3 follicular adenomas (FA), 4 follicular carcinomas (FTC) and 1 anaplastic carcinoma (AC)].

Measurements  RET/PTC1 and RET/PTC3 expression was evaluated by reverse transcriptase‐polymerase chain reaction, whereas screening of BRAF (exon 15) and RAS (HRAS, KRAS2 and NRAS) mutations were performed, respectively, by single strand conformation polymorphism and denaturing high‐pressure liquid chromatography.

Results  RET/PTC expressions was positive in 5/43 (11·6%) PTC and in none of the non‐PTC tumour. Similarly, BRAF mutations were positive only in PTC, but with a higher prevalence (24/43 positives, 55·8%). All but one BRAF mutation resulted in the prototypic substitution of valine 600 with a glutamic acid. In one case, a somatic in‐frame insertion of three bases at codon 599 resulted in the insertion of an additional valine. RET/PTC expression and BRAF mutations were mutually exclusive. Screening of the RAS gene allowed identification of oncogenic mutations in 1/3 (33·3%) FA and 3/4 (75%) FTC. None of the PTCs was positive for RAS.

Conclusions  These data indicate that BRAF mutations are the most frequent genetic event in PTC and that RAS mutations, besides being a genetic hallmark of follicular tumours, are rare or completely absent in PTC from our area. Together, BRAF mutations and rarer RET rearrangements accounted for a genetic event in two‐thirds of PTCs. This study showed a novel and presumably oncogenic mutation of BRAF, which is BRAFV599Ins.
Does growth hormone cause cancer?
Authors: Jenkins P. J. , Mukherjee A. , Shalet S. M.
Published: November 2005

The ability of GH, via its mediator peptide IGF‐1, to influence regulation of cellular growth has been the focus of much interest in recent years. In this review, we will explore the association between GH and cancer. Available experimental data support the suggestion that GH/IGF‐1 status may influence neoplastic tissue growth. Extensive epidemiological data exist that also support a link between GH/IGF‐1 status and cancer risk. Epidemiological studies of patients with acromegaly indicate an increased risk of colorectal cancer, although risk of other cancers is unproven, and a long‐term follow‐up study of children deficient in GH treated with pituitary‐derived GH has indicated an increased risk of colorectal cancer. Conversely, extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk. However, given the experimental evidence that indicates GH/IGF‐1 provides an antiapoptotic environment that may favour survival of genetically damaged cells, longer‐term surveillance is necessary; over many years, even a subtle alteration in the environmental milieu in this direction, although not inducing cancer, could result in acceleration of carcinogenesis. Finally, even if GH/IGF‐1 therapy does result in a small increase in cancer risk compared to untreated patients with GH deficiency, it is likely that the eventual risk will be the same as the general population. Such a restoration to normality will need to be balanced against the known morbidity of untreated GH deficiency.
Apoptosis is reduced in the colonic mucosa of patients with acromegaly
Authors: Bogazzi Fausto , Russo Dania , Locci Maria Teresa , Chifenti Barbara , Ultimieri Federica , Raggi Francesco , Cosci Chiara , Sardella Chiara , Costa Aurelio , Gasperi Maurizio , Bartalena Luigi , Martino Enio
Published: November 2005

Background  Patients with acromegaly have an increased risk of developing colonic tumours; reduced apoptosis is considered a leading mechanism in tumorigenesis. GH and IGF‐1 decrease apoptosis in several cell lines including human colonic adenocarcinoma, but it is unknown whether epithelial cells of colonic mucosa of patients with acromegaly have reduced apoptosis.

Aim  The aim of the study was to evaluate the degree of apoptosis in a cross‐sectional study, in biopsy samples of colonic mucosa obtained from patients with acromegaly.

Patients and methods  Eleven patients with active, untreated acromegaly (AcroUntr), 16 patients with acromegaly in remission (AcroRem) and 23 controls were enrolled in the study. Samples of colonic mucosa were obtained during colonoscopy; apoptosis was evaluated by either DNA fragmentation or terminal deoxynucleotidyl transferase assay.

