bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of low-frequency lambda-doublet transitions of the free
12
CH and
13
CH radicals
Authors: McCarthy M. C. , Mohamed S. , Brown J. M. , Thaddeus P.
Published: August 2006

By Fourier transform microwave spectroscopy, lambda-doubling transitions of
12
CH and
13
CH in the lowest rotational levels of the
X
2
∏
1/2
ground state have been directly detected, which has not been done previously. For both radicals, hyperfine-split lines have been measured to an accuracy of better than 1 ppm between 3 and 15 GHz, an improvement of at least 2 orders of magnitude over previous laboratory data. The measured frequencies have been combined with all previous data for CH and
13
CH in the
v
= 0 level of the
X
2
∏ electronic state to determine improved hyperfine parameters. The production of CH from various gases also has been studied and, with methanol, the yield of CH relative to OH. Astronomical studies of CH in higher rotational levels and
13
CH can now be undertaken on the basis of the present work.
Interferometric observations of large biologically interesting interstellar and cometary molecules
Authors: Snyder Lewis E.
Published: August 2006

Interferometric observations of high-mass regions in interstellar molecular clouds have revealed hot molecular cores that have substantial column densities of large, partly hydrogen-saturated molecules. Many of these molecules are of interest to biology and thus are labeled “biomolecules.” Because the clouds containing these molecules provide the material for star formation, they may provide insight into presolar nebular chemistry, and the biomolecules may provide information about the potential of the associated interstellar chemistry for seeding newly formed planets with prebiotic organic chemistry. In this overview, events are outlined that led to the current interferometric array observations. Clues that connect this interstellar hot core chemistry to the solar system can be found in the cometary detection of methyl formate and the interferometric maps of cometary methanol. Major obstacles to understanding hot core chemistry remain because chemical models are not well developed and interferometric observations have not been very sensitive. Differentiation in the molecular isomers glycolaldehdye, methyl formate, and acetic acid has been observed, but not explained. The extended source structure for certain sugars, aldehydes, and alcohols may require nonthermal formation mechanisms such as shock heating of grains. Major advances in understanding the formation chemistry of hot core species can come from observations with the next generation of sensitive, high-resolution arrays.
Mutational analysis of DJ-1 in
Drosophila
implicates functional inactivation by oxidative damage and aging
Authors: Meulener Marc C. , Xu Kexiang , Thomson Leonor , Ischiropoulos Harry , Bonini Nancy M.
Published: August 2006

Inherited mutations in
PARK7
, the gene encoding DJ-1, are associated with loss of protein function and early-onset parkinsonism. Like human DJ-1 (hDJ-1),
Drosophila
DJ-1b protects against oxidative insult and is modified with oxidation. We demonstrate that hDJ-1 rescues flies mutant for DJ-1b, and that a conserved cysteine residue in the fly protein (C104, analogous to C106 in hDJ-1) is critical for biological antioxidant function
in vivo
. Targeted mutagenesis suggests that modification of DJ-1b at this residue inactivates the protective activity of the protein against oxidative stress. Further studies show that DJ-1 modification increases dramatically with age in flies, mice, and humans, with aged flies showing strikingly increased susceptibility to oxidative stress and markedly enhanced DJ-1b modification upon oxidative challenge. Overoxidation of DJ-1 with age and exposure to oxidative toxins may lead to inactivation of DJ-1 function, suggesting a role in susceptibility to sporadic Parkinson’s disease.
The essential GTPase YphC displays a major domain rearrangement associated with nucleotide binding
Authors: Muench Stephen P. , Xu Ling , Sedelnikova Svetlana E. , Rice David W.
Published: August 2006

The structure of a
Bacillus subtilis
YphC/GDP complex shows that it contains two GTPase domains that pack against a central domain whose fold resembles that of an RNA binding KH-domain. Comparisons of this structure to that of a homologue in
Thermotoga maritima
reveals a dramatic rearrangement in the position of the N-terminal GTPase domain with a shift of up to 60 Å and the formation of a totally different interface to the central domain. This rearrangement appears to be triggered by conformational changes of the switch II region in this domain in response to nucleotide binding. Modeling studies suggest that this motion represents transitions between the “on” and “off” states of the GTPase, the effect of which is to alternately expose and bury a positively charged face of the central domain that we suggest is involved in RNA recognition as part of the possible role of this enzyme in ribosome binding.
Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes
Authors: Chaparro Rodolfo José , Konigshofer Yves , Beilhack Georg F. , Shizuru Judith A. , McDevitt Hugh O. , Chien Yueh-hsiu
Published: August 2006

Before the onset of autoimmune destruction, type 1 diabetic patients and an animal model, the nonobese diabetic (NOD) mouse, show morphological and functional abnormalities in target organs, which may act as inciting events for leukocyte infiltration. To better understand these abnormalities, but without the complications associated with lymphocytic infiltrates, we examined genes expressed in autoimmune target tissues of NOD/severe combined immunodeficient (scid) mice and of autoimmune-resistant C57BL/6/scid mice. Our results suggest that the NOD genetic background may predispose them to diabetic complications, including insulin resistance in the absence of high circulating glucose levels and without autoimmune destruction of their β cells. Several of these genes lie within known type 1 and 2 diabetes loci. These data suggest that the NOD mouse may be a good candidate to study an interface between type 1 and type 2 diabetes.
Resorcinarenes are hexameric capsules in solution
Authors: Evan-Salem Tamar , Baruch Inbal , Avram Liat , Cohen Yoram , Palmer Liam C. , Rebek Julius
Published: August 2006

