bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimizing Hardwood Reforestation in Old Fields: The Effects of Treeshelters and Environmental Factors on Tree Seedling Growth and Physiology
Authors: Laliberté Etienne , Bouchard André , Cogliastro Alain
Published: September 2007

Strong competition for water is largely recognized as the main factor explaining the resistance of herbaceous old fields to tree invasion. Therefore, site preparation as well as chemical and mechanical vegetation control are recommended when establishing hardwood tree plantations on such sites, but those methods are sometimes socially or ecologically inappropriate. The main objective of this study was to analyze whether treeshelters could improve early tree growth in herbaceous old fields, when mulching alone is used to partially control herbaceous competition. Our results indicate that treeshelters can facilitate tree growth in those conditions but that this was not caused by an improvement of tree water relations. Rather, it appeared to be related to an optimization of light levels inside the shelter, where light intensity was low enough to lead to a photosynthetic system less costly to maintain due to a greater specific leaf area but high enough to have no adverse effects on photosynthetic rates. Although treeshelters increased tree growth when surrounding herbaceous vegetation was low (either height or standing biomass), allowing high light levels, they reduced growth when surrounding vegetation was high and blocked a substantial quantity of light. Therefore, environmental factors such as light availability need to be considered to optimize the success of hardwood plantations when treeshelters are used in recently abandoned agricultural fields.
Intralesional recordings and epileptogenic zone in focal polymicrogyria
Authors: Chassoux Francine , Landre Elisabeth , Rodrigo Sebastian , Beuvon Frédéric , Turak Baris , Semah Franck , Devaux Bertrand
Published: September 2007

Summary

Purpose: Polymicrogyria (PMG) is recognized as an epileptogenic lesion but few data concerning organization of the epileptogenic zone (EZ) are available.

Methods: We analyzed the distribution of the EZ according to Stereo‐EEG (SEEG) with intralesional recordings in four patients evaluated for intractable partial epilepsy associated with focal unilateral PMG, involving the posterior temporal region in two, the perisylvian area in one and the temporoparietal junction in the other. All had ictal scalp EEG, high‐resolution structural and functional MRI, fluorodeoxyglucose positron emission tomography (FDG‐PET), and SEEG. For each patient, several depth electrodes were implanted both within the PMG and in extralesional areas.

Results: In three patients, the PMG displayed high‐frequency spiking activity. However, interictal and ictal recordings demonstrated a large epileptogenic network, which was more widespread than the PMG, including the mesial temporal structures in two. In another patient, interictal spiking and seizure onset site were located within the hippocampus and outside of the PMG, although it was rapidly involved during seizure spread. Overall, EZ was considered to be larger than the PMG in all patients although hypometabolic areas detected by PET were concordant with EZ. Three patients underwent extensive surgery including the PMG and are seizure free with a follow‐up >2 years.

Discussion: Although intralesional recordings demonstrated intrinsic epileptogenicity in PMG, our data provide evidence that unilateral focal PMG belongs to a large epileptogenic network extending beyond the MRI lesion. SEEG may be helpful for planning surgery with favorable outcome, providing large resections are feasible, even in apparently focal PMG.
Generic Products of Antiepileptic Drugs (AEDs): Is It an Issue?
Authors: Bialer Meir
Published: September 2007

Summary:  The availability of generic products of antiepileptic drugs (AEDs) has raised the following concerns: (1) Do generic AEDs work as well as brand AEDs in terms of their efficacy, safety and quality? (2) Can generic AEDs be used as substitutions for brand AEDs? and (3) Can generic products of AEDs be used interchangeably? The traditional average bioequivalence analysis addresses concern 1 but does not provide a complete adequate response to concerns 2 and 3. Drug interchangeability can be classified as drug prescribability or drug switchability. Drug prescribability refers to the situation where a patient is treated for the first time so that either a brand or a bioequivalent generic AED can be chosen. Drug switchability refers to the situation in which a brand AED is switched to a bioequivalent generic product of the same AED. The traditional average bioequivalence approach is sufficient to evaluate the prescribability of generic products, but does not ensure the switchability between prescribable formulations. The necessity of assuring switchability of two formulations can be addressed by individual bioequivalence.

While the switch to generic AEDs is well tolerated by many patients and in general cost‐effective, seizure control should not be sacrificed on the basis of cost alone, as the major end point in treating epilepsy with AEDs is seizure control without side effects. Until we have individual (within patient) bioequivalence data on generic AEDs and/or the tools to a priori identify the subset of patients susceptible to the generic switch, a switch of AED products in seizure‐free patients is not recommended.
High Risk of Reading Disability and Speech Sound Disorder in Rolandic Epilepsy Families: Case–Control Study
Authors: Clarke Tara , Strug Lisa J. , Murphy Peregrine L. , Bali Bhavna , Carvalho Janessa , Foster Suzanne , Tremont Geoffrey , Gagnon Bernadine R. , Dorta Nelson , Pal Deb K.
Published: September 2007

Summary

Purpose: Associations between rolandic epilepsy (RE) with reading disability (RD) and speech sound disorder (SSD) have not been tested in a controlled study. We conducted a case–control study to determine whether (1) RD and SSD odds are higher in RE probands than controls and (2) an RE proband predicts a family member with RD or SSD, hence suggesting a shared genetic etiology for RE, RD, and SSD.

Methods: Unmatched case–control study with 55 stringently defined RE cases, 150 controls in the same age range lacking a primary brain disorder diagnosis, and their siblings and parents. Odds ratios (OR) were calculated by multiple logistic regression, adjusted for sex and age, and for relatives, also adjusted for comorbidity of RD and SSD in the proband.

