bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex
Authors: Hao Jiandong , Rapp Peter R. , Janssen William G. M. , Lou Wendy , Lasley Bill L. , Hof Patrick R. , Morrison John H.
Published: June 2007

We previously reported that long-term cyclic estrogen (E) treatment reverses age-related impairment of cognitive function mediated by the dorsolateral prefrontal cortex (dlPFC) in ovariectomized (OVX) female rhesus monkeys, and that E induces a corresponding increase in spine density in layer III dlPFC pyramidal neurons. We have now investigated the effects of the same E treatment in young adult females. In contrast to the results for aged monkeys, E treatment failed to enhance dlPFC-dependent task performance relative to vehicle control values (group young OVX+Veh) but nonetheless led to a robust increase in spine density. This response was accompanied by a decline in dendritic length, however, such that the total number of spines per neuron was equivalent in young OVX+Veh and OVX+E groups. Robust effects of chronological age, independent of ovarian hormone status, were also observed, comprising significant age-related declines in dendritic length and spine density, with a preferential decrease in small spines in the aged groups. Notably, the spine effects were partially reversed by cyclic E administration, although young OVX+Veh monkeys still had a higher complement of small spines than did aged E treated monkeys. In summary, layer III pyramidal neurons in the dlPFC are sensitive to ovarian hormone status in both young and aged monkeys, but these effects are not entirely equivalent across age groups. The results also suggest that the cognitive benefit of E treatment in aged monkeys is mediated by enabling synaptic plasticity through a cyclical increase in small, highly plastic dendritic spines in the primate dlPFC.
Dual personality of GABA/glycine-mediated depolarizations in immature spinal cord
Authors: Jean-Xavier Céline , Mentis George Z. , O'Donovan Michael J. , Cattaert Daniel , Vinay Laurent
Published: June 2007

The inhibitory action of glycine and GABA in adult neurons consists of both shunting incoming excitations and moving the membrane potential away from the action potential (AP) threshold. By contrast, in immature neurons, inhibitory postsynaptic potentials (IPSPs) are depolarizing; it is generally accepted that, despite their depolarizing action, these IPSPs are inhibitory because of the shunting action of the Cl
−
conductance increase. Here we investigated the integration of depolarizing IPSPs (dIPSPs) with excitatory inputs in the neonatal rodent spinal cord by means of both intracellular recordings from lumbar motoneurons and a simulation using the compartment model program “Neuron.” We show that the ability of IPSPs to suppress suprathreshold excitatory events depends on
E
Cl
and the location of inhibitory synapses. The depolarization outlasts the conductance changes and spreads electrotonically in the somatodendritic tree, whereas the shunting effect is restricted and local. As a consequence, dIPSPs facilitated AP generation by subthreshold excitatory events in the late phase of the response. The window of facilitation became wider as E
Cl
was more depolarized and started earlier as inhibitory synapses were moved away from the excitatory input. GAD65/67 immunohistochemistry demonstrated the existence of distal inhibitory synapses on motoneurons in the neonatal rodent spinal cord. This study demonstrates that small dIPSPs can either inhibit or facilitate excitatory inputs depending on timing and location. Our results raise the possibility that inhibitory synapses exert a facilitatory action on distant excitatory inputs and slight changes of
E
Cl
may have important consequences for network processing.
Fas-activated serine/threonine phosphoprotein (FAST) is a regulator of alternative splicing
Authors: Simarro Maria , Mauger David , Rhee Kirsten , Pujana Miguel A. , Kedersha Nancy L. , Yamasaki Satoshi , Cusick Michael E. , Vidal Marc , Garcia-Blanco Mariano A. , Anderson Paul
Published: June 2007

Fas-activated serine/threonine phosphoprotein (FAST) is a survival protein that is tethered to the outer mitochondrial membrane. In cells subjected to environmental stress, FAST moves to stress granules, where it interacts with TIA1 to modulate the process of stress-induced translational silencing. Both FAST and TIA1 are also found in the nucleus, where TIA1 promotes the inclusion of exons flanked by weak splice recognition sites such as exon IIIb of the fibroblast growth factor receptor 2 (FGFR2) mRNA. Two-hybrid interaction screens and biochemical analysis reveal that FAST binds to several alternative and constitutive splicing regulators, suggesting that FAST might participate in this process. The finding that FAST is concentrated at nuclear speckles also supports this contention. We show that FAST, like TIA1, promotes the inclusion of exon IIIb of the FGFR2 mRNA. Both FAST and TIA1 target a U-rich intronic sequence (IAS1) adjacent the 5′ splice site of exon IIIb. However, unlike TIA1, FAST does not bind to the IAS1 sequence. Surprisingly, knockdown experiments reveal that FAST and TIA1 act independently of one another to promote the inclusion of exon IIIb. Mutational analysis reveals that FAST-mediated alternative splicing is separable from the survival effects of FAST. Our data reveal that nuclear FAST can regulate the splicing of FGFR2 transcripts.
Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice
Authors: Hayashi Mansuo L. , Rao B. S. Shankaranarayana , Seo Jin-Soo , Choi Han-Saem , Dolan Bridget M. , Choi Se-Young , Chattarji Sumantra , Tonegawa Susumu
Published: June 2007

