bluuebunny/crossref_metadata_2025 huggingface dataset:
MAPK target networks inArabidopsis thalianarevealed using functional protein microarrays
Authors: Popescu Sorina C. , Popescu George V. , Bachan Shawn , Zhang Zimei , Gerstein Mark , Snyder Michael , Dinesh-Kumar Savithramma P.
Published: December 2008

Signaling through mitogen-activated protein kinases (MPKs) cascades is a complex and fundamental process in eukaryotes, requiring MPK-activating kinases (MKKs) and MKK-activating kinases (MKKKs). However, to date only a limited number of MKK–MPK interactions and MPK phosphorylation substrates have been revealed. We determined whichArabidopsis thalianaMKKs preferentially activate 10 different MPKs in vivo and used the activated MPKs to probe high-density protein microarrays to determine their phosphorylation targets. Our analyses revealed known and novel signaling modules encompassing 570 MPK phosphorylation substrates; these substrates were enriched in transcription factors involved in the regulation of development, defense, and stress responses. Selected MPK substrates were validated by in planta reconstitution experiments. A subset of activated and wild-type MKKs induced cell death, indicating a possible role for these MKKs in the regulation of cell death. Interestingly, MKK7- and MKK9-induced death requiresSgt1, a known regulator of cell death induced during plant innate immunity. Our predicted MKK–MPK phosphorylation network constitutes a valuable resource to understand the function and specificity of MPK signaling systems.
Compounds with a `stuffed' anti-bixbyite-type structure, analysed in terms of the Zintl–Klemm and coordination-defect concepts
Authors: Vegas Angel , Martin Raymond L. , Bevan D. J. M.
Published: December 2008

The bixbyite structure (Mn2O3) (Ia\bar 3) is often described as a distorted face-centered cubic (f.c.c.) array of Mn atoms, with O atoms occupying 3/4 of the tetrahedral holes. The empty M
4 tetrahedra are centred at 16c. In anti-bixbyite structures (Mg3N2), cation vacancies are centred in empty N4 tetrahedra. If 16 hypothetical atoms were located at this site they would form the structure of γ-Si. This means that anti-bixbyite structures are ideally prepared to accommodate Si(Ge) atoms at these holes. Several compounds (Li3AlN2 and Li3ScN2) fully satisfy this expectation. They are really anti-bixbyites `stuffed' with Al(Sc). The presence of these atoms in 16c is illuminated in the light of the extended Zintl–Klemm concept (EZKC) [Vegas & García-Baonza (2007). Acta Cryst. B63, 339–345], from which a compound would be the result of `multiple resonance' pseudo-structures, emerging from electron transfers between any species pair (like or unlike atoms, cations or anions). The coordination-defect (CD) concept [Bevan & Martin (2008). J. Solid State Chem.
181, 2250–2259] is also consistent with the EZKC description of the pseudo-structures. A more profound insight into crystal structures is gained if one is not restricted to the contemplation of classical anions and cations in their conventional oxidation states.
Alternative presentation of the Brown–Wu bond-valence parameters for some s
2 cation/O2− ion pairs
Authors: Sidey Vasyl
Published: December 2008

Using the least-squares refinement procedure, high-performance Brown–Wu bond-valence parameters, r
0 and n, reported for the Sn2+/O2−, Sb3+/O2−, Te4+/O2− and I5+/O2− ion pairs have been converted into the commonly used bond-valence parameters, r
0 and b. The r
0 and b values obtained can be recommended as a replacement for the conventional bond-valence parameters based on the `universal constant' b = 0.37 Å.
Characterization of the pelagic shark‐fin trade in north‐central Chile by genetic identification and trader surveys
Authors: Sebastian H. , Haye P. A. , Shivji M. S.
Published: December 2008

Shark fins have become a highly valued commodity with the major Asian fin‐trade centres supplied from global sources, including Chile. With growing concerns about the resilience of shark populations to heavy fishing pressure, there is a need for better information on shark landings to aid management efforts. In the widespread absence of shark landing records especially by species, monitoring the fin trade has been proposed as a way to assess species exploitation levels. Here, the first species assessment of the Chilean shark‐fin trade was provided. The goals of this study were to (1) determine the species composition and relative species proportion of sharks utilized in the fin trade, (2) determine the relationship between fin trader market names and species and (3) assess trader accuracy in identifying shark fin species based on fin photographs. Fins were analysed from two different fin drying facilities (n = 654) (secaderos) and two fin‐storage warehouses (n = 251). In contrast to official government landing records that only document four species in the landings, molecular species identification of the fins demonstrated that at least 10 pelagic shark species are present in the north‐central Chilean shark fin trade: Alopias superciliosus, Alopias vulpinus, Carcharhinus obscurus, Galeorhinus galeus, Isurus oxyrinchus, Isurus paucus, Lamna nasus, Prionace glauca, Sphyrna lewini, Sphyrna zygaena. The species composition of the fins from the secaderos was P. glauca (83·9%), I. oxyrinchus (13·6%), L. nasus (1·7%) and A. superciliosus (0·2%). There was generally good agreement between market names and single shark species for the trade categories ‘Azulejo’, ‘Tiburon’, ‘Tintorera’, ‘Cola de zorro’ and ‘Martillo’. In contrast, the market category ‘Carcharhinus’ consisted of a mixture of at least five species. The molecular results also identified two species (S. lewini and I. paucus) not previously recorded in Chilean waters. The fin identification survey given to nine regional traders demonstrated that they were highly accurate in recognizing pictures of fins from P. glauca and I. oxyrinchus. The overall strong concordance between market categories and fins from single species and the trader accuracy in survey fin identification suggests that monitoring the Chilean fin trade by market names will provide a reasonably accurate picture of the volume of sharks landed by species.
Changes in scale circulus spacings of an endangered Atlantic salmon Salmo salar population: evidence of a shift in marine migration?
Authors: Hubley P. B. , Amiro P. G. , Gibson A. J. F.
Published: December 2008