The host–guest complexes of resorcin[4]arenes with small molecules in organic solutions are examined using modern NMR spectroscopic methods. The complexation of glutaric acid and β-methyl
d
-glucopyranoside in chloroform were investigated through 2D COSY, 2D NOESY, 1D NOE, and diffusion-ordered NMR spectroscopy (DOSY) techniques. These methods indicate that the complex is a self-assembled capsule composed of six resorcinarenes that surround six guest molecules of glutaric acid or three molecules of β-methyl
d
-glucopyranoside inside. The multiplicity of guest proton signals shows that the capsule provides an asymmetric magnetic environment that persists on the
1
H NMR time scale. The encapsulation of these guests and common solvents suggests that the phenomenon of reversible encapsulation in chemistry may be a century old.
Analysis of Aurignacian interstratification at the Châtelperronian-type site and implications for the behavioral modernity of Neandertals
Authors: Zilhão João , d’Errico Francesco , Bordes Jean-Guillaume , Lenoble Arnaud , Texier Jean-Pierre , Rigaud Jean-Philippe
Published: August 2006

The Châtelperronian is a Neandertal-associated archeological culture featuring ornaments and decorated bone tools. It is often suggested that such symbolic items do not imply that Neandertals had modern cognition and stand instead for influences received from coeval, nearby early modern humans represented by the Aurignacian culture, whose precocity would be proven by stratigraphy and radiocarbon dates. The Grotte des Fées at Châtelperron (France) is the remaining case of such a potential Châtelperronian–Aurignacian contemporaneity, but reanalysis shows that its stratification is poor and unclear, the bone assemblage is carnivore-accumulated, the putative interstratified Aurignacian lens in level B4 is made up for the most part of Châtelperronian material, the upper part of the sequence is entirely disturbed, and the few Aurignacian items in levels B4-5 represent isolated intrusions into otherwise
in situ
Châtelperronian deposits. As elsewhere in southwestern Europe, this evidence confirms that the Aurignacian postdates the Châtelperronian and that the latter’s cultural innovations are better explained as the Neandertals’ independent development of behavioral modernity.
Ice-age endurance: DNA evidence of a white spruce refugium in Alaska
Authors: Anderson Lynn L. , Hu Feng Sheng , Nelson David M. , Petit Rémy J. , Paige Ken N.
Published: August 2006

Paleorecords offer key information for evaluating model simulations of species migration in response to forecast climatic change. However, their utility can be greatly compromised by the existence of glacial refugia that are undetectable in fossil records (cryptic refugia). Despite several decades of investigation, it remains controversial whether Beringia, the largely unglaciated area extending from northeastern Siberia to the Yukon Territory, harbored small populations of certain boreal tree species during the last glaciation. Here, we present genetic evidence for the existence of a glacial refuge in Alaska that helps to resolve this long-standing controversy. We sequenced chloroplast DNA (cpDNA) of white spruce (
Picea glauca
), a dominant boreal tree species, in 24 forest stands across northwestern North America. The majority of cpDNA haplotypes are unique, and haplotype diversity is relatively high in Alaska, arguing against the possibility that this species migrated into the region from areas south of the Laurentide Ice Sheet after the end of the last glaciation. Thus, white spruce apparently survived long glacial episodes under climatic extremes in a heterogeneous landscape matrix. These results suggest that estimated rates of tree migration from fossil records may be too high and that the ability of trees to track anthropogenic warming may be more limited than previously thought.
The first three domains of the insulin receptor differ structurally from the insulin-like growth factor 1 receptor in the regions governing ligand specificity
Authors: Lou Meizhen , Garrett Thomas P. J. , McKern Neil M. , Hoyne Peter A. , Epa V. Chandana , Bentley John D. , Lovrecz George O. , Cosgrove Leah J. , Frenkel Maurice J. , Ward Colin W.
Published: August 2006

The insulin receptor (IR) and the type-1 insulin-like growth factor receptor (IGF1R) are homologous multidomain proteins that bind insulin and IGF with differing specificity. Here we report the crystal structure of the first three domains (L1–CR–L2) of human IR at 2.3 Å resolution and compare it with the previously determined structure of the corresponding fragment of IGF1R. The most important differences seen between the two receptors are in the two regions governing ligand specificity. The first is at the corner of the ligand-binding surface of the L1 domain, where the side chain of
F39
in IR forms part of the ligand binding surface involving the second (central) β-sheet. This is very different to the location of its counterpart in IGF1R,
S35
, which is not involved in ligand binding. The second major difference is in the sixth module of the CR domain, where IR contains a larger loop that protrudes further into the ligand-binding pocket. This module, which governs IGF1-binding specificity, shows negligible sequence identity, significantly more α-helix, an additional disulfide bond, and opposite electrostatic potential compared to that of the IGF1R.
Severe acute respiratory syndrome-associated coronavirus 3a protein forms an ion channel and modulates virus release
Authors: Lu Wei , Zheng Bo-Jian , Xu Ke , Schwarz Wolfgang , Du Lanying , Wong Charlotte K. L. , Chen Jiadong , Duan Shuming , Deubel Vincent , Sun Bing
Published: August 2006

