bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for an essential function of the N terminus of a small heat shock protein
in vivo
, independent of
in vitro
chaperone activity
Authors: Giese Kim C. , Basha Eman , Catague Belmund Y. , Vierling Elizabeth
Published: December 2005

To investigate the mechanism of small heat shock protein (sHsp) function, unbiased by current models of sHsp chaperone activity, we performed a screen for mutations of
Synechocystis
Hsp16.6 that reduced the ability of the protein to provide thermotolerance
in vivo
. Missense mutations at 17 positions throughout the protein and a C-terminal truncation of 5 aa were identified, representing the largest collection of sHsp mutants impaired in function
in vivo
. Ten mutant proteins were purified and tested for alterations in native oligomeric structure and
in vitro
chaperone activity. These biochemical assays separated the mutants into two groups. The C-terminal truncation and six mutations in the α-crystallin domain destabilized the sHsp oligomer and reduced
in vitro
chaperone activity. In contrast, the other three mutations had little effect on oligomer stability or chaperone activity
in vitro
. These mutations were clustered in the N terminus of Hsp16.6, pointing to a previously unrecognized, important function for this evolutionarily variable domain. Furthermore, the fact that the N-terminal mutations were impaired in function
in vivo
, but active as chaperones
in vitro
, indicates that current biochemical assays do not adequately measure essential features of the sHsp mechanism of action.
The glycosphingolipid globotriaosylceramide in the metastatic transformation of colon cancer
Authors: Kovbasnjuk Olga , Mourtazina Rakhilya , Baibakov Boris , Wang Thomas , Elowsky Christian , Choti Michael A. , Kane Anne , Donowitz Mark
Published: December 2005

The most devastating aspect of cancer is the emergence of metastases. Thus, identification of potentially metastatic cells among a tumor cell population and the underlying molecular changes that switch cells to a metastatic state are among the most important issues in cancer biology. Here we show that, although normal human colonic epithelial cells lack the glycosphingolipid globotriaosylceramide (Gb
3
), this molecule is highly expressed in metastatic colon cancer. In addition, a subpopulation of cells that are greatly enriched in Gb
3
and have an invasive phenotype was identified in human colon cancer cell lines. In epithelial cells in culture, Gb
3
was necessary and sufficient for cell invasiveness. Transfection of Gb
3
synthase, resulting in Gb
3
expression in noncancerous polarized epithelial cells lacking endogenous Gb
3
, induced cell invasiveness. Furthermore, Gb
3
knockdown by small inhibitory RNA in colon cancer epithelial cells inhibited cell invasiveness. Gb
3
is the plasma membrane receptor for Shiga toxin 1. The noncatalytic B subunit of Shiga toxin 1 causes apoptosis of human colon cancer cells expressing Gb
3
. Injections of the B subunit of Shiga toxin 1 into HT29 human colon cancer cells engrafted into the flanks of nude mice inhibited tumor growth. These data demonstrate the appearance of a subpopulation of Gb
3
containing epithelial cells in the metastatic stage of human colon cancer and suggest their possible role in colon cancer invasiveness.
Abnormal centrosome amplification in cells through the targeting of Ran-binding protein-1 by the human T cell leukemia virus type-1 Tax oncoprotein
Authors: Peloponese Jean-Marie , Haller Kerstin , Miyazato Akiko , Jeang Kuan-Teh
Published: December 2005

Human T cell leukemia virus type-1 (HTLV-1) is an oncogenic retrovirus etiologically causal of adult T cell leukemia. The virus encodes a Tax oncoprotein that functions in transcriptional regulation, cell cycle control, and transformation. Because adult T cell leukemia like many other human cancers is a disease of genomic instability with frequent gains and losses of chromosomes, to understand this disease it is important to comprehend how HTLV-1 engenders aneuploidy in host cells. In this regard, loss of cell cycle checkpoints permits tolerance of aneuploidy but does not explain how aneuploidy is created. We show here that HTLV-1 Tax causes abnormal centrosome fragmentation in the mitotic phase of the cell cycle. We report that Tax directly binds Ran and Ran-binding protein-1, locates to centrosomes/spindle poles, and causes supernumerary centrosomes.
Femtochemistry of orange II in solution and in chemical and biological nanocavities
Authors: Douhal Abderrazzak , Sanz Mikel , Tormo Laura
Published: December 2005

In this work, we report on studies of the nature of the dynamics and hydrophobic binding in cyclodextrins and human serum albumin protein complexes with orange II. With femtosecond time resolution, we examined the proton-transfer and trans-cis isomerization reactions of the ligand in these nanocavities and in pure solvents. Because of confinement at the ground state, the orientational motion in the formed phototautomer is restricted, leading to a rich dynamics. Therefore, the emission lifetimes span a large window of tens to hundreds of picoseconds in the cavities. Possible H-bond interactions between the guest and cyclodextrin do not affect the caged dynamics. For the protein–ligand complexes, slow diffusional motion (≈630 ps) observed in the anisotropy decay indicates that the binding structure is not completely rigid, and the embedded guest is not frozen with the hydrophobic pocket. The ultrafast isomerization and decays are explained in terms of coupling motions between N–N and C–N stretching modes of the formed tautomer. We discuss the role of confinement on the trans-cis isomerization with the cavities and its relationships to frequency and time domains of nanostructure emission.
Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage
Authors: Perier Celine , Tieu Kim , Guégan Christelle , Caspersen Casper , Jackson-Lewis Vernice , Carelli Valerio , Martinuzzi Andrea , Hirano Michio , Przedborski Serge , Vila Miquel
Published: December 2005