Fragile X syndrome (FXS), the most commonly inherited form of mental retardation and autism, is caused by transcriptional silencing of the
fragile X mental retardation 1 (FMR1
) gene and consequent loss of the fragile X mental retardation protein. Despite growing evidence suggesting a role of specific receptors and biochemical pathways in FXS pathogenesis, an effective therapeutic method has not been developed. Here, we report that abnormalities in
FMR1
knockout (KO) mice, an animal model of FXS, are ameliorated, at least partially, at both cellular and behavioral levels, by an inhibition of the catalytic activity of p21-activated kinase (PAK), a kinase known to play a critical role in actin polymerization and dendritic spine morphogenesis. Greater spine density and elongated spines in the cortex, morphological synaptic abnormalities commonly observed in FXS, are at least partially restored by postnatal expression of a dominant negative (dn)
PAK
transgene in the forebrain. Likewise, the deficit in cortical long-term potentiation observed in
FMR1
KO mice is fully restored by the
dnPAK
transgene. Several behavioral abnormalities associated with
FMR1
KO mice, including those in locomotor activity, stereotypy, anxiety, and trace fear conditioning are also ameliorated, partially or fully, by the
dnPAK
transgene. Finally, we demonstrate a direct interaction between PAK and fragile X mental retardation protein
in vitro
. Overall, our results demonstrate the genetic rescue of phenotypes in a FXS mouse model and suggest that the PAK signaling pathway, including the catalytic activity of PAK, is a novel intervention site for development of an FXS and autism therapy.
A role for Rab5 in structuring the endoplasmic reticulum
Authors: Audhya Anjon , Desai Arshad , Oegema Karen
Published: June 2007

The endoplasmic reticulum (ER) is a contiguous network of interconnected membrane sheets and tubules. The ER is differentiated into distinct domains, including the peripheral ER and nuclear envelope. Inhibition of two ER proteins, Rtn4a and DP1/NogoA, was previously shown to inhibit the formation of ER tubules in vitro. We show that the formation of ER tubules in vitro also requires a Rab family GTPase. Characterization of the 29 Caenorhabditis elegans Rab GTPases reveals that depletion of RAB-5 phenocopies the defects in peripheral ER structure that result from depletion of RET-1 and YOP-1, the C. elegans homologues of Rtn4a and DP1/NogoA. Perturbation of endocytosis by other means did not affect ER structure; the role of RAB-5 in ER morphology is thus independent of its well-studied requirement for endocytosis. RAB-5 and YOP-1/RET-1 also control the kinetics of nuclear envelope disassembly, which suggests an important role for the morphology of the peripheral ER in this process.
Down-regulation of inhibitor of apoptosis levels provides competence for steroid-triggered cell death
Authors: Yin Viravuth P. , Thummel Carl S. , Bashirullah Arash
Published: June 2007

A pulse of the steroid hormone ecdysone triggers the destruction of larval salivary glands during Drosophila metamorphosis through a transcriptional cascade that converges on reaper (rpr) and head involution defective (hid) induction, resulting in caspase activation and cell death. We identify the CREB binding protein (CBP) transcriptional cofactor as essential for salivary gland cell death. We show that CBP acts 1 d before the onset of metamorphosis in apparent response to a mid-third instar ecdysone pulse, when CBP is necessary and sufficient for down-regulation of the Drosophila inhibitor of apoptosis 1 (DIAP1). It is only after DIAP1 levels are reduced that salivary glands become competent to die through rpr/hid-mediated cell death. Before this time, high levels of DIAP1 block salivary gland cell death, even in the presence of ectopic rpr expression. This study shows that naturally occurring changes in inhibitor of apoptosis levels can be critical for regulating cell death during development. It also provides a molecular mechanism for the acquisition of competence in steroid signaling pathways.
Expansion and tissue infiltration of an allospecific CD4+CD25+CD45RO+IL-7Rαhigh cell population in solid organ transplant recipients
Authors: Codarri Laura , Vallotton Laure , Ciuffreda Donatella , Venetz Jean-Pierre , Garcia Miguel , Hadaya Karine , Buhler Leo , Rotman Samuel , Pascual Manuel , Pantaleo Giuseppe
Published: June 2007

It has been recently shown (Seddiki, N., B. Santner-Nanan, J. Martinson, J. Zaunders, S. Sasson, A. Landay, M. Solomon, W. Selby, S.I. Alexander, R. Nanan, et al. 2006. J. Exp. Med. 203:1693–1700.) that the expression of interleukin (IL) 7 receptor (R) α discriminates between two distinct CD4 T cell populations, both characterized by the expression of CD25, i.e. CD4 regulatory T (T reg) cells and activated CD4 T cells. T reg cells express low levels of IL-7Rα, whereas activated CD4 T cells are characterized by the expression of IL-7Rαhigh. We have investigated the distribution of these two CD4 T cell populations in 36 subjects after liver and kidney transplantation and in 45 healthy subjects. According to a previous study (Demirkiran, A., A. Kok, J. Kwekkeboom, H.J. Metselaar, H.W. Tilanus, and L.J. van der Laan. 2005. Transplant. Proc. 37:1194–1196.), we observed that the T reg CD25+CD45RO+IL-7Rαlow cell population was reduced in transplant recipients (P < 0.00001). Interestingly, the CD4+CD25+CD45RO+IL-7Rαhigh cell population was significantly increased in stable transplant recipients compared with healthy subjects (P < 0.00001), and the expansion of this cell population was even greater in patients with documented humoral chronic rejection compared with stable transplant recipients (P < 0.0001). The expanded CD4+CD25+CD45RO+IL-7Rαhigh cell population contained allospecific CD4 T cells and secreted effector cytokines such as tumor necrosis factor α and interferon γ, thus potentially contributing to the mechanisms of chronic rejection. More importantly, CD4+IL-7Rα+and CD25+IL-7Rα+ cells were part of the T cell population infiltrating the allograft of patients with a documented diagnosis of chronic humoral rejection. These results indicate that the CD4+CD25+IL-7Rα+ cell population may represent a valuable, sensitive, and specific marker to monitor allospecific CD4 T cell responses both in blood and in tissues after organ transplantation.
Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis
Authors: Wojciechowski Sara , Tripathi Pulak , Bourdeau Tristan , Acero Luis , Grimes H. Leighton , Katz Jonathan D. , Finkelman Fred D. , Hildeman David A.
Published: June 2007

