bluuebunny/crossref_metadata_2025 huggingface dataset:
Propagation of the cardiac impulse in the diabetic rat heart: reduced conduction reserve
Authors: Nygren A. , Olson M. L. , Chen K. Y. , Emmett T. , Kargacin G. , Shimoni Y.
Published: December 2006

Diabetes mellitus is a growing epidemic with severe cardiovascular complications. Although much is known about mechanical and electrical cardiac dysfunction in diabetes, few studies have investigated propagation of the electrical signal in the diabetic heart and the associated changes in intercellular gap junctions. This study was designed to investigate these issues, using hearts from control and diabetic rats. Diabetic conditions were induced by streptozotocin (STZ), given i.v. 7–14 days before experiments. Optical mapping with the voltage‐sensitive dye di‐4‐ANEPPS, using hearts perfused on a Langendorff apparatus, showed little change in baseline conduction velocity in diabetic hearts, reflecting the large reserve of function. However, both the gap junction uncoupler heptanol (0.5–1 mm) and elevated potassium (9 mm, to reduce cell excitability) produced a significantly greater slowing of impulse propagation in diabetic hearts than in controls. The maximal action potential upstroke velocity (an index of the sodium current) and resting potential was similar in single ventricular myocytes from control and diabetic rats, suggesting similar electrical excitability. Immunoblotting of connexin 43 (Cx43), a major gap junction component, showed no change in total expression. However, immunofluorescence labelling of Cx43 showed a significant redistribution, apparent as enhanced Cx43 lateralization. This was quantified and found to be significantly larger than in control myocytes. Labelling of two other gap junction proteins, N‐cadherin and β‐catenin, showed a (partial) loss of co‐localization with Cx43, indicating that enhancement of lateralized Cx43 is associated with non‐functional gap junctions. In conclusion, conduction reserve is smaller in the diabetic heart, priming it for impaired conduction upon further challenges. This can desynchronize contraction and contribute to arrhythmogenesis.
Parallel activation of mitochondrial oxidative metabolism with increased cardiac energy expenditure is not dependent on fatty acid oxidation in pigs
Authors: Zhou Lufang , Cabrera Marco E. , Huang Hazel , Yuan Celvie L. , Monika Duda K. , Sharma Naveen , Bian Fang , Stanley William C.
Published: December 2006

Steady state concentrations of ATP and ADP in vivo are similar at low and high cardiac workloads; however, the mechanisms that regulate the activation of substrate metabolism and oxidative phosphorylation that supports this stability are poorly understood. We tested the hypotheses that (1) there is parallel activation of mitochondrial and cytosolic dehydrogenases in the transition from low to high workload, which increases NADH/NAD+ ratio in both compartments, and (2) this response does not require an increase in fatty acid oxidation (FAO). Anaesthetized pigs were subjected to either sham treatment, or an abrupt increase in cardiac workload for 5 min with dobutamine infusion and aortic constriction. Myocardial oxygen consumption and FAO were increased 3‐ and 2‐fold, respectively, but ATP and ADP concentrations did not change. NADH‐generating pathways were rapidly activated in both the cytosol and mitochondria, as seen in a 40% depletion in glycogen stores, a 3.6‐fold activation of pyruvate dehydrogenase, and a 50% increase in tissue NADH/NAD+. Simulations from a multicompartmental computational model of cardiac energy metabolism predicted that parallel activation of glycolysis and mitochondrial metabolism results in an increase in the NADH/NAD+ ratio in both cytosol and mitochondria. FAO was blocked by 75% in a third group of pigs, and a similar increase in and the NAHD/NAD+ ratio was observed. In conclusion, in the transition to a high cardiac workload there is rapid parallel activation of substrate oxidation that results in an increase in the NADH/NAD+ ratio.
Reversed somatodendritic Ih gradient in a class of rat hippocampal neurons with pyramidal morphology
Authors: Bullis James B. , Jones Terrance D. , Poolos Nicholas P.
Published: December 2006

In CA1 and neocortical pyramidal neurons, Ih is present primarily in the dendrites. We asked if all neurons of a pyramidal morphology have a similar density of Ih. We characterized a novel class of hippocampal neurons with pyramidal morphology found in the stratum radiatum, which we termed the ‘pyramidal‐like principal’ (PLP) neuron. Morphological similarities to pyramidal neurons were verified by filling the neurons with biocytin. PLPs did not stain for markers associated with interneurons, and projected to both the septum and olfactory bulb. By using cell‐attached patch‐clamp recordings, we found that these neurons expressed a high density of Ih in the soma that declined to a lower density in the dendrites, a pattern that is reversed compared to pyramidal neurons. The voltage‐dependent activation and activation time constants of Ih in the PLPs were similar to pyramidal neurons. Whole‐cell patch‐clamp recordings from the soma and dendrites of PLP neurons showed no significant differences in input resistance and local temporal summation between the two locations. Blockade of Ih by ZD7288 increased the input resistance and temporal summation of simulated EPSPs, as in pyramidal neurons. When NMDA receptors were blocked, temporal summation at the soma of distal synaptic potentials was similar to that seen with current injections at the soma, suggesting a ‘normalization’ of temporal summation similar to that observed in pyramidal neurons. Thus, we have characterized a principal neuronal subtype in the hippocampus with a similar morphology but reversed Ih somatodendritic gradient to that previously observed in CA1 hippocampal and neocortical pyramidal neurons.
Tryptophan‐scanning mutagenesis in the S1 domain of mammalian HCN channel reveals residues critical for voltage‐gated activation
Authors: Ishii Takahiro M. , Nakashima Noriyuki , Ohmori Harunori
Published: December 2006

Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels are essential regulators in rhythmic activity, membrane excitability and synaptic transmission. There are four subtypes in mammals (HCN1–4); HCN4 has the slowest activation kinetics and HCN1 the fastest. Although voltage gating originates with the voltage‐dependent motion of the S4 segment, the different activation kinetics between HCN1 and HCN4 are generated mainly by S1 and the S1–S2 loop. In this study, we investigate the structural basis of the ability of S1 to affect activation kinetics by replacing each individual S1 residue in HCN1 with a tryptophan (Trp) residue, a Trp perturbation scan. Robust currents were generated in 11 out of 19 Trp mutants. Hyperpolarization‐activated currents were not detected in four mutants, and two other mutants generated only small currents. Presence or absence of current reflected the predicted α‐helical structure of the S1 transmembrane segment. Tryptophan replacements of residues responsible for the different kinetics between HCN1 and HCN4 made the activation kinetics slower than the wild‐type HCN1. Tryptophan mutations introduced in the middle of S1 (L139W and V143W) prevented normal channel closure. Furthermore, a negatively charged residue at position 139 (L139D) induced a positive voltage shift of activation by 125 mV. Thus, L139 and V143 probably face a mobile part of the S4 voltage sensor and may interact with it. These results suggest that the secondary structure of S1 is α‐helical and profoundly affects the motion of the voltage sensor.
A "Silent" Polymorphism in the
MDR
1 Gene Changes Substrate Specificity
Authors: Kimchi-Sarfaty Chava , Oh Jung Mi , Kim In-Wha , Sauna Zuben E. , Calcagno Anna Maria , Ambudkar Suresh V. , Gottesman Michael M.
Published: December 2006

Synonymous single-nucleotide polymorphisms (SNPs) do not produce altered coding sequences, and therefore they are not expected to change the function of the protein in which they occur. We report that a synonymous SNP in the
Multidrug Resistance
1 (
MDR
1) gene, part of a haplotype previously linked to altered function of the
MDR
1 gene product P-glycoprotein (P-gp), nonetheless results in P-gp with altered drug and inhibitor interactions. Similar mRNA and protein levels, but altered conformations, were found for wild-type and polymorphic P-gp. We hypothesize that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.
FRAGMENTATION PRODUCTION CROSS-SECTIONS IN RELATIVISTIC COLLISIONS
Authors: DEMİRKOL İSKENDER
Published: December 2006

In this study, the fragmentation production cross-sections of heavy residual nuclides in the reactions 238 U (1 A GeV ) + p and p (1.2 GeV ) + 232 Th were calculated and the production of more than 370 different isotopes for this incident reactions was presented. The calculations were made by using the Cascade-Exciton Model including pre-equilibrium effect, the Intranuclear Cascade Model, the empirical and the semi-empirical parametrization. The results of the cross-sections obtained were compared with available experimental data and examined the relation between each other. It is seen that the precision of this models to estimate residue production cross-sections is still far from the performance required for technical applications and this incident model should be improved to obtain a deeper understanding of the reaction mechanisms involved in the production of isotopes.
BLACK HOLE GEOMETRIES IN NONCOMMUTATIVE STRING THEORY
Authors: KAR SUPRIYA , MAJUMDAR SUMIT
Published: December 2006

We obtain a generalized Schwarzschild (GS) and a generalized Reissner–Nordstrom (GRN) black hole geometries in 3+1 dimensions, in a noncommutative string theory. In particular, we consider an effective theory of gravity on a curved D3-brane in presence of an electromagnetic (EM) field. Two different length scales, inherent in its noncommutative counterpart, are exploited to obtain a theory of effective gravity coupled to an U(1) noncommutative gauge theory to all orders in Θ. It is shown that the GRN-black hole geometry, in the Planckian regime, reduces to the GS-black hole. However in the classical regime it may be seen to govern both the Reissner–Nordstrom and the Schwarzschild geometries. The emerging notion of 2D black holes evident in the framework are analyzed. It is argued that the D-string in the theory may be described by the near horizon 2D black hole geometry, in the gravity decoupling limit. Finally, our analysis explains the nature of the effective force derived from the nonlinear EM-field and accounts for the Hawking radiation phenomenon in the formalism.
GENERALIZED HEISENBERG RELATION AND QUANTUM HARMONIC OSCILLATORS
Authors: NARAYANA SWAMY P.
Published: December 2006

We study the consequences of the generalized Heisenberg uncertainty relation which admits a minimal uncertainty in length such as the case in a theory of quantum gravity. In particular, the theory of quantum harmonic oscillators arising from such a generalized uncertainty relation is examined. We demonstrate that all the standard properties of the quantum harmonic oscillators prevail when we employ a generalized momentum. We also show that quantum electrodynamics and coherent photon states can be described in the familiar standard manner despite the generalized uncertainty principle.
NEAREST NEIGHBOR DISCRIMINANT ANALYSIS
Authors: QIU XIPENG , WU LIDE
Published: December 2006

