bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum Uric Acid and Lipid Levels While Taking Topiramate for Migraine
Authors: Koçer Abdulkadir , Dikici Süber , Atakay Selcuk , Okuyucu Efika
Published: July 2008

Objective.— Topiramate (TPM) therapies for epilepsy or migraine are long‐time therapies with unknown mechanisms and special side effects. TPM influences cholesterol (TC) and lipoprotein serum levels. In addition, TPM may cause uric acid (UA) stone formation.

Material and Methods.— Serum UA, TC, and triglyceride (TG) levels were measured in 53 migraine patients receiving TPM and in 44 age‐ and sex‐matched controls. Compared with controls, patients on TPM showed significantly higher UA and nonsignificantly higher TC and TG values. We recorded pre‐ and posttreatment levels of UA, TC, and TG levels in 23 patients.

Results.— We found increased serum levels of UA with TPM use (P < .01). There was a significant and positive correlation between serum UA levels and male gender (P < .01).The changes in serum UA levels before and after TPM treatment differed significantly (P < .01).

Conclusion.— Our results suggest a need for monitoring serum UA levels in patients receiving TPM. We should perhaps prescribe a low‐UA diet and advice to drink much more water in these patients.
Common CX3CR1 Alleles Are Associated With a Reduced Risk of Headaches
Authors: Combadière Christophe , Godin Ophelia , Vidal Cécile , Cangialosi Arnaud , Proust Carole , Tzourio Christophe
Published: July 2008

Objectives.— The aim of this study was to investigate the role of the chemokine receptor CX3CR1 in headaches and migraine.

Methods.— Distribution of 2 polymorphisms of the chemokine receptor CX3CR1 (V249I and T280M) was determined in a population‐based sample of 1179 elderly individuals.

Results.— Heterozygotes for both CX3CR1 polymorphisms had a reduced risk of recurrent headaches, with an odds ratio (OR) of 0.64 (95% confidence interval [CI] = 0.46‐0.90) for the I249 allele and 0.55 (95% CI = 0.38‐0.81) for the M280 allele. Haplotype analysis showed that carriers of the rarer CX3CR1 I249‐M280 haplotype had a reduced risk of recurrent headaches, with an OR of 0.57 (95% CI = 0.41‐0.80, P = .001). This association was seen for both nonmigraine headaches (OR = 0.47, 95% CI = 0.28‐0.79, P = .004) and migraine (OR = 0.65, 95% CI = 0.43‐0.98, P = .041).

Conclusions.— These results need to be replicated but suggest that the chemokine receptor CX3CR1 may play a role in recurrent headaches.
Chronic Daily Headache With Analgesics Overuse in Professional Women Breath‐Hold Divers
Authors: Choi Jay Chol , Lee Jung Seok , Kang Sa‐Yoon , Kang Ji‐Hoon , Bae Jong‐Myon
Published: July 2008

Objective.— The object of this study is to investigate the prevalence and characteristics of headache in Korean professional women breath‐hold divers, including their overuse of analgesics.

Background.— Headache is a common problem encountered in clinical practice, and undersea divers exhibit unique causes of headache in addition to other common primary headaches. Many scuba divers are known to use various types of drugs to overcome dive‐related symptoms or to enhance their underwater performance.

Methods.— The target population of this study was women divers in the northern district of Jeju Island who were registered in the divers’ union. Data were collected using telephone interviews with a structured questionnaire. Headache was diagnosed and classified according to criteria of the International Headache Society.

Results.— Nine hundred and eleven (80.3%) divers responded to the telephone interview. The prevalence rates of headache were 21.4% for tension‐type headache and 9.1% for migraine. One hundred and four divers (11.4%) fulfilled the criteria for chronic daily headache (CDH). Overuse of combination analgesics was reported by 70.7% of divers. Women divers with CDH were significantly older and they complained more of tinnitus and dizziness, and had a greater history of hypertension than divers without headache.

Conclusion.— The prevalence of CDH is high in Korean professional women breath‐hold divers, with many of them being combination‐analgesics overusers.
Epidemiology, Risk Factors, and Treatment of Chronic Migraine: A Focus on Topiramate
Authors: Silberstein Stephen , Diener Hans‐Christoph , Lipton Richard , Goadsby Peter , Dodick David , Bussone Genaro , Freitag Fred , Schwalen Susan , Ascher Steven , Morein Jacqueline , Greenberg Steven , Biondi David , Hulihan Joseph
Published: July 2008

The term chronic daily headache refers to a heterogeneous group of headache disorders characterized by a frequency of headaches on ≥15 days per month. Chronic migraine is a subtype of chronic daily headache. The prevalence of chronic migraine is ∼1%. Baseline attack frequency and acute medication overuse have been identified as potential risk factors for the progression of migraine from an episodic disorder to a chronic condition. There is an unmet patient need for effective and safe treatments for patients with chronic migraine, but data from rigorous controlled trials are limited. Previous studies have demonstrated that topiramate is an effective and safe preventive treatment for episodic migraine. In addition, pilot studies have suggested the utility of topiramate for the prevention of chronic migraine. Two randomized, double‐blind, placebo‐controlled, multicenter trials investigating the efficacy and safety of topiramate in the treatment of patients with chronic migraine have recently been completed. This review presents comparative data from these 2 clinical trials, which suggest that topiramate at a dose of 100 mg daily is effective and generally well tolerated in chronic migraine.
Abnormal response of motor cortex to photic stimulation in idiopathic generalized epilepsy
Authors: Groppa Sergiu , Siebner Hartwig R. , Kurth Christoph , Stephani Ulrich , Siniatchkin Michael
Published: July 2008

Background: Intermittent photic stimulation (IPS) shortens the cortical silent period (CSP) elicited by transcranial magnetic stimulation (TMS) over the primary motor hand area (M1HAND). This response is absent in healthy individuals with a photoparoxysmal response (PPR). Here we combined TMS of the M1HANDwith IPS to examine whether patients with idiopathic generalized epilepsy (IGE) exhibit an abnormal cortical response pattern to IPS.