We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2−/− mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim+/−Bcl-2−/− mice, but were largely restored in Bim−/−Bcl-2−/− mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim−/−, T cells. Further, T cells from Bim+/−Bcl-2−/− mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8+ T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4+ T cells did not. In contrast, Bim+/−Bcl-2−/− mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim+/−Bcl-2−/− mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells.
Time-periodic solutions for a generalized Boussinesq model with Neumann boundary conditions for temperature
Authors: Climent-Ezquerra Blanca , Guillén-González Francisco , Rojas-Medar Marko Antonio
Published: June 2007

The aim of this work is to prove the existence of regular time-periodic solutions for a generalized Boussinesq model (with nonlinear diffusion for the equations of velocity and temperature). The main idea is to obtain higher regularity (of
H
3
type) for temperature than for velocity (of
H
2
type), using specifically the Neumann boundary condition for temperature. In fact, the case of Dirichlet condition for temperature remains as an open problem.
A Riemann–Hilbert approach to the Akhiezer polynomials
Authors: Chen Yang , Its Alexander R
Published: June 2007

In this paper, we study those polynomials, orthogonal with respect to a particular weight, over the union of disjoint intervals, first introduced by N. I. Akhiezer, via a reformulation as a matrix factorization or Riemann–Hilbert problem. This approach complements the method proposed in a previous paper, which involves the construction of a certain meromorphic function on a hyperelliptic Riemann surface. The method described here is based on the general Riemann–Hilbert scheme of the theory of integrable systems and will enable us to derive, in a very straightforward way, the relevant system of Fuchsian differential equations for the polynomials and the associated system of the Schlesinger deformation equations for certain quantities involving the corresponding recurrence coefficients. Both of these equations were obtained earlier by A. Magnus. In our approach, however, we are able to go beyond Magnus' results by actually solving the equations in terms of the Riemanni
Θ
-functions. We also show that the related Hankel determinant can be interpreted as the relevant
τ
-function.
Periods of hyperelliptic integrals expressed in terms of
θ
-constants by means of Thomae formulae
Authors: Enolski Victor , Richter Peter
Published: June 2007

Expressions for the periods of first- and second-kind integrals on hyperelliptic curves are given in terms of
θ
-constants. They are derived with the help of Thomae's classical formulae and Picard–Fuchs equations for complete integrals as functions of the parameters of the curves. The example of genus 2 is considered in detail.
Quantitative trait loci with additive effects on growth and carcass traits in a Wagyu–Limousin F2 population
Authors: Alexander L. J. , Geary T. W. , Snelling W. M. , MacNeil M. D.
Published: June 2007

A whole‐genome scan for carcass traits [average daily gain during the pre‐weaning, growth and finishing periods; birth weight; hot carcass weight and longissimus muscle area (LMA)] was performed on 328 F2 progeny produced from Wagyu × Limousin‐cross parents derived from eight founder Wagyu bulls. Nine significant (P ≤ 0.05) and four suggestive (P ≤ 0.1) QTL affecting seven growth and carcass traits were identified. Significant QTL were located on bovine chromosomes 2, 4, 7, 9, 12, 16, 17 and 29. A QTL previously reported on chromosome 2 for LMA was also detected in this study. These results provide insight into genetic differences between the Wagyu and Limousin breeds.
Computer simulation of the structure and dynamics of phenol in sodium montmorillonite hydrates
Authors: Lock P. A. , Skipper N. T.
Published: June 2007

Monte Carlo and molecular dynamics computer simulations have been used to study the structure and dynamics of phenol‐water solutions in the bulk and confined within the interlayer pores of sodium montmorillonite clays, as a function of pressure and temperature. Conditions have been chosen to mimic those encountered at burial depths of up to 6 km, thereby enabling us to shed light on subsurface processes including groundwater contamination and oil and gas migration. The structural data show that the phenol molecules are able to form a donor hydrogen bond to the clay surface. In addition, the phenolic –OH group is solvated by approximately three water molecules, and is also able to coordinate directly to an interlayer sodium cation. The phenolic aromatic ring is surrounded by approximately 25 water molecules in the bulk, compared to 18 in the compacted clay. Interlayer diffusion increases by an order of magnitude as temperature is increased from 275 K to 460 K. However, diffusion decreases by a factor of 2–4 as we move from the bulk into a clay hydrate of layer spacing ∼17 Å. For example, at 275 K the diffusion coefficient of phenol is 8.3 × 10−10 m2 s−1 in bulk solution, compared to 2.5 × 10−10 m2 s−1 in the clay.
A fibrotic focus is a prognostic factor and a surrogate marker for hypoxia and (lymph)angiogenesis in breast cancer: review of the literature and proposal on the criteria of evaluation
Authors: Van den Eynden G G , Colpaert C G , Couvelard A , Pezzella F , Dirix L Y , Vermeulen P B , Van Marck E A , Hasebe T
Published: June 2007

