bluuebunny/crossref_metadata_2025 huggingface dataset:
Attitude change during mild intoxication
Authors: Nordstrom Erik
Published: July 2002

The effects of mild alcohol intoxication on specific attitudes were investigated in two experiments. The first experiment consisted of two sessions in which 48 subjects gave ratings on seven attitudes and two beliefs. The two sessions were separated by an interval of 1 month. In the second session, half the subjects were administered sufficient ethanol to produce a 0.02‐0.03% blood level during the rating, while the other half repeated the ratings after a non‐alcoholic drink. Only the group receiving ethanol showed significant changes in ratings. The magnitude and direction of these changes varied with the attitude or belief rated. In the second experiment, 48 different subjects gave ratings on seven attitudes on two occasions separated by an interval of 1 month. On the second occasion, all subjects were administered sufficient ethanol to produce a 0.02‐0.03% blood level during the rating. Significant changes in ratings were again observed, with the direction and magnitude of changes consistent with that seen in experiment 1. Whether subjects were rated as relatively high or low consumers of alcohol was not significantly associated with changes in ratings. It is concluded that the changes in attitudes and beliefs that are observed during mild intoxication are specific to the object of the attitude or belief. Mechanisms for such an effect, and its legal and social implications, are discussed.
Acute reactions to alcohol
Authors: WHITFIELD J. B.
Published: July 2002

Where the experience of alcohol is unpleasant because of adverse reactions to small amounts, alcohol consumption is likely to be low and alcohol dependence rare. This is shown by many studies of Asian subjects who experience the alcohol flush reaction (AFR) due to inherited aldehyde dehydrogenase (ALDH) deficiency. Alcohol reactions are less common and on average less severe in non‐Asian subjects, but they do occur and can affect alcohol consumption. Information about alcohol reactions and their consequences in Europeans is reviewed, and such reactions are compared with those caused by mitochondrial ALDH deficiency in Asians.
Fos‐like immunoreactivity in tyrosine hydroxylase and substance P‐like immunoreactive neurones in guinea‐pig brain following intracerebroventricular injection of morphine and U50,488H
Authors: Bot G. , Chahl L. A.
Published: July 2002

Opioid drugs such as morphine have powerful reinforcing effects which lead to drug‐seeking behaviour. Both dopamine‐ and substance P‐containing neurones have been implicated in reward. In the present study twocolour immunohistochemistry was used to investigate whether Fos protein was induced in dopaminergic (tyrosine hydroxylase) and substance P‐containing neurones of guinea‐pig brain following intracerebroventricular administration of the predominantly mu‐receptor agonist, morphine, and the kappa‐receptor agonist, U50,488H, which have been reported to produce rewarding and aversive effects, respectively. The present study has shown that of the large number of neurones showing Fos‐like immunoreactivity following a single injection of morphine or U50,488H, few were tyrosine hydroxylase‐positive (dopaminergic) but a larger number were substance Plike immunoreactive. These results support the proposal that substance P plays a role in reward and reinforcement.
Effects of chronic inhalation of volatile solvents, malnutrition and their interaction on seizures induced by pentylenetetrazole in rats
Authors: Palencia Guadalupe , Calvillo Minerva , Benita Antonio , Sotelo Julio
Published: July 2002

Chronic inhalation of volatile solvents induce severe brain damage. In humans, intense exposure to volatile solvents for recreational purposes is frequently associated with chronic malnutrition. We studied in rats the effects of chronic inhalation of volatile solvents and malnutrition, alone and combined, on the seizures induced by pentylenetetrazole. Animals were subjected to 14 months of either normal rodent diet or malnutrition induced by a diet based on corn derivatives; some animals were subjected for the last 4 months to daily inhalation of volatile solvents (paint thinner). Afterwards, a trial of pentylenetetrazole‐induced seizures was conducted in all animals. When compared with controls, malnutrition, chronic inhalation of volatile solvents and their combination greatly reduced the threshold for both, the forebrain and the brain stem components of seizures. However, an expected lowering of the threshold when malnutrition and solvent inhalation were combined was not observed when compared with each condition alone. It is possible that malnutrition plus solvents exposure induce severe brain damage that interferes with the brain structures involved in the propagation of epileptic seizures.
Additional evidence for an association between the dopamine D4 receptor (D4DR) exon III seven‐repeat allele and substance abuse in opioid dependent subjects: relationship of treatment retention to genotype and personality
Authors: Mel Haim , Horowitz Ronit , Ohel Naomi , Kramer Ilana , Kotler Moshe , Cohen Hagit , Gritsenko Inga , Ebstein Richard P.
Published: July 2002