Dysfunction of mitochondrial complex I is a feature of human neurodegenerative diseases such as Leber hereditary optic neuropathy and Parkinson's disease. This mitochondrial defect is associated with a recruitment of the mitochondrial-dependent apoptotic pathway
in vivo
. However, in isolated brain mitochondria, complex I dysfunction caused by either pharmacological or genetic means fails to directly activate this cell death pathway. Instead, deficits of complex I stimulate intramitochondrial oxidative stress, which, in turn, increase the releasable soluble pool of cytochrome
c
within the mitochondrial intermembrane space. Upon mitochondrial permeabilization by the cell death agonist Bax, more cytochrome
c
is released to the cytosol from brain mitochondria with impaired complex I activity. Given these results, we propose a model in which defects of complex I lower the threshold for activation of mitochondrial-dependent apoptosis by Bax, thereby rendering compromised neurons more prone to degenerate. This molecular scenario may have far-reaching implications for the development of effective neuroprotective therapies for these incurable illnesses.
A dynamic switch between inhibitory and excitatory currents in a neuronal glutamate transporter
Authors: Melzer Nico , Torres-Salazar Delany , Fahlke Christoph
Published: December 2005

Excitatory amino acid transporters (EAATs) terminate glutamatergic synaptic transmission and maintain extracellular glutamate concentrations in the central nervous system below excitotoxic levels. In addition to sustaining a secondary-active glutamate transport, EAAT glutamate transporters also function as anion-selective channels. Here, we report a gating process that makes anion channels associated with a neuronal glutamate transporter, EAAT4, permeable to cations and causes a selective increase of the open probability at voltages negative to the actual current reversal potential. The activation process depends on both membrane potential and extracellular glutamate concentration and causes an accumulation of EAAT4 anion channels in a state favoring cation influx and anion efflux. Gating of EAAT4 anion channels thus allows a switch between inhibitory currents in resting cells and excitatory currents in electrically active cells. This transporter-mediated conductance could modify the excitability of Purkinje neurons, providing them with an unprecedented mechanism for adaptation.
Correlation between evolutionary structural development and protein folding
Authors: Nagao Chioko , Terada Tomoki P. , Yomo Tetsuya , Sasai Masaki
Published: December 2005

Evolution should have played important roles in determining folding mechanisms and structures of proteins. In this article we discuss how the folding mechanisms had been affected by the early stage of evolution through which the uniqueness of structure had developed. Although the process of such early-time evolution has remained a mystery, a plausible scenario is that the evolution of proteins toward the ordered structures was guided by functional selection pressure as demonstrated
in vitro
and
in silico
. We examine the
in silico
functional selection of sequences and show that there is a significant correlation between two different processes toward the unique 3D structure, the evolutionary development of structure through sequence selection, and the folding process of the resultant sequence. This finding could be rephrased as protein folding recapitulates the emergence of topology in the molecular evolution. The correlation suggests a guideline for engineering foldable proteins.
Structure of the mid-region of tropomyosin: Bending and binding sites for actin
Authors: Brown Jerry H. , Zhou Zhaocai , Reshetnikova Ludmilla , Robinson Howard , Yammani Rama D. , Tobacman Larry S. , Cohen Carolyn
Published: December 2005

Tropomyosin is a two-chain α-helical coiled coil whose periodic interactions with the F-actin helix are critical for thin filament stabilization and the regulation of muscle contraction. Here we deduce the mechanical and chemical basis of these interactions from the 2.3-Å-resolution crystal structure of the middle three of tropomyosin's seven periods. Geometrically specific bends of the coiled coil, produced by clusters of core alanines, and variable bends about gaps in the core, produced by isolated alanines, occur along the molecule. The crystal packing is notable in signifying that the functionally important fifth period includes an especially favorable protein-binding site, comprising an unusual apolar patch on the surface together with surrounding charged residues. Based on these and other results, we have constructed a specific model of the thin filament, with the N-terminal halves of each period (i.e., the so-called “α zones”) of tropomyosin axially aligned with subdomain 3 of each monomer in F-actin.
Mechanistic insight into the allosteric activation of a ubiquitin-conjugating enzyme by RING-type ubiquitin ligases
Authors: Özkan Engin , Yu Hongtao , Deisenhofer Johann
Published: December 2005