Linear Discriminant Analysis (LDA) is a popular feature extraction technique in statistical pattern recognition. However, it often suffers from the small sample size problem when dealing with high-dimensional data. Moreover, while LDA is guaranteed to find the best directions when each class has a Gaussian density with a common covariance matrix, it can fail if the class densities are more general. In this paper, a novel nonparametric linear feature extraction method, nearest neighbor discriminant analysis (NNDA), is proposed from the view of the nearest neighbor classification. NNDA finds the important discriminant directions without assuming the class densities belong to any particular parametric family. It does not depend on the nonsingularity of the within-class scatter matrix either. Then we give an approximate approach to optimize NNDA and an extension to k-NN. We apply NNDA to the simulated data and real world data, the results demonstrate that NNDA outperforms the existing variant LDA methods.
JUNCTION IN A THIN MULTIDOMAIN FOR A FOURTH ORDER PROBLEM
Authors: GAUDIELLO ANTONIO , ZAPPALE ELVIRA
Published: December 2006

We consider a thin multidomain of ℝN, N ≥ 2, consisting (e.g. in a 3D setting) of a vertical rod upon a horizontal disk. In this thin multidomain we introduce a bulk energy density of the kind W(D2U), where W is a convex function with growth p ∈ ]1,+∞[, and D2U denotes the Hessian tensor of a scalar (or vector-valued) function U. By assuming that the two volumes tend to zero with the same rate, under suitable boundary conditions, we prove that the limit model is well-posed in the union of the limit domains, with dimensions, respectively, 1 and N - 1. Moreover, we show that the limit problem is uncoupled if [Formula: see text], "partially" coupled if [Formula: see text], and coupled if N - 1 < p. The main result is applied in order to derive the equilibrium configuration of two joint beams, T-shaped, clamped at the three endpoints and subject to transverse loads. The main result is also applied in order to describe the equilibrium configuration of a wire upon a thin film with contact at the origin, when the thin structure is filled with a martensitic material.
DYNAMICS OF A STRUCTURED SLUG POPULATION MODEL IN THE ABSENCE OF SEASONAL VARIATION
Authors: BEES M. A. , ANGULO O. , LÓPEZ-MARCOS J. C. , SCHLEY D.
Published: December 2006

We develop a novel, nonlinear structured population model for the slug Deroceras reticulatum, a highly significant agricultural pest of great economic impact, in both organic and non-organic settings. In the absence of seasonal variations, we numerically explore the effect of life history traits that are dependent on an individual's size and measures of population biomass. We conduct a systematic exploration of parameter space and highlight the main mechanisms and implications of model design. A major conclusion of this work is that strong size dependent predation significantly adjusts the competitive balance, leading to non-monotonic steady state solutions and slowly decaying transients consisting of distinct generational cycles. Furthermore, we demonstrate how a simple ratio of adult to juvenile biomass can act as a useful diagnostic to distinguish between predated and non-predated environments, and may be useful in agricultural settings.
STEADY-STATE FLOWS OF THERMAL VISCOUS INCOMPRESSIBLE FLUIDS WITH CONVECTIVE-RADIATION EFFECTS
Authors: CONSIGLIERI LUISA
Published: December 2006

The work deals with the coupled system constituted by the equations of motion and energy with nonlinear and nonlocal boundary conditions in order to describe the thermal flow motion of a class of non-Newtonian fluids and the convective-radiation balance, respectively. For the constitutive laws in an n-dimensional space (n = 2,3), the stress tensor and the heat flux are considered related with the (p,q) coercivity parameters for p > 2n/(n + 1) and q > np/(p(n + 1) - n), respectively. The radiation character on the boundary condition presents an additional difficulty to the problem which already includes energy-dependent viscosity and conductivity behaviors. In the framework of nonstandard Sobolev spaces we prove the existence of steady-state solutions applying a fixed point argument. We also study the existence of a solution to a coupled system motivated by the buoyancy driven flows from geophysical and astrophysical models.
Lipopolysaccharide opposes the induction of CYP26A1 and CYP26B1 gene expression by retinoic acid in the rat liver in vivo
Authors: Zolfaghari Reza , Cifelli Christopher J. , Lieu Siam O. , Chen Qiuyan , Li Nan-qian , Ross A. Catharine
Published: December 2006

Retinoic acid (RA), a principal metabolite of vitamin A (retinol), is an essential endogenous regulator of gene transcription and an important therapeutic agent. The catabolism of RA must be well regulated to maintain physiological concentrations of RA. The cytochrome P450 (CYP) gene family CYP26, which encodes RA-4-hydroxylase activity, is strongly implicated in the oxidation of RA. Inflammation alters the expression of numerous genes; however, whether inflammation affects CYP26 expression is not well understood. We investigated the regulation of CYP26A1 and CYP26B1 mRNA levels by RA and LPS in the rat liver, as the liver is centrally involved in retinoid metabolism and the acute-phase response to LPS. Both CYP26A1 and CYP26B1 mRNA were induced in <4 h by a single oral dose of all- trans-RA. RA-induced responses of both CYP26A1 and CYP26B1 were significantly attenuated in rats with LPS-induced inflammation whether LPS was given concurrently with RA or after the RA-induced increase in CYP26A1 and CYP26B1 mRNA levels. When RA and LPS were administered simultaneously (6-h study), LPS alone had little effect on either CYP26A1 or CP26B1 mRNA, but LPS reduced by 80% the RA-induced increase in CYP26A1 mRNA ( P < 0.02), with a similar trend for CYP26B1 mRNA. When LPS was administered 4 h after RA (16-h study), it abrogated the induction of CYP26A1 ( P < 0.02) and CYP26B1 ( P < 0.01). Overall, these results suggest that inflammation can potentially disrupt the balance of RA metabolism and maintenance of RA homeostasis, which may possibly affect the expression of other RA-regulated genes.
Aberrant Promoter Methylation Profile and Association with Survival in Patients with Non–Small Cell Lung Cancer
Authors: Gu Jian , Berman David , Lu Charles , Wistuba Ignacio I. , Roth Jack A. , Frazier Marsha , Spitz Margaret R. , Wu Xifeng
Published: December 2006

Purpose: The aim of this study was to investigate the prognostic value of hypermethylation of tumor suppressor genes in patients with non-small cell lung cancer (NSCLC).