Fourteen ORFs have been identified in the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) genome. ORF 3a of SARS-CoV codes for a recently identified transmembrane protein, but its function remains unknown. In this study we confirmed the 3a protein expression and investigated its localization at the surface of SARS-CoV-infected or 3a-cDNA-transfected cells. Our experiments showed that recombinant 3a protein can form a homotetramer complex through interprotein disulfide bridges in 3a-cDNA-transfected cells, providing a clue to ion channel function. The putative ion channel activity of this protein was assessed in 3a-complement RNA-injectedXenopusoocytes by two-electrode voltage clamp. The results suggest that 3a protein forms a potassium sensitive channel, which can be efficiently inhibited by barium. After FRhK-4 cells were transfected with an siRNA, which is known to suppress 3a expression, followed by infection with SARS-CoV, the released virus was significantly decreased, whereas the replication of the virus in the infected cells was not changed. Our observation suggests that SARS-CoV ORF 3a functions as an ion channel that may promote virus release. This finding will help to explain the highly pathogenic nature of SARS-CoV and to develop new strategies for treatment of SARS infection.
The Decline of the Temporary Worker: A Regional Perspective
Authors: Biggs David
Published: August 2006

Employment of temporary workers has been affected by new legislation in 2002 and the stabilisation of the economy in the early 21st century. These factors are hypothesised to reduce the overall level of temporary employment in the UK economy. To confirm this hypothesis, data from 28 Labour Force Survey (LFS) studies carried out between the periods of December 1997 and November 2004 were analysed alongside turnover data for the Employment Agency Industry. The results revealed a reduction of over a quarter of a million temporary workers in the UK Economy over 6 years. Qualitative interviews with ten large temporary worker employers confirmed that legislation and employers' preference for permanent workers reduced the demand for temporary workers. Nonetheless, regional differences were apparent with some regions such as Northern Ireland and Wales increasing their employment of temporary workers.
Local-Authority led Economic Regeneration Strategies in the Aftermath of the Foot-and-Mouth Disease Crisis of 2001
Authors: Taylor Ian , Tricker Mike
Published: August 2006

The Foot-and-Mouth Disease (FMD) outbreak of 2001 in the UK was completely unprecedented in its scale and severity, with over four million animals culled and a cost to the Exchequer of over £4 billion. Local authorities were at the front line in dealing with the outbreak, in coordinating the cull of livestock, the disposal of carcasses as well as attempting to deal with its aftermath and, in particular, the impact on the wider rural economy. This article examines the impacts of this crisis on three local authorities, Devon, Herefordshire and Cumbria. It examines how far the crisis acted as a catalyst in developing strategies to deal with a future outbreak as well as new local initiatives to promote regeneration in the areas most adversely affected. It focuses on developments that can be directly attributed to the crisis and shows that FMD had a considerable impact on communications and ‘joined-up’ activity within local authorities and with local stakeholders.
What is the Role of Universities in High-tech Economic Development? The Case of Portland, Oregon, and Washington, DC
Authors: Mayer Heike
Published: August 2006

This paper focuses on two regions in the United States that have emerged as high-technology regions in the absence of major research universities. The case of Portland's Silicon Forest is compared to Washington, DC. In both regions, high-technology economies grew because of industrial restructuring processes. The paper argues that in both regions other actors—such as firms and government laboratories—spurred the development of knowledge-based economies and catalysed the engagement of higher education institutions in economic development. The paper confirms and advances the triple helix model of university–government–industry relationships and posits that future studies have to examine degrees of university-region engagement.
Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments
Authors: Lampugnani Maria Grazia , Orsenigo Fabrizio , Gagliani Maria Cristina , Tacchetti Carlo , Dejana Elisabetta
Published: August 2006

Receptor endocytosis is a fundamental step in controlling the magnitude, duration, and nature of cell signaling events. Confluent endothelial cells are contact inhibited in their growth and respond poorly to the proliferative signals of vascular endothelial growth factor (VEGF). In a previous study, we found that the association of vascular endothelial cadherin (VEC) with VEGF receptor (VEGFR) type 2 contributes to density-dependent growth inhibition (Lampugnani, G.M., A. Zanetti, M. Corada, T. Takahashi, G. Balconi, F. Breviario, F. Orsenigo, A. Cattelino, R. Kemler, T.O. Daniel, and E. Dejana. 2003. J. Cell Biol. 161:793–804). In the present study, we describe the mechanism through which VEC reduces VEGFR-2 signaling. We found that VEGF induces the clathrin-dependent internalization of VEGFR-2. When VEC is absent or not engaged at junctions, VEGFR-2 is internalized more rapidly and remains in endosomal compartments for a longer time. Internalization does not terminate its signaling; instead, the internalized receptor is phosphorylated, codistributes with active phospholipase C–γ, and activates p44/42 mitogen-activated protein kinase phosphorylation and cell proliferation. Inhibition of VEGFR-2 internalization reestablishes the contact inhibition of cell growth, whereas silencing the junction-associated density-enhanced phosphatase-1/CD148 phosphatase restores VEGFR-2 internalization and signaling. Thus, VEC limits cell proliferation by retaining VEGFR-2 at the membrane and preventing its internalization into signaling compartments.
PKCα: a versatile key for decoding the cellular calcium toolkit
Authors: Reither Gregor , Schaefer Michael , Lipp Peter
Published: August 2006

Conventional protein kinases C (cPKCs) play an essential role in signal transduction and are believed to integrate both global Ca2+ transients and diacylglycerol signals. We provide evidence that PKCα is a ubiquitous readout sensor for the cellular Ca2+ toolkit, including highly restricted elementary Ca2+ release.