Ubiquitin-conjugating enzymes (E2s) collaborate with the ubiquitin-activating enzyme (E1) and ubiquitin ligases (E3s) to attach ubiquitin to target proteins. RING-containing E3s simultaneously bind to E2s and substrates, bringing them into close proximity and thus facilitating ubiquitination. We show herein that, although the E3-binding site on the human E2 UbcH5b is distant from its active site, two RING-type minimal E3 modules lacking substrate-binding functions greatly stimulate the rate of ubiquitin release from the UbcH5b–ubiquitin thioester. Using statistical coupling analysis and mutagenesis, we identify and characterize clusters of coevolving and functionally linked residues within UbcH5b that span its E3-binding and active sites. Several UbcH5b mutants are defective in their stimulation by E3s despite their abilities to bind to these E3s, to form ubiquitin thioesters, and to release ubiquitin at a basal rate. One such mutation, I37A, is distant from both the active site and the E3-binding site of UbcH5b. Our studies reveal structural determinants for communication between distal functional sites of E2s and suggest that RING-type E3s activate E2s allosterically.
High-dimensional and large-scale phenotyping of yeast mutants
Authors: Ohya Yoshikazu , Sese Jun , Yukawa Masashi , Sano Fumi , Nakatani Yoichiro , Saito Taro L. , Saka Ayaka , Fukuda Tomoyuki , Ishihara Satoru , Oka Satomi , Suzuki Genjiro , Watanabe Machika , Hirata Aiko , Ohtani Miwaka , Sawai Hiroshi , Fraysse Nicolas , Latgé Jean-Paul , François Jean M. , Aebi Markus , Tanaka Seiji , Muramatsu Sachiko , Araki Hiroyuki , Sonoike Kintake , Nogami Satoru , Morishita Shinichi
Published: December 2005

One of the most powerful techniques for attributing functions to genes in uni- and multicellular organisms is comprehensive analysis of mutant traits. In this study, systematic and quantitative analyses of mutant traits are achieved in the budding yeast
Saccharomyces cerevisiae
by investigating morphological phenotypes. Analysis of fluorescent microscopic images of triple-stained cells makes it possible to treat morphological variations as quantitative traits. Deletion of nearly half of the yeast genes not essential for growth affects these morphological traits. Similar morphological phenotypes are caused by deletions of functionally related genes, enabling a functional assignment of a locus to a specific cellular pathway. The high-dimensional phenotypic analysis of defined yeast mutant strains provides another step toward attributing gene function to all of the genes in the yeast genome.
On the mechanism of sensing unfolded protein in the endoplasmic reticulum
Authors: Credle Joel J. , Finer-Moore Janet S. , Papa Feroz R. , Stroud Robert M. , Walter Peter
Published: December 2005

Unfolded proteins in the endoplasmic reticulum (ER) activate the ER transmembrane sensor Ire1 to trigger the unfolded protein response (UPR), a homeostatic signaling pathway that adjusts ER protein folding capacity according to need. Ire1 is a bifunctional enzyme, containing cytoplasmic kinase and RNase domains whose roles in signal transduction downstream of Ire1 are understood in some detail. By contrast, the question of how its ER-luminal domain (LD) senses unfolded proteins has remained an enigma. The 3.0-Å crystal structure and consequent structure-guided functional analyses of the conserved core region of the LD (cLD) leads us to a proposal for the mechanism of response. cLD exhibits a unique protein fold and is sufficient to control Ire1 activation by unfolded proteins. Dimerization of cLD monomers across a large interface creates a shared central groove formed by α-helices that are situated on a β-sheet floor. This groove is reminiscent of the peptide binding domains of major histocompatibility complexes (MHCs) in its gross architecture. Conserved amino acid side chains in Ire1 that face into the groove are shown to be important for UPR activation in that their mutation reduces the response. Mutational analyses suggest that further interaction between cLD dimers is required to form higher-order oligomers necessary for UPR activation. We propose that cLD directly binds unfolded proteins, which changes the quaternary association of the monomers in the membrane plane. The changes in the ER lumen in turn position Ire1 kinase domains in the cytoplasm optimally for autophosphorylation to initiate the UPR.
Perinatal anoxia degrades auditory system function in rats
Authors: Strata F. , deIpolyi A. R. , Bonham B. H. , Chang E. F. , Liu R. C. , Nakahara H. , Merzenich M. M.
Published: December 2005

Little is known about the neural bases of the reduced auditory and cortical processing speeds that have been recorded in language-impaired, autistic, schizophrenic, and other disabled human populations. Although there is strong evidence for genetic contributions to etiologies, epigenetic factors such as perinatal anoxia (PA) have been argued to be contributors, or causal, in a significant proportion of cases. In this article, we explored the consequences of PA on this elementary aspect of auditory behavior and on auditory system function in rats that were briefly perinatally anoxic. PA rats had increased acoustic thresholds and reduced processing efficiencies recorded in an auditory behavioral task. These rats had modestly increased interpeak intervals in their auditory brainstem responses, and substantially longer latencies in poststimulus time histogram responses recorded in the primary auditory cortex. The latter were associated with degraded primary auditory cortex receptive fields and a disrupted tonotopy. These processing deficits are consistent with the parallel behavioral and physiological deficits recorded in children and adults with a history of language-learning impairment and autism.
The role of microRNA genes in papillary thyroid carcinoma
Authors: He Huiling , Jazdzewski Krystian , Li Wei , Liyanarachchi Sandya , Nagy Rebecca , Volinia Stefano , Calin George A. , Liu Chang-gong , Franssila Kaarle , Suster Saul , Kloos Richard T. , Croce Carlo M. , de la Chapelle Albert
Published: December 2005