The long form of the dopamine D4 receptor (D4DR) exon III repeat polymorphism has been linked in some but not all studies to impulsive, extravagant and novelty‐seeking personality traits that are prominent in affiliated behaviours such as attention deficit disorder and substance abuse. In particular, we have reported previously an increased frequency of the long seven‐repeat D4DR exon III allele in a group of 141 opioiddependent subjects compared to 110 control subjects. In order to further substantiate the role of D4DR in contributing to heroin addiction we have genotyped an additional, smaller cohort of opioid‐dependent subjects. In this new group of 57 opioid‐dependent subjects compared to an expanded group of 143 control subjects a significant difference was observed in overall genotype frequency (p=0.04). An excess of the seven‐repeat allele of the D4DR receptor gene was also observed compared to control subjects (p=0.06). The frequency of the seven‐repeat allele is 15.8% in the heroin addict population vs. 8.1% in the control group, conferring a relative risk of 2.07 (95% CI: 0.98–4.38). An association between two polymorphisms considered together (D4DR and dopamine D3 receptor) and treatment retention was observed (p=0.02). In a subgroup of 38 opioid‐dependent subjects, who were successfully administered the TPQ, higher Harm Avoidance (p< 0.001) and Novelty Seeking (NS3; extravagant vs. reserved, p< 0.001) scores were found. In contrast to some previous reports, no relationship was apparent between TPQ scores and treatment retention in this small group of opioid‐dependent subjects.
β‐Carbolines in alcohol‐dependent intensive care patients during prophylactics and therapy of alcohol withdrawal syndrome
Authors: SPIES CLAUDIA D. , MORCINIEC PAWEL , LENZENHUBER ERIKA , MÜLLER CHRISTIAN , MARKS CHRISTIAN , HELLING KAI , RUNKEL NORBERT , BERGER GERD , BLUM SUSANNE , ROMMELSPACHER HANS
Published: July 2002

The primary aim of this study was to investigate whether the naturally occurring beta‐carbolines norharman and harman differed between alcohol‐dependent patients who developed alcohol withdrawal syndrome (AWS) and those who did not. The secondary aim was to determine whether different treatment regimens influenced the levels of the beta‐carbolines. Thirty chronic alcoholics with carcinoma of the upper digestive tract were included in this study. They were prophylactically treated by two different medical regimens: flunitrazepam and clonidine (FNZ regimen) and gamma‐hydroxybutyrate and clonidine (GHB regimen). Patients exceeding the Revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA‐Ar) score of 20 were assigned to the AWS therapy group and received haloperidol in addition to their prevous prophylactic treatment. Patients without AWS remained in the prophylactic group. From days 1–4 of the intensive care unit (ICU) stay norharman, but not harman, was increased in the AWS therapy group. In the FNZ regimen, six of 16 patients (38%) and in the GHB regimen, nine of 14 patients (64%) developed AWS (p= 0.14). Norharman levels did not differ between the two regimens. However, harman levels were increased in the GHB treated regimen on days 1, 2 and 4 following admission to the ICU and correlated with the severity of alcohol withdrawal syndrome. As norharman was elevated in the therapeutically treated ICU patients, this marker appears to be involved in the pathogenesis of AWS. As harman was elevated before and during hallucinations on the GHB regimen, it seems reasonable to carry out further investigations into the potential role of harman as a hallucinatory substance.
Nifedipine but not verapamil inhibits subjective effects of i.v. morphine in opiate‐dependent patients
Authors: SOPHRONOV A. , ZVARTAU E. , KUZMIN A.
Published: July 2002

The influence of verapamil and nifedipine after single and subchronic treatment on morphine‐induced subjective responses were studied in opiate addicts. Heroin‐dependent subjects were injected via an antecubetal vein with 20 mg of morphine or placebo using a randomized cross‐over design. In Experiment one, either verapamil 80 mg or nifedipine 60 mg or placebo was administered per os 1 hour prior morphine or placebo injection. In experiment two calcium blockers were administered weekly prior morphine administration. Administration of nifedipine (40 mg) reduced, not significantly, the subjective scaling of morphine effects and shifted the discrimination of morphine effects towards those of weak opiates. Acute treatment with verapamil (80 mg) increased, not significantly, the subjective rating of morphine effects. Pre‐treatment of heroin abusers with nifedipine 60 mg daily for a week resulted in a remarkable inhibition of opiate‐induced effects both expression and duration in comparison with placebo and verapamil pre‐treatment. Patients pre‐treated with nifedipine were also unable to discriminate properly morphine from other psychotropic compounds. Thus, nifedipine but not verapamil markedly inhibited but did not reduce completely the central effects of morphine. It is concluded that nifedipine can potentially offer a new interesting approach to the treatment programmes of opiate abuse.
Cocaethylene: effects on brain systems and behavior
Authors: HOROWITZ JUDITH M. , TORRES GERMAN
Published: July 2002

Cocaethylene is a psychoactive metabolite formed during the combined consumption of cocaine and ethanol. In this brief review, we discuss several well‐characterized effects of this metabolite with an emphasis on the neurobiological and behavioral correlates of polydrug addiction. Included herein are the descriptions of some of the changes in trans‐synaptic transmission and their relationship to pathological behaviors associated with a chronic, drug‐dependent state that may be altered by the spatial or temporal dynamics of cocaethylene.
Lack of association of the dopamine D4 receptor gene polymorphism with alcoholism in a Brazilian population
Authors: ROMAN TATIANA , BAU CLAITON H. D. , ALMEIDA SILVANA , HUTZ MARA H.
Published: July 2002

The dopaminergic system has been implicated in alcoholism, but most of the past investigations concentrated on the dopamine D2 receptor (DRD2), with conflicting results. The dopamine D4 receptor gene (DRD4) is in the same class as DRD2, but presents different pharmacological properties. This gene has an expressed highly variable 48 base pair (bp) tandem repeat polymorphism (VNTR), which could be of functional relevance.We screened 100 Caucasians and 100 Afro‐Brazilians to determine the allele distribution of this polymorphism in a southern Brazilian population. The allele frequencies observed are significantly different from those described in the literature except when Afro‐Brazilians and African Bantus are compared. A group of 136 male alcoholics, classified according to DSM‐III‐R criteria for alcohol dependence, was also ascertained. The results of the association study were negative for comparisons between white and black alcoholics and controls, and no association was disclosed when either subtypes of alcoholics and different aspects of this condition were considered. These results, together with those available in the literature for other ethnic groups, suggest a minor role, if any, of the DRD4 gene in the susceptibility to alcoholism.
Book and media reviews
Authors: COOK CHRIS
Published: July 2002