Threshold stimulations of cells with Ca2+-mobilizing agonists resulted in PKCα translocation events with limited spatial spreads (<4 μm) comprising two groups of lifetimes; brief events (400–1,500 ms) exclusively mediated by Ca2+–C2 domain membrane interactions and long-lasting events (>4 s) resulting from longer DAG-C1a domain–mediated membrane interactions.

Although upon uncaging NP-EGTA, which is a caged Ca2+ compound, WT-PKCα displayed rapid membrane translocations within <250 ms, PKCα constructs with C2 domains mutated in their Ca2+-binding region lacked any Ca2+-dependent translocation. Flash photolysis of diazo-2, a photosensitive caged Ca2+ buffer, revealed a biphasic membrane dissociation (slow and fast period) of WT-PKCα. The slow phase was absent in cells expressing PKCα-constructs containing mutated C1a-domains with largely reduced DAG binding. Thus, two groups of PKCα membrane interactions coexist; C2- and C1a-mediated interactions with different lifetimes but rapid interconversion.

We conclude that PKCα can readout very fast and, spatially and temporally, very complex cellular Ca2+ signals. Therefore, cPKCs are important transducers for the ubiquitous cellular Ca2+ signaling toolkit.
Public injecting and the need for ‘safer environment interventions’ in the reduction of drug‐related harm
Authors: Rhodes Tim , Kimber Jo , Small Will , Fitzgerald John , Kerr Thomas , Hickman Matthew , Holloway Greg
Published: August 2006

Background  One key structural dimension in the distribution of drug‐related harm associated with injecting drug use is the injecting environment. Epidemiological evidence associates elevated blood‐borne viral risk with injecting in ‘public’ and ‘semipublic’ environments. Yet the quality of evidence on public injecting and related viral risk is variable, and is lacking in many countries such as the United Kingdom.

Aim  This commentary considers the micro‐injecting environment as a critical dimension of risk, exploring the need for ‘safer injecting environment interventions’.

Methods  We draw upon published research evidence and qualitative case examples. 

Results  We note the limits in epidemiological evidence on public injecting and emphasize the need for ethnographic research to determine the ‘social relations’ of how drug users and risk practices interact with injecting environments. We identify three main forms of ‘safer environment intervention’: purpose‐built drug consumption rooms; interventions within existing spatial relations; and spatial programming and urban design. While drug consumption rooms find evidence‐based support, they are not a panacea. We emphasize the potential of interventions embedded within existing spatial and social relations. These include low‐cost pragmatic interventions enhancing facilities and safety at public and semipublic injecting sites and, primarily, peer‐based interventions, including peer‐supervised injecting sites. We caution against spatial programming and urban design interventions which can cause the displacement of socially marginalized populations and the redistribution of harm.

Conclusions  Public health interventions in the addictions field have in the past focused upon individual behavioural change at the cost of social interventions and environmental change. We wish to focus greater attention on reducing risks related to public injecting and encourage greater debate on ‘safer environment interventions’ in harm reduction.
HIV prevalence among injection drug users in rural Guangxi China
Authors: Liu Wei , Chen Jie , Rodolph Michelle , Beauchamp Geetha , Mâsse Benoît , Wang Shaoping , Li Rongjian , Ruan Yuhua , Zhou Feng , Leung Man‐kit , Lai Shenghan , Shao Yiming , Jackson J. Brooks
Published: August 2006

Aims  To determine the HIV‐1 seroprevalence, risk behaviors and demographic characteristics associated with HIV‐1 infection among injection drug users (IDU) in rural Guangxi, China.

Design and setting  Between July and November 2002, 702 IDU were screened for HIV‐1 antibody through community outreach in rural Guangxi, China for enrollment in an HIV sero‐incidence study.

Participants  A total of 702 active high‐risk IDU were screened. High‐risk injection was defined as anyone who reported injecting drugs at least three times per week in the last month or injected drugs with shared equipment on at least three occasions in the last 3 months. 

Measurements  HIV‐1 antibody testing with confirmation by Western blot was performed on all subjects. Demographic and risk assessment survey data were collected at screening from everyone whose baseline HIV antibody status was known. 

Findings  HIV‐1 antibody prevalence among 702 IDU at baseline was 25% with a median age of 26.7 years (18.2–43.2). Based on a multivariate logistic regression model using risk factors identified in univariate analyses, the following risk factors were associated significantly with an increase in risk for HIV seropositivity: age > 26 years (OR 1.50; 95% CI 1.04, 2.17), sharing of rinse water (OR = 1.24; 95% CI 1.09, 1.40), not having sex in the last 6 months (OR = 1.62; 95% CI 1.08, 2.43).