Results  Apoptotic cells were 60·0 ± 2·5% in samples of colonic mucosa of controls, 62·0 ± 3·4% in those from patients with AcroRem (P = ns vs. controls), and 39·0 ± 4·1% in those from patients with AcroUntr (P < 0·0001 vs. the other groups). Apoptosis was inversely related to serum IGF‐I (r = 0·771, P < 0·001) or GH (r = 0·404, P = 0·05) levels and less to the estimated duration of disease (r = 0·384, P = 0·07). PPARγ is considered to be a tumour suppressor gene the expression of which might be involved in colonic tumorigenesis. The expression of PPARγ was lower in the colonic mucosa of patients with AcroUntr (2845 ± 947 transcripts) than in that of controls (35 200 ± 2450 transcripts) or AcroRem (29 547 ± 3650 transcripts) (P < 0·005). The recovery of PPARγ expression was associated with apoptosis in most cells. The lower degree of apoptosis in patients with AcroUntr was associated with a reduced expression of the antiapoptotic Bax protein.

Conclusion  In conclusion, patients with AcroUntr have reduced apoptosis in colonic mucosa that is apparently reversed after acromegaly is cured. It is conceivable that reduced apoptosis may represent an early event in colonic tumorigenesis of patients with acromegaly.
Is the anteroposterior and transverse diameter ratio of nonpalpable thyroid nodules a sonographic criteria for recommending fine‐needle aspiration cytology?
Authors: Cappelli Carlo , Pirola Ilenia , Cumetti Davide , Micheletti Linda , Tironi Andrea , Gandossi Elena , De Martino Elvira , Cherubini Laura , Agosti Barbara , Castellano Maurizio , Mattanza Chiara , Rosei E. Agabiti
Published: November 2005

Background  As a consequence of the increasing application of ultrasound (US) technology, the detection of asymptomatic nonpalpable thyroid nodules has generally increased. The aim of our study was to assess if the anteroposterior and transverse diameter ratio of nonpalpable thyroid nodules (A/T) ≥ 1 could be a sonographic criterion for recommending fine‐needle aspiration cytology (FNAC).

Methods  From January 2002 to January 2004, 828 consecutive solid nonpalpable thyroid nodules were evaluated by ultrasonography, colour‐Doppler and FNAC in our department. Cases were selected from 2217 patients, referred to our thyroid unit for US‐guided FNAC from the greater Brescia area, an endemic zone for goitre. Entry criteria included the presence at US of a solid thyroid nodule that was nonpalpable at physical examination, euthyroid condition and no previous diagnosis of thyroid malignancy. All patients with suspicious or malignant cytology underwent surgery.

Results  One hundred and twenty‐seven nodules with inadequate cytology were excluded from the study. Thyroid malignancy was observed in 67 (9·6%) nodules. At US, cancers presented a solid hypoechoic appearance in 79·1% of cases, blurred margins in 47·8%, microcalcification in 73·1%, intranodular vascular pattern in 56·7% and A/T ≥ 1 in 83·6%. A hypoechoic appearance (OR 4·3), blurred margins (OR 2·6), microcalcification (OR 6·1), intranodular vascular pattern (OR 10·2) and A/T ≥ 1 (OR 22·4) were independent risk factors of malignancy.

Conclusions  A/T ≥ 1 in conjunction with at least one other sonographic risk factor is able to detect the majority of carcinoma and, moreover, it limits the FNAC procedures to only 15·9% of all the nodules.
Obstructive sleep apnoea syndrome, plasma adiponectin levels, and insulin resistance
Authors: Makino Shinya , Handa Hiroshi , Suzukawa Koji , Fujiwara Masayoshi , Nakamura Masaharu , Muraoka Shogo , Takasago Ikumi , Tanaka Yasushi , Hashimoto Kozo , Sugimoto Tamotsu
Published: November 2005

Objective  To investigate whether sleep‐disordered breathing and/or plasma adiponectin levels are associated with insulin resistance independent of obesity or fat distribution in obstructive sleep apnoea syndrome (OSAS).

Design  Cross‐sectional clinical study.