Book reviewed in this article:

Book reviews in this column will primarily be of titles focusing completely, or in part, on biological aspects of addiction. However, significant titles of general relevance to the addictions field will also be included, even if they are not “biological”, as will titles of general methodological and clinical relevance, even if they are not on “addictions”. Similar considerations will apply to other media (software, audio tapes and CDs, videos, etc). However, specific “addictions” software applications seem to be relatively uncommon and, as these items are rarely reviewed elsewhere, we will endeavour to include reviews of some of the older programmes that are still useful, as well as new titles that appear. I would appreciate suggestions of any items suitable for reviews, but especially software and other media of specific relevance to the addictions. Please contact: Professor Chris Cook, Kent Institute of Medicine and Health Sciences, University of Kent at Canterbury, Kent CT2 7NR, UK. Email: http://www.c.c.h.cook@ukc.ac.uk

Ninth Special Report to the US Congress on Alcohol and Health from the Secretary of Health and Human Services, June 1997 NATIONAL INSTITUTE OF ALCOHOL ABUSE AND ALCOHOLISM

The Myth of Addiction JOHN BOOTH DAVIES

Addictive Behaviour: Molecules to Mankind ‐ Perspectives on the Nature of Addiction A. BONNER & J. WATERHOUSE (Eds)

Addiction Intervention R. K. WRIGHT & D. G. WRIGHT

Nicotine, Caffeine and Social Drinking: behaviour and brain function J. SNEL & M. M. LORIST (Eds)

New Treatments for Opiate Dependence SUSAN M. STINE & T. R. KOSTEN (Eds)

Alcohol Use and Abuse among Latinos. Issues and examples of culturally competent services MELVIN DELGADO

Cancer & Clinical Biochemistry PETER PANNALL & DUSAN KOTASEK

Drug Data 2: a multimedia encyclopaedia on drugs and drug use

Drug Discovery and Evaluation Pharmacological Assays H. G. VOGEL & W. H. VOGEL (Eds)

The Cell “Unit of Life” ‐ A Visual Primer ALEXANDER N. GLAZER
Investigating parental views of involvement in pre‐school speech and language therapy
Authors: Glogowska Margaret , Campbell Rona
Published: July 2002

Today, speech and language therapists working with the pre‐school population routinely involve parents in their children's treatment programmes. Also, there is increasing recognition of the importance of considering client and carer views in evaluating services. Thus, in both clinical and research terms, the rôle of parents is key. This paper reports an aspect of a study that investigated parents’ views and perceptions of their pre‐school children's speech and language difficulties and the speech and language therapy (SLT) they received. The methodology of the study was qualitative and data were collected from the parents of 16 pre‐school children, using in‐depth interviews. The parents’ perceptions could be characterized as a process with three phases. On the whole, parents viewed their involvement in SLT positively but crucially, the interviews highlighted discrepancies between therapists’ and parents’ perceptions of the therapy process. The study demonstrates that when parents’ views are considered, a fuller understanding of the effectiveness and acceptability of treatment can emerge.
Developing communication in adults with profound and multiple learning difficulties using objects of reference
Authors: Jones Frances , Pring Tim , Grove Nicola
Published: July 2002

Objects of reference were used to develop communication in adults with profound and multiple learning difficulties (PMLD). The use of objects specific to individuals is recommended, but it makes heavy demands on care staff who implement such programmes. This study investigated the effectiveness of using a standard set of objects with a group of 13 adults with PMLD. Progress was monitored over a 20−week training period using an assessment based upon the cues provided by staff to promote the use of the objects. Results indicated that the group as a whole made significant gains, although a plateau effect was reached after the first 10 weeks of training. Some individuals within the group were near to ceiling performance after training, while others, though progressing, still made limited use of the objects. There was evidence, as suggested in the literature, that greater and more sustained progress was made with objects at the index level of representation. The views of the care staff who implemented the training programme were sought through semistructured interviews. Although the use of a standard set of objects presents a number of difficulties, it is concluded that it is desirable in situations where the use of individual objects with each client is unfeasible. It has the additional advantages that it instructs and motivates care staff and provides a means by which the use of objects of reference by individual clients may be assessed and planning for the development of their communication may be informed.
Aggregation As a Determinant of Protein Fate in Post-Golgi Compartments: Role of the Luminal Domain of Furin in Lysosomal Targeting
Authors: Wolins Nathan , Bosshart Herbert , Küster Helmut , Bonifacino Juan S.
Published: July 2002