Post‐smolt scale circulus spacing patterns for two Atlantic salmon Salmo salar populations from the Southern Upland (SU) of Nova Scotia, Canada, were compared with spacings from two endangered populations from the inner Bay of Fundy (iBoF) Nova Scotia and New Brunswick, to determine if growth patterns differed among these populations, and if growth patterns had changed as the abundance of these populations declined. An analysis of numbers of marine circuli from scales of post‐smolts and one‐sea‐winter adults of known age indicated that circuli were deposited at a rate of about one circulus per week in summer and slowed to one every 2 weeks in winter. During the summer and the autumn, mean circulus spacing in the iBoF populations, known to have occupied the outer Bay of Fundy during these seasons, was lower than in the SU populations, which are known to migrate to the North Atlantic. Similar circulus spacing patterns within SU populations is suggestive of a common marine distribution for these populations. In contrast, a cluster analysis revealed that within the geographically intermediate Big Salmon River (iBoF), some individuals exhibited wider spacing patterns that resemble the distant migrating SU populations, while others exhibited narrower spacing similar to other iBoF S. salar. Within the Big Salmon River, the relative abundance of the wider and the narrower spacing patterns varied in the earlier years, but all fish sampled since 1999, exhibited wider spacings similar to distant migrating SU S. salar. The apparent disappearance of the narrower pattern, characteristic of localized migration and indicative of historical iBoF populations, suggests that local migration may not presently be a successful strategy for these populations.
Date mussel harvesting favours some blennioids
Authors: Parravicini V. , Donato M. , Morri C. , Villa E. , Bianchi C. N.
Published: December 2008

The consequences of date mussel Lithophaga lithophaga harvesting (DMH) on blennioid assemblages was evaluated at Capo Noli‐Bergeggi (Savona, north‐western Mediterranean Sea) in summer 2005, under the hypothesis that holes bored by L. lithophaga, and left empty by the collection of the bivalve, may represent refuges for these cryptobenthic fishes. Blenniidae and Tripterygiidae were identified to species, and their individuals counted together with the number of empty L. lithophaga holes. The results were compared between ‘impact’ sites affected by the destructive DMH and control sites using two‐way ANOVA, and showed that extensive removal of the boring mussels, dramatically increasing the availability of empty holes, favours total number of observed blennioid species and especially Parablennius zvonimiri abundance.
Norwegian spring‐spawning herring as the test case of piecewise linear regression method for detecting maturation from growth patterns
Authors: Baulier L. , Heino M.
Published: December 2008

Data from Norwegian spring‐spawning herring Clupea harengus, were used empirically to assess the performance of a regression method aimed at detecting the time of the onset of maturation from growth trajectories. At the level of the whole dataset, the piecewise linear‐regression method was accurate and showed only a minor bias (−0·17 years) relative to age at maturation visually read from scales. The method, however, was relatively imprecise and provided an estimate of age at maturation equal to the one read from the scale in less than half of the cases (47·6%). Moreover, bias was strongly dependent on age at maturation: the age at maturation of early maturing fish was often overestimated, whereas the opposite was true for late‐maturing fish. Accuracy and precision of the regression method relative to visual readings also depended on the growth type (determined by the nursery area of young C. harengus) and cohort but not on sex. Modifying the original regression method enabled marginally improving the precision of the approach but a strong maturation age‐dependent bias persisted. The results with C. harengus suggested that age‐at‐maturation estimates from the piecewise linear regression method should be treated with caution.
Difference in diet and size‐related trophic level in two sympatric fish species, the red mullets Mullus barbatus and Mullus surmuletus, in the Gulf of Lions (north‐west Mediterranean Sea)
Authors: Bautista‐Vega A. A. , Letourneur Y. , Harmelin‐Vivien M. , Salen‐Picard C.
Published: December 2008

Stable‐isotope ratios (δ15N and δ13C) and diet of the red mullets Mullus barbatus and Mullus surmuletus were analysed in two zones differently subjected to the Rhône River runoff in the Gulf of Lions (north‐west Mediterranean sea) in May and October 2004. δ15N and δ13C increased significantly with fish size in M. barbatus in both zones and seasons, whereas no significant trend was evidenced in M. surmuletus. A clear size‐related shift in diet was observed in M. barbatus, with an increase in polychaete and shrimp consumption with size and a decrease in small crustacean consumption. In M. surmuletus, a diet shift was observed only between medium and large individuals. Large M. surmuletus preyed on shrimps, polychaetes, bivalves, ophiurids and amphipods, and ingested prey of lower mean mass than M. barbatus of similar size. Difference in size‐related increase in δ15N between the two mullid fish species were related to difference of trophic level of their main prey. Sub‐surface deposit‐feeding polychaetes, carnivorous polychaetes, shrimps and brachyurans presented higher δ15N values than bivalves, small crustaceans and ophiurids. The lower δ13C values observed in M. barbatus compared to M. surmuletus were related to a higher consumption of sub‐surface polychaetes in the former species. Significantly, lower δ13C were recorded in fishes collected off the Rhône River, particularly in spring, suggesting an influence of river inputs as a source of particular organic matter for mullids in this zone after the flooding season. Thus, these closely related sympatric fish species displayed diet divergences that were reflected in their stable isotopic signatures.
Growth characteristics of eastern mosquitofishGambusia holbrookiin a northern habitat (Brittany, France)
Authors: Beaudouin R. , Ginot V. , Monod G.
Published: December 2008