Apart from alterations in the RET/PTC-RAS-BRAF pathway, comparatively little is known about the genetics of papillary thyroid carcinoma (PTC). We show that numerous microRNAs (miRNAs) are transcriptionally up-regulated in PTC tumors compared with unaffected thyroid tissue. A set of five miRNAs, including the three most up-regulated ones (miR-221, -222, and -146), distinguished unequivocally between PTC and normal thyroid. Additionally, miR-221 was up-regulated in unaffected thyroid tissue in several PTC patients, presumably an early event in carcinogenesis. Tumors in which the up-regulation (11- to 19-fold) of miR-221, -222, and -146 was strongest showed dramatic loss of
KIT
transcript and Kit protein. In 5 of 10 such cases, this down expression was associated with germline single-nucleotide changes in the two recognition sequences in
KIT
for these miRNAs. We conclude that up-regulation of several miRs and regulation of
KIT
are involved in PTC pathogenesis, and that sequence changes in genes targeted by miRNAs can contribute to their regulation.
A 200-kb region of human chromosome 22q11.2 confers antipsychotic-responsive behavioral abnormalities in mice
Authors: Hiroi Noboru , Zhu Hongwen , Lee MoonSook , Funke Birgit , Arai Makoto , Itokawa Masanari , Kucherlapati Raju , Morrow Bernice , Sawamura Takehito , Agatsuma Soh
Published: December 2005

Human chromosome 22q11.2 has been implicated in various behavioral abnormalities, including schizophrenia and other neuropsychiatric/behavioral disorders. However, the specific genes within 22q11.2 that contribute to these disorders are still poorly understood. Here, we show that an ≈200-kb segment of human 22q11.2 causes specific behavioral abnormalities in mice. Mice that overexpress an ≈200-kb region of human 22q11.2, containing
CDCrel
,
GP1B
β,
TBX1
, and
WDR14
, exhibited spontaneous sensitization of hyperactivity and a lack of habituation. These effects were ameliorated by antipsychotic drugs. The transgenic mice were also impaired in nesting behavior. Although
Tbx1
has been shown to be responsible for many physical defects associated with 22q11.2 haploinsufficiency,
Tbx1
heterozygous mice did not display these behavioral abnormalities. Our results show that the ≈200-kb region of 22q11.2 contains a gene(s) responsible for behavioral abnormalities and suggest that distinct genetic components within 22q11.2 mediate physical and behavioral abnormalities.
Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation
Authors: Lu Xiaohui , Levine Ross , Tong Wei , Wernig Gerlinde , Pikman Yana , Zarnegar Sara , Gilliland D. Gary , Lodish Harvey
Published: December 2005

A recurrent somatic activating mutation in the nonreceptor tyrosine kinase
JAK2
(
JAK2V617F
) occurs in the majority of patients with the myeloproliferative disorders polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and, less commonly, chronic myelomonocytic leukemia. We do not understand the basis for the specificity of the
JAK2V617F
mutation in clonal disorders of the myeloid, but not lymphoid, lineage, nor has the basis for the pleiotropic phenotype of JAK2V617F-associated myeloproliferative disorders been delineated. However, the presence of the identical mutation in patients with related, but clinicopathologically distinct, myeloid disorders suggests that interactions between the JAK2V617F kinase and other signaling molecules may influence the phenotype of hematopoietic progenitors expressing JAK2V617F. Here, we show that coexpression of the JAK2V617F mutant kinase with a homodimeric Type I cytokine receptor, the erythropoietin receptor (EpoR), the thrombopoietin receptor, or the granulocyte colony-stimulating-factor receptor, is necessary for transformation of hematopoietic cells to growth-factor independence and for hormone-independent activation of JAK-STAT signaling. Furthermore, EpoR mutations that impair erythropoietin-mediated JAK2 or STAT5 activation also impair transformation mediated by the JAK2V617F kinase, indicating that JAK2V617F requires a cytokine receptor scaffold for its transforming and signaling activities. Our results reveal the molecular basis for the prevalence of JAK2V617F in diseases of myeloid lineage cells that express these Type I cytokine receptors but not in lymphoid lineage cells that do not.
The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases
Authors: Ungewickell Alexander , Hugge Christopher , Kisseleva Marina , Chang Shao-Chun , Zou Jun , Feng Yucheng , Galyov Edouard E. , Wilson Monita , Majerus Philip W.
Published: December 2005

Numerous inositol polyphosphate 5-phosphatases catalyze the degradation of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P
2
) to phosphatidylinositol-4-phosphate (PtdIns-4-P). An alternative pathway to degrade PtdIns-4,5-P
2
is the hydrolysis of PtdIns-4,5-P
2
by a 4-phosphatase, leading to the production of PtdIns-5-P. Whereas the bacterial IpgD enzyme is known to catalyze this reaction, no such mammalian enzyme has been found. We have identified and characterized two previously undescribed human enzymes, PtdIns-4,5-P
2
4-phosphatase type I and type II, which catalyze the hydrolysis of PtdIns-4,5-P
2
to phosphatidylinositol-5-phosphate (PtdIns-5-P). Both enzymes are ubiquitously expressed and localize to late endosomal/lysosomal membranes in epithelial cells. Overexpression of either enzyme in HeLa cells increases EGF-receptor degradation upon EGF stimulation.
Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains
Authors: Yokote Hideyuki , Fujita Koji , Jing Xuefeng , Sawada Takahiro , Liang Sitai , Yao Li , Yan Xiaomei , Zhang Yueqiang , Schlessinger Joseph , Sakaguchi Kazushige
Published: December 2005