Methods: In 13 PPR‐positive and 12 PPR‐negative patients with IGE and in 13 PPR‐negative healthy controls, we used focal TMS to the M1HANDto study how cortical excitability is changed by concurrent IPS at 50 Hz.

Results: IPS at 50 Hz reduced the duration of the CSP in healthy PPR‐negative individuals, whereas IPS had no effect on the CSP in PPR‐positive and PPR‐negative patients with generalized epilepsy. The failure of IPS to shorten the CSP was independent of antiepileptic medication. Single‐pulse or paired‐pulse TMS only without concurrent IPS showed a higher motor threshold in PPR‐positive patients with epilepsy, presumably caused by antiepileptic medication. No additional differences in cortical excitability were found among groups.

Conclusions: Because the CSP is mediated by intracortical GABAergic mechanisms, our results indicate that IGEs are associated with an altered responsiveness of GABAergic inhibitory circuits in the M1HAND. This electrophysiological trait is independent of photosensitivity. Excitability changes at the cortical or thalamic level may mediate this abnormal cortical response pattern in patients with IGE.
Benefit of combination therapy in epilepsy: A review of the preclinical evidence with levetiracetam
Authors: Kaminski Rafal M. , Matagne Alain , Patsalos Philip N. , Klitgaard Henrik
Published: July 2008

Levetiracetam (Keppra) is an antiepileptic drug (AED) characterized by a novel mechanism of action, unique profile of activity in seizure models, and broad‐spectrum clinical efficacy. The present report critically reviews several preclinical studies focused on combination therapy with levetiracetam and other anticonvulsants in various seizure and epilepsy models. Administration of levetiracetam together with many different clinically used AEDs or other anticonvulsants generally enhances their protective activity and, among existing AEDs, this was particularly prevalent with valproate. The protective activity of other AEDs was also enhanced by levetiracetam, which seems to be a universal finding that is independent of seizure model or drug combination studied. However, particularly strong enhancement was observed when levetiracetam was combined with agents either enhancing GABAergic or reducing glutamatergic neurotransmission. Importantly, these combinations were not associated with exacerbation of side effects or pharmacokinetic interactions. Based on the available preclinical data, it appears that combination treatment with levetiracetam and other anticonvulsants provides additional therapeutic benefit that may be attributed to its novel and distinct mechanism of action. Moreover, combinations of levetiracetam with clinically used AEDs that enhance GABAergic inhibition may be considered for rational polytherapy, which is often necessary in drug‐resistant patients.
Good surgical outcome in discordant ictal EEG‐MRI unilateral mesial temporal sclerosis patients
Authors: Castro Luiz H. , Serpa Mauricio H. , Valério Rosa M. , Jorge Carmen L. , Ono Carla R. , Arantes Paula R. , Rosemberg Sergio , Wen Hung Tzu
Published: July 2008

Summary

Purpose: Video electroencephalography (vEEG) monitoring of patients with unilateral mesial temporal sclerosis (uMTS) may show concordant or discordant seizure onset in relation to magnetic resonance imaging (MRI) evidence of MTS. Contralateral seizure usually leads to an indication of invasive monitoring. Contralateral seizure onset on invasive monitoring may contraindicate surgery. We evaluated long‐term outcome after anteromesial temporal lobectomy (AMTL) in a consecutive series of uMTS patients with concordant and discordant vEEG findings, uniformly submitted to AMTL on the MRI evidence of MTS side without invasive monitoring.

Methods: We compared surgical outcome of all uMTS patients undergoing vEEG monitoring between January 1999 and April 2005 in our service. Discordant cases were defined by at least one seizure onset contralateral to the MRI evidence of MTS. Good surgical outcome was considered as Engel's class I. We also evaluated ictal SPECT concordance to ictal EEG and surgical outcome.

Results: Fifty‐four patients had concordant (C) and 22 had discordant (D) scalp EEG and MRI. Surgical outcome was similar in both groups (C = 74% versus D = 86%). Duration of follow‐up was comparable in both groups: C = 56.1 ± 20.7 months versus D = 59.8 ± 21.2 months (p = 0.83, nonsignificant).
Discordant single‐photon emission computed tomography (SPECT) results did not influence surgical outcome.