Experimental Design: We examined the methylation status of nine genes in 155 tumors from patients with NSCLC using quantitative methylation-specific PCR. We analyzed the associations between gene methylation status and overall patient survival.

Results: The methylation index, defined as the ratio between the number of methylated genes and the number of genes tested, was significantly higher in adenocarcinomas (0.38 ± 0.20) than in squamous cell carcinomas (0.30 ± 0.22; P = 0.027), in tumors from older patients (0.37 ± 0.20) than younger patients (0.30 ± 0.22; P = 0.040), and in tumors from heavier smokers (0.39 ± 0.21) than lighter smokers (0.29 ± 0.20; P = 0.042). In the Cox proportional hazards model, p16 methylation was associated with significantly poorer survival [hazard ratio, 1.95; 95% confidence interval (95% CI), 1.21-3.39]. Kaplan-Meier survival curves showed that patients with hypermethylated p16 had significantly shorter survival (median = 21.7 months) than patients without p16 hypermethylation (median = 62.5 months; P = 0.0001, log-rank test). Hypermethylation of CDH1 or TIMP3 gene was associated with significantly better survival with hazard ratios of 0.51 (95% CI, 0.29-0.90) and 0.59 (95% CI, 0.36-0.97), respectively. Joint analysis of these three genes showed a significant trend for poorer survival as the number of unfavorable events increased (P = 0.0007).

Conclusion: Hypermethylation of multiple genes exhibited significant differential effect on NSCLC patient survival. Assessment of the effect of each methylated gene on survival is needed to provide optimal prognostic value.
Identification of a Highly Immunogenic HLA-A*01-Binding T Cell Epitope of WT1
Authors: Asemissen Anne Marie , Keilholz Ulrich , Tenzer Stefan , Müller Margret , Walter Steffen , Stevanovic Stefan , Schild Hansjörg , Letsch Anne , Thiel Eckhard , Rammensee Hans-Georg , Scheibenbogen Carmen
Published: December 2006

Purpose: The transcription factor Wilms tumor protein 1 (WT1) belongs to a new generation of tumor antigens, as it is essential for tumor cell proliferation and is highly expressed in various hematologic and solid malignancies. The aim of this study was to apply a modified reverse immunology strategy to identify immunogenic epitopes of WT1 which could be useful for immunotherapy.

Experimental Design: Potential HLA-A*01 epitopes predicted by a MHC binding algorithm were screened for recognition by peripheral blood mononuclear cells (PBMC) from patients with spontaneous T cell responses using intracellular cytokine cytometry. Epitope processing was shown by proteasomal cleavage. Epitope-specific T cells were generated from CD4+CD25+ regulatory T cell–depleted PBMC.

Results: One of five predicted HLA-A*01-binding candidate epitopes showed high immunogenicity as 5 of 14 patients with hematologic malignancies had WT1.317-327–reactive T cells ranging from 0.4% to 1.5% of CD3+CD8+ T cells. Proteasomal degradation assays indicated the cleavage of WT1.317-327. The depletion of regulatory T cells from PBMCs enabled the rapid expansion of WT1.317-327–specific CTL, whereas no CTL could be generated from unfractionated PBMC. WT1.317-327–specific CTL efficiently lysed an autologous WT1-expressing tumor cell line but not HLA-A*01–negative WT1-expressing tumor cells. Immunogenicity of the epitope across histologies was verified by the demonstration of spontaneous ex vivo WT1.317-327–specific T cell responses in two of six patients with HLA-A*01–positive melanoma or lung cancer.

Conclusion: In this study, a modified reverse immunology strategy was employed to identify a first immunogenic HLA-A*01–restricted T cell epitope of the tumor antigen WT1, which is of considerable interest for use in vaccination trials.
Rapid Androgen Cycling as Treatment for Patients with Prostate Cancer
Authors: Feltquate David , Nordquist Luke , Eicher Caitlin , Morris Michael , Smaletz Oren , Slovin Susan , Curley Tracy , Wilton Andrew , Fleisher Martin , Heller Glenn , Scher Howard I.
Published: December 2006

Purpose: To investigate the safety and feasibility of rapid androgen cycling for men with progressive prostate cancer.

Experimental Design: Schedule 1 included a 4-week induction of androgen depletion, followed by 4-week treatment cycles of a monthly gonadotropin-releasing hormone agonist, testosterone on days 1 to 7, and an estrogen patch on days 8 to 21. Schedule 2 included a 12-week induction of androgen depletion followed by 4-week cycles of gonadotropin-releasing hormone agonist and testosterone, but no estrogens for patients with a prostate-specific antigen (PSA) nadir <1 ng/mL after induction. The primary end point was serially declining PSA trough values over six treatment cycles.

