bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement in the Retinal Circulation after Superficial Temporal to Middle Cerebral Artery Bypass
Authors: Standefer Michael , Little John R. , Tomsak Robert , Furlan Anthony J. , Zegarra Hernando , Williams George
Published: August 2004

The retinal circulation of 35 patients (age, 30 to 71 years) with symptomatic internal carotid occlusion (22 cases) or severe inaccessible stenosis (13 cases) was studied both before and after superficial temporal to middle cerebral artery (STA-MCA) bypass surgery using ophthalmodynamometry (ODM) and intravenous fundus fluorescein angiography (IVFA). Ninety-four per cent of the patients were found preoperatively to have funduscopic findings or symptoms indicative of ocular ischemia. ODM values were abnormal preoperatively in 32 of 35 patients (91%), and improvement in ODM values for the ipsilateral eye was noted postoperatively in 25 patients (71%). ODM values obtained during the early (<3 months) and late (>3 months) postoperative periods were significantly improved when compared to the preoperative values. IVFA values were abnormal in 25 of 29 patients (86%) preoperatively, and significant improvement was noted in 22 of 25 patients (88%) postoperatively. Preoperative patients with normal fundus examinations (10 cases) had significantly better values for IVFA and ODM than patients with venous stasis retinopathy. The findings of the study showed that STA-MCA anastomosis is beneficial in treating retinal ischemia secondary to ipsilateral severe inaccessible carotid artery stenosis or occlusion.
Cervical Diastematomyelia: A Case Report with Operative Management
Authors: Kuchner Eugene F. , Anand Azad K. , Kaufman Barry M.
Published: August 2004

A case of midcervical diastematomyelia presenting as acute traumatic hemiplegia in an adult is discussed, with emphasis upon features reflecting this particular location. Advantages of metrizamide computed tomographic imaging in the diagnosis of this entity are presented, and a method of operative management is outlined. (Neurosurgery 16: 538-542, 1985)
Three Phases of Cerebral Arteriopathy in Meningitis: Vasospasm and Vasodilatation Followed by Organic Stenosis
Authors: Yamashima Tetsumori , Kashihara Kengo , Ikeda Kiyonobu , Kubota Toshihiko , Yamamoto Shinjiro
Published: August 2004

A systematic radiological and pathological study of the cerebral arteries was made in an autopsy case of meningitis associated with three phases of cerebral arteriopathy. The latter consisted of vasospasm, vasodilatation, and organic stenosis. A marked change in the caliber of the cerebral arteries was demonstrated 3 times. Vasospasm, the stimulus phenomenon, was produced by the surrounding purulent material. Vasodilatation, the paralytic phenomenon, was presumably due to decreased contractile energy in association with myonecrosis. Organic stenosis, the repair process, was due to the organization of subendothelial edema with resultant intimal thickening. Evidence of increased endothelial permeability, subendothelial proliferation of smooth muscle cells, and necrosis of the latter in the media is presented in both light and electron micrographs.
Acremonium kiliense Osteomyelitis of the Calvarium
Authors: Brabender Wayne , Ketcherside Joseph , Hodges Glenn R. , Rengachary Setti , Barnes William G.
Published: August 2004

A 35-year-old man with osteomyelitis of the calvarium, from which Acremonium kiliense was consistently isolated, was successfully treated with amphotericin-B and ketoconazole in addition to craniectomy. Subsequent acrylic cranioplasty produced a good cosmetic result.
Communicating Triventricular Hydrocephalus and Its Treatment with a Lumboperitoneal Shunt
Authors: Aoki Nobuhiko , Mizutani Hiroshi
Published: August 2004

With computed tomography, triventricular hydrocephalus shows enlargement of the 3rd and both lateral ventricles with a nearly normal size 4th ventricle. Triventricular hydrocephalus has been described as noncommunicating because of aqueductal stenosis or obstruction. The authors, however, have encountered three patients whose computed tomographic (CT) images were those of triventricular hydrocephalus despite a patent aqueduct. This condition may be suitably referred to as communicating triventricular hydrocephalus because in all cases metrizamide CT cisternography demonstrated the communication between the spinal subarachnoid space and both lateral ventricles. The authors discuss its treatment with a lumboperitoneal shunt.
Surgical Management of Intracerebral Hematomas
Authors: Tsementzis S.A.
Published: August 2004