The two coefficients of the von Bertalanffy growth model [maximal standard length (LS∞) and initial growth rate (a)] were determined in eastern mosquitofishGambusia holbrookiin the most northern area where it is established (Rennes, Brittany, France). The estimated meanLS∞was 57·7 and 25·0 mm in females and males, respectively. The value ofawas identical for both males and females before the males diverged from the females by slowing down their growth, probably because of the onset of puberty. The sexual competition reported in males would be responsible for higher interindividual variability ofLS∞in males than in females.awas positively correlated with water temperature and could be modulated by fish density and length at birth. Moreover, interindividual variability ofawas influenced in a complex way by interactions between water temperature, length at birth and fish density. When compared to the data from studies inG. holbrookiinhabiting their native range or the southern introduced range, the present results suggest that the thermal tolerance domain for growth was altered and that males exhibited a shorter length at sexual maturity and a shorterLS∞in the population established in Rennes.
Reproductive strategy and recruitment dynamics of amphidromous goby Sicyopterus japonicus as revealed by otolith microstructure
Authors: Shen K. N. , Tzeng W. N.
Published: December 2008

The daily ages of 312 of 879 newly recruited postlarvae of Sicyopterus japonicus, collected from the Shuang‐Chi Estuary in north‐eastern Taiwan during February 1996 to April 1997, were determined from daily growth increments in their otoliths. Pelagic larval duration, growth rate of the marine larval stage and hatching dates were estimated, and recruitment timing was linked to environmental factors. The mean ±s.d. total length (LT) and daily ages of S. japonicus at recruitment to the estuary were estimated to be 33·95 ± 1·31 mm (range 30·7 to 38·1, n = 317) and 163·72 ± 12·79 days (range 130 to 198, n = 312), respectively. The recruitment of S. japonicus larvae is size dependent not age dependent because LT of the larvae is independent of age at recruitment. Periodic analysis indicated that LT and growth rate of the larvae were inversely correlated with the age at recruitment, which means that the fast‐growing individuals recruited earlier. The growth rate of S. japonicus in the marine larval stage was synchronous with marine productivity in this subtropical area, i.e. the spring cohort recruited in the autumn had a higher growth rate than the autumn cohort recruited the following spring. The main spawning season of S. japonicus as backcalculated from otolith daily increments was in autumn, a relatively low productivity period compared with spring. During this season, there were fewer competitors and predators than in the more productive spring. The recruitment of 95% of postlarva coincided with low salinity (14) and low water temperature (23° C) in the river mouth that provided a buffer area for the adaptation of the larvae for upstream migration. This unique reproduction strategy and prolonged larval duration facilitated the widespread distribution of the fish along the coasts of East Asia.
The carp M1 muscle‐specific creatine kinase subisoform is adaptive to the synchronized changes in body temperature and intracellular pH that occur in the common carp Cyprinus carpio
Authors: Wu C. L. , Liu C. W. , Sun H. W. , Chang H. C. , Huang C. J. , Hui C. F. , Wu J. L.
Published: December 2008

The three previously cloned Cyprinus carpio muscle‐specific subisoforms of creatine kinase (CK, EC 2.7.3.2) designated M1‐, M2‐ and M3‐CK were examined. At temperatures <15° C and at pH >7·7, specific activities of M1‐CK were three to eight‐fold higher than specific activities of M3‐ and rabbit (R) M‐CK. At pH 8·0, M1‐CK exhibited its highest specific activity at 15° C. Michaelis constants of PCr () and ADP () of M1‐CK were relatively stable at pH between 7·1–8·0 and 25–5° C. Its calculated activation energy of catalysis (Ea) at pH 8·0 was lower than at pH 7·1. Circular dichroism spectroscopy results showed that changes in secondary structures in M1‐CK at the pH and temperatures studied were much less than in the cases of RM‐ and M3‐CK. The M1‐CK enzyme seemed to have evolved to adapt to the synchronized changes in body temperature and intracellular pH of C. carpio.
Identification of a fljA gene on a linear plasmid as the repressor gene of fliC in Salmonella enterica serovar Typhi
Authors: Zou Xin , Huang Xinxiang , Xu Shungao , Zhou Liping , Sheng Xiumei , Zhang Haifang , Xu Huaxi , Ezaki Takayuki
Published: December 2008