Results: Thirty-six patients were treated; 27 were evaluable after cycling, of whom 8 of 12 (67%) and 9 of 15 (60%) on schedules 1 and 2, respectively, reached the end point. Five patients with PSA >1 ng/mL following induction did not cycle. No patient progressed radiographically or clinically during cycling. Three posttherapy PSA patterns were observed: a decline followed by a rapid increase in trough levels, a sustained decline with a plateau at a detectable nadir, and a decline to an undetectable nadir. Mean testosterone levels were castrate at the time of trough and in the normal physiologic range following androgen repletion. Major toxicities included grades 1 and 2 fatigue, hepatitis, gynecomastia, and hot flashes.

Conclusions: Rapid hormonal cycling is feasible and well tolerated, and successive declines in PSA troughs are achievable. Although the sample size was small, the proportion of patients achieving declining PSA at the end of six cycles was comparable with that reached with continuous androgen depletion therapy.
Naltrexone-Assisted Rapid Methadone Discontinuation: A Pilot Study
Authors: Camarasa Xavier , Khazaal Yasser , Besson Jacques , Zullino Daniele Fabio
Published: December 2006

Slow downtitration as a methadone discontinuation method is time-consuming and associated to high dropout rates. Whereas ultra-rapid opiate detoxification methods have recently gained some popularity, they are expensive and may be associated with particular problems in methadone patients. In the present study, a 3-day detoxification procedure accelerated with a unique dose of naltrexone was used in 10 methadone-substituted patients. Whereas the treatment resulted in a shortened withdrawal syndrome, which was satisfactorily controlled by the drugs used, a two-phase course was observed, some symptoms reappearing between the end of day 2 and the beginning of day 3. The first phase of withdrawal symptoms was attributed to the antagonistic effect of naltrexone, which possibly also improved under the weakening of naltrexone. The second phase of withdrawal symptoms may be related to falling methadone plasma levels.
Origin of the Comorbidity of Anxiety Disorders and Alcohol Dependence: Findings of a General Population Study
Authors: Marquenie Loes A. , Schadé Annemiek , van Balkom Anton J.L.M. , Comijs Hannie C. , de Graaf Ron , Vollebergh Wilma , van Dyck Richard , van den Brink Wim
Published: December 2006

A representative general population sample (n = 7,076) was used to study retrospectively and prospectively the nature of the relationship between co-morbid alcohol dependence and anxiety disorders. Four different models were tested: (1) anxiety disorders increase the risk of alcohol dependence; (2) alcohol dependence increases the risk of anxiety disorders; (3) family history or childhood traumatisation increase the risk of both alcohol dependence and anxiety disorders, and (4) comorbid conditions are a separate psychopathological entity. The data show that alcohol dependence does not precede the onset of anxiety disorders, that anxiety disorders do precede the onset of alcohol dependence, that family history is not very likely to be the third factor explaining the elevated comorbidity, and that in women childhood trauma might be partially responsible for the association between both disorders. The data are inconsistent with regard to comorbidity as a distinct psychopathological entity. These findings are of great importance for treatment planning in patients with alcohol dependence and comorbid anxiety disorders.
The Role of Pharmacies in the Care of Drug Users: What Has Changed in Ten Years
Authors: Samitca Sanda , Huissoud Thérèse , Jeannin André , Dubois-Arber Françoise
Published: December 2006

This article assesses changes over 10 years in the role of pharmacies in the care of drug misusers – needle/syringe provision and methadone treatment supervision – in the Swiss French-speaking Canton of Vaud (636,000 inhabitants, 238 pharmacies). A review of data collected in four surveys (1991, 1994, 1996, 2003) on the provision of sterile material (and methadone treatment supervision in 2003) including all the pharmacists of the Canton of Vaud was conducted, as well as a review of data of the monitoring of needle exchange programmes introduced since 1996 in this canton, and of methadone treatment statistics. In 2003, interviews with pharmacists complemented the survey. Pharmacies play an important role in the ‘frontline’ services to drug misusers: the provision of needles/syringes to drug users by pharmacies remains important in spite of a decrease in the provision of sterile material by them since the advent of needle exchange programmes, and they are included in the supervision of two thirds of the methadone treatments. However, they do not feel integrated enough in the network of care to drug misusers and ask for more training and better recognition of their role.
5-Year Trends in Use of Hallucinogens and Other Adjunct Drugs among UK Dance Drug Users
Authors: McCambridge Jim , Winstock Adam , Hunt Neil , Mitcheson Luke
Published: December 2006

Aims: To describe and assess trends in the use of hallucinogens and other adjunct drugs over a 5-year period. Design: Repeated-measures cross-sectional survey. Setting and Participants: Annual magazine-based survey targeting people who use drugs in dance contexts. Measurements: Lifetime use prevalence (ever used); age of first use; current use prevalence (any use within the last month), and extent of use within the last month (number of days used) for LSD, psilocybin, ketamine, GHB and nitrates. Findings: Prevalence increases for psilocybin, ketamine, GHB and nitrates use have been detected, with a sharp recent rise in current psilocybin use in 2002–2003 contrasting with more gradual and comprehensive evidence of increased ketamine use throughout the period 1999–2003. The declining prevalence of LSD use in general population surveys is replicated in this sentinel population study. Conclusions: The rise in prevalence of hallucinogen and other adjunct drugs identified among dance drug users may be mirrored by wider prevalence increases among young people with a consequent need to study these trends carefully and to develop effective interventions, where required.
Sugar Transport Systems of Bifidobacterium longum NCC2705
Authors: Parche Stephan , Amon Johannes , Jankovic Ivana , Rezzonico Enea , Beleut Manfred , Barutçu Hande , Schendel Inke , Eddy Mike P. , Burkovski Andreas , Arigoni Fabrizio , Titgemeyer Fritz
Published: December 2006