A fibrotic focus is a scar‐like area in the centre of a carcinoma and can be regarded as a focus of exaggerated reactive tumour stroma formation. Although modern surgical pathology uses different histopathological and molecular markers to assess the aggressiveness and predict the behaviour of malignant tumours, markers reflecting stromal cell behaviour and interactions between epithelial cells and stromal cells are scarce. In this review we summarize all studies investigating the value of a fibrotic focus as a prognostic factor and as a surrogate marker for hypoxia and (lymph)angiogenesis in patients with breast cancer. These data show that a fibrotic focus can be used as a practical, easily assessable and reproducible integrative histological prognostic parameter in breast cancer. We propose a consensus methodology to assess the fibrotic focus in breast cancer.
Humoral immunity to HIV‐1: neutralization and beyond
Authors: Huber M. , Trkola A.
Published: June 2007

Humoral immunity is considered a key component of effective vaccines against HIV‐1. Hence, an enormous effort has been put into investigating the neutralizing antibody response to HIV‐1 over the past 20 years which generated key information on epitope specificity, potency, breadth and in vivo activity of the neutralizing antibodies. Less clear is still the role of antibody‐mediated effector functions (antibody‐dependent cellular cytotoxicity, phagocytosis, complement system) and uncertainty prevails whether Fc‐mediated mechanisms are largely beneficial or detrimental for the host. The current knowledge on the manifold functions of the humoral immune response in HIV infection, their underlying mechanisms and potential in vaccine‐induced immunity will be discussed in this review.
Diabetes mellitus as a prothrombotic condition
Authors: Grant P. J.
Published: June 2007

Diabetes mellitus (DM) is characterized by fasting hyperglycaemia and a high risk of atherothrombotic disorders affecting the coronary, cerebral and peripheral arterial trees. The risk of myocardial infarction (MI) is 3‐5 fold higher in Type 2 DM and a DM subject with no history of MI has the same risk as a non‐DM subject with a past history of MI. In total around 70% of deaths are vascular with poorer outcomes to both acute events and cardiological interventions. It was proposed that clustering of vascular risk factors (hyperinsulinaemia, dysglycaemia, dyslipidaemia and hypertension) around insulin resistance (IR) accounted for the increase in risk with Type 2 DM. The importance of this became apparent with the recognition that risk clustering occurs in normoglycaemic and impaired glucose tolerance (IGT) subjects with IR, in total around 25% of the population in addition to long‐standing Type 1 subjects with renal disease. Evidence indicates that thrombotic risk clustering also occurs in association with IR, suppression of fibrinolysis due to elevated concentrations of the fibrinolytic inhibitor, plasminogen activator inhibitor‐1 (PAI‐1) is invariable with IR and there is evidence that this is regulated by the effects of triglyceride on the PAI‐1 gene promoter. Other studies indicated that prothrombotic risk (coagulation factors VII, XII and fibrinogen) also associates with the IR syndrome. The development of endothelial cell dysfunction with suppression of nitric oxide and prostacyclin synthesis, combined with platelet resistance to the anti‐aggregatory effects of these hormones leads to loss of control over platelet activation. In addition, hyperglycaemia and glycation have marked effects on fibrin structure function, generating a clot which has a denser structure, resistant to fibrinolysis. The combination of increased circulating coagulation zymogens, inhibition of fibrinolysis, changes in fibrin structure/function and alterations in platelet reactivity creates a thrombotic risk clustering which underpins the development of cardiovascular disease.
Perceived stress and risk of colorectal cancer in men and women: a prospective cohort study
Authors: Nielsen N. R. , Kristensen T. S. , Strandberg‐Larsen K. , Zhang Z.‐F. , Schnohr P. , Grønbæk M.
Published: June 2007

Objective.  We aim to assess the relationship between stress and risk of primary colorectal cancer in men and women.

Design.  A prospective cohort study

Setting.  The Copenhagen City Heart Study, Denmark

Subjects.  A total of 6488 women and 5426 men were included in the study. The participants were asked about intensity and frequency of stress at baseline in 1981–1983 and were followed until the end of 2000 in the Danish Cancer Registry. Less than 0.1% was lost to follow‐up.

Main outcome measures.  First time incidence of primary colorectal cancer.

Results.  During follow‐up 162 women and 166 men were diagnosed with colorectal cancer. Women with moderate and high stress intensity had a hazard ratio of 0.60 (95% CI: 0.37–0.98) and 0.52 (0.23–1.14) for colorectal cancer, respectively, compared to women with no stress. For colon cancer, a one‐unit increase on a seven‐point stress‐score was associated with an 11% lower incidence of the disease (HR = 0.89, 95% CI: 0.81–0.99) amongst women. There was no consistent evidence of an association between stress and colorectal cancer in men.