Results: RD was strongly associated with RE after adjustment for sex and age: OR 5.78 (95% CI: 2.86–11.69). An RE proband predicts RD in family members: OR 2.84 (95% CI: 1.38–5.84), but not independently of the RE proband's RD status: OR 1.30 (95% CI: 0.55–12.79). SSD was also comorbid with RE: adjusted OR 2.47 (95%CI: 1.22–4.97). An RE proband predicts SSD in relatives, even after controlling for sex, age and proband SSD comorbidity: OR 4.44 (95% CI: 1.93–10.22).

Conclusions: RE is strongly comorbid with RD and SSD. Both RD and SSD are likely to be genetically influenced and may contribute to the complex genetic etiology of the RE syndrome. Siblings of RE patients are at high risk of RD and SSD and both RE patients and their younger siblings should be screened early.
The effectiveness of low‐frequency stimulation for mapping cortical function
Authors: Zangaladze Andro , Sharan Ashwini , Evans James , Wyeth Dale H. , Wyeth Edmund G. , Tracy Joseph I. , Chervoneva Inna , Sperling Michael R.
Published: September 2007

Summary

Objective: To establish the efficacy and safety of low‐frequency electrical stimulation for cortical brain mapping.

Methods: Cortical function was mapped using electrical stimulation in epilepsy patients with chronically implanted intracranial subdural electrodes. Contacts overlying motor, sensory, visual, and language cortex were stimulated at frequencies of 5, 10, and 50 Hz, using current levels ranging from 1 to 17.5 mA for 3–5 s. The current intensity and incidence at which functional alterations and afterdischarges (ADs) occurred were recorded. The modified McNemar test for nonindependent measures was used to analyze the data.

Results: 122 electrode contact pairs were electrically stimulated at least two different frequencies in 14 patients. Functional alterations were obtained at all stimulation frequencies (5, 10, and 50 Hz) at generally similar rates. The likelihood of producing an AD correlated with stimulation frequency, and lower‐frequency stimulation was less likely to provoke an AD. Higher current intensity was required to induce both functional responses and ADs at low‐frequency stimulation than high‐frequency stimulation. While overall rates of producing functional changes were similar, differences in functional response with regard to frequency were noted at individual cortical sites.

Conclusion: 5‐ and 10‐Hz stimulation are as effective for mapping cortical function as 50‐Hz stimulation and produce fewer ADs. We recommend that mapping of cortical function be started with 5‐Hz‐frequency stimulation. Higher frequencies should be used in suspect cortex if no symptoms or signs are produced with 5‐Hz stimulation.
Protective effect of topiramate on kainic acid–induced cell death in mice hippocampus
Authors: Park Hae Jeong , Kim Hak Jae , Park Hi Joon , Ra Jehyun , Zheng Long Tai , Yim Sung Vin , Chung Joo‐Ho
Published: September 2007

Summary

The protective effect of topiramate (TPM) on seizure‐induced neuronal injury is well known; however, its molecular basis has yet to be elucidated. We investigated the effect and signaling mediators of TPM on seizure‐induced hippocampal cell death in kainic acid (KA)‐treated ICR mice. KA‐induced hippocampal cell death was identified by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling. Immunoreactivity (IR) of p‐Erk, p‐Jnk, p‐P38, and caspase‐3, and caspase‐3 activity were observed in the hippocampal region 3 h after KA (0.1 μg/5 μL, i.c.v.) administration, and/or TPM (100 mg/kg, i.p.) pretreatment. TPM attenuated seizure‐induced neuronal cell death and reduced KA‐induced p‐Erk IR in the CA3 region of the hippocampus, but did not affect p‐Jnk and p‐P38. In addition, TPM reduced caspase‐3 IR and activation by KA. KA‐induced seizures were also suppressed by TPM pretreatment. TPM inhibits seizures, and decreases Erk phosphorylation and caspase‐3 activation by KA, thereby contributing to protection from neuronal injury.
Pathways to discovery in epilepsy research: Rethinking the quest for cures
Authors: Lowenstein Daniel H.
Published: September 2007

Summary

This paper, based on the 4th Annual Hoyer Lecture presented at the 2006 annual meeting of the American Epilepsy Society, first provides a general view of the current limitations in therapies aimed at achieving the goal of “no seizures, no side effects” for patients living with epilepsy. Some of the seminal discoveries in epilepsy research over the past 100 years are then reviewed, with an emphasis on the pivotal role of basic and clinical/translational science in leading the way to new and effective means for diagnosing and treating for epilepsy. The paper concludes with a view of the future course of epilepsy research. Scientific advances will increasingly rely on the collaboration of multidisciplinary teams of reseachers using the analytic and storage capabilities of machines, and linked together by communication tools such as the Internet and related technologies.
Focal reduction of neuronal glutamate transporters in human neocortical epilepsy
Authors: Rakhade Sanjay N. , Loeb Jeffrey A.
Published: September 2007

Summary

Purpose: To study the differential expression of excitatory amino acid transporters (EAATs) at localized epileptic foci compared to nonepileptic regions in human neocortical epilepsy. Decreased expression of EAATs, the predominant mechanism to remove synaptic‐released glutamate, may explain mechanisms of heightened excitability at these epileptic foci.