Here we present the complement of the carbohydrate uptake systems of the strictly anaerobic probiotic Bifidobacterium longum NCC2705. The genome analysis of this bacterium predicts that it has 19 permeases for the uptake of diverse carbohydrates. The majority belongs to the ATP-binding cassette transporter family with 13 systems identified. Among them are permeases for lactose, maltose, raffinose, and fructooligosaccharides, a commonly used prebiotic additive. We found genes that encode a complete phosphotransferase system (PTS) and genes for three permeases of the major facilitator superfamily. These systems could serve for the import of glucose, galactose, lactose, and sucrose. Growth analysis of NCC2705 cells combined with biochemical characterization and microarray data showed that the predicted substrates are consumed and that the corresponding transport and catabolic genes are expressed. Biochemical analysis of the PTS, in which proteins are central in regulation of carbon metabolism in many bacteria, revealed that B. longum has a glucose-specific PTS, while two other species (Bifidobacterium lactis and Bifidobacterium bifidum) have a fructose-6-phosphate-forming fructose-PTS instead. It became obvious that most carbohydrate systems are closely related to those from other actinomycetes, with a few exceptions. We hope that this report on B. longum carbohydrate transporter systems will serve as a guide for further in-depth analyses on the nutritional lifestyle of this beneficial bacterium.
The Phosphotransferase System of Lactobacillus casei: Regulation of Carbon Metabolism and Connection to Cold Shock Response
Authors: Monedero Vicente , Mazé Alain , Boël Grégory , Zúñiga Manuel , Beaufils Sophie , Hartke Axel , Deutscher Josef
Published: December 2006

Genome sequencing of two different Lactobacillus casei strains (ATCC334 and BL23) is presently going on and preliminary data revealed that this lactic acid bacterium possesses numerous carbohydrate transport systems probably reflecting its capacity to proliferate under varying environmental conditions. Many carbohydrate transporters belong to the phosphoenolpyruvate:sugar phosphotransferase system (PTS), but all different kinds of non-PTS transporters are present as well and their substrates are known in a few cases. In L. casei regulation of carbohydrate transport and carbon metabolism is mainly achieved by PTS proteins. Carbon catabolite repression (CCR) is mediated via several mechanisms, including the major P-Ser-HPr/catabolite control protein A (CcpA)-dependent mechanism. Catabolite response elements, the target sites for the P-Ser-HPr/CcpA complex, precede numerous genes and operons. PTS regulation domain-containing antiterminators and transcription activators are also present in both L. casei strains. Their activity is usually controlled by two PTS-mediated phosphorylation reactions exerting antagonistic effects on the transcription regulators: P∼EIIB-dependent phosphorylation regulates induction of the corresponding genes and P∼His-HPr-mediated phosphorylation plays a role in CCR. Carbohydrate transport of L. casei is also regulated via inducer exclusion and inducer expulsion. The presence of glucose, fructose, etc. leads to inhibition of the transport or metabolism of less favorable carbon sources (inducer exclusion) or to the export of accumulated non-metabolizable carbon sources (inducer expulsion). While P-Ser-HPr is essential for inducer exclusion of maltose, it is not necessary for the expulsion of accumulated thio-methyl-β-D-galactopyranoside. Surprisingly, recent evidence suggests that the PTS of L. casei also plays a role in cold shock response.
A New Piece of an Old Jigsaw: Glucose Kinase Is Activated Posttranslationally in a Glucose Transport-Dependent Manner in Streptomyces coelicolor A3(2)
Authors: van Wezel Gilles P. , König Miriam , Mahr Kerstin , Nothaft Harald , Thomae Andreas W. , Bibb Mervyn , Titgemeyer Fritz
Published: December 2006

Members of the soil-dwelling prokaryotic genus Streptomyces are indispensable for the recycling of complex polysaccharides, and produce a wide range of natural products. Nutrient limitation is likely to be a major signal for the onset of their development, resulting in spore formation by specialized aerial hyphae. Streptomycetes grow on numerous carbon sources, which they utilize in a preferential manner. The main signaling pathway underlying this phenomenon is carbon catabolite repression, which in streptomycetes is totally dependent on the glycolytic enzyme glucose kinase (Glk). How Glk exerts this fascinating dual role (metabolic and regulatory) is still largely a mystery. We show here that while Glk is made constitutively throughout the growth of Streptomyces coelicolor A3(2), its catalytic activity is modulated in a carbon source-dependent manner: while cultures growing exponentially on glucose exhibit high Glk activity, mannitol- grown cultures show negligible activity. Glk activity was directly proportional to the amount of two Glk isoforms observed by Western blot analysis. The activity profile of GlcP, the major glucose permease, correlated very well with that of Glk. Our data are consistent with a direct interaction between Glk and GlcP, suggesting that a Glk-GlcP permease complex is required for efficient glucose transport by metabolic trapping. This is supported by the strongly reduced accumulation of glucose in glucose kinase mutants. A model to explain our data is presented.
Nitrogen Metabolism and Nitrogen Control in Corynebacteria: Variations of a Common Theme
Authors: Walter Britta , Hänssler Eva , Kalinowski Jörn , Burkovski Andreas
Published: December 2006