Conclusion.  Perceived stress was associated with lower risk of particularly colon cancer in women, whilst there was no clear relationship between stress and colorectal cancer in men.
Glycinebetaine accumulation is more effective in chloroplasts than in the cytosol for protecting transgenic tomato plants against abiotic stress
Authors: PARK EUNG‐JUN , JEKNIĆ ZORAN , PINO MARÍA‐TERESA , MURATA NORIO , CHEN TONY HWEI‐HWANG
Published: June 2007

Tomato (Lycopersicon esculentum Mill. cv. Moneymaker) plants were transformed with a gene for choline oxidase (codA) from Arthrobacter globiformis. The gene product (CODA) was targeted to the chloroplasts (Chl–codA), cytosol (Cyt–codA) or both compartments simultaneously (ChlCyt–codA). These three transgenic plant types accumulated different amounts and proportions of glycinebetaine (GB) in their chloroplasts and cytosol. Targeting CODA to either the cytosol or both compartments simultaneously increased total GB content by five‐ to sixfold over that measured from the chloroplast targeted lines. Accumulation of GB in codA transgenic plants was tissue dependent, with the highest levels being recorded in reproductive organs. Despite accumulating, the lowest amounts of GB, Chl–codA plants exhibited equal or higher degrees of enhanced tolerance to various abiotic stresses. This suggests that chloroplastic GB is more effective than cytosolic GB in protecting plant cells against chilling, high salt and oxidative stresses. Chloroplastic GB levels were positively correlated with the degree of oxidative stress tolerance conferred, whereas cytosolic GB showed no such a correlation. Thus, an increase in total GB content does not necessarily lead to enhanced stress tolerance, but additional accumulation of chloroplastic GB is likely to further raise the level of stress tolerance beyond what we have observed.
Demonstration of In vivo Expression of a Hypothetical Open Reading Frame (ORF‐14) Encoded by the RD1 Region of Mycobacterium tuberculosis
Authors: Amoudy H. A. , Ahmad S. , Thole J. E. , Mustafa A. S.
Published: June 2007

Previously we identified a novel antigenic open reading frame (ORF), designated as ORF‐14, on the RD1 region of Mycobacterium tuberculosis that was not originally predicted by Mahairas or by annotation of the M. tuberculosis H37 Rv genome. Here we show that anti‐ORF‐14 antibodies either from mice immunized with recombinant ORF‐14 protein or isolated from serum samples from tuberculosis patients, react with a protein in culture filtrate but not in cytoplasmic or cell wall fractions from M. tuberculosis. Our data indicate that the ORF‐14 protein is expressed as a secreted protein, representing one more secreted protein antigen not previously identified by genomics.
Crustal thinning and mafic underplating beneath the Neogene Volcanic Province (Betic Cordillera, SE Spain): evidence from crustal xenoliths
Authors: Álvarez‐Valero A. M. , Kriegsman L. M.
Published: June 2007

Three metapelitic xenolith suites in the Neogene Volcanic Province (NVP) of SE Spain (from SW to NE: El Hoyazo, Mazarrón and Mar Menor) originated by partial melting at different crustal depths, decreasing from 20–25 km in the SW to 9–12 km in the NE. Peak temperatures reached c. 900 °C. The xenolith source level is equated with the base of a felsic upper crust of high melting potential (‘fertility’). At El Hoyazo, this matches a thin, intracrustal low‐velocity zone recently inferred from seismic studies. Isostatic calculations indicate that this zone increases in thickness from SW to NE. A model of increasing upper crustal thinning from SW to NE in the NVP, accompanied by mafic underplating, is consistent with the 9 Ma petrological data, with current heat flow, seismic data and gravimetry. It is concluded that significant crustal extension occurred in the NVP in the late Miocene, i.e. after the main phase of widespread extension, exhumation of high‐pressure rocks and formation of the Alborán Sea.
Executive functioning in children and adolescents with phenylketonuria
Authors: VanZutphen KH , Packman W , Sporri L , Needham MC , Morgan C , Weisiger K , Packman S
Published: June 2007

This study addresses the effects of dietary adherence, phenylalanine (phe) levels, and age on performance of executive functioning (EF) tasks in children and adolescents with phenylketonuria (PKU). We herein collate formerly discrete findings to understand the relationship among actual clinical parameters and EF in PKU. Fifteen subjects (age range 8–20 years) with PKU were compared with the normative sample on the Delis–Kaplan EF Battery and on the Wechsler Abbreviated Scales of Intelligence to examine the relationship between EF skills, phe levels, age, and dietary adherence. At the time of the assessment, the mean age of participants was 14.8 years, mean lifetime phe levels ranged from 216 to 1200 μM (mean 594 μM); and concurrent phe levels ranged from 222 to 1730 μM (mean 660 μM). Children and adolescents with PKU showed lower performance in several EF skills: initiation of problem solving, concept formation, and reasoning. Performance on EF tasks requiring inhibitory control, cognitive flexibility and set shifting decreased at higher phe levels. Phe levels were positively correlated to age and inversely related to dietary adherence. We conclude that dynamic clinical parameters appear to govern EF in patients with PKU. We suggest that when adolescents decrease dietary compliance, changes in EF skills occur. Therefore, there is a need to specifically monitor EF skills in patients with PKU during the transition to, and during, adolescence.
Genetic Diversity in Monilinia laxa Populations in Peach Orchards in Spain
Authors: Gell I. , Larena I. , Melgarejo P.
Published: June 2007