Conclusions  HIV infection among IDU in Guangxi, one of China’s major HIV epidemic regions, is high and the infection occurs predominantly among older IDU males who share rinse water.
Stimulant effects of 3,4‐methylenedioxymethamphetamine (MDMA) 75 mg and methylphenidate 20 mg on actual driving during intoxication and withdrawal
Authors: Ramaekers J. G. , Kuypers K. P. C. , Samyn N.
Published: August 2006

Background  3,4‐methylenedioxymethamphetamine (MDMA) is currently one of the most popular drugs of abuse in Europe. Its increasing use over the last decade has led to concern regarding possible adverse effects on driving. The aims of the present study were to investigate the acute effects of MDMA on actual driving performance during the intoxication and withdrawal phase.

Methods  Eighteen recreational MDMA‐users (nine males, nine females) aged 21–39 years participated in a double‐blind, placebo‐controlled, three‐way cross‐over study. MDMA 75 mg, methylphenidate 20 mg and placebo were administered on day 1 of treatment (intoxication phase). Driving tests were conducted between 3 and 5 hours post‐drug. Subjects returned the following day for a repetition of the driving tests between 27 and 29 hours post‐drug (withdrawal phase). On‐the‐road driving tests consisted of a road‐tracking test and a car‐following test. Its main parameters were standard deviation of lateral position (SDLP), time to speed adaptation (TSA), brake reaction time (BRT) and gain.

Findings  MDMA and methylphenidate significantly decreased SDLP in the road‐tracking tests by about 2 cm relative to placebo on day 1 (intoxication phase). In addition, MDMA intoxication decreased performance in the car‐following test as indicated by a significant rise in the ‘overshoot’ of the subjects’ response to speed decelerations of the leading vehicle. Driving performance was not affected by treatments during withdrawal on day 2.

Conclusion  Collectively, these data indicate that MDMA is a stimulant drug that may improve certain aspects of the driving task, such as road‐tracking performance, but may reduce performance in other aspects of the driving task, such as accuracy of speed adaptation during car‐following performance.
Topiramate reduces the harm of excessive drinking: implications for public health and primary care
Authors: Ma Jennie Z. , Ait‐Daoud Nassima , Johnson Bankole A.
Published: August 2006

Aims  Having demonstrated previously the efficacy of topiramate—a sulfamate‐substituted fructopyranose derivative—as pharmacotherapy for treating alcohol dependence, promoting abstinence and reducing the harmful psychosocial consequences of drinking, we investigated whether topiramate also promoted ‘safe’ levels of drinking: ≤ 1 and ≤ 2 standard drinks/day for women and men, respectively, among alcohol‐dependent individuals.

Design, setting and participants  In a double‐blind, randomized, controlled, 12‐week clinical trial conducted in San Antonio, Texas, 75 alcohol‐dependent adults received topiramate and 75 received placebo as an adjunct to weekly standardized medication compliance management.

Measurements  For this secondary analysis of data from that trial, we calculated, based on self‐reports, specific intervals of up to 30 days of continuous ‘safe’ drinking for each subject.

Findings  The average longest ‘safe’ drinking period was 16.7 days for topiramate recipients versus 8.9 days for placebo recipients. By day 50 of treatment, 44% versus 26.4% had achieved ≥ 7 and 30.8% versus 10% had achieved ≥ 14 continuous ‘safe’ drinking days. Similarly, topiramate increased the relative likelihood of continuous ‘safe’ drinking from 77% for ≥ 7 days [relative risk (RR) for achieving continuous ‘safe’ drinking = 1.77] to threefold for ≥ 14 days (RR = 3.37) and fourfold for ≥ 28 days (RR = 4.07). Thus, participants who received topiramate were more likely to achieve longer periods of ‘safe’ drinking compared with those who received placebo.

Conclusions  For alcohol‐dependent individuals who drank within an abstinence‐oriented treatment program, topiramate promoted ‘safe’ drinking. Topiramate’s potential to decrease the public health consequences of hazardous drinking needs to be established in future long‐term studies.
Substance use disorders: Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM‐IV) and International Classification of Diseases, tenth edition (ICD‐10)
Authors: Hasin Deborah , Hatzenbuehler Mark L. , Keyes Katherine , Ogburn Elizabeth
Published: August 2006

Aims  Two major nomenclatures, Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM‐IV) and International Classification of Diseases, tenth edition (ICD‐10), currently define substance use disorders for broad audiences of users with different training, experience and interests. A comparison of these definitions and their implications for DSM‐V and ICD‐11 has not been available.

Methods  The background for the dependence concept and abuse, harmful use, withdrawal, substance‐induced disorders and remission and other substance‐related conditions is reviewed. Reliability evidence is presented, as is validity evidence from approaches including psychometric, genetic and animal studies. The relevance of the DSM‐IV and ICD‐10 compared to alternative systems (e.g. the Addiction Severity Index) is considered.

Results  Reliability and psychometric validity evidence for substance dependence is consistently strong, but more mixed for abuse and harmful use. Findings on the genetics of alcohol disorders support the validity of the dependence concept, while animal studies underscore the centrality of continued use despite negative consequences to the concept of dependence. While few studies on substance‐induced disorders have been conducted, those published show good reliability and validity when elements of DSM‐IV and ICD‐10 are combined. 