Traditional and recent developments in the management of spontaneous intracranial hematomas are reviewed. A comprehensive account of the epidemiological characteristics worldwide with an etiological analysis including prevention and prophylaxis introduce the size and clinical significance of this neurological problem. The usefulness and limitations of the available diagnostic methods are described. Most of the emphasis, however, is placed on the management and medicosurgical treatment of intracranial hematomas in correlation with their clinical presentation and localization.
Dynamic Computed Tomography: Intracranial Applications
Authors: Wasenko John J. , Cacayorin Edwin D. , Petro George R. , Salibi Naman A. , Hodge Charles H. , Modesti Luciano M. , King Robert B.
Published: August 2004

Rapid sequential computed tomography of the brain after the bolus injection of contrast material provides invaluable information as to the characteristic blood flow of intracranial lesions in a noninvasive manner. Plotted dynamic curves permit accurate diagnosis of particularly difficult cases of infarcts and neoplasms. Dynamic computed tomographic (CT) scanning has become a part of the CT work-up for infarcts, which has allowed their earlier demonstration, detected as areas of hypoperfusion not clearly evident on an initial conventional CT study. Quantitative assessment of vasogenic edema and hypoperfusion are helpful in establishing the diagnosis of infarction and neoplasia. Orbital and parasellar neoplasms can be distinguished accurately from vascular lesions. Dynamic CT studies complemented conventional film screen arteriography in the evaluation of three cases of intracavernous internal carotid artery aneurysm, defining thrombus formation and wall thickness and thus influencing the therapeutic approach. In addition, this modality is useful in differentiating jugular fossa neoplasm from vascular malformation. This review elaborates on the technique involved in dynamic CT scanning and the subsequent results.
Test‐Retest Reliability of Adolescents’ Self‐Report of Substance Use
Authors: Levy Sharon , Sherritt Lon , Harris Sion Kim , Gates Elizabeth C. , Holder David W. , Kulig John W. , Knight John R.
Published: August 2004

Background: Adolescent substance abuse is a serious problem for which effective interventions are needed. To conduct trials of new therapies, investigators need reliable means of identifying potential participants and of measuring outcomes. The objective of this study was to determine the 1‐week test‐retest reliability of the CRAFFT screening test and of the timeline follow‐back (TLFB) calendar method for measuring alcohol, cannabis, and other drug use.

Methods: Ninety‐three 12‐ to 18‐year‐old patients presenting for routine medical care to three urban adolescent clinics were administered the CRAFFT screen in both lifetime and past‐year versions and a 90‐day TLFB. Both measures were completed on the day of the clinic visit and again 1 week later. We computed κ coefficients and the intraclass correlation coefficient (ICC) for the CRAFFT and computed the ICC separately for TLFB self‐reports of alcohol and cannabis.

Results: For the CRAFFT, κ for individual items ranged from 0.31 to 0.86, and the ICC was 0.93 (95% confidence interval, 0.90–0.95). However, the total score of the lifetime CRAFFT at time 2 was significantly lower than at time 1; there was no difference in time 1 and time 2 total scores for the past‐year version. The ICCs for past‐90‐days TLFB variables were as follows: drinking days, 0.92; drinks per occasion, 0.87; cannabis days, 0.83; and joints per occasion, 0.76. Past‐30‐day and past‐60‐day intervals compared favorably to past‐90‐day intervals.

Conclusions: The CRAFFT screen is a reliable means of screening adolescents for substance abuse, although we recommend using the past‐year version. The TLFB is a reliable method of quantifying adolescents’ alcohol and cannabis use at intervals of 30, 60, or 90 days.
Antenatal Risk Factors Associated With Postpartum Comorbid Alcohol Use and Depressive Symptomatology
Authors: Homish Gregory G. , Cornelius Jack R. , Richardson Gale A. , Day Nancy L.
Published: August 2004

Background: High rates of comorbid depression and alcohol use disorders have been reported in epidemiological studies; little work has considered comorbidity in women during the perinatal period. The goal of this work was to identify prenatal factors (at each trimester) that predicted postpartum comorbid depressive symptoms and alcohol use in women.

Methods: The data are from an ongoing longitudinal study of pregnancy outcome that is now in its 16th year of follow‐up. The first four assessments were used in this study (fourth and seventh prenatal months, delivery, and 8 months after delivery; n= 595). Prenatal variables in five domains (psychological, substance use, social, obstetrical, and demographic) were considered in analyses to predict postpartum comorbid depressive symptoms and alcohol use in women.