Discussion: Surgical outcome was not influenced by contralateral vEEG seizure onset or contralateral increased flow on ictal SPECT. Although vEEG monitoring should still be performed in these patients, to rule out psychogenic seizures and extratemporal seizure onset, a potentially risky procedure such as invasive monitoring may not only not be indicated in this patient population, but may also lead to patients erroneously being denied surgery.
The clinical impact of pharmacogenetics on the treatment of epilepsy
Authors: Löscher Wolfgang , Klotz Ulrich , Zimprich Fritz , Schmidt Dieter
Published: July 2008

Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA‐B*1502, are at a higher risk for Stevens‐Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy.
Role of Major NMDA or AMPA Receptor Subunits in MK‐801 Potentiation of Ethanol Intoxication
Authors: Palachick Benjamin , Chen Yi‐Chyan , Enoch Abigail J. , Karlsson Rose‐Marie , Mishina Masayoshi , Holmes Andrew
Published: July 2008

Background: The glutamate system plays a major role in mediating EtOH’s effects on brain and behavior, and is implicated in the pathophysiology of alcohol‐related disorders.N‐methyl‐D‐aspartate receptor (NMDAR) antagonists such as MK‐801 (dizocilpine) interact with EtOH at the behavioral level, but the molecular basis of this interaction is unclear.

Methods: We first characterized the effects of MK‐801 treatment on responses to the ataxic (accelerating rotarod), hypothermic and sedative/hypnotic effects of acute EtOH administration in C57BL/6J and 129/SvImJ inbred mice. Effects of another NMDAR antagonist, phencyclidine, on EtOH‐induced sedation/hypnosis were also assessed. Gene knockout of the NMDAR subunit NR2A orl‐alpha‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate GluR1 or pharmacological antagonism of the NMDAR subunit NR2B (via Ro 25‐6981) was employed to examine whether inactivating any one of these glutamate signaling molecules modified MK‐801’s effect on EtOH‐related behaviors.

Results: MK‐801 markedly potentiated the ataxic effects of 1.75 g/kg EtOH and the sedative/hypnotic effects of 3.0 g/kg EtOH, but not the hypothermic effects of 3.0 g/kg EtOH, in C57BL/6J and 129/SvImJ mice. Phencyclidine potentiated EtOH‐induced sedation/hypnosis in both inbred strains. Neither NR2A nor GluR1 KO significantly altered basal EtOH‐induced ataxia, hypothermia, or sedation/hypnosis. Ro 25‐6981 modestly increased EtOH‐induced sedation/hypnosis. The ability of MK‐801 to potentiate EtOH‐induced ataxia and sedation/hypnosis was unaffected by GluR1 KO or NR2B antagonism. NR2A KO partially reduced MK‐801 + EtOH‐induced sedation/hypnosis, but not ataxia or hypothermia.

Conclusions: Data confirm a robust and response‐specific potentiating effect of MK‐801 on sensitivity to EtOH’s intoxicating effects. Inactivation of three major components of glutamate signaling had no or only partial impact on the ability of MK‐801 to potentiate behavioral sensitivity to EtOH. Further work to elucidate the mechanisms underlying NMDAR × EtOH interactions could ultimately provide novel insight into the role of NMDARs in alcoholism and its treatment.
Prediction of Serotonergic Treatment Efficacy Using Age of Onset and Type A/B Typologies of Alcoholism
Authors: Roache John D. , Wang Yanmei , Ait‐Daoud Nassima , Johnson Bankole A.
Published: July 2008

Background:  Previously, we reported that ondansetron was efficacious at treating early‐onset (≤25‐years old) but not late‐onset (≥26‐years old) alcoholics in a double‐blind, randomized, placebo‐controlled clinical trial (n = 321 enrolled patients, 271 of them randomized). Randomized participants underwent 11 weeks of treatment with ondansetron (1, 4, or 16 μg/kg twice daily; n = 67, 77, and 71, respectively) or identical placebo (n = 56), plus weekly standardized group cognitive behavioral therapy.

Methods:  For this study, we reanalyzed the original sample to determine whether the Type A/B typological classification predicts ondansetron treatment response. In this comparative analysis, k‐means clustering was applied to 19 baseline measures of drinking behavior, psychopathology, and social functioning, similar to those used by Babor in the original typological derivation. A 2‐factor solution described robustly 2 groups phenomenologically consistent with Type A/B classification. Subjects were subdivided into early‐ and late‐onset alcoholics.

Results:  Seventy‐two percent of Type B subjects had early‐onset alcoholism (EOA); 67% of Type A subjects had late‐onset alcoholism (LOA). The A/B typology better discriminated 2 clusters based upon baseline severity of alcoholism. There was a significant effect (p < 0.05) for Type B alcoholics to respond to ondansetron (4 μg/kg); however, Type A alcoholics receiving ondansetron showed no beneficial effect. Early‐onset vs. late‐onset classification predicted ondansetron response substantially better than Type A/B classification, which did not add to the prediction of treatment outcome. Further analyses showed that ondansetron was effective in the 33% of Type A alcoholics with EOA but ineffective in the 28% of Type B alcoholics with LOA.

Conclusions:  Type A/B classification best discriminates alcoholic subtypes based upon baseline severity. Early‐ vs. late‐onset classification is, however, a better predictor of response to ondansetron treatment because it might be more closely related to fundamental neurobiological processes associated with the underlying pathophysiology of alcoholism.
Maturation‐Dependent Alcohol Resistance in the Developing Mouse: Cerebellar Neuronal Loss and Gene Expression During Alcohol‐Vulnerable and ‐Resistant Periods
Authors: Karaçay Bahri , Li Shenglan , Bonthius Daniel J.
Published: July 2008

Background: Alcohol abuse during pregnancy injures the fetal brain. One of alcohol’s most important neuroteratogenic effects is neuronal loss. Rat models have shown that the cerebellum becomes less vulnerable to alcohol‐induced neuronal death as it matures.We determined if maturation‐dependent alcohol resistance occurs in mice and compared patterns of gene expression during the alcohol resistant and sensitive periods.

