bluuebunny/crossref_metadata_2025 huggingface dataset:
Temperature dependence of the surface plasmon coupling with an InGaN∕GaN quantum well
Authors: Lu Yen-Cheng , Chen Cheng-Yen , Yeh Dong-Ming , Huang Chi-Feng , Tang Tsung-Yi , Huang Jeng-Jie , Yang C. C.
Published: May 2007

The authors demonstrate the temperature-dependent behavior of the surface plasmon (SP) coupling with two InGaN∕GaN quantum-well (QW) structures of different internal quantum efficiencies. The SP modes are generated at the interface between the QW structures and Ag thin films coated on their tops. It is observed that the SP-QW coupling rate increases with temperature. Such a trend may rely on several factors, including the availability of carriers with sufficient momenta for transferring the energy and momentum into the SP modes and possibly the variation of the SP density of state with temperature. Although the required momentum matching condition only needs the thermal energy corresponding to a few tens of Kelvins, the carrier delocalization process results in a significantly higher probability of SP-carrier momentum matching and hence SP-QW coupling.
CLUMPP: a cluster matching and permutation program for dealing with label switching and multimodality in analysis of population structure
Authors: Jakobsson Mattias , Rosenberg Noah A.
Published: May 2007

Motivation: Clustering of individuals into populations on the basis of multilocus genotypes is informative in a variety of settings. In population-genetic clustering algorithms, such as BAPS, STRUCTURE and TESS, individual multilocus genotypes are partitioned over a set of clusters, often using unsupervised approaches that involve stochastic simulation. As a result, replicate cluster analyses of the same data may produce several distinct solutions for estimated cluster membership coefficients, even though the same initial conditions were used. Major differences among clustering solutions have two main sources: (1) ‘label switching’ of clusters across replicates, caused by the arbitrary way in which clusters in an unsupervised analysis are labeled, and (2) ‘genuine multimodality,’ truly distinct solutions across replicates.

Results: To facilitate the interpretation of population-genetic clustering results, we describe three algorithms for aligning multiple replicate analyses of the same data set. We have implemented these algorithms in the computer program CLUMPP (CLUster Matching and Permutation Program). We illustrate the use of CLUMPP by aligning the cluster membership coefficients from 100 replicate cluster analyses of 600 chickens from 20 different breeds.

Availability:  CLUMPP is freely available at http://rosenberglab.bioinformatics.med.umich.edu/clumpp.html

Contact:  mjakob@umich.edu
Substitution or deletion mutations between nt 54 and 70 in the 5′ non-coding region of dengue type 2 virus produce variable effects on virus viability
Authors: Sirigulpanit Wipawan , Kinney Richard M. , Leardkamolkarn Vijittra
Published: May 2007

A C57U nucleotide mutation in a predicted RNA stem structure (nt 11–16/56–61) of the 5′ non-coding region (5′NCR) of dengue 2 (DEN-2) 16681 virus is partially attenuating, but unstable during serial passage of certain candidate DEN-2 PDK-53-based vaccine viruses containing this mutation. Here, 11 different mutations (one or more point substitution and/or deletion) between nt 54 and 70 in the 5′NCR of the pD2/IC-30P-A (16681) infectious clone are described. Four mutants were infectious. Three mutants with single point substitutions replicated well in cell culture and exhibited variable neurovirulence in mice. Constructs containing multiple substitutions or any deletions failed to produce infectious viruses. Unexpectedly, a double C57U+G58C mutant replicated as efficiently as D2/IC-30P-A virus, and was more neurovirulent for newborn ICR mice. Thus, despite its predicted additional disruption of the RNA stem structure, the engineered contiguous secondary G58C mutation caused reversion of the partially attenuated phenotype caused by the 5′NCR-C57U mutation.
Avian reovirus core protein μA expressed in Escherichia coli possesses both NTPase and RTPase activities
Authors: Su Yu Pin , Shien Jui Huang , Liu Hung Jen , Yin Hsien Sheng , Lee Long Huw
Published: May 2007

Analysis of the amino acid sequence of core protein μA of avian reovirus has indicated that it may share similar functions to protein μ2 of mammalian reovirus. Since μ2 displayed both nucleotide triphosphatase (NTPase) and RNA triphosphatase (RTPase) activities, the purified recombinant μA ( μA) was designed and used to test these activities. μA was thus expressed in bacteria with a 4.5 kDa fusion peptide and six His tags at its N terminus. Results indicated that  μA possessed NTPase activity that enabled the protein to hydrolyse theβ–γphosphoanhydride bond of all four NTPs, since NDPs were the only radiolabelled products observed. The substrate preference was ATP>CTP>GTP>UTP, based on the estimatedkcatvalues. Alanine substitutions for lysines 408 and 412 (K408A/K412A) in a putative nucleotide-binding site of  μA abolished NTPase activity, further suggesting that NTPase activity is attributable to protein  μA. The activity of  μA is dependent on the divalent cations Mg2+or Mn2+, but not Ca2+or Zn2+. Optimal NTPase activity of  μA was achieved between pH 5.5 and 6.0. In addition,  μA enzymic activity increased with temperature up to 40 °C and was almost totally inhibited at temperatures higher than 55 °C. Tests of phosphate release from RNA substrates with  μA or K408A/K412A  μA indicated that  μA, but not K408A/K412A  μA, displayed RTPase activity. The results suggested that both NTPase and RTPase activities of  μA might be carried out at the same active site, and that protein μA could play important roles during viral RNA synthesis.
Screening of differentially expressed transcripts in infectious bursal disease virus-induced apoptotic chicken embryonic fibroblasts by using cDNA microarrays
Authors: Wong Raymond Tsz-Yeung , Hon Chung-Chau , Zeng Fanya , Leung Frederick C.-C.
Published: May 2007