Salmonella enterica serovar Typhi z66‐positive strain contains an fljBA‐like operon on a linear plasmid and the fliC gene on the chromosome encoding d or j antigen. The fljB‐like gene has been identified as the gene encoding z66 antigen. To investigate the function of the fljA‐like gene in S. enterica serovar Typhi, a z66‐positive wild‐type strain GIFU10007 and its phase variation j positive strain 007j+ were used in the present study. After deletion of the fljA‐like gene, the wild‐type strain that only expressed FljB:z66 could express both FliC:j and FljB:z66 at the same time. A recombinant plasmid, pBADfljA, containing the fljA‐like gene was prepared. SDS‐PAGE and western blot analysis of secreted proteins showed that when the strain 007j+ was transformed by the recombinant plasmid, pBADfljA, the expression of FliC:j was inhibited. The fliC::lacZ fusion of the strain 007j+ was constructed. β‐Galactosidase activity was decreased approximately 100‐fold after harboring the plasmid pBADfljA in the fliC::lacZ mutant strain. However, the fliC mRNA level investigated by RT‐PCR was decreased only approximately seven‐fold in the strain 007j+ after harboring the plasmid pBADfljA. These results demonstrated that the fljA‐like gene on a linear plasmid of S. enterica serovar Typhi is a fljA gene, the repressor of fliC gene, and the inhibition by FljA is likely at the post‐transcriptional level.
Cadherin‐7 interacts with melanoma inhibitory activity protein and negatively modulates melanoma cell migration
Authors: Winklmeier Andreas , Contreras‐Shannon Veronica , Arndt Stephanie , Melle Christian , Bosserhoff Anja‐Katrin
Published: December 2008

Melanoma inhibitory activity (MIA) has been identified as a small protein secreted from malignant melanoma cells, which strongly enhances melanoma cell migration and invasion. Detailed analyses performed by our group showed interaction of MIA with extracellular matrix proteins and integrin α4β1 and α5β1 leading to cellular detachment. In this study, we identified cadherin‐7 as a new MIA‐binding protein using surface‐enhanced laser desorption/ionization‐mass spectrometry technology and co‐immunoprecipitation. Cadherin‐7 is a classical cell–cell adhesion molecule which was shown to be upregulated in malignant melanoma. We demonstrated enhanced expression of cadherin‐7 in primary tumor cells compared to metastatic cells. Upregulation of cadherin‐7 expression in metastatic cell lines but also downregulation of expression in cells derived from primary melanomas resulted in reduced cell migration. In addition, we speculate that MIA/cadherin‐7 interaction may regulate cell–cell adhesion of malignant melanoma cells influencing the migration of the cells. Interestingly, overexpression of cadherin‐7 resulted in a decreased MIA mRNA expression. In addition, MIA effects on cell migration were abrogated in cell clones overexpressing cadherin‐7. In conclusion, these findings suggest that cadherin‐7 regulates the expression and activity of MIA and the migration of melanoma cells playing a role in tumor development of malignant melanoma. (Cancer Sci 2009; 100: 261–268)
V‐PROLI/NO, a nitric oxide donor prodrug, protects liver cells from arsenic‐induced toxicity
Authors: Qu Wei , Liu Jie , Dill Anna L. , Saavedra Joseph E. , Keefer Larry K. , Waalkes Michael P.
Published: December 2008

Inorganic arsenic shows great promise in human cancer chemotherapy, although hepatotoxicity is a major limiting side‐effect. O2‐Vinyl 1‐[2‐(Carboxylato)pyrrolidin‐1‐yl]diazen‐1‐ium‐1,2‐diolate (V‐PROLI/NO) [Correction added after publication 19 December 2008: 1‐[2‐(Carboxylato)pyrrolidin‐1‐yl]diazen‐1‐ium‐1,2‐diolate (V‐PROLI/NO) was corrected to O2‐Vinyl 1‐[2‐(Carboxylato)pyrrolidin‐1‐yl]diazen‐1‐ium‐1,2‐diolate (V‐PROLI/NO)] is a nitric oxide (NO) donor prodrug that is metabolized by liver cytochromes P450 to release NO. Other NO‐releasing agents have been shown to mitigate arsenic toxicity. Thus, the effects of V‐PROLI/NO pretreatment on the toxicity of inorganic arsenic (as NaAsO2) were studied in vitro in a human liver (HepG2) cell line. HepG2 cells acted upon the prodrug to release NO, as assessed by nitrite levels, in a dose‐ and time‐dependent fashion to maximal levels of 57‐fold above control levels. In cells pretreated with V‐PROLI/NO (200 µM, 24 h) then exposed to arsenic for an additional 24 h, arsenic was much less toxic (LC50 = 151.9 ± 5.9 µM) than in control cells (LC50 = 90.5 ± 6.5 µM) and the reduced cytolethality was directly related to the level of NO produced. V‐PROLI/NO also increased CYP2E1 transcriptional expression in a dose‐dependent manner and CYP2E1 expression was directly related to the level of NO produced and the reduction in arsenic cytotoxicity. V‐PROLI/NO pretreatment markedly reduced arsenic‐induced apoptosis as measured by DNA fragmentation. Pretreatment with V‐PROLI/NO suppressed phosphorylation of JNK1/2 after arsenic exposure. Arsenic increased metallothionein, a metal‐binding protein important in arsenic tolerance, and V‐PROLI/NO pretreatment caused additional increases in metallothionein levels. Thus, the prodrug, V‐PROLI/NO, protects against arsenic toxicity in cultured human liver cells, reducing cytolethality, apoptosis and dysregulation of mitogen‐activated protein kinases, through generation of NO formed after metabolism by liver cell enzymes, possibly including CYP2E1. (Cancer Sci 2009; 100: 382–388)
Impaired Tax‐specific T‐cell responses with insufficient control of HTLV‐1 in a subgroup of individuals at asymptomatic and smoldering stages
Authors: Shimizu Yukiko , Takamori Ayako , Utsunomiya Atae , Kurimura Mayumi , Yamano Yoshihisa , Hishizawa Masakatsu , Hasegawa Atsuhiko , Kondo Fumiaki , Kurihara Kiyoshi , Harashima Nanae , Watanabe Toshiki , Okamura Jun , Masuda Takao , Kannagi Mari
Published: December 2008