Methods: Neonatal mice received alcohol daily over postnatal day (PD) 2 to 4 or PD8 to 10. Purkinje cells and granule cells were quantified on PD25. The temporal expression patterns of 4 neuro‐developmental genes and 3 neuro‐protective genes in the cerebellum were determined daily over PD0 to 15 to determine how gene expression changes as the cerebellum transitions from alcohol‐vulnerable to alcohol‐resistant. The effect of alcohol on expression of these genes was determined when the cerebellum is alcohol sensitive (PD4) and resistant (PD10).

Results: Purkinje and granule cells were vulnerable to alcohol‐induced death at PD2 to 4, but not at PD8 to 10. Acquisition of maturation‐dependent alcohol resistance coincided with changes in the expression of neurodevelopmental genes. The vulnerability of cerebellar neurons to alcohol toxicity declined in parallel with decreasing levels of Math1 and Cyclin D2, markers of immature granule cells. Likewise, the rising resistance to alcohol toxicity paralleled increasing levels of GABA α‐6 and Wnt‐7a, markers of mature granule neurons. Expression of growth factors and genes with survival promoting function (IGF‐1, BDNF, and cyclic AMP response element binding protein) did not rise as the cerebellum transitioned from alcohol‐vulnerable to alcohol‐resistant. All 3 were expressed at substantial levels during the vulnerable period and were not expressed at higher levels later. Acute alcohol exposure altered the expression of neurodevelopmental genes and growth factor genes when administered either during the alcohol vulnerable period or resistant period. However, the patterns in which gene expression changed varied among the genes and depended on timing of alcohol administration.

Conclusions: Mice have a temporal window of vulnerability in the first week of life, during which cerebellar neurons are more sensitive to alcohol toxicity than during the second week. Expression of genes governing neuronal maturation changes in synchrony with the acquisition of alcohol resistance. Growth factors do not rise as the cerebellum transitions from alcohol‐vulnerable to alcohol‐resistant. Thus, a process intrinsic to neuronal maturation, rather than rising levels of growth factors, likely underlies maturation‐dependent alcohol resistance.
Peptidergic Agonists of Activity‐Dependent Neurotrophic Factor Protect Against Prenatal Alcohol‐Induced Neural Tube Defects and Serotonin Neuron Loss
Authors: Zhou Feng C. , Fang Yuan , Goodlett Charles
Published: July 2008

Introduction: Prenatal alcohol exposure via maternal liquid diet consumption by C57BL/6 (B6) mice causes conspicuous midline neural tube deficit (dysraphia) and disruption of genesis and development of serotonin (5‐HT) neurons in the raphe nuclei, together with brain growth retardation. The current study tested the hypothesis that concurrent treatment with either an activity‐dependent neurotrophic factor (ADNF) agonist peptide [SALLRSIPA, (SAL)] or an activity‐dependent neurotrophic protein (ADNP) agonist peptide [NAPVSIPQ, (NAP)] would protect against these alcohol‐induced deficits in brain development.

Methods: Timed‐pregnant B6 dams consumed alcohol from embryonic day 7 (E7, before the onset of neurulation) until E15. Fetuses were obtained on E15 and brain sections processed for 5‐HT immunocytochemistry, for evaluation of morphologic development of the brainstem raphe and its 5‐HT neurons. Additional groups were treated either with SAL or NAP daily from E7 to E15 to assess the potential protective effects of these peptides. Measures of incomplete occlusion of the ventral canal and the frequency and extent of the openings in the rhombencephalon were obtained to assess fetal dysraphia. Counts of 5‐HT‐immunostained neurons were also obtained in the rostral and caudal raphe.

Results: Prenatal alcohol exposure resulted in abnormal openings along the midline and delayed closure of ventral canal in the brainstem. This dysraphia was associated with reductions in the number of 5‐HT neurons both in the rostral raphe nuclei (that gives rise to ascending 5‐HT projections) and in the caudal raphe (that gives rise to the descending 5‐HT projections). Concurrent treatment of the alcohol‐consuming dams with SAL prevented dysraphia and protected against the alcohol‐induced reductions in 5‐HT neurons in both the rostral and caudal raphe. NAP was less effective in protecting against dysraphia and did not protect against 5‐HT loss in the rostral raphe, but did protect against loss in the caudal raphe.

Conclusions: These findings further support the potential usefulness of these peptides for therapeutic interventions in pregnancies at risk for alcohol‐induced developmental deficits. Notably, the ascending 5‐HT projections of the rostral raphe have profound effects in regulating forebrain development and function, and the descending 5‐HT projections of the caudal raphe are critical for regulating respiration. Protection of the rostral 5‐HT‐system may help prevent structural and functional deficits linked to abnormal forebrain development, and protection of the caudal systems may also reduce the increased risk for sudden infant death syndrome associated with prenatal alcohol exposure.
The Healthy Moms Study: The Efficacy of Brief Alcohol Intervention in Postpartum Women
Authors: Fleming Michael F. , Lund Michael R. , Wilton Georgiana , Landry Mary , Scheets Dawn
Published: July 2008

Background:  The prevention and treatment of alcohol use disorders among women of reproductive age have been well described. However, there is limited information on women specifically during the postpartum period. This period in a woman’s life is a time of transition and it provides an ideal opportunity for primary care providers to intervene.