Infectious bursal disease virus (IBDV) induces apoptosis and immunosuppression. To understand the molecular mechanisms involved in the pathogenesis of infectious bursal disease (IBD) and the host-directed antiviral responses, cDNA microarrays were used to identify the differentially expressed transcripts in IBDV-infected chicken embryonic fibroblasts. The results suggest a general suppression of surface receptors, including CD40 ligand and SEMA4D. These are related to T- and B-cell activation and differentiation, which may contribute to the immunosuppression of IBD. In addition, activation of genes involved in Toll-like receptor- and interferon (IFN)-mediated antiviral responses was detected. In particular, upregulation of Toll-like receptor 3, a double-stranded (ds) RNA receptor, and MX1, an IFN-inducible antiviral GTPase, may represent the possible host-directed defence responses against the virus and its dsRNA genome. Interestingly, several lines of evidence suggest the modulation of G protein-coupled receptors and receptor tyrosine kinase signalling pathways, especially the possible transactivation of epidermal growth factor receptor by lysophosphatidic acid. Alteration of these may contribute to the previously reported activation of mitogen-activated protein kinases upon IBDV infection, resulting in macrophage activation and inflammatory responses. Additionally, numerous target genes and inducers of nuclear factor kappa B (NF-κB) were upregulated profoundly, implying that IBDV may modulate host-cell survival and apoptosis to support its replication and facilitate viral spread through NF-κB activation. In summary, this investigation of host-gene expression unravelled the candidate physiological pathways involved in host–virus interaction on a molecular level, providing a foundation for researchers to design experiments based on testable hypotheses targeting individual genes.
Evidence for recombination in natural populations of porcine circovirus type 2 in Hong Kong and mainland China
Authors: Ma Ching-Man , Hon Chung-Chau , Lam Tsan-Yuk , Li Vince Yik-Yeung , Wong Creany Ka-Wai , de Oliveira Tulio , Leung Frederick Chi-Ching
Published: May 2007

Porcine circovirus type 2 (PCV2) belongs to the family Circoviridae, and is the causative agent of post-weaning multisystemic wasting syndrome (PMWS) in pigs. In this study, phylogenetic analyses of three complete PCV2 genomic sequences from Hong Kong suggest that natural recombination happened among different lineages of PCV2. A preliminary investigation of the parental strains of these potential recombinants was carried out using bootscanning. Statistical significance of this recombination event was tested and positions of the potential recombination breakpoints were estimated in a maximum-likelihood framework. The recombinant breakpoints were estimated to be located within the origin of replication (ori) and replicase (rep) gene of PCV2. Interestingly, several GenBank sequences of PCV2 in mainland China were found to have a recombination pattern similar to that of the potential PCV2 recombinants from Hong Kong, implying that this recombinant genotype might already be widespread within mainland China.
Molecular characterization of African orthobunyaviruses
Authors: Yandoko E. Nakouné , Gribaldo S. , Finance C. , Le Faou A. , Rihn B. H.
Published: May 2007

The genus Orthobunyavirus is composed of segmented, negative-sense RNA viruses that are responsible for mild to severe human diseases. To date, no molecular studies of bunyaviruses in the genus Orthobunyavirus from central Africa have been reported, and their classification relies on serological testing. Four new primer pairs for RT-PCR amplification and sequencing of the complete genomic small (S) RNA segments of 10 orthobunyaviruses isolated from the Central African Republic and pertaining to five different serogroups have been designed and evaluated. Phylogenetic analysis showed that these 10 viruses belong to the Bunyamwera serogroup. The S segment sequences differ from those of the Bunyamwera virus reference strain by 5–15 % at the nucleotide level, and both overlapping reading frames, encoding the nucleocapsid (N) and non-structural (NS) proteins, were evident in sequenced genomes. This study should improve diagnosis and surveillance of African bunyaviruses.
Membrane and protein dynamics in live plant nuclei infected with Sonchus yellow net virus, a plant-adapted rhabdovirus
Authors: Goodin Michael M. , Chakrabarty Romit , Yelton Sharon , Martin Kathleen , Clark Anthony , Brooks Robert
Published: May 2007

Sonchus yellow net virus (SYNV) serves as the paradigm for the cell biology of plant-adapted rhabdoviruses. Fluorescence recovery after photobleaching (FRAP) demonstrated that SYNV-induced intranuclear membranes are contiguous with the endomembrane system. Fluorescence intensity measurements of a green fluorescent protein-tagged nuclear envelope marker were consistent with electron microscopy studies, which suggest that infection by SYNV results in invagination of the inner nuclear membrane. Fusions of a red fluorescent protein to five SYNV-encoded proteins were used to determine the relationship between virus-induced intranuclear membranes and the localization of viral proteins. These data establish definitively that localization in the context of infected cells provides a superior means to predict protein function compared with localization studies conducted in mock-inoculated cells. Substructure has been identified within the viroplasm, the putative site of virus replication, which suggests that the nucleocapsid (N) protein occupies a region at the junction between the viroplasm and intranuclear membranes that largely excludes the phosphoprotein. Within virus-infected nuclei, the SYNV matrix (M) protein and glycoprotein (G) were associated predominantly with membranes, whereas sc4, the predicted movement protein, accumulated primarily at punctate loci on the periphery of cells. Coexpression of differently tagged SYNV protein fusions in combination with FRAP analyses suggest a model whereby the replication and morphogenesis of SYNV are spatially separated events. Finally, an M protein-containing complex was discovered that appears to bud from the nucleus and that moves on ER membranes. Taken together, these data represent the most comprehensive analyses of rhabdoviral protein localization conducted in the context of infected cells.
Rapid and sustained CD4+ T-cell-independent immunity from adenovirus-encoded vaccine antigens
Authors: Holst Peter J. , Bartholdy Christina , Stryhn Annette , Thomsen Allan R. , Christensen Jan P.
Published: May 2007