One‐hundred and forty‐four random amplified polymorphic DNA markers, of which 59 were polymorphic and 85 monomorphic, were used to assess the genetic diversity and to study the structure of Monilinia laxa populations in Spain. Twenty‐one isolates collected from several orchards (subpopulations), in various years and in various hosts, were used. The analysis of population structure revealed that genetic diversity within orchards (HS) accounted for 97% of the total genetic diversity (HT), while genetic diversity among the orchards represented only 3%. The relative magnitude of gene differentiation between subpopulations (GST) and the estimate of the number of migrants per generation (Nm) averaged 0.032 and 15.1 respectively. The results obtained in dendrograms were in accordance with the gene diversity analysis. Grouping of isolates in the dendrogram was independent of whether they came from the same or different orchards. There was no relationship between clustering among isolates from distinct years and hosts. The relative importance of several evolutionary forces in populations of M. laxa is discussed, together with implications for the management of brown rot.
Gastric antisecretory and antiulcer effects of simvastatin in rats
Authors: Tariq Mohammad , Khan Haseeb A , Elfaki Ibrahim , Arshaduddin Mohammad , Al Moutaery Meshal , Al Rayes Hannan , Al Swailam Ramiz
Published: June 2007

Background and Aim:  Recently, statins have appeared to have additional benefits beyond their lipid lowering effects, which has led to the interest in the use of this class of drugs outside the realm of cardiovascular disease. Simvastatin (SIM) is a commonly prescribed statin with anti‐inflammatory and antioxidant properties. Excessive generation of oxygen‐derived free radicals (ODFR) and proinflammatory mediators has been implicated in the pathogenesis of gastric ulcers. This investigation aimed to study the effect of SIM on experimentally induced gastric acid secretion and ulcer formation.

Methods:  Adult Wistar rats were divided into experimental groups containing six animals. Acid secretion studies were undertaken using pylorus‐ligated rats pretreated with SIM (20, 40, and 60 mg/kg). The effect of orally administered SIM was also studied on indomethacin‐ and ethanol‐induced gastric ulcers. The levels of myeloperoxidase (MPO), non‐protein sulfhydryls (NP‐SH), nitric oxide (NO), antioxidant enzymes, and gastric wall mucus were measured in the glandular stomach of rats following ethanol‐induced gastric lesions.

Results:  Administration of SIM significantly and dose‐dependently inhibited the volume of gastric secretion and the acidity. Pretreatment with SIM significantly reduced the formation of indomethacin‐ and ethanol‐induced gastric lesions. The antiulcer activity of SIM was associated with significant attenuation of adverse effects of ethanol on gastric wall mucus, NP‐SH and MPO. SIM modified the gastric NO levels and reversed the ethanol‐induced decrease in glutathione‐S‐transferase and increase in superoxide dismutase and catalase.

Conclusions:  These findings clearly suggest the involvement of proinflammatory agents and ODFR in the pathogenesis of gastric lesions. The gastroprotective effects of SIM are mediated by inhibition of neutrophils activity, reduction of oxidative stress, and maintenance of vascular integrity. This study was conducted in rats; its relevance to human gastric ulcers is not known and warrants further study.
Iatrogenic perforation associated with therapeutic colonoscopy: A multicenter study in Japan
Authors: Taku Keisei , Sano Yasushi , Fu Kuang‐I , Saito Yutaka , Matsuda Takahisa , Uraoka Toshio , Yoshino Takayuki , Yamaguchi Yuichirou , Fujita Mikio , Hattori Santa , Ishikawa Tsutomu , Saito Daizo , Fujii Takahiro , Kaneko Eizo , Yoshida Shigeaki
Published: June 2007

Background and Aim:  Colonic perforation is the serious accidental complication. The aim of this study is to analyze the clinical presentation and management of recent iatrogenic perforations during therapeutic colonoscopy.

Methods:  Consecutive patients referred to four academic cancer centers in Japan were retrospectively reviewed using each center's endoscopy database of medical records. Data was obtained by means of an extensive data collection sheet. Since we evaluated the data including iatrogenic perforation during newly developed therapeutic procedure such as endoscopic submucosal dissection (ESD) or hemoclips, the collection of patient data was set from the period of the beginning of ESD technique in each hospital in this study.

Results:  The overall rate of occurrence of perforation was 0.15% (23/15, 160). Perforation rate for EMR (0.58%) showed a significantly higher rate (P < 0.0001) than that for hot biopsy and polypectomy. The rate for ESD (14%) showed a markedly higher rate (P < 0.0001) than that for other standard procedures. Of those perforations, endoscopic clipping was performed in 56.5% of the patients, and conservative treatment was successful in 100% of the patients with successful closure. Both CT scan findings and seology results (WBC, CRP) after perforation were poor predictors for need for surgery as opposed to conservative management.

Conclusions:  Further improvements in EMR with special knife techniques are required to simply and safely remove large colorectal neoplasms, because perforation rate for ESD shows a markedly higher. Conservative management may be possible in patients who have undergone complete endoscopic clipping.
Hyperbaric oxygen therapy as a prophylactic and treatment against ileus and recurrent intestinal obstruction soon after surgery to relieve adhesive intestinal obstruction
Authors: Ambiru Satoshi , Furuyama Nobuaki , Kimura Fumio , Shimizu Hiroaki , Yoshidome Hiroyuki , Miyazaki Masaru , Shimada Hideaki , Ochiai Takenori
Published: June 2007

Background and Aim:  Nonoperative management of cases of adhesive intestinal obstruction would be ideal, especially for patients who have recently undergone surgery to relieve the same condition. We aimed to examine whether hyperbaric oxygen (HBO) therapy might have therapeutic potential for the treatment of postoperative paralytic ileus and recurrent adhesive intestinal obstruction soon after surgery, to relieve adhesive intestinal obstruction, because of its unique mechanisms in these contexts.