Methods: The differential expression of EAAT1‐4 at the mRNA and protein levels was measured in electrically mapped human neocortical tissues using quantitative real‐time PCR and immunoblotting. This required a novel way to prevent aggregation of EAAT proteins through cold solubilization. Layer‐specific neuronal densities were measured to control for potential differences in neuronal density.

Results: While focal epileptic brain regions show marked increases in immediate early genes, they have significant reductions in the neuronal glutamate transporter mRNAs (EAAT3 and EAAT4). These changes were not associated with changes in relative neuronal density, suggesting a reduction in EAAT mRNA per neuron. Immunohistochemical staining of epileptic human neocortex confirmed the presence of EAAT1 and EAAT2 proteins in astroglial cells and EAAT3 and EAAT4 proteins in human cortical neurons. At the protein level, western blots of the same epileptic and nonepileptic regions for a subset of these patients showed a similar decrease of EAAT3 and EAAT4. Despite no change in EAAT2 mRNA, EAAT2 protein expression was significantly reduced at epileptic foci.

Conclusion: Regional reductions in EAAT expression at human neocortical epileptic foci could produce increased local glutamate levels that in turn may contribute to both hyperexcitability and the spontaneous generation of epileptic discharges that characterize human epileptic foci.
Hypotheses, tests, methods, and innovation: The balancing act in research
Authors: Berg Anne T.
Published: September 2007

Summary

Clinical and epidemiological research studies are essential to advancing our understanding of human health conditions such as epilepsy. To be of value, studies must not only address important questions, they must do so in such a way as to contribute usefully to existing knowledge. Comprehensive understanding of the subject matter is only one component of successful research and research reports. A firm grasp of research methods and statistical issues and a scholarly command of the relevant and current literature are essential components to high‐quality research. No single study, however, is perfect nor can any single study definitively answer a given single research question. Studies must be designed and evaluated in light of historical, scientific, pragmatic, and ethical realities that may constrain them. Selected but essential methodological and statistical concepts are discussed along with the need to balance innovation and novelty against methodological rigor.
Surgery for medically intractable temporal lobe epilepsy during early life
Authors: Maton Bruno , Jayakar Prasanna , Resnick Trevor , Morrison Glenn , Ragheb John , Duchowny Michael
Published: September 2007

Summary

Purpose: Temporal lobe epilepsy (TLE) in early life is often a catastrophic disorder with pharmacoresistant seizures and secondary neurological deterioration. There is little data available regarding epilepsy surgery performed in infants and young children and no prior study has focused on TLE.

Methods: We analyzed the results of temporal resection for epilepsy as the primary indication in children less than age 5 years who had at least 2 years of follow‐up.

Results: 20 children (14 males) were identified with a mean age at surgery of 26 months and a mean age at seizure onset of 12 months. Clinical presentation was diverse. Typical psychomotor seizures (n = 4; mean age at surgery 37 months) were followed by prominent motor changes (n = 7; 30 months) and were occasionally isolated (n = 3; 23 months). Epileptic spasms were noted in six patients and were frequently associated with lateralizing features. The interictal EEG was lateralizing in 15 patients and the ictal EEG was lateralizing in 18 patients. Brain MRI provided localizing value in 16 patients, ictal SPECT was concordant in 4/8 cases. Invasive EEG was employed in six cases. At mean follow‐up of 5.5 years, 65% of the children were seizure‐free and 15% had >90% seizure reduction. Morbidity included infection and hydrocephalus in one case and stroke‐related hemiparesis in two cases. Cortical dysplasia was identified in eight children, tumors in eight including two DNET, two ganglioglioma, and four malignant tumors. Hippocampal sclerosis was present in four cases, always as dual pathology.

Conclusion: TLE presents in early life with varied and severe manifestations. Excisional procedures in this age group are associated with favorable seizure reduction similar to older children and in adults.
Emerging role of mitogen‐activated protein kinases in peripheral neuropathies
Authors: Cavaletti Guido , Miloso Mariarosaria , Nicolini Gabriella , Scuteri Arianna , Tredici Giovanni
Published: September 2007

Abstract  Among the different families of intracellular molecules that can be modulated during cell damage and repair, mitogen‐activated protein kinases (MAPKs) are particularly interesting because they are involved in several intracellular pathways activated by injury and regeneration signals. Despite most of the studies have been performed in non‐neurological models, recently a causal role for MAPKs has been postulated in central nervous system disorders. However, also in some peripheral neuropathies, MAPK changes can occur and these modifications might be relevant in the pathogenesis of the damage as well as during regeneration and repair. In this review, the current knowledge on the role of MAPKs in peripheral neuropathies will be discussed.
Expression of metalloproteinases (MMP‐2, MMP‐9, and TACE) and TNF‐α in the nerves of leprosy patients
Authors: Teles Rosane M. B. , Antunes Sérgio L. G. , Jardim Márcia R. , Oliveira Ariane L. , Nery José A. C. , Sales Ana M. , Sampaio Elizabeth P. , Shubayev Veronica , Sarno Euzenir N.
Published: September 2007