The mammalian endopeptidase furin is a type 1 integral membrane protein that is predominantly localized to the TGN and is degraded in lysosomes with a t1/2 = 2–4 h. Whereas the localization of furin to the TGN is largely mediated by sorting signals in the cytosolic tail of the protein, we show here that targeting of furin to lysosomes is a function of the luminal domain of the protein. Inhibition of lysosomal degradation results in the accumulation of high molecular weight aggregates of furin; aggregation is also dependent on the luminal domain of furin. Temperature and pharmacologic manipulations suggest that furin aggregation occurs in the TGN and thus precedes delivery to lysosomes. These findings are consistent with a model in which furin becomes progressively aggregated in the TGN, an event that leads to its transport to lysosomes. Our observations indicate that changes in the aggregation state of luminal domains can be potent determinants of biosynthetic targeting to lysosomes and suggest the possible existence of quality control mechanisms for disposal of aggregated proteins in compartments of the secretory pathway other than the endoplasmic reticulum.
Involvement of Receptor-like Protein Tyrosine Phosphatase ζ/RPTPβ and Its Ligand Pleiotrophin/Heparin-binding Growth-associated Molecule (HB-GAM) in Neuronal Migration
Authors: Maeda Nobuaki , Noda Masaharu
Published: July 2002

Pleiotrophin/heparin-binding growth-associated molecule (HB-GAM) is a specific ligand of protein tyrosine phosphatase ζ (PTPζ)/receptor-like protein tyrosine phosphatase β (RPTPβ) expressed in the brain as a chondroitin sulfate proteoglycan. Pleiotrophin and PTPζ isoforms are localized along the radial glial fibers, a scaffold for neuronal migration, suggesting that these molecules are involved in migratory processes of neurons during brain development. In this study, we examined the roles of pleiotrophin-PTPζ interaction in the neuronal migration using cell migration assay systems with glass fibers and Boyden chambers. Pleiotrophin and poly-l-lysine coated on the substratums stimulated cell migration of cortical neurons, while laminin, fibronectin, and tenascin exerted almost no effect. Pleiotrophin-induced and poly-l-lysine–induced neuronal migrations showed significant differences in sensitivity to various molecules and reagents. Polyclonal antibodies against the extracellular domain of PTPζ, PTPζ-S, an extracellular secreted form of PTPζ, and sodium vanadate, a protein tyrosine phosphatase inhibitor, added into the culture medium strongly suppressed specifically the pleiotrophin-induced neuronal migration. Furthermore, chondroitin sulfate C but not chondroitin sulfate A inhibited pleiotrophin-induced neuronal migration, in good accordance with our previous findings that chondroitin sulfate constitutes a part of the pleiotrophin-binding site of PTPζ, and PTPζ-pleiotrophin binding is inhibited by chondroitin sulfate C but not by chondroitin sulfate A. Immunocytochemical analysis indicated that the transmembrane forms of PTPζ are expressed on the migrating neurons especially at the lamellipodia along the leading processes. These results suggest that PTPζ is involved in the neuronal migration as a neuronal receptor of pleiotrophin distributed along radial glial fibers.
Unc-45 Mutations in Caenorhabditis elegans Implicate a CRO1/She4p-like Domain in Myosin Assembly
Authors: Barral José M. , Bauer Christopher C. , Ortiz Irving , Epstein Henry F.
Published: July 2002

The Caenorhabditis elegans unc-45 locus has been proposed to encode a protein machine for myosin assembly. The UNC-45 protein is predicted to contain an NH2-terminal domain with three tetratricopeptide repeat motifs, a unique central region, and a COOH-terminal domain homologous to CRO1 and She4p. CRO1 and She4p are fungal proteins required for the segregation of other molecules in budding, endocytosis, and septation. Three mutations that lead to temperature-sensitive (ts) alleles have been localized to conserved residues within the CRO1/She4p-like domain, and two lethal alleles were found to result from stop codon mutations in the central region that would prevent translation of the COOH-terminal domain. Electron microscopy shows that thick filament accumulation in vivo is decreased by ∼50% in the CB286 ts mutant grown at the restrictive temperature. The thick filaments that assemble have abnormal structure. Immunofluorescence and immunoelectron microscopy show that myosins A and B are scrambled, in contrast to their assembly into distinct regions at the permissive temperature and in wild type. This abnormal structure correlates with the high degree of instability of the filaments in vitro as reflected by their extremely low yields and shortened lengths upon isolation. These results implicate the UNC-45 CRO1/She4p-like region in the assembly of myosin isoforms in C. elegans and suggest a possible common mechanism for the function of this UCS (UNC-45/CRO1/She4p) protein family.
Dissection of the Molecular Basis of pp60v-src Induced Gating of Connexin 43 Gap Junction Channels
Authors: Zhou Lan , Kasperek Eileen M. , Nicholson Bruce J.
Published: July 2002

Suppression of gap-junctional communication by various protein kinases, growth factors, and oncogenes frequently correlates with enhanced mitogenesis. The oncogene v-src appears to cause acute closure of gap junction channels. Tyr265 in the COOH-terminal tail of connexin 43 (Cx43) has been implicated as a potential target of v-src, although v-src action has also been associated with changes in serine phosphorylation. We have investigated the mechanism of this acute regulation through mutagenesis of Cx43 expressed in Xenopus laevis oocyte pairs. Truncations of the COOH-terminal domain led to an almost complete loss of response of Cx43 to v-src, but this was restored by coexpression of the independent COOH-terminal polypeptide. This suggests a ball and chain gating mechanism, similar to the mechanism proposed for pH gating of Cx43, and K+ channel inactivation. Surprisingly, we found that v-src mediated gating of Cx43 did not require the tyrosine site, but did seem to depend on the presence of two potential SH3 binding domains and the mitogen-activated protein (MAP) kinase phosphorylation sites within them. Further point mutagenesis and pharmacological studies in normal rat kidney (NRK) cells implicated MAP kinase in the gating response to v-src, while the stable binding of v-src to Cx43 (in part mediated by SH3 domains) did not correlate with its ability to mediate channel closure. This suggests a common link between closure of gap junctions by v-src and other mitogens, such as EGF and lysophosphatidic acid (LPA).
Afadin
Authors: Ikeda Wataru , Nakanishi Hiroyuki , Miyoshi Jun , Mandai Kenji , Ishizaki Hiroyoshi , Tanaka Miki , Togawa Atushi , Takahashi Kenichi , Nishioka Hideo , Yoshida Hisahiro , Mizoguchi Akira , Nishikawa Shin-ichi , Takai Yoshimi
Published: July 2002