A yeast two-hybrid analysis has shown that the juxtamembrane region of FGF receptor 3 (FGFR3) interacts with the cytoplasmic domain of EphA4, which is a member of the largest family of receptor tyrosine kinases. Complex formation between the two receptors was shown to be mediated by direct interactions between the juxtamembrane domain of FGFR1, FGFR2, FGFR3, or FGFR4 and the N-terminal portion of the tyrosine kinase domain of EphA4. Activation of FGFR1 in transfected cells resulted in tyrosine phosphorylation of a kinase-negative EphA4 mutant and activation of EphA4 led to tyrosine phosphorylation of a kinase-negative FGFR1 mutant. Moreover, both receptors stimulate tyrosine phosphorylation of the docking protein FRS2α and induce mitogen-activated protein kinase stimulation with a time course and intensity that depends on the ligand that is applied. We also demonstrate that FGF-receptor-mediated mitogen-activated protein kinase stimulation is potentiated in cells costimulated with ephrin-A1. The direct interaction between EphA4 and FGFRs and the potentiation of FGF response that is induced by ephrin-A1 stimulation may modulate the biological responses that are mediated by these receptor families in cells or tissues in which the two receptors are coexpressed.
Implementation of brief alcohol intervention in primary health care: do nurses' and general practitioners' attitudes, skills and knowledge change?
Authors: AALTO MAURI , PEKURI PETTERI , SEPPÄ KAIJA
Published: December 2005

Brief alcohol intervention reduces heavy drinking, but its implementation has been challenging. The purpose was to evaluate self‐reported changes in attitudes, skills and knowledge regarding brief intervention among nurses and general practitioners (GPs) during an implementation project. A questionnaire survey was used before and after the implementation to all nurses and GPs working at the time in the seven primary health‐care centres of the city of Tampere, Finland. Several positive changes indicate an increased amount of knowledge regarding brief intervention among the professionals during the implementation. This was found especially among the nurses. The success in increasing the knowledge can also be seen in a decrease of training needs. Instead, attitudes and skills among the professionals did not seem to develop positively. Increasing motivational skills especially seems to be the future challenge.
Process evaluation of an out‐patient detoxification service
Authors: SANNIBALE CLAUDIA , FUCITO LISA , O'CONNOR DANNY , CURRY KENNETH
Published: December 2005

This paper describes the process evaluation of an out‐patient detoxification service (ODS) established by Drug Health Services (DHS) to increase the supervised withdrawal options for substance users in a Sydney metropolitan Area Health Service. The ODS aimed to provide a safe and effective supervised withdrawal to substance users who were at low risk of severe withdrawal, engage those with severe dependence in further treatment and increase the involvement of general practitioners (GPs) in the medical care of ODS clients. During its first 10 months of operation, the ODS received 199 inquiries, assessed 82 individuals and admitted 76 clients for detoxification. Withdrawal treatment proceeded without complications and within the expected time frames. Fifty‐four clients completed withdrawal, 10 ceased treatment, 10 remained in treatment without completing withdrawal and two were transferred elsewhere. Clients who injected substances (mainly heroin) daily at admission, compared to others, were less likely to complete withdrawal and more likely to use a range of non‐prescribed substances during withdrawal. One‐fifth of clients went on to further treatment with DHS, attending at least once. Overall, the ODS met its goals, providing a safe and effective supervised withdrawal to local residents, especially women, young people and those withdrawing from benzodiazepines who had significant substance dependence, impairment and previous alcohol and other drug (AOD) treatment. Non‐injecting substance users benefited most from the ODS in terms of withdrawal completion and ongoing treatment. The level of GP involvement in the conjoint care of ODS clients remained constant over time. The development and expansion of the ODS are discussed.
Cannabis use in adolescents: the impact of risk and protective factors and social functioning
Authors: BEST DAVID , GROSS SAMANTHA , MANNING VICTORIA , GOSSOP MICHAEL , WITTON JOHN , STRANG JOHN
Published: December 2005

The study uses a school‐based sample to test the social and familial risk and protective factors relating to cannabis use. Based on a self‐completion survey of 2078 14–16‐year‐olds (mean age of 15 years) attending seven standard state‐run secondary schools in south London, an assessment was made of rates and risk factors for cannabis use. Twenty‐four per cent of the total sample had ever used cannabis, with 15% having done so in the month prior to assessment. In addition to greater likelihood of illicit drug use, lifetime cannabis users were less likely to spend time regularly with both their mothers and fathers, but more likely to spend free time with friends who smoked, drank alcohol and used illicit drugs, and with friends involved in criminal activities. Among those who had ever used cannabis, frequency of cannabis use was predicted (using linear regression) by two onset factors (earlier initiation of drinking and cannabis use were both linked to more frequent use) and two social factors (more time spent with drug‐using friends and less time spent with the mother). Overall, the study showed that early onset, itself predicted by social networks, is linked to more frequent use of cannabis and that this appears to be sustained by less time spent with parents and more with drug‐using peers.
The management of alcohol, tobacco and illicit drug use problems by general practitioners in Australia
Authors: DEGENHARDT LOUISA , KNOX STEPHANIE , BARKER BRIDGET , BRITT HELENA , SHAKESHAFT ANTHONY
Published: December 2005