The published genome sequences of Corynebacterium diphtheriae, Corynebacterium efficiens, Corynebacterium glutamicum and Corynebacterium jeikeium were screened for genes encoding central components of nitrogen source uptake, nitrogen assimilation and nitrogen control systems. Interestingly, the soil-living species C. efficiens and C. glutamicum exhibit a broader spectrum of genes for nitrogen transport and metabolism than the pathogenic species C. diphtheriae and C. jeikeium. The latter are characterized by gene decay and loss of functions like urea metabolism and nitrogen-dependent transcription control. The global regulator of nitrogen regulation AmtR and its DNA-binding motif are conserved in C. diphtheriae, C. efficiens and C. glutamicum, while in C. jeikeium, an AmtR-encoding gene as well as putative AmtR-binding motifs are missing.
C-kit Asp-816-Val Mutation Analysis in Patients with Mastocytosis
Authors: Verzijl A. , Heide R. , Oranje A.P. , van Schaik R.H.N.
Published: December 2006

Background:Mastocytosis is a heterogeneous group of disorders characterized by abnormal accumulation of mast cells. Objective: Skin biopsies from 24 patients (23 with proven mastocytosis) were screened for the presence of the c-kit Asp-816-Val mutation. Methods: In frozen biopsies, RNA was isolated, cDNA synthesis and PCR, the expected PCR product of 346 bp was obtained from 23 patients. Results:In patients with urticaria pigmentosa, the mutation was detected in 38% of the adults and 25% of the children. With regard to the clinical presentation of the disease, no difference was found between adult patients with and without the mutation, as detected with our assay. One out of the 2 children with the mutation had an atypical presentation of the disease. Conclusion: the mutation could not be detected in all the patients, probably due to lack of sensitivity of the methods.
Pyoderma Vegetans Associated with Severe Psoriatic Arthritis: Good Response to Etanercept
Authors: Carrera Cristina , Mascaró Jr. Jose M. , Moreno-Romero Juan A. , Iranzo Pilar , Palou Josep , Zamora Esther , Herrero Carmen
Published: December 2006

Pyoderma vegetans (PV) is an inflammatory dermatosis, characterized clinically by large exudative vegetating plaques, and histopathologically by epidermal pseudoepitheliomatous hyperplasia and dense inflammatory infiltrates. Although PV is a very rare condition, it is a chronic disorder that may accompany any systemic process that compromises immunity. Treatment is very difficult, and correction of predisposing causes may be useful. We present a 49-year-old woman affected by severe psoriatic arthritis since she was 19, with giant verrucous plaques on her lower limbs that had worsened progressively during the last 15 years. After ruling out other vegetating cutaneous disorders, PV was diagnosed in association with psoriasis. Despite numerous previous systemic and topical therapeutic attempts no response was observed. Etanercept was introduced, which resulted in a marked improvement within 3 weeks. Herein, we report a diagnostic and therapeutic challenge of the first case of PV associated with psoriasis that presented a good response to etanercept.
The Contribution of Prosody to the Perception of Foreign Accent
Authors: Mareüil Philippe Boula de , Vieru-Dimulescu Bianca
Published: December 2006

The general goal of this study was to expand our understanding of what ismeant by ‘foreign accent’. More specifically, it deals with the role of prosody (timingand melody), which has rarely been examined. New technologies, includingdiphone speech synthesis (experiment 1) and speech manipulation (experiment2), are used to study the relative importance of prosody in what is perceived as aforeign accent. The methodology we propose, based on the prosody transplantationparadigm, can be applied to different languages or language varieties. Here,it is applied to Spanish and Italian. We built up a dozen sentences which are spokenin almost the same way in both languages (e.g. ha visto la casa del presidenteamericano ‘you/(s)he saw the American president’s house’). Spanish/Italian monolingualsand bilinguals were recorded. We then studied what is perceived whenthe segmental specification of an utterance is combined with suprasegmental featuresbelonging to a different language. Under these conditions, results obtainedwith Spanish and Italian listeners suggest that prosody is important in identifyingSpanish-accented Italian and Italian-accented Spanish.
Transient Sixth Nerve Palsies and Torticollis Secondary to Parietal Arteriovenous Malformation
Authors: Per Hüseyin , Tucer Bülent , Gümüs Hakan , Kurtsoy Ali , Kumandas Sefer
Published: December 2006

Arteriovenous malformations (AVMs) can compress on any intracranial structures, and the presence and nature of ophthalmologic symptoms and signs depend on the size and location of the AVMs. We report an 11-month-old girl with parietal fistulous AVM, transient bilateral sixth nerve palsies and torticollis. The postoperative period was uneventful and she was discharged in a good condition. The patient recovered from transient bilateral abducens nerve palsies and torticollis; she was asymptomatic during the 18-month follow-up period.
Glucocorticoids Down-Regulate Lipopolysaccharide-Induced de novo Production of Neurotensin mRNA in the Rat Hypothalamic, Paraventricular, Corticotrophin-Releasing Hormone Neurons
Authors: Loum-Ribot Elodie , Lafon Pierrette , Chaigniau Michel , Tramu Gerard , Corio Marc
Published: December 2006