Abstract  Matrix metalloproteinases (MMPs) and tumor necrosis factor alpha (TNF‐α) play important and related roles in the pathogenesis of nerve injury. MMP‐dependent and TNF‐α‐dependent processes of neurodegeneration, such as blood‐nerve breakdown and immune cell recruitment, are characteristic of leprosy nerve damage. Our work has contributed to the understanding of the role of cytokines in the process, but the role of MMPs in the pathogenesis of neuritic leprosy has not been investigated. This study analyzed the changes in mRNA expression and immunodistribution of MMP‐2, MMP‐9, TNF‐α‐converting enzyme (TACE), TNF‐α in nerves of 27 pure neuritic leprosy (PNL) patients, both acid‐fast bacilli positive (AFB+) and acid‐fast bacilli negative (AFB−), and 8 non‐leprosy patients with control peripheral neuropathic conditions. MMP‐2, MMP‐9, and TNF‐α mRNA expression was significantly induced in the AFB− relative to the AFB+ neuritic leprosy group and nonlepritic controls; TACE levels were also elevated in the AFB− group, but this change was not statistically significant. Immunoreactive profiles for TNF‐α and MMPs demonstrated strong reactivity of myelinated axons, infiltrating macrophages, Schwann cells, endothelial cells, and perineurial cells in neuritic leprosy biopsies. This study provides the evidence of the involvement of MMPs in the pathogenesis of PNL neuropathy.
Morphometric aspects of peripheral nerves in adults and the elderly
Authors: Moriyama Hiroshi , Amano Kaori , Itoh Masahiro , Shimada Kazuyuki , Otsuka Naruhito
Published: September 2007

Abstract  There have been inconsistencies among reports of age‐related differences in human peripheral nerves (PNs). For such studies, normal control values are necessary. Moreover, the diversity of methods employed makes it difficult to compare results. We used the same histological procedures and methods to measure 12 PNs: 8 in the cranial nerves, 2 motor nerves in the lower limb, and 2 nerves in the autonomic system. We performed a morphometric analysis of nerve fibers and estimated the change in the total number (TN) and average transverse area (ATA) of myelinated axons from adulthood to old age. The spinal nerves demonstrated notable age‐related changes in TN and ATA. Most of the cranial nerves also demonstrated notable age‐related changes in TN and ATA. However, some nerves demonstrated no such age‐related changes and were affected more by other factors. With regards to the autonomic nerves, the lesser splanchnic nerve indicated age‐related changes in TN, but the greater splanchnic nerve indicated no age‐related changes in either TN or ATA. The autonomic nerves were affected not only by the aging process but also by the pathological changes to the peripheral tissues that they innervate.
The Total Neuropathy Score as an assessment tool for grading the course of chemotherapy‐induced peripheral neurotoxicity: comparison with the National Cancer Institute‐Common Toxicity Scale
Authors: Cavaletti Guido , Frigeni Barbara , Lanzani Francesca , Piatti Marialuisa , Rota Stefania , Briani Chiara , Zara Gabriella , Plasmati Rosaria , Pastorelli Francesca , Caraceni Augusto , Pace Andrea , Manicone Mariagrazia , Lissoni Andrea , Colombo Nicoletta , Bianchi Giulia , Zanna Claudio ,   Italian NETox Group
Published: September 2007

Abstract  Chemotherapy‐induced peripheral neurotoxicity (CIPN) is a major side effect of several antineoplastic drugs. However, despite its clinical importance, there is no agreement as to the best way to assess the severity and changes in CIPN. We have previously demonstrated a correlation between the severity of CIPN, assessed using the Total Neuropathy Score (TNS) or its reduced versions, and several common toxicity scales. In this study, we investigated two series of patients (total number = 173) who were evaluated at baseline and during chemotherapy with the TNS (n= 122) or the TNSc (the TNS version based exclusively on the clinical evaluation of the patients, n= 51) and with the National Cancer Institute‐Common Toxicity Criteria (NCI‐CTC) 2.0, with the aim of comparing the sensitivity to the changes in CIPN severity. In both series, the TNS and the TNSc had a significant correlation with the NCI‐CTC in scoring the severity of CIPN, confirming the results of previous studies. Moreover, both the TNS and the TNSc showed a higher sensitivity to CIPN changes. We, therefore, propose the TNSc as a reliable method for assessing not only the severity but also the changes in CIPN.
Two‐dimensional digital video ankle motion analysis for assessment of function in the rat sciatic nerve model
Authors: De Ruiter Godard C. , Spinner Robert J. , Alaid Awad O. , Koch Anthony J. , Wang Huan , Malessy Martijn J. A. , Currier Bradford L. , Yaszemski Michael J. , Kaufman Kenton R. , Windebank Anthony J.
Published: September 2007

Abstract  Ankle motion analysis may provide a better method to assess function in the rat sciatic nerve model than the standard method, the sciatic functional index (SFI), but it is not widely used in experiments on nerve regeneration possibly because of complicated analysis. In this study, we investigated the practical use of a two‐dimensional (2D) digital video motion analysis system. Reproducibility was investigated in normal rats. Recovery of ankle motion was analyzed after sciatic, tibial, and peroneal nerve crush injury. Results were compared with scores for the SFI. Results were not significantly different from animal‐to‐animal and day‐to‐day. Interobserver variability also was small. In the analysis of recovery after separate nerve crush injuries, subtle differences in ankle plantar flexion and dorsiflexion could be detected. The method was also more sensitive than the SFI: whereas scores for the SFI had returned to normal 4 weeks after sciatic nerve crush injury, the ankle angle at mid‐stance was still significantly different from that in sham‐operated animals 6 weeks after the injury. 2D digital video ankle motion analysis is a practical and sensitive method to assess function in the rat sciatic nerve model.
Diagnostic role of deep tendon reflex latency measurement in small‐fiber neuropathy
Authors: Sharma Khema R. , Saadia Daniela , Facca Alicia G. , Resnick Steven , Ayyar D. Ram
Published: September 2007