Conclusions  Dependence in DSM‐V and ICD‐11 should be retained, standardizing both criteria sets and adding a severity measure. The consequences of heavy use should be measured independently of dependence; add cannabis withdrawal if further research supports existing evidence; conduct further studies of the substance‐induced psychiatric categories; standardize their criteria across DSM‐V and ICD‐11; develop a theoretical basis for better remission criteria; consider changing substance ‘abuse’ to substance ‘dysfunction disorder’; and conduct clinician education on the value of the diagnostic criteria.
Should there be both categorical and dimensional criteria for the substance use disorders in DSM‐V?
Authors: Helzer John E. , Van Den Brink Wim , Guth Sarah E.
Published: August 2006

Aims As discussed in the following literature review, the relative advantages of categorical and dimensional criteria for classifying the substance use disorders (SUDs) have been debated for many years. The scheduled revision of theDiagnostic and Statistical Manual(DSM) offers an opportunity to re‐examine this question. Both categorical and dimensional approaches to diagnosis offer advantages, both may in fact be necessary for a comprehensive taxonomy.

Methods One means of resolving debate about the direction to take in revising DSM‐V and simultaneously of achieving maximum taxonomic utility is to include both categorical and dimensional criteria in DSM‐V. This could be accomplished by first defining a set of categorical criteria, as in the previous editions of the DSM. Corresponding dimensional criteria could then be created using a more empirical methodology. In this paper we review some of the relevant literature, offer a specific proposal for a dimensional component for the DSM‐V substance use disorders that also preserves the categorical definitions and suggest areas for additional research relevant the this agenda.

Results There is evidence that alcohol and other forms of substance abuse and dependence are heterogeneous categories and that the SUDs can be conceptualized viably as arrayed along a continuum. Amplifying clinically derived categorical definitions with more empirically derived dimensional components to better capture this variability is a particularly important consideration for a substance use research agenda for DSM‐V.

Conclusion It is crucial that a dimensional approach be offered in some form in DSM‐V; but it is also vital that any dimensional approach be linked to the categorical definition. The proposal offered herein provides a model for amplifying categorical definitions with a dimensional component in a way that is evolutionary and not disruptive to the existing taxonomy.
Should criteria for drug dependence differ across drugs?
Authors: Hughes John R.
Published: August 2006

Aim To examine the pros and cons of using the same diagnostic criteria for dependence across all drugs versus using dependence criteria specific to the drug of interest.

Methods A qualitative review of the similarities and differences in nicotine versus alcohol and opiate dependence is used as an example of the utility of using generic versus drug‐specific criteria.

Results Many scientists implicitly recognize that nicotine dependence is different when they do not include nicotine dependence when studying ‘drug dependence’. Nicotine and alcohol/opiate dependence have many similarities (e.g. both can cause withdrawal). Among the several differences, the most important is that nicotine dependence does not cause acute behavioral impairment. Some of the generic dependence criteria do not apply to nicotine dependence (e.g. giving up activities to use the drug) and some well‐validated measures of nicotine dependence (e.g. time to first cigarette) are not included in the generic criteria.

Conclusion Empirical tests of the relative utility of generic versus drug‐specific criteria are needed.
Characteristics of nosologically informative data sets that address key diagnostic issues facing the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM‐V) and International Classification of Diseases, eleventh edition (ICD‐11) substance use disorders workgroups
Authors: Cottler Linda B. , Grant Bridget F.
Published: August 2006

Aims  Over the past two decades, many nosological issues have been addressed by the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD) substance use disorders workgroups. Even with those efforts, there are key issues that have not been resolved and must be revisited, or addressed de novo, by the workgroups. These lingering points are broad, due to the array of substances classified under the diagnostic umbrella of substance use disorders. They include substantive issues ranging from dimensional approaches, similar criteria for each substance, cut‐points and thresholds, distinct abuse and dependence classifications, new criteria and drugs, to less substantive ones, such as the adjectives used to describe the severity of the behaviors. 

Results  This paper describes the characteristics of the data sets that will be needed to resolve the key nosological issues. Ten points are described: (1) data must be true to nomenclature under study; (2) flexible regarding rearrangements of scoring algorithms; (3–4) able to assess substances individually and retain former versions of the criteria; (5) not rely on shortened versions; (6) utilize samples that are generalizable; (7) make diagnoses with transparent algorithms; (8) combine mixed methods for corroborating data; (9) utilize assessments that collect reliable and valid diagnoses and criteria; and (10) stretch the limits by allowing for new discoveries.

Conclusions  This paper describes each of these and gives examples of the limitations and strengths of data for the purpose of defining a useful, unified concept of addictive behaviors.
Should addictive disorders include non‐substance‐related conditions?
Authors: Potenza Marc N.
Published: August 2006

Aims  In anticipation of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐V), to consider whether addictive disorders should include non‐substance use disorders.

Methods  The author reviewed data and provided perspective to explore whether disorders such as pathological gambling (PG) should be grouped together with substance dependence, given that they share many features.

Results  PG and substance dependence currently reside in the DSM, fourth edition, text revision (DSM‐IV‐TR) within separate categories, with PG classified as an impulse control disorder (ICD) and substance dependence as a substance use disorder (SUD). Arguments can be forwarded to support each categorization, as well as to justify their inclusion together as addictions. 