Purpose:  The goal of this report was to present the results of a brief alcohol intervention conducted in 34 obstetrical practices with women seeking routine postpartum care.

Methods:  A randomized clinical trial was conducted from 2002 to 2005 in a diverse sample of women located in 15 Wisconsin counties. This report presents 6‐month follow‐up data.

Results:  A total of 8,706 women were screened for high‐risk alcohol use during routine postpartum care with 997 (12%) of these women testing positive for at‐risk drinking. A total of 235 women met inclusion criteria and were randomized to either “usual care” or “brief intervention.” The 4‐session intervention was delivered by outpatient obstetrical nurses and research staff. The mean age of the women in the sample was 28, 19.3% were from minority groups, 60.8% were married, 53.2% reported current tobacco use, and 17.9% had used marijuana in the previous 30 days. At the 6 month follow‐up appointment, there were significant reductions in mean number of total drinks in the previous 28 days (p < 0.013), number of drinking days (p < 0.024) and heavy drinking days (p < 0.019). In addition to a statistical difference between groups, there was a 19% difference in the mean number of drinks and number of drinking days, and a 36% difference in the number of heavy drinking days in favor of the intervention group.

Conclusion:  The findings of the Healthy Moms Trial support the implementation of brief alcohol intervention during the postpartum period.
The Role of Behavioral Impulsivity in the Development of Alcohol Dependence: A 4‐Year Follow‐Up Study
Authors: Rubio Gabriel , Jiménez Mónica , Rodríguez‐Jiménez Roberto , Martínez Isabel , Ávila César , Ferre Francisco , Jiménez‐Arriero Miguel Angel , Ponce Guillermo , Palomo Tomás
Published: July 2008

Background:  Although many studies have established a close relation between impulsivity and alcohol use disorders, little is known about the role of behavioral impulsivity in the development of these disorders.

Objectives:  To determine the role of 2 laboratory paradigms of impulsivity in the development of alcohol use disorders.

Methods:  Follow‐up study carried out with 471 participants diagnosed as heavy drinkers (HD) and followed‐up for 4 years. Initially, they were compared with a healthy control group. Assessment of behavioral impulsivity was carried out with the Continuous Performance Test (CPT), and the Stop‐Signal Task (SST) assessed behavioral inhibitory control. Differential reinforcement for low‐rate responding (DRLR) was used to evaluate the delay reward dimension. The Structured Clinical Interview (SCID‐DSM‐IV) was used to diagnose alcohol dependence.

Results:  The HD performed worse than the control group in all the behavioral tests of impulsivity. Performance in DRLR was the only behavioral impulsivity test that classified the HD correctly compared to controls. Logistic regression analysis indicated that performance on SST was a significant predictor [odds = 1.52(CI = 1.08–2.31)] of developing alcohol dependence.

Conclusions:  Our results support the relation between behavioral impulsivity and alcohol use disorders. The paradigm related to delay of reward may be a factor associated with the use of alcohol and the incapacity to control inhibition as dependence develops.
Neonatal Alcohol‐Induced Region‐Dependent Changes in Rat Brain Neurochemistry Measured by High‐Resolution Magnetic Resonance Spectroscopy
Authors: O’Leary‐Moore Shonagh K. , McMechan Andrew P. , Galloway Matthew P. , Hannigan John H.
Published: July 2008

Background:  Maternal drinking during pregnancy can lead to a range of deleterious outcomes in the developing offspring that have been collectively termed fetal alcohol spectrum disorders (FASDs). There is interest and recognized value in using non‐invasive neuroimaging techniques such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to characterize, respectively, structural and biochemical alterations in individuals with FASDs. To date, however, results with MRS have been inconsistent regarding the degree and/or nature of abnormalities.

Methods:  High‐resolution magic angle spinning (HR‐MAS) proton (1H) MRS is an ex vivo neuroimaging technique that can acquire spectra in small punches of intact tissue, providing clinically relevant neurochemical information about discrete brain regions. In this study, HR‐MAS 1H MRS was used to examine regional neurochemistry in frontal cortex, striatum, hippocampus, and cerebellum of young rats previously exposed to ethanol as neonates. Key neurochemicals of interest included N‐acetyl‐aspartate (NAA), glutamate, GABA, glutamine, creatine, choline and myo‐inositol.

Results:  Daily neonatal alcohol exposure from postnatal day 4 (PN4) through PN9 significantly reduced levels of NAA and taurine in the cerebellum and striatum, and induced sex‐dependent reductions in cerebellar glutamate when measured on PN16. In addition, myo‐inositol was significantly increased in cerebellum. The frontal cortex and hippocampus were virtually unaffected by this neonatal alcohol exposure.