Methods:  A total of 133 patients were enrolled in the present study. We examined non–per os periods, hospital stay, and clinical course according to the postoperative course of the 133 patients.

Results:  After surgical intervention, 75 patients left the hospital without morbidity. Nineteen patients were successfully administered prophylactic HBO therapy to facilitate intestinal motility and to prevent paralytic ileus. The remaining 39 patients suffered from postoperative paralytic ileus or early recurrence of obstruction during the same hospitalization period. The patients who underwent prophylactic HBO therapy had significantly shorter non–per os periods and hospital stays after surgery than those who were not initially given HBO therapy (P < 0.05). Similarly, there were significant differences in duration of hospital stay after surgery between patients with HBO therapy as treatment and those who received other conservative therapies (P < 0.05).

Conclusions:  HBO therapy may have a prophylactic effect on postoperative paralytic ileus and may be of therapeutic benefit in the management of early recurrent adhesive intestinal obstruction following surgery to relieve adhesive intestinal obstruction.
Prospective evaluation of adjunctive ketamine on sphincter of Oddi motility in humans
Authors: Varadarajulu Shyam , Tamhane Ashutosh , Wilcox C Mel
Published: June 2007

Background and Aim:  Performance of sphincter of Oddi manometry (SOM) at endoscopic retrograde cholangio‐pancreatogram (ERCP) is technically demanding and requires that the patient be well sedated. Droperidol is used as an adjunctive agent in patients who are difficult to sedate. Concerns regarding the safety profile of droperidol and its effects on sphincter of Oddi motility has resulted in the search for other potent sedative agents that do not influence SOM readings. Ketamine, a dissociative anesthetic, is increasingly being used as an adjunctive agent for conscious sedation. This study evaluates the effect of ketamine on sphincter of Oddi motility when used as an adjunctive sedative agent during ERCP.

Patients and Methods:  This is a prospective study of 30 consecutive patients undergoing SOM who were difficult to sedate and required adjunctive ketamine. Manometry was initially performed with intravenous administration of diazepam plus meperidine or a combination of diazepam plus meperidine and midazolam. After the initial two pull‐throughs, 20 mg of ketamine was administered intravenously and the measurements were repeated 5 min later.

Results:  The basal pressures of the biliary sphincter and of the pancreatic sphincter were not significantly altered by ketamine. By using a definition for sphincter of Oddi dysfunction of a basal pressure ≥40 mmHg, concordance (normal vs abnormal) between the basal sphincter pressure before and after ketamine was seen in 28 patients (93%). Ketamine also did not lead to a difference in phasic wave amplitude, duration, or frequency. No complication was associated with ketamine use.

Conclusions:  Ketamine at 20 mg did not significantly affect SOM parameters. Further studies are required to confirm our preliminary findings before ketamine can be added to the armamentarium of agents used for performance of sphincter of Oddi manometry.
Mouse model mimics multiple sclerosis in the clinico‐radiological paradox
Authors: Wuerfel Jens , Tysiak Eva , Prozorovski Timour , Smyth Maureen , Mueller Susanne , Schnorr Joerg , Taupitz Matthias , Zipp Frauke
Published: June 2007

The value of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, in deriving novel diagnostic and therapeutic input has been subject to recent debate. This study is the first to report a disseminated distribution of plaques including cranial nerves, prior to or at early stages of disease in murine adoptive transfer EAE, irrespective of the development of clinical symptoms. We induced EAE by adoptive proteolipid protein‐specific T‐cell transfer in 26 female SJL/J mice, and applied high‐field‐strength magnetic resonance imaging (MRI) scans longitudinally, assessing blood–brain barrier (BBB) disruption by gadopentate dimeglumine enhancement. We visualized inflammatory nerve injury by gadofluorine M accumulation, and phagocytic cells in inflamed tissue by very small anionic iron oxide particles (VSOP‐C184). MRI was correlated with immunohistological sections. In this study, we discovered very early BBB breakdown of white and grey brain matter in 25 mice; one mouse developed exclusively spinal cord inflammation. Widely disseminated contrast‐enhancing lesions preceded the onset of disease in 10 animals. Such lesions were present despite the absence of any clinical disease formation in four mice, and coincided with the first detectable symptoms in others. Cranial nerves, predominantly the optic and trigeminal nerves, showed signal intensity changes in nuclei and fascicles of 14 mice. At all sites of MRI lesions we detected cellular infiltrates on corresponding histological sections. The discrepancy between the disease burden visualized by MRI and the extent of disability indeed mimics the human clinico‐radiological paradox. MRI should therefore be implemented into evaluational in vivo routines of future therapeutic EAE studies.
Pseudomonas aeruginosa cupA‐encoded fimbriae expression is regulated by a GGDEF and EAL domain‐dependent modulation of the intracellular level of cyclic diguanylate
Authors: Meissner Andree , Wild Verena , Simm Roger , Rohde Manfred , Erck Christian , Bredenbruch Florian , Morr Michael , Römling Ute , Häussler Susanne
Published: June 2007