Many novel vaccine strategies rely on recombinant viral vectors for antigen delivery, and adenovirus vectors have emerged among the most potent of these. In this report, we have compared the immune response induced through priming with adenovirus vector-encoded full-length viral protein to that elicited with an adenovirus-encoded minimal epitope covalently linked toβ2-microglobulin. We demonstrate that theβ2-microglobulin-linked epitope induced an accelerated and augmented CD8+T-cell response. Furthermore, the immunity conferred by vaccination withβ2-microglobulin-linked lymphocytic choriomeningitis virus (LCMV)-derived epitopes was long-lived and protective. Notably, in contrast to full-length protein, the response elicited with theβ2-microglobulin-linked LCMV-derived epitope was CD4+T-cell independent. Furthermore, virus-specific CD8+T cells primed in the absence of CD4+T-cell help were sustained in the long term and able to expand and control a secondary challenge with LCMV. Our results demonstrate that modifications to the antigen used in adenovirus vaccines may be used to improve the induced T-cell response. Such a strategy for CD4+T-cell-independent immunity from adenovirus vectors offers prospects for vaccination against opportunistic pathogens in AIDS patients and possibly immunotherapy in chronic virus infections.
Avian metapneumovirus SH gene end and G protein mutations influence the level of protection of live-vaccine candidates
Authors: Naylor Clive J. , Ling Roger , Edworthy Nicole , Savage Carol E. , Easton Andrew J.
Published: May 2007

A prototype avian metapneumovirus (AMPV) vaccine (P20) was previously shown to give variable outcomes in experimental trials. Following plaque purification, three of 12 viruses obtained from P20 failed to induce protection against virulent challenge, whilst the remainder retained their protective capacity. The genome sequences of two protective viruses were identical to the P20 consensus, whereas two non-protective viruses differed only in the SH gene transcription termination signal. Northern blotting showed that the alterations in the SH gene-end region of the non-protective viruses led to enhanced levels of dicistronic mRNA produced by transcriptional readthrough. A synthetic minigenome was used to demonstrate that the altered SH gene-end region reduced the level of protein expression from a downstream gene. The genomes of the remaining eight plaque-purified viruses were sequenced in the region where the P20 consensus sequence differed from the virulent progenitor. The seven protective clones were identical, whereas the non-protective virus retained the virulent progenitor sequence at two positions and contained extensive alterations in its attachment (G) protein sequence associated with a reduced or altered expression pattern of G protein on Western blots. The data indicate that the efficacy of a putative protective vaccine strain is affected by mutations altering the balance of G protein expression.
Prions in the peripheral nerves of bovine spongiform encephalopathy-affected cattle
Authors: Masujin Kentaro , Matthews Danny , Wells Gerald A. H. , Mohri Shirou , Yokoyama Takashi
Published: May 2007

With the use of increasingly sensitive methods for detection of the abnormal isoform of prion protein (PrPSc) and infectivity in prion diseases, it has recently been shown that parts of the peripheral nervous system (PNS) of bovine spongiform encephalopathy (BSE)-affected cattle may become infected. It has been reported that prions spread to the central nervous system (CNS) via the PNS in sheep scrapie, but the pathogenesis of BSE in cattle is less well understood. To determine whether parts of the PNS other than those implicated directly in the hypothetical pathogenetic spread of agent from the intestine to the CNS become involved before or after the CNS is affected, PrPScdistribution was investigated by a highly sensitive Western blotting technique in dorsal root ganglia, stellate ganglion, phrenic, radial and sciatic nerves, adrenal gland and CNS of cattle that were inoculated orally with BSE-affected brain and culled sequentially. In experimentally BSE-affected cattle, PrPScwas first detected in the CNS and dorsal root ganglia; subsequently, PrPScaccumulation was detected in the peripheral nerve trunks. PrPScwas also detected in the adrenal glands of cattle that showed clinical signs. No PrPScwas detected in the PNS of BSE-negative cattle. This study shows that, with respect to dorsal root ganglia, a paravertebral sympathetic ganglion and the somatic nerves examined, PrPScis detected in the PNS during the disease course at the same time as, or after, it accumulates in the CNS.
Characterization of Junín arenavirus cell entry
Authors: Martinez M. Guadalupe , Cordo Sandra M. , Candurra Nélida A.
Published: May 2007