Afadin is an actin filament–binding protein that binds to nectin, an immunoglobulin-like cell adhesion molecule, and is colocalized with nectin at cadherin-based cell–cell adherens junctions (AJs). To explore the function of afadin in cell–cell adhesion during embryogenesis, we generated afadin−/− mice and embryonic stem cells. In wild-type mice at embryonic days 6.5–8.5, afadin was highly expressed in the embryonic ectoderm and the mesoderm, but hardly detected in the extraembryonic regions such as the visceral endoderm. Afadin−/− mice showed developmental defects at stages during and after gastrulation, including disorganization of the ectoderm, impaired migration of the mesoderm, and loss of somites and other structures derived from both the ectoderm and the mesoderm. Cystic embryoid bodies derived from afadin−/− embryonic stem cells showed normal organization of the endoderm but disorganization of the ectoderm. Cell–cell AJs and tight junctions were improperly organized in the ectoderm of afadin−/− mice and embryoid bodies. These results indicate that afadin is highly expressed in the ectoderm- derived cells during embryogenesis and plays a key role in proper organization of AJs and tight junctions of the highly expressing cells, which is essential for proper tissue morphogenesis.
Adp Ribosylation Factor-like Protein 2 (Arl2) Regulates the Interaction of Tubulin-Folding Cofactor D with Native Tubulin
Authors: Bhamidipati Arunashree , Lewis Sally A. , Cowan Nicholas J.
Published: July 2002

The ADP ribosylation factor-like proteins (Arls) are a family of small monomeric G proteins of unknown function. Here, we show that Arl2 interacts with the tubulin-specific chaperone protein known as cofactor D. Cofactors C, D, and E assemble the α/β- tubulin heterodimer and also interact with native tubulin, stimulating it to hydrolyze GTP and thus acting together as a β-tubulin GTPase activating protein (GAP). We find that Arl2 downregulates the tubulin GAP activity of C, D, and E, and inhibits the binding of D to native tubulin in vitro. We also find that overexpression of cofactors D or E in cultured cells results in the destruction of the tubulin heterodimer and of microtubules. Arl2 specifically prevents destruction of tubulin and microtubules by cofactor D, but not by cofactor E. We generated mutant forms of Arl2 based on the known properties of classical Ras-family mutations. Experiments using these altered forms of Arl2 in vitro and in vivo demonstrate that it is GDP-bound Arl2 that interacts with cofactor D, thereby averting tubulin and microtubule destruction. These data establish a role for Arl2 in modulating the interaction of tubulin-folding cofactors with native tubulin in vivo.
Tea2p Is a Kinesin-like Protein Required to Generate Polarized Growth in Fission Yeast
Authors: Browning Heidi , Hayles Jacqueline , Mata Juan , Aveline Lauren , Nurse Paul , McIntosh J. Richard
Published: July 2002

Cytoplasmic microtubules are critical for establishing and maintaining cell shape and polarity. Our investigations of kinesin-like proteins (klps) and morphological mutants in the fission yeast Schizosaccharomyces pombe have identified a kinesin-like gene, tea2+, that is required for cells to generate proper polarized growth. Cells deleted for this gene are often bent during exponential growth and initiate growth from improper sites as they exit stationary phase. They have a reduced cytoplasmic microtubule network and display severe morphological defects in genetic backgrounds that produce long cells. The tip-specific marker, Tea1p, is mislocalized in both tea2-1 and tea2Δ cells, indicating that Tea2p function is necessary for proper localization of Tea1p. Tea2p is localized to the tips of the cell and in a punctate pattern within the cell, often coincident with the ends of cytoplasmic microtubules. These results suggest that this kinesin promotes microtubule growth, possibly through interactions with the microtubule end, and that it is important for establishing and maintaining polarized growth along the long axis of the cell.
Murine Cutaneous Mastocytosis and Epidermal Melanocytosis Induced by Keratinocyte Expression of Transgenic Stem Cell Factor
Authors: Kunisada Takahiro , Lu Shu-Zhuang , Yoshida Hisahiro , Nishikawa Satomi , Nishikawa Shin-ichi , Mizoguchi Masako , Hayashi Shin-ichi , Tyrrell Lynda , Williams David A. , Wang Xiaomei , Jack Longley B.
Published: July 2002