Human T‐cell leukemia virus type‐1 (HTLV‐1)‐specific T‐cell immunity, a potential antitumor surveillance system in vivo, is impaired in adult T‐cell leukemia (ATL). In this study, we aimed to clarify whether the T‐cell insufficiency in ATL is present before the disease onset or occurs as a consequence of the disease. We investigated T‐cell responses against Tax protein in peripheral blood mononuclear cells (PBMCs) from individuals at earlier stages of HTLV‐1‐infection, including 21 asymptomatic HTLV‐1 carriers (ACs) and four patients with smoldering‐type ATL (sATL), whose peripheral lymphocyte count was in normal range. About 30% of samples tested showed clear Tax‐specific interferon (IFN)‐γ producing responses. Proviral loads in this group were significantly lower than those in the other less‐specific response group. The latter group was further divided to two subgroups with or without emergence of Tax‐specific responses following depletion of CC chemokine receptor 4 (CCR4)+ cells that contained HTLV‐1‐infected cells. In the PBMCs with Tax‐specific responses, CD8+ cells efficiently suppressed HTLV‐1 p19 production in culture. The remaining group without the emergence of Tax‐specific response after CCR4+ cell‐depletion included at least two sATL and one AC samples, which spontaneously produced HTLV‐1 p19 in culture, where tetramer‐binding, Tax‐specific cytotoxic T‐lymphocytes were either undetectable or unresponsive. Our results indicated that HTLV‐1‐specific T‐cell responsiveness widely differed among HTLV‐1 carriers, and that impairment of HTLV‐1‐specific T‐cell responses was observed not only in advanced ATL patients but also in a subpopulation at earlier stages, which was associated with insufficient control of HTLV‐1. (Cancer Sci 2009; 100: 481–489)
Alternative lengthening of telomeres frequently occurs in mismatch repair system‐deficient gastric carcinoma
Authors: Omori Yasuhiro , Nakayama Fumihito , Li Dong , Kanemitsu Kiyonori , Semba Shuho , Ito Akihiko , Yokozaki Hiroshi
Published: December 2008

Maintenance of telomeric ends by the telomerase ribonucleoprotein complex or the telomerase‐independent alternative lengthening of telomeres is necessary for the immortalization of human cells. The significance of alternative lengthening of telomeres has been suggested in DNA mismatch repair system‐deficient cells; however, much remains unknown in human malignancies. In this study, we investigated the telomere maintenance mechanism in gastric carcinoma. In formalin‐fixed and paraffin‐embedded sections of the high frequency of microsatellite instability (MSI‐H) and non‐MSI‐H gastric carcinomas, there was no difference in telomere length monitored by telomere intensity ratio using telomere‐fluorescent in situ hybridization. Immunoreactivity of hTERT, the catalytic subunit of telomerase, was detected in 48% of MSI‐H gastric carcinomas. The frequency was significantly lower than that in non‐MSI‐H gastric carcinomas (86%, P = 0.02). Conversely, the number of the alternative lengthening of telomeres‐associated promyelocytic leukemia bodies (APBs) detected by combined promyelocytic leukemia immunofluorescence and telomere‐fluorescent in situ hybridization was statistically higher (57%) in the MSI‐H gastric carcinomas compared to that in non‐MSI‐H gastric carcinomas (19%, P = 0.026). The cases with hTERT(+)APBs(–) were more frequent in non‐MSI‐H gastric carcinomas (76%) than in MSI‐H gastric carcinomas (24%), and the cases with hTERT(–)APBs(+) were more frequent in MSI‐H gastric carcinomas (33%) than in non‐MSI‐H gastric carcinomas (10%). These results suggest that alternative lengthening of telomeres‐mediated telomere maintenance plays an important role for microsatellite instability‐mediated stomach carcinogenesis, as well as the telomerase ribonucleoprotein complex, although the incidence of MSI‐H is low. Defects of the mismatch repair system may lead to homeologous recombination of telomeric ends for the telomerase‐independent telomere maintenance in gastric carcinomas. (Cancer Sci 2009; 100: 413–418)
Clinical trial: pilot study of metformin for the treatment of non‐alcoholic steatohepatitis
Authors: LOOMBA R. , LUTCHMAN G. , KLEINER D. E. , RICKS M. , FELD J. J. , BORG B. B. , MODI A. , NAGABHYRU P. , SUMNER A. E. , LIANG T. J. , HOOFNAGLE J. H.
Published: December 2008

Background Non‐alcoholic steatohepatitis (NASH) is a form of progressive fatty liver disease that is strongly associated with insulin resistance, which suggests that insulin sensitizing agents such as metformin may be beneficial for NASH.

Aim To assess the effects of metformin on insulin sensitivity, body composition, serum alanine aminotransferase (ALT) levels and liver histology in patients with NASH.

Methods Patients underwent liver biopsy, metabolic profiling and imaging studies before and at the end 48 weeks of metformin (2000 mg/day) therapy. The primary endpoint was a three‐point improvement in the histological NASH activity index.