Patients  Two‐hundred and thirteen Japanese patients with OSAS aged 27–80 years were divided into three groups: 30 with mild OSAS [apnoea–hypopnoea index (AHI) = 10·3 ± 0·9 episodes/h, minimum oxygen saturation (min SpO2) = 87·3 ± 0·9%], 98 with moderate OSAS (AHI = 28·9 ± 0·6 episodes/h, min SpO2 = 82·1 ± 0·7%), and 85 with severe OSAS (AHI = 68·1 ± 2·8 episodes/h, min SpO2 = 72·3 ± 1·6%). Twenty‐one patients undergoing diabetic treatments (two mild, nine moderate and 10 severe) were excluded from the assessment of insulin resistance and plasma adiponectin measurements.

Measurements  Fat distribution [evaluated according to visceral (V) and subcutaneous (S) fat areas using computed tomography scanning at the umbilical level], blood pressure, metabolic parameters and hormones including insulin and adiponectin were measured. After full polysomnography, venous blood was collected between 0600 and 0700 h.

Results  Severe OSAS patients were more hypertensive than mild and moderate OSAS. Fasting plasma glucose (FPG) and fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA‐IR) levels were all higher in severe OSAS than mild and moderate OSAS patients. HOMA‐IR was correlated not only with obesity [body mass index (BMI), V and S areas] but also with apnoea (AHI, min SpO2 and desaturation time). Additionally, HOMA‐IR was correlated positively with haemoglobin (Hb)A1c, systolic (SBP) and diastolic blood pressure (DBP), triglycerides and free fatty acids (FFA), and negatively with high density lipoprotein (HDL)‐cholesterol, suggesting that insulin resistance is a key component of the metabolic syndrome in OSAS. Plasma adiponectin levels were not different between mild, moderate and severe OSAS groups. Plasma adiponectin levels were correlated with HOMA‐IR and V area, but not AHI or min SpO2. Stepwise multiple regression analysis, however, revealed that BMI, AHI and plasma adiponectin were independently associated with HOMA‐IR.

Conclusion  Sleep‐disordered breathing was associated with insulin resistance independent of obesity. Although plasma adiponectin was also an independent determinant of HOMA‐IR in OSAS patients, plasma adiponectin was more closely related to obesity than to sleep apnoea. Although treatment of sleep‐disordered breathing with nasal continuous positive airway pressure reportedly improves insulin sensitivity, our findings suggest that treatment of obesity is also essential in ameliorating insulin resistance at least through increased plasma adiponectin levels in OSAS.
Breast cyst fluids increase the proliferation of breast cell lines in correlation with their hormone and growth factor concentration
Authors: Enriori Pablo J. , Vázquez Stella Maris , Chiauzzi Violeta , Pérez Cecilia , Fischer Carlos R. , Gori Jorge R. , Etkin Alberto E. , Charreau Eduardo , Calandra Ricardo S. , Lüthy Isabel A.
Published: November 2005

Objective and design  Gross cystic disease (GCD) of the breast is reported to occur in 7% of women in the developed world and, although not premalignant, is thought to be associated with an increased risk of breast cancer. Hormone and growth factor concentration levels were measured in breast cyst fluid (BCF) to correlate them with their mitogenic activity in tumour (MCF‐7) or nontransformed (MCF‐10A) cells.

Results  Oestradiol (E2), oestrone (E1), E2‐sulfate (E2‐S), E1‐sulfate (E1‐S) and epidermal growth factor (EGF) concentrations were, as expected, significantly higher in type I than in type II cysts, while transforming growth factor‐beta 2 (TGF‐β2) showed higher levels in type II cysts. Fifty per cent of the BCF samples stimulated [3H]‐thymidine incorporation into MCF‐7 cells while 34·5% inhibited this parameter. In MCF‐10A cells, most BCF samples were stimulatory (85%). E2, E1 and EGF concentrations in BCF samples correlated significantly and positively with cell proliferation in MCF‐7 cells, whereas a significant negative correlation was found for TGF‐β2. In MCF‐10A cells, only E2‐S and E1‐S exhibited significant positive correlation, whereas a significant negative correlation was found for TGF‐β2. Progesterone (Pg), E2 and EGF incubated under the same conditions had a stimulatory effect on [3H]‐thymidine incorporation into MCF‐7 cells, whereas TGF‐β2 inhibited this parameter. Pg, E2, E1 and EGF significantly stimulated this parameter in MCF‐10A cells.