Junín virus (JUNV) entry is conducted by receptor-mediated endocytosis. To explore the cellular entry mechanism of JUNV, inhibitory effects of drugs affecting the main endocytic pathways on JUNV entry into Vero cells were analysed. Compounds that impair clathrin-mediated endocytosis were shown to reduce virus internalization without affecting virion binding. In contrast, drugs that alter lipid-raft microdomains, impairing caveola-mediated endocytosis, were not able to block virus entry. To show direct evidence of JUNV entry, transmission electron microscopy was performed; it showed JUNV particles of about 60–100 nm in membrane depressions that had an electron-dense coating. In addition, JUNV particles were found within invaginations of the plasma membrane and vesicles that resembled those of pits and clathrin-coated vesicles. Taken together, these results demonstrate that clathrin-mediated endocytosis is the main JUNV entry pathway into Vero cells and represent an important contribution to the characterization of the arenavirus multiplication cycle.
Increased complexity of wild-type adeno-associated virus–chromosomal junctions as determined by analysis of unselected cellular genomes
Authors: Drew Horace R. , Lockett Linda J. , Both Gerald W.
Published: May 2007

Adeno-associated virus (AAV) undergoes preferential Rep-mediated integration into the AAVS1 region of human chromosome 19 during latent infection, at least in highly-selected cell cultures. However, integration at the level of the whole eukaryotic genome in unselected cells has not yet been monitored for AAV as it has been for retro- and lentiviruses. Here we have used ligation-mediated PCR (LMPCR) to monitor the formation of AAV–chromosome junctions within unselected genomic DNA after infection. Our analyses show that, in the absence of selection, the complexity of junction formation is much greater than for selected cells. Sequencing of more than 50 authentic LMPCR clones showed that AAV formed junctions with many different chromosomal sites via DNA micro-homologies that frequently involved GGTC motifs located within the AAV p5 element. One site at position 280 was preferred. Even greater complexity was found when unselected junctions identified by LMPCR were analysed by direct PCR amplification and cloning of genomic DNA. No clones containing AAV–AAVS1 chromosome 19 junctions were identified among the LMPCR clones, although they were readily obtained using chromosomal PCR primers, suggesting that junctions with AAVS1 constituted only a small portion of the total. Thus, we have identified an additional means by which AAV sequences may join to human chromosomes, although the detailed molecular mechanisms remain to be elucidated. These data may have implications for the design of new-generation AAV vectors.
Transtensional fault‐termination basins: an important basin type illustrated by the Pliocene San Jose Island basin and related basins in the southern Gulf of California, Mexico
Authors: Umhoefer Paul J. , Schwennicke Tobias , Del Margo Maya T. , Ruiz‐Geraldo Gabriela , Ingle James C. , McIntosh William
Published: May 2007

Transtensional basins are sparsely described in the literature compared with other basin types. The oblique‐divergent plate boundary in the southern Gulf of California has many transtensional basins: we have studied those on San Jose island and two other transtensional basins in the region. One major type of transtensional basin common in the southern Gulf of California region is a fault‐termination basin formed where normal faults splay off of strike‐slip faults. These basins suggest a model for transtensional fault‐termination basins that includes traits that show a hybrid nature between classic rift and strike‐slip (pull‐apart) basins. The traits include combinations of oblique, strike‐slip and normal faults with common steps and bends, buttress unconformities between the fault steps and beyond the ends of faults, a common facies pattern of terrestrial strata changing upward and away from the faults into marine strata, small fault blocks within the basin that result in complex lateral facies relations, common Gilbert deltas, dramatic termination of the margin of the basin by means of fault reorganization and boundary faults dying and an overall short basin history (few million years). Similar transtensional fault‐termination basins are present in Death Valley and other parts of the Eastern California shear zone of the western United States, northern Aegean Sea and along ancient strike‐slip faults.
Ethnic differences in TSH but not in free T4 concentrations or TPO antibodies during pregnancy
Authors: Benhadi N. , Wiersinga W. M. , Reitsma J. B. , Vrijkotte T. G. M. , Van Der Wal M. F. , Bonsel G. J.
Published: May 2007

Objective  To describe the TSH, free T4 and thyroid peroxidase antibody (TPO‐Ab) concentrations during pregnancy among four ethnic groups and to determine reference values for these parameters during normal pregnancy.

Methods  Cross‐sectional study of a cohort of 3270 pregnant women living in the city of Amsterdam. Blood samples were drawn at first booking in the first or second trimester. TSH, free T4 and TPO‐Ab concentrations were determined. Four ethnic groups were studied: Dutch, Surinam, Turkish and Moroccan.

Results  Plasma TSH increased and free T4 decreased from the first to the second trimester of pregnancy for all the ethnic groups. Ethnic differences were observed in TSH concentrations, with Dutch females having the highest TSH levels compared to the other three ethnic groups. The median TSH difference was 0·16 mU/l between the Dutch and Moroccan women, 0·15 mU/l between the Dutch and Surinam women and 0·10 mU/l between the Dutch and Turkish women. These could not be explained by differences in age, parity and current smoking status. No differences were seen in free T4 concentrations between the four ethnic groups. The prevalence of TPO‐Ab was comparable across the ethnic groups (about 6% in each); the concentration of TPO‐Ab was also comparable among the ethnic groups. The Dutch women had a higher lower‐limit (2·5 percentile) of the TSH reference range than the Surinam, Turkish and Moroccan women, ranging from 0·14 mU/l for the Surinam and Moroccan to 0·27 mU/l for the Dutch women.