The aim of this study was to document the frequency of the management of illicit drug, alcohol and tobacco problems in general practice in Australia. Data from the Bettering the Evaluation and Care of Health (BEACH) study of general practice, April 1998 to March 2003, were analysed. BEACH is an ongoing national study of general practice in Australia. Each year a random sample of approximately 1000 general practitioners (GPs) participate, each providing details of 100 patient encounters. Samples are drawn from the Medicare data held by the Health Insurance Commission. Patient demographic breakdowns, medication, other treatment, referrals and other medical procedures ordered were examined for all problems labelled by GPs as illicit, alcohol and tobacco problems. Annually in Australia, it was estimated that 615 000 GP encounters—or 0.6% of all encounters—involved the management of illicit drug use problems presumably most commonly for problematic heroin use. Despite a much higher population prevalence of use and use disorders, the management of alcohol or tobacco use problems was less common, with 0.4% and 0.3% of encounters, respectively, comprising treatment of these problems. Clear demographic differences existed across the groups. The management of problems also differed, with illicit drug use problems more likely to involve provision of medication, and alcohol and tobacco treatment more likely to involve counselling and/or health advice. Despite higher rates of alcohol and tobacco use problems among patients seeing GPs in Australia, the rate of treatment for such problems was relatively lower than it was for illicit drug use problems. More efforts need to be directed towards assisting GPs to identify and target problematic alcohol and tobacco use among their patients.
Drug ‘hot‐spots’, alcohol availability and violence
Authors: GORMAN D. M. , ZHU LI , HOREL SCOTT
Published: December 2005

Ecological studies have shown a relationship between alcohol outlet densities and violence and between the location of crimes related to illicit drug use (so‐called ‘hot spots’) and violence. To date, no study has compared the effects of alcohol outlets and drug hot spots on rates of violence. The present study examined this relationship in the City of Houston, Texas. An ecological study design was employed, using a sample of 439 census tracts from Houston, Texas. Neighborhood socio‐structural, alcohol outlet density, drug crime density and violent crime density data were collected from archival sources and analyzed using multivariate and spatial statistics. Using ordinary least‐squares analysis, the neighborhood socio‐structural covariates explained about 40% of the variability in violent crime. Adding alcohol outlet density in the target census tracts explained an additional 6%, while the addition of drug crime density explained an additional 32%. In the final model, that controlled for the effects of autocorrelated error, both drug crime density in the target and adjacent census tracts remained significant predictors of violent crime, while only off‐sale density in the target census tract remained significant in the model. The findings indicate that drug crime density explained a greater amount of variance in violent crime rates than the alcohol outlet density. The methodological and policy implications of these findings are discussed, along with the shortcomings of the analysis presented.
Mortality and population drinking: a review of the literature
Authors: NORSTRÖM THOR , RAMSTEDT MATS
Published: December 2005

The aim of this review was to review research addressing the relationship between population drinking and health, particularly mortality. The review is based primarily on articles published in international journals after 1994 to February 2005, identified via Medline. The method used in most studies is time‐series analysis based on autoregressive intergrated moving average (ARIMA) modelling. The outcome measures covered included the following mortality indicators: mortality from liver cirrhosis and other alcohol‐related diseases, accident mortality, suicide, homicide, ischaemic heart disease (IHD) mortality and all‐cause mortality. The study countries included most of the EU member states as of 1995 (14 countries), Canada and the United States. For Eastern Europe there was only scanty evidence. The study period was in most cases the post‐war period. There was a statistically significant relationship between per capita consumption and mortality from liver cirrhosis and other alcohol‐related diseases in all countries. In about half the countries, there was a significant relationship between consumption, on one hand, and mortality from accidents and homicide as well as all‐cause mortality on the other hand. A link between alcohol and suicide was found in all regions except for mid‐ and southern Europe. There was no systematic link between consumption and IHD mortality. Overall, a 1‐litre increase in per capita consumption was associated with a stronger effect in northern Europe and Canada than in mid‐ and southern Europe. Research during the past decade has strengthened the notion of a relationship between population drinking and alcohol‐related harm. At the same time, the marked regional variation in the magnitude of this relationship suggests the importance of drinking patterns for modifying the impact of alcohol. By and large, there was little evidence for any cardioprotective effect at the population level. It is a challenge for future research to reconcile this outcome with the findings from observational studies, most of which suggest a protective effect of moderate drinking.
Alcohol‐related associative strength and drinking behaviours: concurrent and prospective relationships
Authors: KELLY ADRIAN B. , MASTERMAN PAUL W. , MARLATT G. ALAN
Published: December 2005

The first part of this research assessed the longitudinal relationships between alcohol‐related associative strength and alcohol use measured at two time‐points, 6 months apart. Cross‐lagged results support the utility of alcohol‐related associative strength to predict drinking behaviours prospectively and vice versa. These results remained after competing explanations of previous use, autocorrelations between memory measures, sensation seeking and background variables of age and gender were accounted for. Findings offer further evidence for an implicit cognitions approach to drinking processes. In the second part of our study, cross‐sectional analysis investigated potential mediating mechanisms in the relation of associative strength to quantity and frequency dimensions of drinking. Mediational models provide preliminary evidence that implicit memory processes may have differential effects on quantity and frequency dimensions of drinking behaviours. The results point to the possibility that increasing awareness of implicit alcohol‐related associations may have utility in interventions for young adults.
Alcohol policy and harm reduction in Australia
Authors: LOXLEY Associate Professor WENDY , GRAY DENNIS , WILKINSON CELIA , CHIKRITZHS TANYA , MIDFORD RICHARD , MOORE DAVID
Published: December 2005