Conclusions  The stimulatory action of BCF on cell proliferation in a model of human breast epithelial cells could partly explain the increased incidence of breast cancer in cyst‐bearing women.
Comprehensive study of urinary cortisol metabolites in hyperthyroid and hypothyroid patients
Authors: Hoshiro M. , Ohno Y. , Masaki H. , Iwase H. , Aoki N.
Published: November 2005

Objective To further analyse the significance and mutual relationship of thyroid function‐linked alterations in cortisol metabolism that have been separately and variously reported.

Patients and measurements Twenty‐four‐hour urine samples from 21 patients with hyperthyroidism (Graves’ disease), 16 patients with hypothyroidism (Hashimoto's thyroiditis), 21 healthy age‐ and sex‐matched controls for hyperthyroidism, and 16 healthy age‐ and sex‐matched controls for hypothyroidism were evaluated for 6β‐hydroxycortisol (6β‐OHF), tetrahydrocortisol (THF), tetrahydrocortisone (THE), allo‐tetrahydrocortisol (allo‐THF), urinary free cortisol (UFF), urinary free cortisone (UFE) and 17‐hydroxycorticosteroid (17‐OHCS).

Results Urinary 17‐OHCS, THE and allo‐THF levels increased considerably in hyperthyroid patients compared to the controls, while UFF and THF showed no difference between the two groups. Urinary 6β‐OHF was significantly lower in the hyperthyroid patients than in the controls. Both the urinary allo‐THF + THF/THE and the UFF/UFE ratios were significantly lower in the hyperthyroid patients than in the controls, whereas only the former was significantly higher in the hypothyroid patients than in the controls. The urinary allo‐THF/THF ratio was significantly higher in the hyperthyroid patients and significantly lower in the hypothyroid patients than in the controls. In an analysis of pooled subjects including all groups (n = 64), free T4 levels correlated negatively (P < 0·0001) with the urinary allo‐THF + THF/THE ratio but not with the UFF/UFE ratio. The serum levels of free T4 correlated positively (P < 0·0001) with the urinary allo‐THF/THF ratio.

Conclusion The thyroid hormones seem to affect the total 11β‐HSD activity (allo‐THF + THF/THE) more strongly than the renal 11β‐HSD2 activity (UFF/UFE). 5α‐reductase activity (allo‐THF/THF) is also enhanced in hyperthyroidism, while the reduction of urinary 6β‐OHF in hyperthyroidism might be a secondary effect of the altered activity of the total 11β‐HSD and 5α‐reductase.
Low total normal motile count values are associated with increased sperm disomy and diploidy rates in infertile patients
Authors: BERNARDINI LUCA M. , CALOGERO ALDO E. , BOTTAZZI CRISTINA , LANTERI SILVIA , VENTURINI PIER LUIGI , BURRELLO NUNZIATINA , PALMA ADELE DE , CONTE NORY , RAGNI NICOLA
Published: November 2005