Conclusion  The increase in TSH and decrease in free T4 values during pregnancy correspond to previous reported studies. Pregnant Dutch women had consistently higher TSH values than the ethnic group, but corresponding free T4 levels and TPO‐Ab did not differ between these ethnic groups.
Phenotypic variability in 17β‐hydroxysteroid dehydrogenase‐3 deficiency and diagnostic pitfalls
Authors: Lee Yung Seng , Kirk Jeremy M. W. , Stanhope Richard G. , Johnston Derek I. , Harland Sharon , Auchus Richard J. , Andersson Stefan , Hughes Ieuan A.
Published: May 2007

Objective  17β‐hydroxysteroid dehydrogenase type 3 isoenzyme (17β‐HSD3) is required to produce testosterone for male sex differentiation. Mutations in the HSD17B3 gene cause 17βHSD3 deficiency and result in XY sex reversal of varying degree. We report the phenotypes of 14 subjects with 17βHSD3 deficiency in relation to sex of rearing, androgen production, and HSD17B3 mutations.

Design  Cases were identified through the Cambridge Disorders of Sex Development Database where detailed clinical information was recorded, results of hCG stimulation tests were available, and HSD17B3 mutation was identified.

Results  Fourteen subjects from seven pedigrees (four consanguineous) had the following seven mutations: A56T, N130S, E215D, S232L, C268Y, V205E, and a novel mutation M197K. XY sex reversal was classified as complete in 10 infants at birth. Inguinal masses suggestive of androgen insensitivity syndrome (AIS) occurred in five infants. Contrasexual virilization reminiscent of 5α‐reductase deficiency occurred in four subjects at puberty. The median (range) testosterone : androstenedione (T/A) ratio after a short hCG stimulation test was 0·32 (0·12–3·4). The S232L mutation identified in three affected family members caused isolated, severe hypospadias in one member who was raised male; virilization occurred despite in vitro studies showing an inactive mutant enzyme. Ratios of T/A in this pedigree were more than 0·8.

Conclusion  XY sex reversal is sufficiently variable in 17βHSD3 deficiency to cause problems in accurate diagnosis, particularly in distinguishing it from AIS. It should be considered in undervirilized male infants with normal Wolffian duct structures, absent Müllerian ducts, and normal adrenal steroid biosynthesis; or when an assigned female subject virilizes at puberty. Elevated hCG‐stimulated T/A ratio may occur, and sex of rearing may not be concordant within affected families with the same HSD17B3 mutation. The T/A ratio, mutation analysis and functional analysis of the mutant enzyme taken in isolation, respectively, may not conclusively establish a diagnosis of 17βHSD3 deficiency in undervirilized male subjects; the reasons for these discrepancies remain unknown.
Asymptomatic bilateral adrenal pheochromocytoma in a patient with a germline V804M mutation in the RET proto‐oncogene
Authors: Recasens M. , Oriola J. , Fernández‐Real J. M. , Roig J. , Rodríguez‐Hermosa J. I. , Font J. A. , Galofre P. , López‐Bermejo A. , Ricart W.
Published: May 2007

A diagnosis of bilateral pheochromocytoma warrants exclusion of hereditary pheochromocytoma.

Objective  To describe the first case of a bilateral pheochromocytoma associated with V804M mutation in the RET proto‐oncogene.

Patients  The index case was a 54‐year‐old man with bilateral adrenal masses discovered during a CT scan performed for other reasons.

Measurements  Genetic analysis included exons 8–11 and 13–17 in the RET proto‐oncogene, all four exons and flanking intronic regions in the SDHD gene, all eight exons and flanking intronic regions in the SDHB, and all three exons in the VHL gene.

Results  Investigations revealed elevated urinary metanephrines (32·3 µmol/day), and laparoscopic bilateral adrenalectomy confirmed bilateral pheochromocytomas.

A heterozygous V804M mutation in exon 14 of the RET was found in the index case and in four relatives. Total thyroidectomy, performed in four of five affected members in this kindred, disclosed a medullary thyroid carcinoma in the index case and in a 50‐year‐old woman, and nodular C‐cell hyperplasia in the other two subjects.

Conclusions  This clinical case suggests that individuals carrying the germline V804M mutation should be screened annually for the presence of pheochromocytoma.
Cortisol levels and measures of body composition in middle‐aged and older men
Authors: Travison Thomas G. , O'Donnell Amy B. , Araujo Andre B. , Matsumoto Alvin M. , McKinlay John B.
Published: May 2007

Introduction  Similarities in the symptomatic expressions of excess adiposity and hypercortisolaemic conditions suggest that elevated glucocorticoid exposure may influence the pathogenesis of obesity. Circulating cortisol levels are not typically elevated in obese subjects, but data from large prospective samples are rare. We undertook an analysis to determine both cross‐sectional and longitudinal associations between body composition and serum cortisol concentrations in a randomly chosen group of 999 community‐dwelling men, aged 40–79 years.

Methods  Data were obtained from the two follow‐up waves of the Massachusetts Male Ageing Study (T2: 1995–97; T3: 2002–04). Partial correlation and multivariate regression analyses were used to estimate cross‐sectional (T2) and longitudinal associations between serum cortisol concentrations and a range of measures of subjects’ body composition, including weight, body mass index (BMI), waist circumference (WC), waist‐to‐hip girth ratio (WHR), and percentage body fat (measured by bioelectrical impedance at T3); similar analyses were conducted to assess the association between change (T2 to T3) in serum cortisol and simultaneous change in body composition parameters.

Results  We observed weak negative associations between cortisol concentrations and all body composition parameters, with the exception of percentage body fat. Longitudinal results demonstrated similar relationships but associations were of lesser magnitude. T2 cortisol concentrations were not associated with change in body composition over time, whereas T2 body size was positively associated with longitudinal changes in cortisol concentrations, providing limited evidence that weight change drives changes in cortisol concentrations, rather than vice versa. Results were unchanged when age and other covariate effects were controlled.