Conclusion:  Results of this research may have implications for understanding the underlying neurobiology associated with FASDs and aid in testing treatments in the future. Ongoing studies are assessing the developmental persistence of and/or maturational recovery from these changes.
Ethanol‐Induced Malfunction of Neutrophils Respiratory Burst on Patients Suffering From Alcohol Dependence
Authors: Breitmeier Dirk , Becker Nina , Weilbach Christian , Albrecht Knut , Scheinichen Dirk , Panning Bernhard , Schneider Udo , Jüttner Björn
Published: July 2008

Background:  Polymorphonuclear, neutrophil granulocytes (PMN) play a major role in the control of infections, and people who abuse alcohol are susceptible to infections. Resistance against infections ensues intracellularly following initial phagocytosis of microorganisms with the oxygen‐dependent respiratory burst, the key enzyme of which is the respiratory burst oxidase, whereby oxygen radicals are produced for microbial destruction. To date there is insufficient information available in connection with the process of impaired defence against infection in patients suffering from alcohol dependence. Therefore, our investigation was carried out to determine the influence of alcohol exposition on the formation of oxygen radicals and the respiratory burst.

Methods:  4.5 ml of whole blood was taken from 10 healthy adults and 10 patients suffering from alcohol dependence. An additional 3.5 ml of whole blood was taken from the alcoholic patients for determination of the blood alcohol concentration. The respiratory burst of PMN was tested using the Four‐Colour‐Continuous Flow Cytometer. Each experimental procedure consisted of 4 test samples [negative controls, Escherichia coli, FMLP‐supplement (N‐formyl‐l‐methionyl‐l‐leucyl‐l‐phenylalanin), PMA‐supplement (phorbol‐12‐myristate‐13‐acetate)]. Differing concentrations of ethanol were also introduced to each of the tests performed (0.20 to 4.00 g/l).

Results:  Ethanol revealed a marked decrease of burst activity in those patients suffering from alcoholism with increased alcohol concentration. A dependence between the burst activity and the ethanol concentration was seen to be statistically significant. This effect was only evident after stimulation with E. coli and FMLP in those patients with alcohol dependence.

Conclusion:  The results presented in this study show an impairment in the function of PMN in those patients addicted to alcohol due to the decrease in burst activity. In view of the results of the different stimuli, the second‐messenger effects were not evident. A clarification of this phenomenon could well be assumed as an allosteric receptor effect on the burst oxidase, namely, a direct effect on the phagocytosis interaction between circulating granulocytes and causative organisms.
Voluntary Ethanol Intake Enhances Excitatory Synaptic Strength in the Ventral Tegmental Area
Authors: Stuber Garret D. , Hopf F. Woodward , Hahn Junghyun , Cho Saemi L. , Guillory Anitra , Bonci Antonello
Published: July 2008

Background: Addiction has been considered a disorder of motivational control over behavior, and the ventral tegmental area (VTA), in conjunction with other limbic brain structures, is thought to play a critical role in the regulation of a number of motivated behaviors including seeking of addictive drugs such as alcohol. Of particular interest is the ability of prolonged exposure of addictive drugs to enhance the function of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐type glutamatergic receptors (AMPAR) in the VTA, as glutamate receptor activation can significantly regulate VTA neuron activity. Here, we examined whether voluntary ethanol intake altered VTA AMPAR function.

Methods: We utilized in vitro electrophysiology to examine glutamatergic function in the VTA neurons 12 to 24 hours after the last self‐administration bout, which occurred 35 to 50 days after the initiation of ethanol self‐administration under a 2‐bottle intermittent access model.

Results: Voluntary intermittent ethanol intake in a 2‐bottle paradigm enhanced postsynaptic AMPAR function, indicated by an increased ratio of evoked AMPAR to N‐methyl‐d‐aspartic acid receptor currents, and by an increase in the amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) measured in the presence of tetrodotoxin to prevent action potential‐dependent release. In contrast, ethanol self‐administration did not alter evoked presynaptic glutamate release, indicated by no change in the paired‐pulse ratio of 2 AMPAR EPSCs evoked 50 ms apart, although spontaneous glutamate release was significantly enhanced, indicated by enhanced mEPSC frequency.

Conclusions: Our results suggest that postsynaptic AMPAR function in VTA neurons was significantly enhanced after ethanol self‐administration. As increased VTA AMPAR function can significantly regulate firing and enhance the reinforcing and activating effects of drugs of abuse, the increased AMPAR activity observed here may facilitate the drive to consume ethanol.
A Technique for Resection of Invasive Tumors Involving the Trigone Area of the Bladder in Dogs: Preliminary Results in Two Dogs
Authors: SAULNIER‐TROFF FRANCOIS‐GUILLAUME , BUSONI VALERIA , HAMAIDE ANNICK
Published: July 2008

Objective—To describe a surgical technique for resection of the entire bladder neck, including the trigone and proximal urethra in dogs with invasive tumors causing life‐threatening urinary tract obstruction.

Study Design—Clinical case reports.

Animals—Dogs (n=2) with bladder tumors.

Methods—Circumferential excision of the bladder neck and proximal urethra with preservation of the neurovascular pedicles was performed to remove a rhabdomyosarcoma (dog 1) and a transitional cell carcinoma (dog 2) involving the trigone and bladder neck that were causing urinary tract obstruction. Reconstruction of the bladder and proximal urethra included bilateral ureteroneocystostomy. Adjuvant chemotherapy was administered postoperatively to both dogs.

Results—Postoperatively, dogs 1 and 2 were continent after 7 and 17 days, respectively, and regained normal urinary function after resolution of a transient pollakiuria. Dog 1 had no evidence of local or regional recurrence; however, a large solitary pulmonary metastatic lesion was diagnosed 8 months later. The dog was euthanatized despite a lack of clinical signs. Dog 2 had at least 1 metastatic lesion in the abdominal wall 6 months later and was euthanatized at 580 days because of renal failure.