This study was undertaken to evaluate the possibility of identifying men at increased risk of sperm aneuploidy and diploidy on the bases of specific cut‐off values of the total normal motile count (TNMC). Twenty‐seven consecutive, unselected male patients referred to our Unit were studied: 11 patients with normal sperm parameters (group A) suffering from unexplained infertility and 16 infertile patients with abnormal sperm parameters (group B). Disomy rates for chromosomes 1, 4, 8, 12, 18, X and Y were ascertained for each patient by means of triple and double fluorescence in situ hybridization (FISH) experiments. Both univariate and multivariate statistical analyses by principal component analysis (PCA) were performed for comparisons between sperm aneuploidy rates and semen quality (TNMC). TNMC scores in the two groups were significantly different (23.5 × 106 and 1.52 × 106, in groups A and B, respectively, p = 0.00002). In general, higher sperm disomy rates were noted for all chromosomes in group B compared with group A. Statistical significance was observed for disomy 1, total disomy rate (3.36% vs. 1.38%), and diploidy (0.49% vs. 0.19%) (p < 0.01). For disomy 4 and 8, differences resulted close to significance. PCA clearly showed how independent variables were inter‐related. Infertile men with TNMC <2 × 106 (male factor) were found to be at increased risk for sperm aneuploidy and diploidy. Multivariate analysis by PCA resulted as a useful method to visualize the information of the data sets on a bi‐dimensional plot considering all the patients and all the variables at the same time.
Outcomes in couples undergoing ICSI: comparison between fresh and frozen–thawed surgically retrieved spermatozoa
Authors: ULUG ULUN , BENER FARUK , KARAGENC LEVENT , CIRAY NADIR , BAHCECI MUSTAFA
Published: November 2005

We retrospectively evaluated the impact of cryopreservation on spermatozoa obtained from patients with azoospermia and used for intracytoplasmic sperm injection (ICSI). Frozen–thawed epididymal spermatozoa (FTEPS) was used in 34 couples, whereas frozen–thawed testicular spermatozoa (FTTS) was used in 50 couples for ICSI during assisted conception, and these results were compared with results using fresh spermatozoa for ICSI in the same individuals. The fertilization rate (FR) was significantly lower for FTTS (65.8%) but not for FTEPS (73.1%) compared with the FR using fresh spermatozoa (72.3% and 73.2% respectively). In contrast, neither the implantation nor the pregnancy rate was altered when FTEPS or FTTS was used. In conclusion, our results indicate that surgically retrieved spermatozoa can be efficiently used for ICSI after freezing and thawing without compromising the outcome.
Epidemiologic risk factors for chronic prostatitis
Authors: KU JA HYEON , KIM SOO WOONG , PAICK JAE‐SEUNG
Published: November 2005

Chronic prostatitis/chronic pelvic pain syndrome is a multifactorial problem, which affects men of all ages and in all demographics. Recent studies have shown that the prevalence of prostatitis is approximately 2–10% among unselected men in North America, Europe and Asia. This data clearly indicates that chronic prostatitis constitutes an important problem in international health care. Nevertheless, the aetiology and pathogenesis of chronic prostatitis have yet to be clearly delineated, despite the numerous efforts which have been made, with regard to both basic and clinical research. In fact, factors other than leucocytes and bacteria have been shown to contribute to the symptoms typically associated with prostatitis. Studies of the epidemiology and determinants of prostatitis risk factors may also provide clues to the general aetiology of prostatitis. Other epidemiological data appears to indicate that certain as‐yet‐unknown factors might be associated with an increased tendency towards the development of chronic prostatitis. However, findings from most studies are considered to represent only preliminary data, because of the small sample sizes or lack of generalizability inherent to most of the studies. The identification and characterization of these relevant risk factors might accelerate or augment the development of preventive, diagnostic, and therapeutic strategies for the treatment of these syndromes.
An update of EU legislation (Directives and Regulations) on food‐related issues (Safety, Hygiene, Packaging, Technology, GMOs, Additives, Radiation, Labelling): presentation and comments
Authors: Arvanitoyannis Ioannis S. , Choreftaki Stefania , Tserkezou Persefoni
Published: November 2005

This review aims at providing an update of the current European Union (EU) Regulations and Directives on food‐related issues. Initially, a brief presentation of EU legislation in terms of structure (horizontal, vertical) was attempted. EU Regulations and Directives were classified into the following categories: food safety (Hazard Analysis Critical Control Points, pesticides, radioactive, hormones, contaminants, freezing – ionisation, food additives, flavourings, packaging), genetically modified organisms, food quality, labelling, food products of plant or animal origin, imports from third countries. Apart from a synoptical presentation of all laws related to the above‐mentioned topics, proper tables were compiled where the main points of each law are cited in conjunction with its effect on previous laws (repeal, modification, amendments, replacement). In such a way the reader can rapidly acquire a first approach to the topic of his interest.