Conclusions  Circulating cortisol concentrations are somewhat lower in obese than in nonobese community‐dwelling men. There is some evidence that excess adiposity presages increases in cortisol concentrations, rather than the reverse. However, this observation should be greeted with caution, as age‐related weight loss – and not gain – was associated with simultaneous increases in serum cortisol concentrations.
The advantage of measuring spontaneous growth hormone (GH) secretion compared with the insulin tolerance test in the diagnosis of GH deficiency in young adults
Authors: Radetti Giorgio , Di Iorgi Natascia , Paganini Claudio , Gastaldi Roberto , Napoli Flavia , Lorini Renata , Maghnie Mohamad
Published: May 2007

Objective  Reassessment of GH status after the attainment of adult height has important clinical implications in the diagnosis and prognosis of GH deficiency (GHD) in adulthood. The current GH threshold for biochemical definition of GHD in young adults is still a subject of debate.

Design  To investigate the role of pharmacological stimulation tests compared with spontaneous 12‐h nocturnal GH secretion in the diagnosis of permanent GHD in young adults with childhood‐onset GHD.

Patients  Forty‐five young adults (25 males, 20 females) with childhood‐onset GHD, height standard deviation score (SDS) –1·1 ± 1·3 and body mass index (BMI) SDS 1·0 ± 1·6, were re‐evaluated at the age of 19·8 ± 2·7 years. Sixteen subjects showed a normal pituitary gland on magnetic resonance imaging (MRI), while in 29, consistent structural hypothalamic–pituitary abnormalities were found. GH secretion was assessed by means of an insulin tolerance test (ITT) and a 12‐h spontaneous nocturnal profile as well as by IGF‐I assessment. The results were compared with those of 43 healthy controls.

Results  Mean 12‐h spontaneous nocturnal GH secretion was < 3·1 µg/l (the lowest limit of the normal range) in 36 (80%) of the subjects and > 3·1 µg/l in nine (20%). Of these 36 patients, 29 (80%) had abnormal MRI findings and 20 (55%) had multiple pituitary hormone deficiencies (MPHD). All nine subjects with mean spontaneous GH secretion > 3·1 µg/l had a normal pituitary MRI, isolated GHD and a peak GH response to ITT > 5 µg/l. There was a discordance in 14 patients (31%), who showed a peak GH response to ITT > 5 µg/l but a reduced spontaneous GH secretory capacity; 10 had structural hypothalamic–pituitary abnormalities on MRI.

Conclusions  Although the ITT provides valuable information and proves to be a sensitive index of permanent GHD, the results of this study emphasize the potential diagnostic value of assessment of 12‐h spontaneous GH secretion in young adults with childhood‐onset GHD.
Maternal serum adiponectin and infant birthweight: the role of adiponectin isoform distribution
Authors: Ong Gabie K. B. , Hamilton Jill K. , Sermer Mathew , Connelly Philip W. , Maguire Graham , Zinman Bernard , Hanley Anthony J. G. , Retnakaran Ravi
Published: May 2007

Objective  Adiponectin is an insulin‐sensitizing protein that circulates in oligomeric complexes, including trimers, hexamers and high‐molecular‐weight (HMW) multimers. In pregnant women, conflicting associations have been reported between maternal serum levels of total adiponectin (i.e. reflecting all isoforms) and infant birthweight. As the HMW complex has recently been proposed as the primary mediator of metabolic bioactivity, we hypothesized that differences in isoform distribution may underlie these conflicting reports. Therefore, we evaluated the relationship between maternal adiponectin isoforms and infant birthweight.

Design/patients/measurements  HMW and total adiponectin, as well as the ratio of HMW to total adiponectin (ratio known as SA), were measured in healthy pregnant Caucasian women (n = 58) undergoing an oral glucose tolerance test (OGTT), following an abnormal glucose challenge test.

Results  On univariate analysis adjusted for neonate gender and length of gestation, birthweight was positively correlated with weight gain in pregnancy (r = 0·29, P = 0·031) and inversely associated with the ISOGTT index of insulin sensitivity (r = –0·27, P = 0·041), total adiponectin (r = –0·31, P = 0·021), HMW adiponectin (r = –0·34, P = 0·0093) and SA (r = –0·34, P = 0·011). On multiple linear regression analyses, however, total adiponectin was not related to birthweight. By contrast, HMW adiponectin was related at borderline significance (t = –1·87, P = 0·068), while SA emerged as an independent negative determinant of infant birthweight (t = –2·46, P = 0·0175). Adjusted mean neonatal birthweight was significantly higher in the infants of women comprising the lowest tertile of SA compared to women in the highest tertile of SA (3684 vs. 3424 g, P = 0·0375).

Conclusions  The proportion of maternal serum adiponectin in HMW form (SA) is independently and inversely associated with infant birthweight. Thus, adiponectin isoform distribution, rather than total adiponectin concentration, may be a correlate of foetal size.
Focal uptake of 18F‐fluorodeoxyglucose by thyroid in patients with nonthyroidal head and neck cancers
Authors: Nam Soon Yuhl , Roh Jong‐Lyel , Kim Jae Seung , Lee Jeong Hyun , Choi Seung‐Ho , Kim Sang Yoon
Published: May 2007

Objective  To evaluate the prevalence and significance of focal thyroid lesions identified by 18F‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET) in patients with nonthyroidal head and neck cancers (HNC).