Cyclic‐diguanylate (c‐di‐GMP) is a widespread bacterial signal molecule that plays a major role in the modulation of cellular surface components, such as exopolysaccharides and fimbriae, and in the establishment of a sessile life style. Here, we report that intracellular c‐di‐GMP levels influence cupA‐encoded fimbriae expression in Pseudomonas aeruginosa. In an autoaggregative P. aeruginosa small colony variant (SCV) CupA fimbriae and the intracellular c‐di‐GMP concentration were found to be enhanced as compared with the clonal wild‐type. The SCV morphology and the expression of CupA fimbriae were dependent on a functional PA1120 and morA gene both encoding a GGDEF domain. Overexpression of the GGDEF domain protein PA1120 complemented the PA1120 and the morA mutant with respect to CupA fimbriae expression. In agreement with these findings, overexpression of the EAL domain containing phenotypic variance regulator (PvrR) in the SCV resulted in a decreased intracellular level of c‐di‐GMP, a reduced cupA fimbriae expression and a switch to wild‐type colony morphology.
The natural furanone (5Z)‐4‐bromo‐5‐(bromomethylene)‐3‐butyl‐2(5H)‐furanone disrupts quorum sensing‐regulated gene expression in Vibrio harveyi by decreasing the DNA‐binding activity of the transcriptional regulator protein luxR
Authors: Defoirdt Tom , Miyamoto Carol M. , Wood Thomas K. , Meighen Edward A. , Sorgeloos Patrick , Verstraete Willy , Bossier Peter
Published: June 2007

This study aimed at getting a deeper insight in the molecular mechanism by which the natural furanone (5Z)‐4‐bromo‐5‐(bromomethylene)‐3‐butyl‐2(5H)‐furanone disrupts quorum sensing in Vibrio harveyi. Bioluminescence experiments with signal molecule receptor double mutants revealed that the furanone blocks all three channels of the V. harveyi quorum sensing system. In further experiments using mutants with mutations in the quorum sensing signal transduction pathway, the compound was found to block quorum sensing‐regulated bioluminescence by interacting with a component located downstream of the Hfq protein. Furthermore, reverse transcriptase real‐time polymerase chain reaction with specific primers showed that there was no effect of the furanone on luxRVh mRNA levels in wild‐type V. harveyi cells. In contrast, mobility shift assays showed that in the presence of the furanone, significantly lower levels of the LuxRVh response regulator protein were able to bind to its target promoter sequences in wild‐type V. harveyi. Finally, tests with purified LuxRVh protein also showed less shifts with furanone‐treated LuxRVh, whereas the LuxRVh concentration was found not to be altered by the furanone (as determined by SDS‐PAGE). Therefore, our data indicate that the furanone blocks quorum sensing in V. harveyi by rendering the quorum sensing master regulator protein LuxRVh unable to bind to the promoter sequences of quorum sensing‐regulated genes.
Who will lose weight on sibutramine and orlistat? Psychological correlates for treatment success
Authors: Elfhag K. , Finer N. , Rössner S.
Published: June 2007

Aim:  To study the associations between weight loss with sibutramine and orlistat with psychological aspects that may interact with patients’ response to these drugs.

Methods:  A total of 478 obese patients with a mean body mass index of 42 ± 12 kg/m2 gave self‐reported, retrospective data on different types of previous weight loss treatments (sibutramine and orlistat, and Weight Watchers used as a control condition) including the amount of weight lost with these treatments, eating behaviour (Dutch Eating Behaviour Questionnaire) and personality (NEO Personality Inventory – Revised).

Results:  Greater weight loss with sibutramine was associated with lower levels of restrained eating and higher levels of ‘neuroticism’, in particular ‘anxiety’ and ‘depression’. Greater weight loss with orlistat was associated with aspects of the personality dimension ‘conscientiousness’ (e.g. ‘order’ and ‘deliberation’).

Conclusion:  Sibutramine may exert its greatest effect in patients whose eating is a ‘natural’ response to hunger rather than regulated by cognitions and conscious controls. Patients with low levels of restraint could be more sensitive to the satiety‐enhancing effect of sibutramine. They may be able to reduce their food intake without cognitive interference and/or start to control their eating most radically in response to enhanced satiety. Enhanced satiety may also help patients withstand a wish to eat triggered by psychological distress. Possible central nervous system effects on mood could also have reduced eating, which was related to distress. The administration regimen of orlistat is more demanding, requiring greater adherence. This can account for the finding that personality attributes such as conscientiousness are important for success.
Diabetic neuropathy: new strategies for treatment
Authors: Várkonyi Tamás , Kempler Peter
Published: June 2007

Current therapeutic possibilities can be divided into two groups: the pathogenetically oriented and the symptomatic therapy. One of the most important component of etiology‐based treatment is the stabilization of glycemic control. Based on efficacy and safety data benfotiamine and alpha‐lipoic acid should be considered as first choices among pathogenetically oriented treatments of diabetic neuropathy. Promising data were published about the aldose reductase inhibitor ranirestat. The symptomatic effect of antiepileptic drugs in diabetic painful neuropathy (DPN) is originated from several possible pharmacological properties. Pregabalin and gabapentin have the highest efficacy and the lowest frequency of adverse events among these drugs. Antidepressants also extensively used for symptomatic treatment in DPN. In the last years several studies were published about the benefial effect of duloxetine. Most likely combination therapy will be frequently applied in the future for the treatment of DPN, the optimal choice could be to combine pathogenetically oriented and symptomatic treatment.