The growth and differentiation of mast cells and melanocytes require stem cell factor (SCF), the ligand for the kit receptor tyrosine kinase. SCF may exist as a membrane-bound or soluble molecule. Abnormalities of the SCF-kit signaling pathway, with increased local concentrations of soluble SCF, have been implicated in the pathogenesis of the human disease cutaneous mastocytosis, but have not yet been shown to play a causal role. To investigate both the potential of SCF to cause mastocytosis and its role in epidermal melanocyte homeostasis, we targeted the expression of SCF to epidermal keratinocytes in mice with two different transgenes controlled by the human keratin 14 promoter. The transgenes contained cDNAs that either produced SCF, which can exist in both membrane-bound and soluble forms, or SCF, which remains essentially membrane bound. Murine epidermal keratinocyte expression of membrane-bound/ soluble SCF reproduced the phenotype of human cutaneous mastocytosis, with dermal mast cell infiltrates and epidermal hyperpigmentation, and caused the maintenance of a population of melanocytes in the interadnexal epidermis, an area where melanocytes and melanin are found in human skin but where they are not typically found in murine skin. Expression of membrane-bound SCF alone resulted in epidermal melanocytosis and melanin production, but did not by itself cause mastocytosis. We conclude, first, that a phenotype matching that of human mastocytosis can be produced in mice by keratinocyte overproduction of soluble SCF, suggesting a potential cause of this disease. Second, we conclude that keratinocyte expression of membrane-bound SCF results in the postnatal maintenance of epidermal melanocytes in mice. Since the resulting animals have skin that more closely approximates human skin than do normal mice, their study may be more relevant to human melanocyte biology than the study of skin of normal mice.
Deletion of Fcγ Receptor IIB Renders H-2b Mice Susceptible to Collagen-induced Arthritis
Authors: Yuasa Takae , Kubo Satoshi , Yoshino Tadashi , Ujike Azusa , Matsumura Kimio , Ono Masao , Ravetch Jeffrey V. , Takai Toshiyuki
Published: July 2002

Autoimmune diseases, like rheumatoid arthritis, result from a dysregulation of the immune response culminating in hyperactivation of effector cells leading to immune-mediated injury. To maintain an appropriate immune response and prevent the emergence of autoimmune disease, activation signals must be regulated by inhibitory pathways. Biochemical and genetic studies indicate that the type IIB low-affinity receptor for immunoglobulin (Ig)G (FcγRIIB) inhibits cellular activation triggered through antibody or immune complexes and may be an important component in preventing the emergence of autoimmunity. To investigate the role of FcγRIIB in the development of type II collagen (CII)-induced arthritis (CIA), a model for rheumatoid arthritis in humans, we have examined its contribution in determining the susceptibility to CIA in the nonpermissive H-2b haplotype. H-2b mice immunized with bovine CII do not develop appreciable disease. In contrast, immunization of the FcγRIIB-deficient, H-2b mice with bovine CII induced CIA at an incidence of 42.2%. The maximal arthritis index of the FcγRIIB-deficient mice developing CIA (6.9 ± 3.6) was comparable to that of DBA/1 mice (8.6 ± 1.9), an H-2q strain susceptible for CIA induction. IgG1, IgG2a, and IgG2b antibody responses against CII were elevated in the FcγRIIB-deficient animals, especially in those mice showing arthritis, but less pronounced than DBA/1 mice. Histological examinations of the arthritic paws from FcγRIIB-deficient mice revealed that cartilage was destroyed and bone was focally eroded in association with marked lymphocyte and monocyte/macrophage infiltration, very similar to the pathologic findings observed in DBA/1 mice. These results indicate that a nonpermissive H-2b haplotype can be rendered permissive to CIA induction through deletion of FcγRIIB, suggesting that FcγRIIB plays a critical role in suppressing the induction of CIA.
A Kinetic Analysis of Calcium-Triggered Exocytosis
Authors: Blank Paul S. , Vogel Steven S. , Malley James D. , Zimmerberg Joshua
Published: July 2002

Although the relationship between exocytosis and calcium is fundamental both to synaptic and nonneuronal secretory function, analysis is problematic because of the temporal and spatial properties of calcium, and the fact that vesicle transport, priming, retrieval, and recycling are coupled. By analyzing the kinetics of sea urchin egg secretory vesicle exocytosis in vitro, the final steps of exocytosis are resolved. These steps are modeled as a three-state system: activated, committed, and fused, where interstate transitions are given by the probabilities that an active fusion complex commits (α) and that a committed fusion complex results in fusion, p. The number of committed complexes per vesicle docking site is Poisson distributed with mean n. Experimentally, p and n increase with increasing calcium, whereas α and the pn ratio remain constant, reducing the kinetic description to only one calcium-dependent, controlling variable, n. On average, the calcium dependence of the maximum rate (Rmax) and the time to reach Rmax (Tpeak) are described by the calcium dependence of n. Thus, the nonlinear relationship between the free calcium concentration and the rate of exocytosis can be explained solely by the calcium dependence of the distribution of fusion complexes at vesicle docking sites.
Global wellposedness of defocusing critical nonlinear Schrödinger equation in the radial case
Authors: Bourgain J.
Published: July 2002

We establish global wellposedness and scattering for the

H

1

H^{1}

- critical defocusing NLS in 3D

i

u

t

+
Δ
u
−
u

|

u

|

4

=
0

\begin{equation*}iu_{t}+\Delta u - u|u|^{4}=0 \end{equation*}

assuming radial data

ϕ
∈

H

s

\phi \in H^{s}

,

s
≥
1

s\geq 1

. In particular, it proves global existence of classical solutions in the radial case. The same result is obtained in 4D for the equation

i

u

t

+
Δ
u
−
u

|

u

|

2

=
0.