Results Of 28 patients enrolled, 26 (13 females; average age 44 years) completed 48 weeks of treatment and underwent repeat metabolic studies, imaging and liver biopsy. Thirty per cent achieved a histological response. Most patients lost weight, the average being 6 kg. There was a marked association between weight loss and improvements in NASH activity index and ALT levels (both,P < 0.01). Insulin sensitivity also improved, but the degree of change did not correlate with histological improvement.

Conclusion Metformin leads to improvements in liver histology and ALT levels in 30% of patients with NASH, probably by its effects in causing weight loss.
Informed consent for epidural analgesia in labour: a survey of UK practice*
Authors: Middle J. V. , Wee M. Y. K.
Published: December 2008

Anaesthetists are legally obliged to obtain informed consent before performing regional analgesia in labour. A postal survey of consultant‐led UK anaesthetic units was performed in September 2007 to assess practice regarding obtaining informed consent before inserting an epidural, and documentation of the risks discussed. The response rate was 72% (161/223). There was great variation between units regarding which risks women were informed about and the likely incidence of that risk. One hundred and twenty‐three respondents out of 157 providing an epidural service (78%) supported a national standardised information card endorsed by the Obstetric Anaesthetists’ Association, with all the benefits and risks stated, to be shown to all women before consenting to an epidural in labour.
Smoking and anaesthesia: the pharmacological implications
Authors: Sweeney B. P. , Grayling M.
Published: December 2008

Anaesthetists are generally familiar with the peri‐operative implications of cigarette smoking. Although there are a number of publications dealing with the wider pharmacological implications of cigarette smoking, the specific interactions which are of direct relevance to anaesthetists are less well known. This review gives an overview of those interactions which are of clinical relevance to anaesthetists and provides, where possible, an explanation of the mechanism. Recent improvements in the understanding of biotransformation of drugs, including streamlining of the classification of hepatic enzymes has allowed better understanding of drug interactions and enables the mechanistic prediction of those involving new drugs.
Tramadol for prevention of postanaesthetic shivering: a randomised double‐blind comparison with pethidine
Authors: Mohta M. , Kumari N. , Tyagi A. , Sethi A. K. , Agarwal D. , Singh M.
Published: December 2008

The present study was conducted with the aims of comparing intravenous tramadol 1, 2 and 3 mg.kg−1 with pethidine 0.5 mg.kg−1 for prophylaxis of postanaesthetic shivering and to find a dose of tramadol that could provide the dual advantage of antishivering and analgesic effect in the postoperative period. The study included 165 patients, randomly allocated to five groups of 33 each. Tramadol in doses of 1, 2 and 3 mg.kg−1, pethidine 0.5 mg.kg−1 or normal saline were administered at the time of wound closure. All three doses of tramadol were effective and comparable to pethidine in preventing postanaesthetic shivering. Tramadol 2 mg.kg−1 had the best combination of antishivering and analgesic efficacy without excessive sedation and thus appeared to be a good choice to be administered at the time of wound closure to provide antishivering effect and analgesia without significant side effects in the postoperative period.
Tolerability, pharmacokinetics and night‐time effects on postural sway and critical flicker fusion of gaboxadol and zolpidem in elderly subjects
Authors: Boyle Julia , Danjou Philippe , Alexander Robert , Calder Nicole , Gargano Cynthia , Agrawal Nancy , Fu Irong , McCrea Jacqueline B. , Murphy M. Gail
Published: December 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Body sway increases in older adults and may lead to an increase in the risk of falling.

• The problem of impaired stability in the elderly may be compounded by the use of hypnotics, which have been associated with an increased risk of next‐day falls as well as drowsiness.

• The potential adverse effects of hypnotic drugs on steadiness may be exacerbated during the night, in the event that an individual needs to get out of bed.

WHAT THIS STUDY ADDS

• This study examines the effects of gaboxadol (an investigational treatment for insomnia), zolpidem (a current hypnotic included as an active control) and placebo on body sway and attention/information processing ability following bedtime dosing in elderly subjects who were woken during the night for assessments.

• Zolpidem and gaboxadol increased body sway at various time points during the night relative to placebo; at 1.5 h post dose, the time of peak concentrations of both drugs, gaboxadol produced less impairment than zolpidem.

• Compared with placebo, neither gaboxadol nor zolpidem impaired attention/information‐processing ability as assessed by critical flicker fusion.

AIMS

To evaluate tolerability, pharmacokinetics and night‐time effects on body sway and critical flicker fusion (CFF) of gaboxadol following bedtime dosing in healthy elderly subjects.

METHODS

Subjects (17 women, seven men) aged 65–75 years received gaboxadol 10 mg, zolpidem 5 mg (active control) or placebo at 22.00 h in a three‐period, randomized, double‐blind crossover study. They were awakened during the night for evaluation of body sway and CFF. Pharmacokinetics of gaboxadol were assessed during a fourth single‐blind treatment period. Adverse events were recorded throughout the study.

RESULTS

The number of subjects with adverse events was 14 for gaboxadol 10 mg, seven for zolpidem and nine for placebo; most were mild or moderate in intensity. Two women discontinued the study following gaboxadol; one vomited and one experienced a severe vasovagal syncope after venepuncture. Mean gaboxadol tmax was 2 h, t½ was 1.7 h, AUC0–∞ was 430 ng·h ml−1 and Cmax was 139 ng ml−1. At 1.5 h and 4 h post dose, zolpidem increased body sway relative to placebo (P < 0.01). Gaboxadol increased body sway at 4 h (P < 0.001) and 8 h (P < 0.05) relative to placebo. At 1.5 h, the time point closest to peak drug concentrations, zolpidem increased body sway compared with gaboxadol (P < 0.01). Gaboxadol and zolpidem had no effects on CFF vs. placebo.