Abstract  Small‐fiber neuropathy (SFN) is diagnosed on the basis of clinical features and specialized tests of small‐fiber function because standard nerve conduction studies are normal. Thus, the objective of this study was to determine the value of deep tendon reflex (DTR) latency measurement in the diagnosis of SFN in patients with preserved DTR on clinical examination. We prospectively examined electromyographic reflexes from the biceps brachii [biceps brachii reflex (BR)], patellar [patellar reflex (PR)], and ankle [ankle reflex (AR)] using a manually operated electronic reflex hammer attached to electromyography machine and recorded by means of surface electrodes in 18 patients with SFN and 38 controls. Intra‐ and inter‐evaluator reliability was good (intraclass correlation coefficient: 0.80–0.91, p < 0.01). In controls, the latencies at all sites were correlated to the height (R= 0.6, p < 0.01). Compared with controls, in patients with SFN, the mean latency in milliseconds was prolonged at all sites (BR: 12.8 ± 1.6 vs. 8.9 ± 1.9, p < 0.01; PR: 23.0 ± 5.8 vs. 17.4 ± 2.4, p < 0.01; and AR: 34.5 ± 4.8 vs. 30.0 ± 2.4, p < 0.01). The sensitivity [61.1% (95% CI: 51–94.9)] and specificity [92% (95% CI: 73–97.3)] of BR latency were roughly equal to those of PR and AR. We conclude that DTR latencies were significantly abnormal in the majority of the patients with SFN, suggestive of subclinical involvement of large myelinated fibers. DTR latency measurement is a reproducible, valuable, sensitive tool in the evaluation of mild subclinical involvement of large fibers.
Ethanol Interactions With Calcium‐Dependent Potassium Channels
Authors: Brodie Mark S. , Scholz Andreas , Weiger Thomas M. , Dopico Alejandro M.
Published: September 2007

In most neurons and other excitable cells, calcium‐activated potassium channels of small (SK) and large conductance (BK; MaxiK) control excitability and neurotransmitter release. The spontaneous activity of dopamine neurons of the ventral tegmental area is increased by ethanol. This ethanol excitation is potentiated by selective blockade of SK, indicating that SK channels modulate ethanol stimulation of neurons that are critical in reward and reinforcement. On the other hand, ethanol directly modulates BK channel activity in a variety of systems, including rat neurohypophysial nerve endings, primary sensory dorsal root ganglia, nucleus accumbens neurons,Caenorhabditis eleganstype‐IV dopaminergic CEP neurons, and nonneuronal preparations, such as rat pituitary cells, cerebrovascular myocytes and human umbilical vein endothelial cells. Ethanol action on BK channels can modify neuropeptide and growth hormone release, nociception, cerebrovascular tone, and endothelial proliferation. Ethanol modulates BK channels even when the drug is evaluated using recombinant BK channel‐forming α (slo) subunits or channel reconstitution in artificial, binary lipid bilayers, indicating that the slo subunit and its immediate lipid microenvironment are the essential targets of ethanol. Consistent with this, single amino acid slo channel mutants display altered ethanol sensitivity. Furthermore,C. elegans slo1null mutants are resistant to ethanol‐induced motor incoordination. On the other hand,Drosophila melanogaster slonull mutants fail to acquire acute tolerance to ethanol sedation. Ethanol action on slo channels, however, may be tuned by a variety of factors, including posttranslational modification of slo subunits, coexpression of channel accessory subunits, and the lipid microenvironment, resulting in increase, refractoriness, or even decrease in channel activity. In brief, both SK and BK channels are important targets of ethanol throughout the body, and interference with ethanol effects on these channels could form the basis for novel pharmacotherapies to ameliorate the actions or consequences of alcohol abuse.
Family‐Based Association Analyses of Alcohol Dependence Phenotypes Across DRD2 and Neighboring Gene ANKK1
Authors: Dick Danielle M. , Wang Jen C. , Plunkett Jevon , Aliev Fazil , Hinrichs Anthony , Bertelsen Sarah , Budde John P. , Goldstein Elianna L. , Kaplan Daniel , Edenberg Howard J. , Nurnberger John , Hesselbrock Victor , Schuckit Marc , Kuperman Sam , Tischfield Jay , Porjesz Bernice , Begleiter Henri , Bierut Laura Jean , Goate Alison
Published: September 2007

Background:  There is an extensive and inconsistent literature on the association of the dopamine D2 receptor gene (DRD2) with alcohol dependence. Conflicting results have been attributed to differences in the severity of the alcohol dependence phenotype across studies, failure to exclude related disorders from comparison groups, and artifacts of population‐stratification. Recently the genetic polymorphism most widely analyzed in DRD2, Taq1A, has been discovered to reside in a neighboring gene, ankyrin repeat and kinase domain containing 1 (ANKK1), located 10 kb downstream from DRD2.

Methods:  To more carefully characterize evidence for association across this region, we genotyped 26 single nucleotide polymorphisms (SNPs) spanning DRD2 and ANKK1 in a sample of 219 Caucasian families (n = 1,923) from the Collaborative Study on the Genetics of Alcoholism (COGA), making this the most extensive analysis to date of association between this region and alcohol dependence. We used family‐based analyses robust to population‐stratification, and we made use of rich phenotypic data to analyze alcohol dependence and subtypes hypothesized in the literature to be more directly influenced by DRD2.