\begin{equation*}iu_{t}+\Delta u -u|u|^{2} =0. \end{equation*}
Competition of Spontaneous Protein Folding and Mitochondrial Import Causes Dual Subcellular Location of Major Adenylate Kinase
Authors: Strobel Gertrud , Zollner Alfred , Angermayr Michaela , Bandlow Wolfhard
Published: July 2002

Sorting of cytoplasmically synthesized proteins to their target compartments usually is highly efficient so that cytoplasmic precursor pools are negligible and a particular gene product occurs at one subcellular location only. Yeast major adenylate kinase (Adk1p/Aky2p) is one prominent exception to this rule. In contrast to most mitochondrial proteins, only a minor fraction (6–8%) is taken up into the mitochondrial intermembrane space, whereas the bulk of the protein remains in the cytosol in sequence-identical form. We demonstrate that Adk1p/Aky2p uses a novel mechanism for subcellular partitioning between cytoplasm and mitochondria, which is based on competition between spontaneous protein folding and mitochondrial targeting and import. Folding is spontaneous and rapid and can dispense with molecular chaperons. After denaturation, enzymatic activity of Adk1p/Aky2p returns within a few minutes and, once folded, the protein is thermally and proteolytically very stable. In an uncoupled cell-free organellar import system, uptake of Adk1p/Aky2p is negligible, but can be improved by previous chaotropic denaturation. Import ensues independently of Hsp70 or membrane potential. Thus, nascent Adk1p/Aky2p has two options: either it is synthesized to completion and folds into an enzymatically active import-incompetent conformation that remains in the cytosol; or, during synthesis and before commencement of significant tertiary structure formation, it reaches a mitochondrial surface receptor and is internalized.
Susceptibility to levofloxacin of clinical isolates of bacteria from intensive care and haematology/oncology patients in Switzerland: a multicentre study
Authors: Siegrist Hans H. , Nepa Mary-Claude , Jacquet Alain
Published: July 2002

The objective of this study was to examine the susceptibility of clinical isolates to levofloxacin, a fluoroquinolone with extended activity against Gram-positive bacteria, and other antibiotics in 12 Swiss clinical microbiology laboratories using the NCCLS disc diffusion technique. Isolates were prospectively collected from intensive care units (ICUs) (59%), oncology wards (7%) and other units with haematology/oncology patients (34%) from June 1995 to March 1996. The levofloxacin breakpoints used were as recommended by the manufacturer. A total of 310 Gram-positive and 580 Gram-negative isolates from the respiratory tract (36%), skin/wounds (12%), blood (16%), urine (17%) and other sources (19%) were tested. The percentage of isolates susceptible to levofloxacin was 100% for Enterococcus spp. (38 strains), Streptococcus agalactiae (13), Streptococcus pneumoniae (65), Acinetobacter spp. (11), Citrobacter diversus (6), Citrobacter freundii (17), Klebsiella oxytoca (39), Morganella morganii (16), Proteus mirabilis (20), Proteus vulgaris (23), Serratia spp. (19), Stenotrophomonas maltophilia (10) and Haemophilus influenzae (41). The percentage of isolates susceptible to levofloxacin for Staphylococcus aureus (95 strains, including 2% MRSA) was 94%, coagulase-negative staphylococci (85) 65%, Enterobacter spp. (75) 99%, Escherichia coli (111) 97%, Klebsiella pneumoniae (45) 98% and Pseudomonas aeruginosa (124) 87%. In conclusion, levofloxacin is a new fluoroquinolone to which the most common clinical isolates in Switzerland are susceptible. The susceptibility of Enterococcus spp. and S. pneumoniae to levofloxacin was particularly remarkable. This compound appears to be a promising therapeutic alternative for the treatment of Gram-positive infections.
Ultraviolet polarization vision in fishes: possible mechanisms for coding e–vector
Authors: Hawryshyn Craig W.
Published: July 2002

Polarization vision in vertebrates has been marked with significant controversy over recent decades. In the last decade, however, models from two laboratories have indicated that the spatial arrangement of photoreceptors provides the basis for polarization sensitivity.Work in my laboratory, in collaboration with I. Novales Flamarique and F. I. Harosi, has shown that polarization sensitivity depends on a well–defined square cone mosaic pattern and that the biophysical properties of the square cone mosaic probably account for polarization vision in the ultraviolet spectrum. The biophysical mechanism appears to be based on the selective reflection of axial–polarized light by the partitioning membrane, formed along the contact zone between the members of the double cones, onto neighbouring ultraviolet–sensitive cones. In this short review, I discuss the historical development of this research problem.
Episodic memory and common sense: how far apart?
Authors: Tulving Endel
Published: July 2002

Research has revealed facts about human memory in general and episodic memory in particular that deviate from both common sense and previously accepted ideas. This paper discusses some of these deviations in light of the proceedings of The Royal Society's Discussion Meeting on episodic memory. Retrieval processes play a more critical role in memory than commonly assumed; people can remember events that never happened; and conscious thoughts about one's personal past can take two distinct forms—‘autonoetic’ remembering and ‘noetic’ knowing. The serial—dependent—independent (SPI) model of the relations among episodic, semantic and perceptual memory systems accounts for a number of puzzling phenomena, such as some amnesic patients' preserved recognition memory and their ability to learn new semantic facts, and holds that episodic remembering of perceptual information can occur only by virtue of its mediation through semantic memory. Although common sense endows many animals with the ability to remember their past experiences, as yet there is no evidence that humanlike episodic memory—defined in terms of subjective time, self, and autonoetic awareness—is present in any other species.
The evolution of human influenza viruses
Authors: Hay Alan J. , Gregory Victoria , Douglas Alan R. , Lin Yi Pu
Published: July 2002