CONCLUSIONS

A bedtime dose of gaboxadol 10 mg was generally well tolerated. Changes in body sway at 1.5 h after bedtime dosing were smaller with gaboxadol 10 mg than with zolpidem 5 mg, whereas changes were similar at 4 h for both treatments and returned to near baseline at 8 h.
Influence of domperidone on pharmacokinetics, safety and tolerability of the dopamine agonist rotigotine
Authors: Braun Marina , Cawello Willi , Boekens Hilmar , Horstmann Rolf
Published: December 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Rotigotine transdermal patch is a new non‐ergolinic dopamine agonist developed for the treatment of Parkinson's disease and restless legs syndrome.

• Peripheral dopaminergic side‐effects of dopamine agonists such as nausea and vomiting can be prevented by the antiemetic agent domperidone.

WHAT THIS STUDY ADDS

• The study results show no evidence for an interaction of domperidone on bioavailability and steady‐state pharmacokinetics of transdermal rotigotine.

• Co‐administration of domperidone and rotigotine does not require dose adjustments for rotigotine transdermal patch.

AIMS

To evaluate the influence of the antiemetic agent domperidone on steady‐state pharmacokinetics, safety and tolerability of multiple‐dose treatment of the transdermally applied non‐ergolinic dopamine agonist rotigotine.

METHODS

Sixteen healthy male subjects (mean age 30.3 years) participated in a randomized, two‐way crossover clinical trial. Treatment A consisted of transdermal rotigotine patch (2 mg (24 h)−1, 10 cm2, total drug content 4.5 mg) applied daily for 4 days, and concomitant oral domperidone (10 mg t.i.d.) for 5 days. For treatment B, subjects received only transdermal rotigotine treatment (daily for 4 days). Pharmacokinetic variables describing systemic exposure and renal elimination of rotigotine and metabolites, and safety and tolerability of the treatment were assessed.

RESULTS

The primary steady‐state pharmacokinetic parameters (Cmax,ss and AUC(0–24),ss) were similar with or without co‐administration of domperidone. Geometric mean ratios were close to 1 and respective 90% confidence intervals were within the acceptance range of bioequivalence (0.8, 1.25): Cmax,ss 0.96 (0.86, 1.08) and AUC(0–24),ss 0.97 (0.87, 1.08). tmax,ss, t1/2, secondary parameters calculated on days 4/5 after repeated patch application (Cmin,ss, Cave,ss, AUC(0–tz)) and renal elimination for unconjugated rotigotine and its metabolites were also similar with and without comedication of domperidone. A reduction in the dopaminergic side‐effect nausea was seen with domperidone comedication.

CONCLUSIONS

No changes of pharmacokinetic parameters describing systemic exposure and renal elimination of rotigotine were observed when domperidone was administered concomitantly with rotigotine. The lack of pharmacokinetic interactions indicates that a dose adjustment of rotigotine transdermal patch is not necessary with concomitant use of domperidone.
A color‐coded orthotopic nude‐mouse treatment model of brain‐metastatic paralyzing spinal cord cancer that induces angiogenesis and neurogenesis
Authors: Hayashi K.  , Yamauchi K.  , Yamamoto N.  , Tsuchiya H.  , Tomita K.  , Bouvet M.  , Wessels J.  , Hoffman R. M. 
Published: December 2008

Objective: Cancer of the spinal cord is highly malignant and often leads to paralysis and death. A realistic mouse model would be an important benefit for the better understanding and treatment of spinal cord glioma.

Materials and methods: To develop an imageable, patient‐like model of this disease, U87 human glioma tumour fragments (expressing red fluorescent protein), were transplanted by surgical orthotopic implantation into the spinal cord of nontransgenic nude mice or transgenic nude mice expressing nestin‐driven green fluorescent protein (ND‐GFP). In ND‐GFP mice, GFP is expressed in nascent blood vessels and neural stem cells. The animals were treated with temozolomide or vehicle control.

Results: The intramedullary spinal cord tumour grew at the primary site, caused hind‐limb paralysis and also metastasized to the brain. Temozolomide inhibited tumour growth (P < 0.01) and prevented metastasis, as well as prevented paralysis in four mice and delayed paralysis in two mice of the six tested (P = 0.005). In the ND‐GFP‐expressing host, ND‐GFP cells staining positively for neuronal class III‐β‐tubulin or CD31, surrounded the tumour. These results suggest that the tumour stimulated both neurogenesis and angiogenesis, respectively.

Conclusion: A patient‐like model of spinal cord glioma was thus developed, which can be used for the discovery of new agents, including those that inhibit invasion and metastasis of the disease as well as those that prevent paralysis.
Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long‐term mineralocorticoid deficiency
Authors: Chan Li F. , Metherell Louise A. , Krude Heiko , Ball Colin , O'Riordan Stephen M. P. , Costigan Colm , Lynch Sally A. , Savage Martin O. , Cavarzere Paolo , Clark Adrian J. L.
Published: December 2008

Objective  Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin–aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification.

Design  Clinical review of patients with nonsense MC2R mutations.

Patients  Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations.

Results  Mild disturbances in the renin–angiotensin–aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement.