Objective: Intraperitoneal injection of the endotoxin lipopolysaccharide (LPS) produces inflammation accompanied by activation of the immune system and the secretion of cytokines. Cytokines stimulate the hypothalamo-pituitary-adrenal (HPA) axis to release the anti-inflammatory corticosterone which controls its own production by acting on the HPA axis. Upstream in the HPA axis are neuroendocrine corticotrophin-releasing hormone (CRH) neurons located in the paraventricular nucleus (PVN), whose multipeptidergic phenotype changes during inflammation: while CRH mRNA is up-regulated in these conditions, neurotensin (NT) mRNA expression is induced de novo. The negative feedback control of glucocorticoids on CRH production is well documented; however, their action on NT production in the PVN of the hypothalamus is poorly documented. The aim of this study was to determine if glucocorticoids modulate the de novo production of NT during inflammation. Methods: Using quantitative in situ hybridization histochemistry, we examined whether the absence (adrenalectomy) or excess (corticosterone implants) of glucocorticoids modulate de novo production of NT mRNA in the PVN during inflammation induced by LPS treatment. Results: A relatively low dose of LPS (50 µg/kg) that is not efficient to induce NT mRNA production in the PVN becomes efficient after adrenalectomy. Moreover, corticosterone excess reduces LPS-induced production of NT mRNA in the PVN. Conclusion: Glucocorticoids exert a negative control on NT mRNA production in the PVN of the hypothalamus, and this effect requires that NT mRNA production be triggered, such as during inflammation.
Peroxisome Proliferator-Activated Receptor-Gamma Is Expressed by Rat Peritoneal Mesothelial Cells: Its Potential Role in Peritoneal Cavity Local Defense
Authors: Zhang Yun Fang , Yang Xiao , Zhang Ya Jie , Sun Yu Ling , Zou Xun Liang , Kong Qing Yu , Dong Xiu Qing , Ye Xiao Qing , Yu Xue Qing
Published: December 2006

Background/Aims: Peritoneal mesothelial cells (PMCs) play an important role in peritoneal inflammatory and immune response. It was reported that the peroxisomal proliferator-activated receptor-γ (PPARγ) ligand could effectively reduce inflammatory processes. However, the expression and function of PPARγ in PMCs has not been reported. This study was to investigate the expression of PPARγ in rat PMCs and the effect of PPARγ activation on the production of CD40 and ICAM-1 induced by lipopolysaccharide (LPS). Methods: Rat PMCs (RPMCs) were harvested from the peritoneal cavity of Sprague-Dawley rats and maintained under defined in vitro conditions. The cells were treated separately with LPS, 15d-PGJ2, and ciglitazone at different time points. The mRNA and protein expression of PPARγ, CD40 and ICAM-1 were detected by RT-PCR and Western blot, respectively. The intracellular distribution of PPARγ was detected by immunocytochemistry. Results: RPMCs expressed PPARγ both at the mRNA and protein level. The specific signals for PPARγ were mainly localized in the nucleus with weak staining in the cytoplasm. Stimulation of RPMCs with LPS resulted in a time-dependent increase in the expression of PPARγ with the peak of mRNA at 3 h and protein at 12 h. Thereafter the expression of PPARγ gradually attenuated. The mRNA expressions for CD40, ICAM-1 and protein expression of ICAM-1 were significantly upregulated following stimulation with LPS. Both 15d-PGJ2 and ciglitazone decreased the expression of CD40 mRNA and ICAM-1 protein. However, ciglitazone was less effective than 15d-PGJ2. Conclusions: There is constitutive expression of PPARγ in cultured RPMCs and PPARγ ligands which strongly inhibit LPS-induced CD40 and ICAM-1 production in RPMCs. It suggested that PPARγ might play a part in the local defense of the peritoneal cavity by downregulating inflammatory mediators, which may play a potential role in preventing peritoneal fibrosis induced by peritonitis. Further in vivo study is needed to demonstrate the long-term effects.
Recalling the Letter: The Uses of Oral Testimony in Historical Studies of Literacy
Authors: Duffy John
Published: December 2006

This article examines the uses of oral testimony in writing about literacy in historical context, especially about the literacy traditions of populations “hidden from history”-immigrants, refugees, and undocumented persons-who are entering U.S. schools and workplaces, and whose literacy histories may be unknown or lost. Drawing on testimonies collected from Laotian Hmong refugees, I offer the following propositions: First, that oral testimonies provide information about literacy that may be unavailable in documentary records. Second, that oral testimonies may reveal deeply held values and attitudes about literacy that cannot be derived from the documentary evidence. Third, that oral testimonies disclose the full range of human experience, rational and emotional, and that this may lead to new understandings of literacy. Finally, that oral histories invite collaboration between researcher and informant in writing new histories of literacy-though not always in ways commonly assumed.
The Operational Policing of Domestic Violence in Singapore
Authors: Ganapathy Narayanan
Published: December 2006

This article examines the formal processing of domestic violence as accomplished by institutionalized policing in Singapore. The description of the process through which domestic calls for assistance were shaped and translated into relevant categories for appropriating a particular police response was facilitated through the use of the participant observation method. The ethnographic fieldwork reported here, including observations of call screening in action, is an attempt to explicate the phenomenological grounds employed by organizational members to constitute calls as instances of categories for practical policing purposes. Theoretically, the data point to the need for a reconceptualization of the problem of policing domestic violence by emphasizing the point that the eventual institutional response be understood as a product of the relationship that exists between police subculture and structural conditions of policing unique to contemporary Singapore society.