The evolution of influenza viruses results in (i) recurrent annual epidemics of disease that are caused by progressive antigenic drift of influenza A and B viruses due to the mutability of the RNA genome and (ii) infrequent but severe pandemics caused by the emergence of novel influenza A subtypes to which the population has little immunity. The latter characteristic is a consequence of the wide antigenic diversity and peculiar host range of influenza A viruses and the ability of their segmented RNA genomes to undergo frequent genetic reassortment (recombination) during mixed infections. Contrasting features of the evolution of recently circulating influenza AH1N1, AH3N2 and B viruses include the rapid drift of AH3N2 viruses as a single lineage, the slow replacement of successive antigenic variants of AH1N1 viruses and the co–circulation over some 25 years of antigenically and genetically distinct lineages of influenza B viruses. Constant monitoring of changes in the circulating viruses is important for maintaining the efficacy of influenza vaccines in combating disease.
Dosimetry of the I‐Plant Model 3500 iodine‐125 brachytherapy source
Authors: Duggan D. M. , Johnson B. L.
Published: July 2002

brachytherapy sources have been widely used for interstitial implants for a number of years in several tumor sites, especially the prostate. The design of the new I‐Plant Model 3500 iodine source is novel, yet its characteristics are similar to those of two existing designs, Model 6711 and the Symmetra. Dosimetry parameters (including dose rate constant, radial dose function, and anisotropy function, as defined by AAPM Task Group 43) were measured with LiF thermoluminescent dosimeters in water‐equivalent plastic phantoms. The dose rate constant was found by direct comparison of calibrated I‐Plant Model 3500 and Model 6711 seeds in a solid water phantom, to be 1.01 (cGy/h)/U. The radial dose function and anisotropy function are similar to those of the Model 6711 and Symmetra seeds.
Automated three‐dimensional registration of magnetic resonance and positron emission tomography brain images by multiresolution optimization of voxel similarity measures
Authors: Studholme Colin , Hill Derek L. G. , Hawkes David J.
Published: July 2002

Approaches using measures of voxel intensity similarity are showing promise in fully automating magnetic resonance (MR) and positron emission tomography (PET) image registration in the head, without requiring extraction and identification of corresponding structures. In this paper a method of multiresolution optimization of these measures is described and five alternative measures are compared: cross correlation, minimization of corresponding PET intensity variation, moments of the distribution of values in the intensity feature space, entropy of the intensity feature space and mutual information. Their ability to recover registration is examined for ten clinically acquired image pairs with respect to the size of initial misregistration, the precision of the final result, and the accuracy assessed by visual inspection. The mutual information measure proved the most robust to initial starting estimate, successfully registering 98.8% of 900 trial misregistrations. Success is defined as providing a visually acceptable solution to a trained observer. A high resolution search ( mm step size) of 30 trial misregistrations showed that optimization using the mutual information measure provided solutions with 0.13 mm, 0.11 mm and 0.17 mm standard deviations in the three Cartesian axes of the translation vector and 0.2°, 0.3° and 0.2° standard deviations for rotations about the three axes. The algorithm takes between 4 and 8 minutes to run on a typical workstation, including visual inspection of the result.
A method for more efficient source localization of interstitial implants with biplane radiographs
Authors: Cai Jialing , Chu James C. H. , Saxena V. Amod , Lanzl Lawrence H.
Published: July 2002

The conventional method for source localization in an interstitial ribbon implant by means of biplane radiographs can be difficult, especially when a large number of seeds are involved. We present a new algorithm for more efficient source localization with the same conventional biplane radiographs. The method does not require a one‐to‐one source correspondence between two radiographs. The user needs only to digitize several points, following the shape of each ribbon from both films. The points that are digitized do not need to be the location of the seeds, and they do not have to correspond to the same points on both films. The algorithm uses the multidimensional minimization method to reconstruct the three‐dimensional locus of the ribbon. The location of each seed is then determined by its pathlength relative to the corresponding starting point. We have used phantom experiments and clinical cases to test the reliability of the algorithm. The results show that the errors in the determination of seed locations are less than 2 mm, and the efficiency in source digitization for data entry can be increased by a factor up to 5.
Quantitative imaging using a time-domain eigenfunction method
Authors: Lin Feng , Nachman Adrian I. , Waag Robert C.
Published: July 2002

An inverse scattering method that uses eigenfunctions of a scattering operator at a single frequency is extended to include the full range of frequencies present in the incident pulse waveform. The resulting so-called time-domain eigenfunction method is shown to yield a modulated version of the scattering potential. The potential is recovered by a demodulation process using cross correlation with a reference. Including an adaptive delay in the reference is shown to compensate partially for the linearization of the Born approximation and to extend its valid range. The k-space window of the time-domain solution is expressed in terms of the incident waveform and shown to be smoother than that of a single-frequency solution. The time-domain method is examined using both calculated and measured data. In the calculations, an exact solution for scattering from one or multiple nonconcentric cylinders is used to obtain the scattered field. In the measurements, a novel ring-transducer system was employed to obtain the incident and total fields. The results of simulations and experiments show that the method is robust and accurate for the size of objects considered and that the point resolution approaches one-half the wavelength at the pulse center frequency.