Patients and measurements  Patients with histologically identified HNC who underwent FDG‐PET and computed tomography (CT) were reviewed retrospectively. We evaluated the prevalence of patients with focal thyroid FDG uptake and the risk of malignancy and proper management in these patients.

Results  Of 689 HNC patients, 19 (2·8%) had focal thyroid FDG uptake. Of the 12 patients with a histological diagnosis by surgery or needle biopsy, 5 (41·7%) had carcinomas, 4 papillary and 1 follicular, whereas the others had benign thyroid lesions. The maximum standardized uptake value on PET was not sufficient to discriminate between malignant and benign thyroid lesions (8·4 ± 13·2 vs. 4·2 ± 4·0; P > 0·4). The identification of incidental thyroid diseases helped guide patient counselling and combined surgery with HNC and thyroidectomy.

Conclusion  Focal thyroid lesions incidentally found on FDG‐PET in patents with nonthyroidal HNC have a high probability of malignancy. These lesions deserve further diagnostic examination before HNC treatment to ensure adequate therapy for incidental thyroid cancers.
Relationship between serum hsCRP concentration and biochemical bone turnover markers in healthy pre‐ and postmenopausal women
Authors: Kim Beom‐Jun , Yu Yong Mi , Kim Euy Nyong , Chung Yun‐Ey , Koh Jung‐Min , Kim Ghi Su
Published: May 2007

Objective   Although osteoporosis and atherosclerosis seem to be related, the mechanisms are not yet understood. We previously observed that women with higher serum concentrations of high sensitivity C‐reactive protein (hsCRP), a strong risk factor for atherosclerosis, had lower bone mineral density (BMD). However, the relationship of hsCRP level with bone turnover rate, an independent risk factor for osteoporotic fracture, is not known.

Design   Cross‐sectional hospital‐based survey.

Patients   Apparently healthy pre‐ and postmenopausal women (n = 39 and 150, respectively).

Measurements   Urinary N‐terminal telopeptide of type I collagen (NTx) and serum bone specific alkaline phosphatase (BALP) were measured using commercially available immunoassay kits. Serum hsCRP concentrations were measured by a particle‐enhanced immunoturbidometric method.

Results   Both urinary NTx (γ = 0·288, P < 0·001) and serum BALP (γ = 0·260, P < 0·001) were positively correlated with serum hsCRP levels. Significance remained even after adjustment for age, body mass index and years since menopause (γ = 0·257, P < 0·001, and γ = 0·163, P = 0·027, respectively). Compared with subjects in the lowest hsCRP quartile (≤ 0·6 mg/l), those in the highest hsCRP quartile (≥ 1·6 mg/l) had significantly higher urinary NTx concentrations (P = 0·001) after adjustment for confounding variables. There was an increasing trend of serum BALP concentrations in the higher hsCRP quartile groups (P = 0·073).

Conclusion   These findings suggest that low grade systemic inflammation may be a common linking factor between development of atherosclerosis and increased bone turnover rate.
Novel polymorphisms and lack of mutations in the ACD gene in patients with ACTH resistance syndromes
Authors: Keegan Catherine E. , Hutz Janna E. , Krause Andrea S. , Koehler Katrin , Metherell Louise A. , Boikos Sosipatros , Stergiopoulos Sotirios , Clark Adrian J. L. , Stratakis Constantine A. , Huebner Angela , Hammer Gary D.
Published: May 2007

Objective  ACTH resistance is a feature of several human syndromes with known genetic causes, including familial glucocorticoid deficiency (types 1 and 2) and triple A syndrome. However, many patients with ACTH resistance lack an identifiable genetic aetiology. The human homolog of the Acd gene, mutated in a mouse model of adrenal insufficiency, was sequenced in 25 patients with a clinical diagnosis of familial glucocorticoid deficiency or triple A syndrome.

Design  A 3·4 kilobase genomic fragment containing the entire ACD gene was analysed for mutations in all 25 patients.

Setting  Samples were obtained by three investigators from different institutions.

Patients  The primary cohort consisted of 25 unrelated patients, primarily of European or Middle Eastern descent, with a clinical diagnosis of either familial glucocorticoid deficiency (FGD) or triple A syndrome. Patients lacked mutations in other genes known to cause ACTH resistance, including AAAS for patients diagnosed with triple A syndrome and MC2R and MRAP for patients diagnosed with familial glucocorticoid deficiency. Thirty‐five additional patients with adrenal disease phenotypes were added to form an expanded cohort of 60 patients.

Measurements  Identification of DNA sequence changes in the ACD gene in the primary cohort and analysis of putative ACD haplotypes in the expanded cohort.

Results  No disease‐causing mutations were found, but several novel single nucleotide polymorphisms (SNPs) and two putative haplotypes were identified. The overall frequency of SNPs in ACD is low compared to other gene families.