With consultations having been held across Australia this year as part of the process of developing a new National Alcohol Strategy, it seemed timely to invite my colleagues from the National Drug Research Institute who are experts in the alcohol field to write this Harm Reduction Digest. The authors have canvassed a range of alcohol policy options and discussed their effectiveness in reducing harm for what is arguably Australia's number one drug problem. Australia's response to alcohol and other drug problems has, historically, been based on ‘harm minimization‐incorporating supply reduction, demand reduction and harm reduction’. At this time where the policy options for alcohol are being set for the next 5 years in a climate of ‘small government’, removing restrictions of ‘fair competition’ in business and a belief in the free market, what does the research have to say about recommended policies and strategies to reduce alcohol‐related harm?
Decreased energy expenditure during prolonged sub‐maximal exercise in a warm environment
Authors: Yamashita Yoichiro , Kaya Mitsuharu , Koyama Katsuhiro , Tsujita Junzo , Hori Seiki
Published: December 2005

The purpose of this study was to investigate the influence of a warm environment on thermoregulation and energy expenditure during sub‐maximal prolonged exercise in humans. Six healthy male subjects cycled for 120 min at an intensity of 60% maximal oxygen uptake (Vo2max) at three environmental temperatures (10°C, CT; 20°C, MT; and 30°C, WT). Although oxygen uptake at WT showed a significantly lower value compared to those at MT and CT, no significant differences of respiratory exchange ratio were observed among the three environmental trials. A remarkable decrease in total energy expenditure during the 120‐min exercise at WT was observed in comparison with those at MT and CT (p<0.05). Changes in rectal temperature, mean skin temperature, and mean body temperature at WT were significantly higher than those at both MT and CT. Although increases in mean body temperature from rest every five minutes during exercise were not different among three environmental temperatures, mean energy expenditures every five minutes at WT were lower compared with those at MT and CT (p<0.05). These results suggest that the increase in energy expenditure for physical exertion is substantially reduced during prolonged sub‐maximal exercise in a warm environment. This acute alteration in the energy metabolism may contribute to inhibition of excess heat production and enable prolonged exercise in a warm environment.
Short article: one's own face is hard to ignore
Authors: Brédart Serge , Delchambre Marie , Laureys Steven
Published: December 2005

One's own face possesses two properties that make it prone to grab attention: It is a face, and, in addition, it is a self-referential stimulus. The question of whether the self-face is actually an especially attention-grabbing stimulus was addressed by using a face–name interference paradigm. We investigated whether interference from a flanking self-face on the processing of a target classmate's name was stronger than interference from a classmate's flanking face on the processing of one's own name as the target. In a control condition a third familiar face served as the flanker for both decisions from the participant's own name and from the classmate's name. The presentation of the self-face as a flanker produced significantly more interference on the identification of a classmate's name than the presentation of that classmate's face did on the identification of one's own name. This result was due to the interfering power of the self-face and not to a particular resistance of one's name to interfering facial stimuli. We argue that the emotional value or the high familiarity of one's own face may explain its attention-grabbing property.
Development and Validation of an Objective Instrument to Measure Surgical Performance at Tonsillectomy
Authors: Roberson David W. , Kentala Erna , Forbes Peter
Published: December 2005

Objectives: The goals of this project were 1) to develop and validate an objective instrument to measure surgical performance at tonsillectomy, 2) to assess its interobserver and interobservation reliability and construct validity, and 3) to select those items with best reliability and most independent information to design a simplified form suitable for routine use in otolaryngology surgical evaluation.

Design: Prospective, observational data collection for an educational quality improvement project.

Methods: The evaluation instrument was based on previous instruments developed in general surgery with input from attending otolaryngologic surgeons and experts in medical education. It was pilot tested and subjected to iterative improvements. After the instrument was finalized, a total of 55 tonsillectomies were observed and scored during academic year 2002 to 2003: 45 cases by residents at different points during their rotation, 5 by fellows, and 5 by faculty. Results were assessed for interobserver reliability, interobservation reliability, and construct validity. Factor analysis was used to identify items with independent information.

Results: Interobserver and interobservation reliability was high. On technical items, faculty substantially outperformed fellows, who in turn outperformed residents (P < .0001 for both comparisons). On the “global” scale (overall assessment), residents improved an average of 1 full point (on a 5 point scale) during a 3 month rotation (P = .01). In the subscale of “patient care,” results were less clear cut: fellows outperformed residents, who in turn outperformed faculty, but only the fellows to faculty comparison was statistically significant (P = .04), and residents did not clearly improve over time (P = .36). Factor analysis demonstrated that technical items and patient care items factor separately and thus represent separate skill domains in surgery.