Conclusion  The current state of knowledge suggests that there exist substantial similarities between PG and SUDs. Further research is indicated prior to categorizing PG and other ICDs together with SUDs.
Should the scope of addictive behaviors be broadened to include pathological gambling?
Authors: Petry Nancy M.
Published: August 2006

Aims  Pathological gambling is currently considered an impulse control disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM). This paper considers the prospect of reclassifying and broadening the substance use disorders to include non‐pharmacological addictions such as pathological gambling.

Methods  Literature reviews were conducted on areas relevant to pathological gambling and its classification and similarities to substance use disorders.

Results  The diagnostic criteria for pathological gambling are outlined across the three versions of the DSM since its initial introduction. The paper also describes instruments that have been used to assess the disorder, basic epidemiology and some biological and genetic data, especially in terms of potential overlap with substance use disorders. Similarities and differences with respect to treatments are reviewed as well.

Conclusions  Both advantages and disadvantages should be considered with respect to expanding the classification system to include pathological gambling within the context of addictive disorders.
Are there empirically supported and clinically useful subtypes of alcohol dependence?
Authors: Hesselbrock Victor M. , Hesselbrock Michie N.
Published: August 2006

Aims This paper provides an overview of several multidimensional empirically derived typologies of alcohol use disorders that have been derived primarily for research purposes in relation to their clinical utility.

Methods Studies using multivariate statistical methods for identifying homogeneous groups of subjects were selected for inclusion. Theoretically based typologies were not included in this review.

Results While formal diagnostic criteria typically identify separate categories of alcohol abuse and dependence, several studies using different statistical methods consistently suggest as many as four homogeneous types of alcoholism: a chronic/severe type, a depressed/anxious type, a mildly affected type and an antisocial type.

Conclusions Even though the longitudinal outcomes of few empirically derived subtypes have been examined, alcoholism typologies remain a viable and potentially valuable tool for investigating etiological pathways, the effectiveness of treatments and the long‐term course of alcohol use disorders.
The empirical basis of substance use disorders diagnosis: research recommendations for the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM‐V)
Authors: Schuckit Marc A. , Saunders John B.
Published: August 2006

Aims  This paper presents the recommendations, developed from a 3‐year consultation process, for a program of research to underpin the development of diagnostic concepts and criteria in the Substance Use Disorders section of the Diagnostic and Statistical Manual of Mental Disorders (DSM) and potentially the relevant section of the next revision of the International Classification of Diseases (ICD).

Methods  A preliminary list of research topics was developed at the DSM‐V Launch Conference in 2004. This led to the presentation of articles on these topics at a specific Substance Use Disorders Conference in February 2005, at the end of which a preliminary list of research questions was developed. This was further refined through an iterative process involving conference participants over the following year.

Results  Research questions have been placed into four categories: (1) questions that could be addressed immediately through secondary analyses of existing data sets; (2) items likely to require position papers to propose criteria or more focused questions with a view to subsequent analyses of existing data sets; (3) issues that could be proposed for literature reviews, but with a lower probability that these might progress to a data analytic phase; and (4) suggestions or comments that might not require immediate action, but that could be considered by the DSM‐V and ICD 11 revision committees as part of their deliberations.

Conclusions  A broadly based research agenda for the development of diagnostic concepts and criteria for substance use disorders is presented.
Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-κB phosphorylation and nuclear factor-κB transcriptional activity through nicotinic acetylcholine receptor α7
Authors: Yoshikawa H , Kurokawa M , Ozaki N , Nara K , Atou K , Takada E , Kamochi H , Suzuki N
Published: August 2006

Macrophages/monocytes and the proinflammatory mediators, such as tumour necrosis factor (TNF)-α, prostaglandin E2 (PGE2), macrophage inflammatory protein (MIP)-1α and MIP-1α, play a critical role in the progression of immunological disorders including rheumatoid arthritis, Behçet’s disease and Crohn’s disease. In addition, the nicotinic acetylcholine receptor-α7 (α7nAChR) subunit is an essential regulator of inflammation. In this study, we evaluated the expression of the α7nAChR subunit on human peripheral monocytes and the effect of nicotine on the production of these proinflammatory mediators by activated monocytes. Fluorescein isothiocyanate (FITC)-labelled α-bungarotoxin demonstrated the cell surface expression of the α7nAchR subunit. Pretreatment with low-dose nicotine caused inhibition of TNF-α, PGE2, MIP-1α and MIP-1α production, and mRNA expression of TNF-α, MIP-1α and MIP-1α and COX-2 in lipopolysaccharide (LPS)-activated monocytes. These suppressive effects of nicotine were caused at the transcriptional level and were mediated through α7nAChR. Nicotine suppressed the phosphorylation of I-κB, and then inhibited the transcriptional activity of nuclear factor-κB. These immunosuppressive effects of nicotine may contribute to the regulation of some immune diseases.
Mixed inflammatory/regulatory cytokine profile marked by simultaneous raise of interferon-γ and interleukin-10 and low frequency of tumour necrosis factor-α+ monocytes are hallmarks of active human visceral Leishmaniasis due toLeishmania chagasiinfection
Authors: Peruhype-Magalhães V , Martins-Filho O A , Prata A , Silva L De A , Rabello A , Teixeira-Carvalho A , Figueiredo R M , Guimarães-Carvalho S F , Ferrari T C A , Van Weyenbergh J , Correa-Oliveira R
Published: August 2006