Conclusion  Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long‐term mineralocorticoid replacement.
Clinical value of the first automated TSH receptor autoantibody assay for the diagnosis of Graves’ disease (GD): an international multicentre trial
Authors: Schott Matthias , Hermsen Derik , Broecker‐Preuss Martina , Casati Marco , Mas Jordi Camara , Eckstein Anja , Gassner Dieter , Golla Ruth , Graeber Claudia , Van Helden Josef , Inomata Keiko , Jarausch Jochen , Kratzsch Jürgen , Miyazaki Naoko , Moreno Miguel Angel Navarro , Murakami Tsukasa , Roth Heinz Jürgen , Stock Werner , Noh Jaeduk Yoshimura , Scherbaum Werner A. , Mann Klaus
Published: December 2008

Background  Most recently, a new rapid and fully automated electrochemiluminescence immunoassay for the determination of TSH receptor autoantibodies (TRAb) based on the ability of TRAb to inhibit the binding of a human thyroid‐stimulating monoclonal antibody (M22) has been established.

Objective  To evaluate this assay system in clinical routine based on an international multicentre trial and to compare the results with other established TRAb assays.

Patients and measurements  Totally 508 Graves’ disease (GD), 142 autoimmune thyroiditis, 107 subacute thyroiditis, 109 nonautoimmune nodular goitre, 23 thyroid cancer patients and 446 normal controls were retrospectively evaluated.

Results  ROC plot analysis revealed an area under curve of 0·99 (95% CI: 0·99–1·0) indicating a high assay sensitivity and specificity. The highest sensitivity (99%) and specificity (99%) was seen at a cut‐off level of 1·75 IU/l. Here, the calculated positive predictive value was 95%, whereas the negative predictive value was 100%. Applying the ROC plot‐derived cut‐off of 1·75 IU/l we found a sensitivity for TRAb positivity within the group of newly diagnosed GD patients of 97% which is in accordance to the sum of different nonautomated porcine TSH receptor‐based assays with a sensitivity of 94% indicating an excellent analytical performance of the new assay format. Detailed comparison of the automated and the sum of manual assays revealed a near identical specificity.

Conclusion  Our results demonstrate that this new assay system has a high sensitivity for detecting GD and specificity for discriminating from other thyroid diseases. This assay may represent the future technology for rapid fully automated TRAb detection.
Quality of life in children and adolescents 1‐year after cure of Cushing syndrome: a prospective study
Authors: Keil Margaret F. , Merke Deborah P. , Gandhi Roma , Wiggs Edythe A. , Obunse Kathy , Stratakis Constantine A.
Published: December 2008

Objective  Cushing syndrome (CS) in children is associated with symptoms that may impair health related quality of life (HRQL). There are no prospective reports of HRQL in children with CS.

Methods  Prospective study of 40 children (mean age 13 ± 3·2 years) with CS evaluated prior to and 1‐year post‐treatment. The Child Health Questionnaire (CHQ) was used to assess HRQL; Wechsler Intelligence Scale for Children (WASI) was used to assess cognitive function, and patient‐reported symptoms were assessed with a CS symptom checklist.

Results  Active CS was associated with low physical and psychosocial summary scores compared to US population data (P < 0·001). Despite improvement from pre‐ to 1‐year postcure, residual impairment remained in physical summary and function, and role‐physical, global health and emotional impact (parent) scores. Incomplete recovery of adrenal function at 1‐year post‐treatment was associated with impaired scores. WASI IQ scores declined and a correlation was noted between age at first evaluation and IQ score changes. Most self‐reported CS symptoms showed improvement, but forgetfulness, unclear thinking and decreased attention span did not improve after cure of CS.

Conclusion  CS in children and adolescents is associated with impaired HRQL, with residual impairment 1 year after cure. Our results also suggest that younger children are more likely to experience negative changes in cognitive function. HRQL is an important outcome measure in children and adolescents with CS and identification of factors that contribute to HRQL may help to diminish the physical and psychological burden of disease in this population of patients.
New advances in regularized inversion of gravity and electromagnetic data
Authors: Zhdanov Michael S.
Published: December 2008

The interpretation of potential and electromagnetic fields observed over 3D geological structures remains one of the most challenging problems of exploration geophysics. In this paper I present an overview of novel methods of inversion and imaging of gravity and electromagnetic data, which are based on new advances in the regularization theory related to the application of special stabilizing functionals, which allow the reconstruction of both smooth images of the underground geological structures and models with sharp geological boundaries. I demonstrate that sharp‐boundary geophysical inversion can improve the efficiency and resolution of the inverse problem solution. The methods are illustrated with synthetic and practical examples of the 3D inversion of potential and electromagnetic field data.
Regulation of different inflammatory diseases by impacting the mevalonate pathway
Authors: Zeiser Robert , Maas Kristina , Youssef Sawsan , Dürr Christoph , Steinman Lawrence , Negrin Robert S.
Published: December 2008

The 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase inhibitors (statins) interfere with the mevalonate pathway. While initially developed for their lipid‐lowering properties, statins have been extensively investigated with respect to their impact on autoantigen and alloantigen driven immune responses. Mechanistically it was shown that statins modify immune responses on several levels, including effects on dendritic cells, endothelial cells, macrophages, B cells and T cells. Several lines of evidence suggest that statins act in a disease‐specific manner and are not effective in each immune disorder. This review discusses possible modes of action of statins in modulating immunity towards autoantigens and alloantigens.