Results:  We found that the evidence for association is strongest in the 5′ linkage disequilibrium block of ANKK1 (that does not contain Taq1A), with weak evidence of association with a small number of SNPs in DRD2. The association in ANKK1 is strongest among the subsets of alcoholics with medical complications and with antisocial personality disorder.

Conclusions:  More extensive genotyping across DRD2 and ANKK1 suggests that the association with alcohol dependence observed in this region may be due to genetic variants in the ANKK1 gene. ANKK1 is involved in signal transduction pathways and is a plausible biological candidate for involvement in addictive disorders.
Association of the Aldehyde Dehydrogenase 2 Promoter Polymorphism With Alcohol Consumption and Reactions in an American Jewish Population
Authors: Fischer Monika , Wetherill Leah Flury , Carr Lucinda G. , You Min , Crabb David W.
Published: September 2007

Background:  Reduction in activity of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) enzyme due to genetic deficiency causes reactions related to alcohol consumption and lowers the risk of alcoholism. ALDH2*2 is the only functionally significant polymorphism of the ALDH2 gene. An additional polymorphic locus in the promoter (G to A substitution approximately 360 bp from the translation start site) may influence ALDH2 activity through effects on transcriptional activity. The A allele is predicted to be less active transcriptionally than the G allele. Therefore, we hypothesized that individuals with 1 or 2 A alleles would have exaggerated reactions to alcohol.

Methods:  Fifty‐three Jewish college students from a Midwestern University and 76 Jewish individuals living in a large Midwestern city (all of Ashkenazi descent) were tested for associations between ALDH2*G and ALDH2*A alleles and self‐reported alcohol consumption and responses to alcohol. Genotype determination was performed using PCR and slot‐blot hybridization. As alcohol drinking behavior differed substantially between the college students and the general population, as well as between males and females, the analyses were performed separately in each group.

Results:  The frequency of the ALDH2*A allele was 0.87 in the 129 Jewish individuals tested. Among the general Jewish population, those who were homozygous for ALDH2*A drank fewer drinks per occasion than individuals who were not homozygous for the ALDH2*A allele, but did not drink significantly less frequently. When the other covariates (ADH1B genotype, gender, and population) were controlled for, there was a marginal association between ALDH2A genotype and quantity of alcohol consumed and the number of drinks consumed before feeling drowsy.

Conclusion:  This study suggests that the ALDH2*A allele status may correlate with variations in alcohol consumption patterns among Jews, independent of the effect of ADH1B genotype.
Unique Facial Features Distinguish Fetal Alcohol Syndrome Patients and Controls in Diverse Ethnic Populations
Authors: Moore Elizabeth S. , Ward Richard E. , Wetherill Leah Flury , Rogers Jeffrey L. , Autti‐Rämö Ilona , Fagerlund Åse , Jacobson Sandra W. , Robinson Luther K. , Hoyme H. Eugene , Mattson Sarah N. , Foroud Tatiana ,   the CIFASD
Published: September 2007

Background:  Effective management of fetal alcohol spectrum disorders (FASD) is dependent on the timely and reliable diagnosis of affected individuals. There are significant diagnostic difficulties because of the reduced prominence of facial features as children age to adulthood as well as potential population or ethnic differences in the most characteristic alcohol‐related facial features.

Methods:  A total of 276 subjects were recruited from 4 sites (Cape Town, South Africa; Helsinki, Finland; Buffalo, New York; and San Diego, California) and completed a detailed dysmorphology evaluation to classify subjects as either fetal alcohol syndrome (FAS; 43%) or control (57%). Computerized anthropometry was employed to identify facial features that could distinguish FAS patients from controls across a wide age range and across ethnically disparate study populations.

Results:  Subjects were placed into 1 of 4 populations based on their ancestry (Cape Coloured, Finnish Caucasian, African American, or North American Caucasian). Analyses performed in each of the 4 study populations were able to identify a unique set of variables which provided excellent discrimination between the 2 groups (FAS, control). In each study group, at least one ocular‐related measurement, shortened palpebral fissure, reduced outer canthal width, or reduced inner canthal width, was included in the final classification model.

Conclusions:  We found measurements that reflected reduced size of the eye orbit to be a consistent feature discriminating FAS and controls across each study population. However, each population had a unique, though often overlapping, set of variables which discriminated the 2 groups, suggesting important ethnic differences in the presentation of FAS. It is possible that these differences were accentuated by the wide age distribution of the study subjects.
Binge Drinking in Madrid, Spain
Authors: Valencia‐Martín José Lorenzo , Galán Iñaki , Rodríguez‐Artalejo Fernando
Published: September 2007

Background:  In Mediterranean countries, the information on the prevalence of binge drinking and associated socio‐demographic variables is very scarce. Moreover, there are no reported data on the amount of alcohol ingested and the type of beverage consumed during drinking episodes. This study describes the prevalence and characteristics of binge drinking in the adult population of Madrid, Spain.

Methods:  Data were taken from a telephone survey conducted during the period 2000 to 2005 on 12,037 persons, representative of the population aged 18 to 64 years in the Madrid Region. Binge drinking was defined as the intake of ≥80 g of alcohol in men or ≥60 g in women, during any drinking session in the preceding 30 days. In this analysis, the threshold between moderate and heavy average weekly alcohol consumption was set at 40 g/d for men and 24 g/d for women.