Considering the complexity of the immunological events triggered during active visceral Leishmaniasis (VL), the relevance of the segregation of the immune response during human VL into type 1 and type 2 still remains unclear. For this purpose, in individuals living in risk areas for VL, we have evaluated especially asymptomatic individuals and patients with active VL, the plasmatic levels of cytokines and reactive nitrogen species under ex vivo conditions. In addition, we have also performed an analysis of intracellular cytokine patterns of circulating leucocytes after short-term culture, particularly in the absence of antigenic-specific stimulation, in order to reflect dynamic events of immune response in vivo during Leishmania chagasi infection. Although asymptomatic individuals and non-infected subjects presented a similar immunological profile, an outstanding inflammatory/regulatory profile, based on higher plasmatic levels of cytokines such as interleukin (IL)-8, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, IL-6 and IL-10, was associated with clinical status observed in active VL. In this context, we hypothesize that IL-10, through its ability to inhibit anti-leishmanial macrophage activation, associated with the lower frequency of TNF-α+ monocytes and ordinary levels of nitrite and nitrate are the major mechanisms associated with disease onset.
Glucocorticoid‐induced tumour necrosis factor receptor family related protein (GITR) mediates inflammatory activation of macrophages that can destabilize atherosclerotic plaques
Authors: Kim Won‐Jung , Bae Eun‐Mi , Kang Yoon‐Joong , Bae Hyung‐Uk , Hong Su Hyung , Lee Joo Y. , Park Jeong‐Euy , Kwon Byoung S. , Suk Kyoungho , Lee Won‐Ha
Published: August 2006

Glucocorticoid‐induced tumour necrosis factor receptor family related protein (GITR) is the 18th member of the tumour necrosis factor receptor superfamily (TNFRSF18) and is known to interact with its cognate ligand GITRL (TNFSF18). We investigated the potential role of GITR in the pro‐inflammatory activation of macrophages. Immunohistochemistry and in situ hybridization analyses of human atherosclerotic plaques demonstrated that GITR and its ligand are expressed mainly in lipid‐rich macrophages. We then investigated the role of GITR in human and mouse monocyte/macrophage functions. Stimulation of GITR caused nuclear factor (NF)‐κB‐dependent activation of matrix metalloproteinase‐9 (MMP‐9) and pro‐inflammatory cytokine expression in both the human and mouse monocytic/macrophage cell lines, THP‐1 and RAW264.7, respectively. These cellular responses were also observed when the THP‐1 cells were treated with phorbol‐12 myristate‐13 acetate (PMA), which is known to induce macrophage differentiation. To demonstrate that these responses are not restricted to cultured cell lines, we tested primary macrophages. Both peritoneal and bone marrow‐derived macrophages responded to GITR stimulation with induction of MMP‐9 and tumour necrosis factor‐α (TNF‐α). Furthermore, the GITR staining pattern overlapped with those of MMP‐9 and TNF‐α in atherosclerotic plaques. These data indicate that GITR‐mediated macrophage activation may promote atherogenesis via the induction of pro‐atherogenic cytokines/chemokines, and destabilize the atherosclerotic plaques via the induction of the matrix‐degrading enzyme, MMP‐9.
Partial coverage restoration systems on molars – comparison of failure load after exposure to a mastication simulator
Authors: STAPPERT C. F. J. , GUESS P. C. , CHITMONGKOLSUK S. , GERDS T. , STRUB J. R.
Published: August 2006

summary  This in vitro study evaluated the failure load of partial coverage restorations (PCR) made of various materials cemented on natural molars after exposure to the mastication simulator. Sixty‐four maxillary molars were divided into four groups of 16 test specimens each. The specimens in one group remained unprepared (group NP); the teeth in the other groups were prepared equally according to standardized guidelines and restored with the following PCR: Group GO (Gold‐Pontor®‐MPF; Metaux Precieux SA, Metalor, Neuchatel, Switzerland), group TA (Targis®; Ivoclar Vivadent AG, Schaan, Liechtenstein) and group EM (IPS‐Empress®; Ivoclar Vivadent AG). The restorations in group GO were cemented conventionally, while those in groups TA and EM were luted adhesively. Groups NP and GO served as control groups. All test specimens were subjected to 1·2 million cycles (F = 49 N) in a mastication simulator. Subsequently, all test specimens were loaded occlusally until fracture occurred using an universal testing machine. All specimens withstood the masticating simulation. The median (IQR = x0·25−x0·75) failure loads were as follows: group NP: 1960·3(1480·5−2227·5) N, group TA: 1478·6(1293·4−1856·7) N and group EM: 1400·1(1043·1−1721·6) N. All test specimens of group GO achieved fracture strength values which exceeded a fracture load of 5500 N. The values of group GO were statistically significantly higher than those of groups NP, TA and EM (P < 0·00001). Furthermore, the results of group NP were significantly higher (P = 0·0226) than those of group EM. The results of groups NP and TA (P = 0·2022) as well as of groups TA and EM (P = 0·5340) did not differ significantly. The median values of all PCR systems obtained were within the limits of clinical acceptance. Long‐term clinical investigations which take additional parameters into consideration are required before the composite‐based Targis® (Ivoclar Vivadent AG) material can be recommended for indirect PCR.