Conclusions: It is possible to objectively measure surgical skill at tonsillectomy with high reliability and good construct validity. Factor analysis demonstrated that patient care is a distinct domain in surgical skill. Although the interobserver reliability for some patient care items reached statistical significance, it was not high enough for “high stakes testing” purposes. Using reliability and factor analysis results, we propose a simplified instrument for use in evaluating trainees in otolaryngologic surgery.
Urgent Surgical Airway Intervention: A 3 Year County Hospital Experience
Authors: Altman Kenneth W. , Waltonen Joshua D. , Kern Robert C.
Published: December 2005

Objectives: To review the indications, complications, and outcomes of patients undergoing urgent surgical airway intervention.

Methods: The inpatient and outpatient charts of patients who underwent awake tracheostomy or were converted from cricothyrostomy to tracheostomy at our institutional‐affiliated County Hospital over a 3 year period were reviewed.

Results: Ninety patients underwent awake tracheotomy, and seven were converted from cricothyrostomy to tracheostomy. Indications for awake tracheotomy included impending airway obstruction from malignancy of the aerodigestive tract or that causing extrinsic compression of the airway in 72 (80%) patients, neck abscess in 4 (4.4%), subglottic stenosis in 3 (3.3%), and a variety of other etiologies in 11 (12.2%). Thirty‐eight (42%) patients were noted to have stridor. On fiberoptic laryngoscopy, 66 (80%) patients had moderate or severe airway obstruction, whereas 17 (20%) had mild or no obstruction. Of the 72 patients with squamous cell carcinoma, only 6 (8%) have been subsequently decannulated. Among the remainder, 13 of 18 (72%) have been decannulated. Complications occurred in seven (7.8%) patients after awake tracheotomy, none with untoward sequelae. Three severe complications occurred among the seven patients converted from cricothyrostomy to tracheostomy: anoxic brain injury in each, leading to death in two.

Conclusions: Awake tracheostomy should be considered in any patient with impending or ongoing airway obstruction or with potential for difficult intubation. This should be performed in a timely manner before an emergent situation arises because the complications of emergency surgical airway can be devastating.
Investigation of C‐Arm Cone‐Beam CT‐Guided Surgery of the Frontal Recess
Authors: Rafferty M A. , Siewerdsen J H. , Chan Y , Moseley D J. , Daly M J. , Jaffray D A. , Irish J C.
Published: December 2005

Objective/Hypothesis: A cone‐beam CT (CBCT) imaging system based on a mobile C‐arm (Siemens PowerMobil) incorporating a high‐performance flat‐panel detector (Varian PaxScan) has been developed in our laboratory. We hypothesize that intraoperative C‐arm CBCT provides image quality and guidance performance sufficient to assist surgical approach to the frontal recess.

Study Design: A preclinical prospective study was conducted using six cadaver heads to assess the performance characteristics and the potential clinical utility of this imaging system.

Methods: The mobile C‐arm was employed for intraoperative CBCT guidance of the endoscopic approach to twelve frontal recesses.

Results: The imaging system is capable of sub‐mm 3D spatial resolution with bone and soft‐tissue visibility and a field of view sufficient for guidance of head and neck surgery. The system can generate intraoperative, volumetric CT images rapidly with an acceptably low radiation exposure to the patient and with image quality sufficient for most surgical tasks. Moreover, the system is portable and compatible with the surgical setup, providing excellent access to the patient. Finally, the accuracy of the system is not bound to a registration process.

Conclusions: The ability to create updated images as surgery progresses introduces the concept of ‘near‐real‐time’ CT guidance for head and neck surgery. We found that the use of CBCT increased surgical confidence in accessing the frontal recess, resolved ambiguities with anatomical variations, and provided valuable teaching information to surgeons in training in both preoperative planning and correlation between tri‐planar CT scans and intraoperative endoscopic findings.
Abnormalities of Axon Growth in Human Olfactory Mucosa
Authors: Holbrook Eric H. , Leopold Donald A. , Schwob James E.
Published: December 2005

Objectives/Hypothesis: Random biopsies of the human adult olfactory mucosa often demonstrate degenerative changes in the olfactory epithelium (OE) in both dysosmic and normosmic patients and, consequently, have limited diagnostic usefulness. However, detailed analysis of the subepithelial tissue with specific attention to the fascicles of the olfactory nerve and abnormalities of axonal growth may improve the correlation of histopathology with sensory function.

Study Design: Retrospective review of human OE biopsies.

Methods: Mucosal biopsies from the olfactory area obtained from 27 subjects were examined by light and electron microscopy, with particular attention to the olfactory nerve fascicles; results were correlated with clinical status. Immunohistochemical analysis was used to characterize the extent of axonal depletion, relative maturity of the parent population, and aberrant axonal growth.

Results: As expected, there are areas of respiratory metaplasia and neuronal depletion in normosmic as well as dysosmic patients. The degree of axon degeneration within the fascicles correlates better with individual olfactory status. Immature neurons predominate, and re‐entrant neuromas develop in patients with olfactory loss caused by disconnection from the olfactory bulb. Individuals with olfactory loss caused by epithelial damage as with chronic rhinosinusitis display evidence of nerve fascicle degeneration and intraepithelial neuromas.

Conclusion: The status of olfactory axons provides useful information on the overall condition of the olfactory periphery and improves the diagnostic usefulness of mucosal biopsies. In addition to an assessment of the epithelium per se, the fascicles of the olfactory nerve need to be characterized for a complete analysis of the olfactory mucosa.