Conclusion—En‐bloc removal of the bladder neck and proximal urethra with preservation of the dorsal vascular and nervous pedicles, although a technically challenging procedure, can be performed without associated urinary incontinence or bladder wall necrosis.

Clinical Relevance—In dogs with invasive bladder tumors causing life‐threatening urinary tract obstruction, resection of the bladder neck and proximal urethra should be considered as a promising surgical alternative to urinary diversion.
TP53 Gene Mutations in Canine Osteosarcoma
Authors: KIRPENSTEIJN JOLLE , KIK MARJA , TESKE ERIK , RUTTEMAN GERARD R.
Published: July 2008

Objective—To investigate mutations of the TP53 gene in canine osteosarcoma (OS).

Study Design—Clinical historic cohort study.

Animals—Client‐owned dogs.

Methods—OS (n=59) were screened for mutations of the complete TP53 gene using polymerase chain reaction and the mutation was analyzed by single‐strand conformational polymorphism. Clinical outcome of dogs with TP53‐mutated OS were compared with dogs with OS without a mutation after complete surgical excision of the primary tumor.

Results—TP53 gene mutations were observed in 24 of 59 (40.7%) OS; 3 mutated OS had 2 mutations. The alterations consisted mainly of point mutations (74%). Dogs with mutated OS had a significantly shorter survival time (ST) after surgery than dogs with normal tumor TP53 gene expression (P=.03). Other significant prognosticators for ST and disease‐free interval included elevated serum alkaline phosphatase (P<.01) and tumor grade (P=.01).

Conclusion—TP53 genetic mutations are common in canine OS and may have a prognostic value.

Clinical Relevance—Mutations of the TP53 gene may influence survival and should be considered when evaluating canine OS.
Marginal Excision of Low‐Grade Spindle Cell Sarcoma of Canine Extremities: 35 Dogs (1996–2006)
Authors: STEFANELLO DAMIANO , MORELLO EMANUELA , ROCCABIANCA PAOLA , IUSSICH SELINA , NASSUATO CLAUDIA , MARTANO MARINA , SQUASSINO CHIARA , AVALLONE GIANCARLO , ROMUSSI STEFANO , BURACCO PAOLO
Published: July 2008

Objective— To evaluate recurrence rate and disease‐free interval (DFI) of dogs with low‐grade soft tissue spindle cell sarcoma of the extremities treated by marginal excision.

Study Design— Retrospective study.

Animals— Dogs (n=35) with soft tissue low‐grade spindle cell sarcoma.

Methods— Medical records were reviewed and dogs that had marginal surgical resection of low‐grade soft tissue spindle cell sarcoma at or distal to elbow and stifle were included.

Results— Histopathologic margins were dirty (12 dogs), clean but close (12), and clean (11). Follow‐up after surgery occurred from 210 to 2202 days (minimum, 180 days). Local recurrence and metastatic rates were 10.8% and 0%, respectively. Median DFI and survival time were not reached, because <50% of dogs died of disease‐related events. Mean DFI and mean survival time were 697.8 days (95% CI: 559.7–836 days) and 703.5 days (95% CI: 566.6–840.5 days), respectively. There were no significant differences among survival functions stratified by histologic margins.

Conclusion— Marginal surgical excision without adjuvant treatment of low‐grade soft tissue spindle cell sarcoma of the extremities results in a low local recurrence rate.

Clinical Relevance— Low‐grade spindle cell sarcomas located at or distal to the elbow and stifle joints can be excised without need for wide or radical surgery.
Histologic Prognosticators in Feline Osteosarcoma: A Comparison with Phenotypically Similar Canine Osteosarcoma
Authors: DIMOPOULOU MARIA , KIRPENSTEIJN JOLLE , MOENS HESTER , KIK MARJA
Published: July 2008

Objective— To investigate the histologic characteristics of feline osteosarcoma (OS) and compare the histologic data with phenotypically comparable canine OS. The effects of histologic and clinical variables on survival statistics were evaluated.

Study Design— Retrospective study.

Animals— Cats (n=62) and dogs (22).

Methods— Medical records of 62 cats with OS were reviewed for clinically relevant data. Clinical outcome was obtained by telephone interview. Histologic characteristics of OS were classified using a standardized grading system. Histologic characteristics in 22 feline skeletal OS were compared with 22 canine skeletal OS of identical location and subtype. Prognostic variables for clinical outcome were determined using multivariate analysis.

Results— Feline OS was characterized by moderate to abundant cellular pleomorphism, low mitotic index, small to moderate amounts of matrix, high cellularity, and a moderate amount of necrosis. There was no significant difference between histologic variables in feline and canine OS. Histologic grade, surgery, and mitotic index significantly influenced clinical outcome as determined by multivariate analysis. Tumor invasion into vessels was not identified as a significant prognosticator.

Conclusion— Feline and canine skeletal OS have similar histologic but different prognostic characteristics.

Clinical Relevance— Prognosis for cats with OS is related to histologic grade and mitotic index of the tumor.
Hypotonic Water as Adjuvant Therapy for Incompletely Resected Canine Mast Cell Tumors: A Randomized, Double‐Blind, Placebo‐Controlled Study
Authors: BROCKS BOUVIEN A.W. , NEYENS ISABELLE J.S. , TESKE ERIK , KIRPENSTEIJN JOLLE
Published: July 2008

Objective—To evaluate efficacy of hypotonic water as adjuvant therapy after marginal resection of canine mast cell tumors (MCT).