Conclusions  No mutations were identified in ACD in this collection of patients with ACTH resistance phenotypes. However, the newly identified SNPs in ACD should be more closely examined for possible links to disease.
The dynamics of western North America: stress magnitudes and the relative role of gravitational potential energy, plate interaction at the boundary and basal tractions
Authors: Flesch Lucy M. , Holt William E. , Haines A. John , Wen Lianxing , Shen-Tu Bingming
Published: May 2007

We investigate the forces involved in driving long-term large-scale continental deformation in western North America, and quantify the vertically averaged deviatoric stress field arising from internal buoyancy forces and the accommodation of relative plate motions. In addition, we investigate the ability of regional models to resolve the level of tractions acting at the base of the lithosphere. We directly solve force-balance equations for vertically averaged deviatoric stresses associated with differences in values of 1/(lithospheric thickness) times the gravitational potential energy per unit area (GPE). The GPE values are inferred using both the ETOPO5 topographic data set and the CRUST2.0 crustal thickness model. Deviatoric stresses associated with basal tractions are calculated globally, with inputs determined from an isoviscous upper mantle (η = 1021 Pa s) 3-D large-scale convection model in which mantle density variations were inferred from tomographic data and the history of subduction. In a 211-parameter iterative inversion we then solve for a stress field boundary condition by fitting stress field indicators (i.e. the directions and relative magnitudes of the principal axes of kinematic strain rates). Magnitudes of the total vertically averaged deviatoric stress field (sum of GPE solution with the boundary condition solution) range from 5 to 10 MPa within a 100-km thick lithosphere. These magnitudes are calibrated by the GPE differences, along with the spatial variation in deformation style. There is a trade-off between the scaling of the basal traction deviatoric stress field and the boundary condition solution. However, the combined boundary conditions plus basal traction solution is robust (in both magnitude and style), and when added to the contribution from GPE differences provides a global minimum of misfit between the total deviatoric stress solution and the stress field indicators. GPE variations account for ∼50 per cent of the deviatoric stress magnitudes driving deformation, while boundary condition stresses account for the remaining ∼50 per cent of deviatoric stress magnitude. By comparing possible end-member strength profiles with our vertically averaged deviatoric stresses we infer that the bulk of the strength within the lithosphere in western North America lies within the brittle seismogenic layer.
Evolution of stress in Southern California for the past 200 years from coseismic, postseismic and interseismic stress changes
Authors: Freed Andrew M. , Ali Syed Tabrez , Bürgmann Roland
Published: May 2007

The seismicity of southern California results from stresses that arise from the relative motion of the Pacific and North American Plates being accommodated along the San Andreas Fault (SAF) system and the Eastern California Shear Zone (ECSZ). Here we calculate how the stress field in southern California has evolved over the past two centuries due to interseismic loading, as inferred from current GPS observations of surface velocities, from redistributions of static stress induced by large (Mw ≥ 6.5) earthquakes since the 1812 Wrightwood quake, and postseismic viscoelastic relaxation associated with these events that serves to transfer coseismic stresses from the deep, warm, lower crust and upper mantle to the overlying seismogenic upper crust. We calculate Coulomb stress changes on vertical strike-slip faults striking parallel to the SAF and at the hypocenters on the rupture planes of all Mw ≥ 6 events over the past two centuries. Our results suggest that the 1857 Mw = 8.2 Fort Tejon earthquake, by far the largest event to have occurred in the region over the past two centuries, had a profound influence on the state of stress in Southern California during the 19th century, inducing significant stress increases to the north (Parkfield region and adjoining creeping SAF) and south (southern SAF and San Jacinto fault), and stress relief across the southern ECSZ. These stress changes were then greatly magnified by postseismic relaxation through the early part of the 20th century. Slow interseismic build-up of stress further loads all major strike-slip faults and works to reload the areas of the ECSZ where stress was relieved by the 1857 quake. Our calculations suggest that only 56% of hypocenters were pushed closer to failure by preceding coseismic stress changes, suggesting that the occurrence of large earthquakes is not strongly determined by coseismic Coulomb stress changes. This percentage rises to 70% when postseismic stress changes are also considered. Our calculations demonstrate the importance of postseismic viscoelastic relaxation in the redistribution of stress following large earthquakes. We find, however, that postseismic processes associated with events more than about a decade old are near completion and thus do not significantly influence the regional velocity field presently observed in southern California.
Cytotoxic molecule expression is predictive of prognosis in Hodgkin's‐like anaplastic large cell lymphoma
Authors: Asano N , Suzuki R , Matsuo K , Kagami Y , Ishida F , Tamaru J‐I , Jin G‐S , Sato Y , Shimoyama Y , Yoshino T , Morishima Y , Nakamura S
Published: May 2007

Aims:  The Revised European American Lymphoma classification uses the term Hodgkin's‐like anaplastic large cell lymphoma (HD‐like ALCL) for borderline cases with features of both anaplastic large cell lymphoma (ALCL) and classical Hodgkin's lymphoma (HL). The aim of this study was to clarify the association between cytotoxic molecule (CM) expression and clinical outcome in HD‐like ALCL.

Methods and results:  Subjects were 59 patients with HD‐like ALCL, defined by nodal presentation without mediastinal bulky lesions, T‐ or null‐cell phenotype, CD30+ anaplastic lymphoma kinase (ALK)– phenotype and by confluent sheets or nodules of large cells mimicking classic Hodgkin and Reed–Sternberg cells. We evaluated the presenting features and prognosis of subjects on categorization into two defined groups, namely CM (TIA1 and/or granzyme B)‐positive (n = 21) and CM‐negative (n = 38). The series consisted of 18 women and 41 men ranging from 16 to 88 years of age (median 59 years). The CM+ group had poorer disease‐specific survival than the CM– group (P = 0.02) despite the absence of differences in other clinical characteristics. Multivariate analysis confirmed that CM expression was an independent prognostic factor, in contrast to phenotypic categorization (T‐cell vs. null‐cell group), which had no prognostic impact on disease‐specific survival.

Conclusion:  CM expression is predictive of prognosis in HD‐like ALCL.