Results:  Prevalence of binge drinking was 14.4% (95% confidence interval, CI: 13.5 to 15.3%) in men and 6.5% (95% CI: 5.8 to 7.1%) in women. Prevalence was higher among persons: in the youngest age group (30.8% among men and 18.2% among women aged 18 to 24 years); having the highest educational level (14.5% in male and 9.2% in female university graduates); and with a heavy average consumption of alcohol (55.3% in men and 50.0% in women). However, 3 of 4 binge drinkers of both sexes showed a moderate average consumption. Among binge‐drinkers, average monthly episodes of binge drinking were 3.2 in men and 2.6 in women, with 5.4 and 2 episodes/person/year, respectively. During each episode, a mean of 119 g of alcohol was ingested by men and 83 g by women, with spirits accounting for 72% of total alcohol intake.

Conclusions:  Prevalence of binge drinking is high in Madrid, particularly among younger men with higher education, and heavy average alcohol consumption. Binge drinking is characterized by frequent episodes, where large amounts of alcohol are ingested, mainly from spirits.
Intact Preference Conditioning in Acute Intoxication Despite Deficient Declarative Knowledge and Working Memory
Authors: Balodis Iris M. , Johnsrude Ingrid. S. , Olmstead Mary C.
Published: September 2007

Background:  The impact of alcohol on implicit, emotional learning is not well understood, partly because family history, drug use, and task demands influence these processes. The conditioned pattern preference (CPP) task provides a more ecologically valid means to investigate implicit cognition in the lab because it has low demand awareness and relies on learning to associate nonverbal cues with reward.

Methods:  This study examined the effects of acute alcohol intoxication on implicit learning using the CPP task in 83 intoxicated and 69 sober young adults. Information on individual drug use, family history, impulsivity, and alcohol expectancies was also collected.

Results:  Alcohol intoxication affected explicit, but not implicit learning on the CPP task. In addition, participants who reported a positive family history of addiction (FH+) or individual recreational drug use did not exhibit a preference for cues previously paired with reward.

Conclusions:  Preference formation on the CPP task recruits motivational neurocircuitry, an effect that is unaltered by alcohol. Group differences in implicit emotional learning on this task may represent neurocognitive differences in individuals at risk for addiction.
Lack of Association of Alcohol Dependence and Habitual Smoking With Catechol‐O‐methyltransferase
Authors: Foroud Tatiana , Wetherill Leah Flury , Dick Danielle M. , Hesselbrock Victor , Nurnberger, Jr John I. , Kramer John , Tischfield Jay , Schuckit Marc , Bierut Laura J. , Xuei Xiaoling , Edenberg Howard J.
Published: September 2007

Objective:  To test whether variation in the gene encoding the enzyme catechol‐O‐methyltransferase (COMT), which catalyzes the breakdown of dopamine and other catecholamine neurotransmitters, is associated with the risk for alcohol dependence and habitual smoking.

Methods:  Single nucleotide polymophisms (SNPs) were genotyped in a sample of 219 multiplex alcohol‐dependent families of European American descent from the Collaborative Study on the Genetics of Alcoholism (COGA). Family‐based tests of association were performed to evaluate the evidence of association between the 18 SNPs distributed throughout COMT, including the functional Val158Met polymorphism, and the phenotypes of alcohol dependence, early onset alcohol dependence, habitual smoking, and comorbid alcohol dependence and habitual smoking.

Results:  No significant, consistent evidence of association was found with alcohol dependence, early onset alcohol dependence, habitual smoking or the comorbid phenotype. There was no evidence that the functional Val158Met polymorphism, previously reported to be associated with these phenotypes, was associated with any of them.

Conclusion:  Despite the substantial size of this study, we did not find evidence to support an association between alcohol dependence or habitual smoking and variation in COMT.
Varieties of Impulsivity in Males With Alcohol Dependence: The Role of Cluster‐B Personality Disorder
Authors: Rubio Gabriel , Jiménez Mónica , Rodríguez‐Jiménez Roberto , Martínez Isabel , Iribarren Martin Miguel , Jiménez‐Arriero Miguel Angel , Ponce Guillermo , Ávila Cesar
Published: September 2007

Background/Rationale:  Impulsivity has been associated with alcohol dependence, but impulsivity in alcohol‐dependent subjects with a Cluster‐B personality disorder (PD) has not been well characterized. Using a variety of laboratory measures of impulsivity, we assessed whether alcohol‐dependent patients (ADP) with borderline personality disorder (BPD) exhibited the same pattern of behavioral impulsivity than ADP with antisocial personality disorder (AntPD). Also, differences between ADP without PDs and healthy controls were assessed.

Methods:  A cross‐sectional patient survey with a community comparison group. Diagnoses were made using the Structured Interview for DSM‐IV. Sustained attention and rapid‐response impulsivity were assessed using the continuous performance test. Inhibitory control was measured by the stop‐signal task. Ability to delay reward task was assessed using differential reinforcement for low‐rate responding (DRLR). A final sample of 247 males with alcohol‐dependence recruited from 2 alcoholism treatment centers was compared with a matched nonsubstance‐abusing comparison group (n = 96).

Results:  Alcohol‐dependent patients with BPD made more omission errors than ADP with AntPD, but individuals with AntPD exhibited the poorest efficiency in DRLR. ADPs with a Cluster‐B PD displayed more impairment across all behavioral measures than ADP without PD and than controls. In contrast, with respect to controls ADP without a Cluster‐B PD showed more impairment only in DRLR.