Study Design—Double‐blinded, placebo‐controlled, prospective, randomized study.

Animals—Dogs (n=30) with spontaneous, cutaneous, solitary MCT.

Methods—The wound bed of MCT, resected with margins <0.5 cm, was injected with either hypotonic or isotonic water according to a standardized protocol. Follow‐up was obtained by clinical examination at 1, 2, 3, 6, and 12 months and annual telephone contact with the owner.

Results—Eighteen dogs were treated with isotonic lactated Ringer's solution and 12 dogs with hypotonic distilled water. All MCT were stage 0 tumors and most grade II. Six tumors (4 isotonic, 2 hypotonic) recurred locally, 3 of these dogs died from disease‐related reasons within 4 months. The surviving 3 dogs were alive with a median survival time (ST) of 1092 days. The calculated 2‐year recurrence‐free rate was 92.7%; the 2‐year disease‐free rate 79.1%; and the 2‐year survival rate 89.5%. No significant differences in local recurrence and ST were observed between treatment groups. Histologic grading was the only significant prognosticator for ST and recurrence‐free periods.

Conclusion—No significant differences in local recurrence and ST were observed between adjunctive hypotonic water and placebo treatment after marginal resection of solitary MCT.

Clinical Relevance—Hypotonic water does not decrease the rate of local recurrence in dogs with solitary MCT after marginal surgical excision.
Reconstruction of Chest Wall Defects After Rib Tumor Resection: A Comparison of Autogenous, Prosthetic, and Composite Techniques in 44 Dogs
Authors: LIPTAK JULIUS M. , DERNELL WILLIAM S. , RIZZO SCOTT A. , MONTEITH GABRIELLE J. , KAMSTOCK DEBRA A. , WITHROW STEPHEN J.
Published: July 2008

Objective—To compare short‐ and long‐term outcome and complications of chest wall reconstruction in dogs using autogenous, prosthetic, and composite autogenous–prosthetic techniques.

Study Design—Historical cohort.

Animals—Dogs (n=44) with spontaneous tumors arising from or involving the chest wall.

Methods—Medical records were reviewed for dogs with rib and/or sternal tumors treated by chest wall resection and reconstruction. Signalment, preoperative clinical features, intraoperative findings and complications, reconstruction technique (autogenous muscle flap, prosthetic mesh, or composite autogenous–prosthetic technique), and short‐ (≤14 days) and long‐term (>14 days) postoperative complications were determined from the medical records and telephone contact with owners and referring veterinarians. Associations between chest wall reconstruction technique and postoperative complications were tested with Cox proportional hazards.

Results—Chest wall defects were reconstructed with autogenous muscle flaps (29 dogs), prosthetic mesh (3), and a composite technique of prosthetic mesh and either autogenous muscle or omental pedicle flap (12). Early postoperative complications were recorded in 8 dogs (18.2%) and included seroma (5) and pleural effusion and peripheral edema (3). One dog had a late complication (2.3%) with a mesh‐related infection 767 days postoperatively. Overall, complications occurred in 10.3% of autogenous, 25.0% of composite, and 66.7% of prosthetic reconstructions. Chest wall reconstruction with Marlex mesh alone was associated with a significantly increased risk of postoperative complications compared with autogenous reconstruction (P=.027). Reconstruction of sternal defects (3), 2 of which were performed with Marlex mesh alone, was associated with a significantly increased risk of complications compared with lateral chest wall reconstructions (P=.037).

Conclusions—Large chest wall defects can be reconstructed with autogenous and composite techniques, but prosthetic mesh should be covered with well‐vascularized autogenous muscle or omentum to decrease the risk of postoperative complications. Sternal defects should be reconstructed with rigid techniques.

Clinical Relevance—Chest wall reconstruction with autogenous muscle flaps or a combination of autogenous techniques with prosthetic mesh is associated with a low rate of infection and other complications.
Examining Links Between Sign‐Out Reporting During Shift Changeovers and Patient Management Risks
Authors: Sharit Joseph , McCane Lorgia , Thevenin Deborah M. , Barach Paul
Published: July 2008

This article reports on a qualitative study that investigated how various risk factors associated with the process of sign‐out reporting across shifts in critical care hospital environments could lead to flawed communication and thus to increased risk of poor patient outcomes. The study was performed in two critical care hospital units: the pediatric intensive care unit (PICU) and the postanesthesia care unit (PACU). We collected data from observations of eight nurses and four resident physicians in the PICU and four nurses and four resident physicians in the PACU giving sign‐out reports during their shift changes. In addition, we conducted semi‐structured interviews with a separate sample of medical providers consisting of nurse managers, attending physicians, nurses, and residents from each of these two units. The issues that were addressed in these interviews included how various methods of conducting sign‐outs and factors such as personality and experience could impact the effectiveness of communication during sign‐out reporting. We also collected data from these medical providers on how failures in communication during sign‐out reporting could lead to potentially adverse patient outcomes. The article concludes with the presentation of a modeling framework that demonstrates how the combined influences of risk factors can generate a particularly important type of failure mode in communication and how interventions can be targeted to serve as barriers to such events. A number of recommendations intended for reducing risks associated with the communication of sign‐out reports are also presented.