Conclusions:  Our findings support the suggestion of 2 paradigms in alcohol dependence. The first, based on inability to delay gratification, might be a vulnerability marker for alcohol dependence. The second was related to inhibitory control and might be specific for AntPD and BPDs.
Decreased Plasma Brain‐Derived Neurotrophic Factor Levels in Patients With Alcohol Dependence
Authors: Joe Keun‐Ho , Kim Yong‐Ku , Kim Tae‐Suk , Roh Sung‐Won , Choi Sam‐Wook , Kim Young‐Bo , Lee Hee‐Jin , Kim Dai‐Jin
Published: September 2007

Background:  Many reports have suggested possible relationships between brain‐derived neurotrophic factor (BDNF) and alcohol dependence. A protective effect of BDNF against ethanol‐induced cell damage has been suggested, and this effect may contribute to the development or maintenance of alcohol dependence. This study was carried out in order to verify the significance of BDNF in alcohol dependence.

Methods:  Peripheral BDNF levels were measured in alcohol‐dependent patients and control subjects using an enzyme‐linked immunosorbent assay. A physician’s interview and standardized questionnaire were used to obtain information regarding each patient’s history of alcohol consumption.

Results:  The mean BDNF level was lower in the alcohol dependence group (389.5 ± 501.7 pg/ml) than in the normal controls (822.5 ± 420.7 pg/ml) by analysis of covariance (ANCOVA) (F = 25.79, p < 0.01). The mean BDNF level was lower in the alcohol‐dependent patients with a positive family history of alcohol dependence (247.6 ± 289.2 pg/ml) than in those with a negative family history of alcohol dependence (583.9 ± 652.8 pg/ml) by ANCOVA (F = 6.51, p = 0.01). The BDNF levels did not correlate significantly with any of the variables analyzed in this study, including Beck depression inventory, state and trait anxiety inventory (STAI‐S and T), and various drinking behaviors.

Conclusions:  Changes in the levels of BDNF might play a role in the pathophysiology and inheritance of alcohol dependence.
Mouse Lines Selected for Alcohol Consumption Differ on Certain Measures of Impulsivity
Authors: Wilhelm Clare J. , Reeves Jamie M. , Phillips Tamara J. , Mitchell Suzanne H.
Published: September 2007

Background:  Alcoholics and heavy drinkers score higher on measures of impulsivity than nonalcoholics and light drinkers. This may be due to factors that predate drug exposure (e.g. genetics) or to neuroadaptations associated with exposure to alcohol. The aim of this study was to examine the role of genetics by comparing impulsivity in short‐term selected lines of mice bred to voluntarily drink either high (STDRHI2) or low (STDRLO2) amounts of 10% ethanol.

Methods:  Independent sets of mice completed 2 experiments designed to measure impulsivity. Using the adjusting amount procedure, we examined preference for smaller, sooner rewards over larger but delayed rewards (delay discounting). This task determines the amount of immediate sucrose equivalent to the discounted value of a 20 μl sucrose reward given following a specific delay (0, 2, 4, 8, or 12 seconds). Using a Go/No‐go task, we examined the ability of mice to inhibit nose‐poking in response to specific cues. These tasks are commonly used to assess different aspects of impulsive behavior, and provide measures that are not highly correlated.

Results:  No significant differences were found between STDRHI2 and STDRLO2 mice in delay discounting. In the Go/No‐go task, STDRHI2 mice made more responses during the pre‐cue period without committing more false alarms, compared with STDRLO2 mice.

Conclusions:  The results suggest that short‐term selective breeding for high relative alcohol consumption may also select for animals that have impaired response inhibition.
The Impact of Gonadectomy and Adrenalectomy on Acute Withdrawal Severity in Male and Female C57BL/6J and DBA/2J Mice Following a Single High Dose of Ethanol
Authors: Gililland Katherine R. , Finn Deborah A.
Published: September 2007

Background: Steroid hormones can influence neuronal excitability and subsequent seizure susceptibility through genomic and nongenomic mechanisms. For example, there are proconvulsant steroids such as estradiol and corticosterone and anticonvulsant steroids such as testosterone, progesterone, and their GABAergic metabolites. Recent findings indicated that a single, acute administration of ethanol increased levels of GABAergic steroids and that the source of this increase was peripheral organs such as the adrenals and gonads. Thus, the purpose of the present study was to determine the impact of removal of the adrenals and/or gonads on withdrawal severity following a single high dose of ethanol in 2 genotypes that differ in ethanol withdrawal severity.

Method: Male and female C57BL/6J (B6) and DBA/2J (D2) mice were either left intact (SHAM), adrenalectomized (ADX), gonadectomized (GDX), or underwent ADX/GDX surgery. Seven days following surgery, baseline handling‐induced convulsions (HICs) were measured prior to administration of a 4 g/kg dose of ethanol. HICs were assessed following the ethanol injection, then hourly for 12 hours and at 24 hours. A separate group of mice were used to measure the impact of surgical status on ethanol metabolism at 30, 60, 120, and 240 minutes after a single 4 g/kg dose of ethanol.

Results: ADX and ADX/GDX treatments in male B6 and D2 mice increased ethanol withdrawal severity following a single dose of ethanol, measured by area under the withdrawal curve and peak HIC scores. Acute ethanol withdrawal also was increased in female D2 mice that had undergone ADX/GDX. In contrast, surgical status did not alter ethanol withdrawal severity in female B6 mice. Surgical status had only minor effects on ethanol metabolism.

Conclusions: Removal of peripherally derived steroids with anticonvulsant properties significantly increased HIC scores during acute ethanol withdrawal following a single dose of ethanol in male and female D2 mice and in male B6 mice. These increases were not due to changes in ethanol metabolism.