Results: At each trimester, higher rates of depressive symptoms, binge drinking (four or more drinks per occasion), and tobacco use were significantly associated with comorbidity at the eighth postpartum month. Third‐trimester anxiety was also significantly associated with postpartum comorbidity. Prenatal social support, obstetrical complications, and demographic factors were not related to an increased risk for postpartum comorbidity.

Conclusions: Women with more depressive symptoms, who binge‐drink, or who smoke cigarettes at any time during their pregnancies are at risk for postpartum comorbidity. Women should be screened for depressive symptoms and substance use, and treatment should be initiated when women exhibit the risk factors described.
Nitric Oxide Synthesis Inhibition Attenuates Conditioned Reinstatement of Ethanol‐Seeking, but Not the Primary Reinforcing Effects of Ethanol
Authors: Liu Xiu , Weiss Friedbert
Published: August 2004

Background: Nitric oxide (NO) signaling has been implicated in regulating aspects of the reinforcing and addictive actions of cocaine. These experiments were designed to examine whether NO‐dependent neurotransmission also participates in mediating the addictive actions of another drug of abuse, ethanol, with emphasis on both the primary reinforcing effects of ethanol and the incentive motivational effects of ethanol‐related contextual stimuli.

Methods: Male Wistar rats were operantly trained to orally self‐administer 10% (w/v) ethanol in daily 30‐min sessions and to associate distinct discriminative stimuli with the availability of ethanol (S+) versus nonreward (S−). Rats were treated with the NO synthase inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME; 0, 10, or 40 mg/kg intraperitoneally) 30 min before self‐administration tests that were conducted after establishment of stable levels of daily ethanol intake and conditioned reinstatement tests that were performed after extinction of ethanol‐maintained operant responding.

Results: l‐NAME did not alter the primary reinforcing effects of ethanol in self‐administration tests. In contrast, l‐NAME dose‐dependently attenuated the recovery of extinguished responding induced by the ethanol S+ in the absence of ethanol availability during reinstatement tests.

Conclusions: These results suggest that the NO system does not play a role in behavior reinforced directly by ethanol. However, the results implicate NO‐dependent neurotransmission in alcohol‐seeking responses elicited by drug‐related contextual stimuli.
Immediate Acceptance of Ethanol in Infant Rats: Ontogenetic Differences With Moderate but Not High Ethanol Concentration
Authors: Truxell Eric , Spear Norman E.
Published: August 2004

Background: During the preweanling period, infant rats consume large quantities of ethanol without initiating procedures. Ethanol intake during this period has seemed to be age related, with peak consumption occurring near the end of the second postnatal week, on postnatal day (P)12, but only a narrow range of conditions has been tested.

Methods: Independent ingestion of ethanol was measured at each of two ages, P12 and P18, with systematic variation in ethanol concentration, duration of exposure, and mode of fluid presentation. Ethanol ingestion was measured in terms of percentage body weight gain, grams of absolute ethanol ingested per unit body weight, and blood ethanol concentration.

Results: Ingestion of 30% ethanol during a 40‐min period led to blood ethanol concentrations approaching 300 mg/100 ml at both P12 and P18. For ethanol concentrations of 10 or 20%, ingestion at P12 was greater than at P18. When ethanol was available from ethanol‐soaked Kimwipe on the floor, ethanol intake transdermally or by inhalation was apparent but accounted for less than half of the overall ethanol intake. It was clear that for older infants, which are susceptible to ethanol's diuretic effects and are much more likely to self‐void than those at P12, measurement of intake by percentage body weight gain can underestimate ethanol ingestion.

Conclusions: The infant rat ingests extraordinarily high levels of ethanol, in concentrations as high as 30%, without initiation procedures. Acceptance of ethanol by infants on first exposure contrasts with the conventional rejection of these concentrations by adults. It is unclear why younger infants (P12) consume more 10 and 20% ethanol than older (P18) infants. These and other differences in ethanol intake between infants and older animals may be due initially to the relative ontogeny of receptors for bitter and sweet taste and subsequently to other factors.
The Genetics of Alcohol Intake and of Alcohol Dependence
Authors: Whitfield John B. , Zhu Gu , Madden Pamela A. , Neale Michael C. , Heath Andrew C. , Martin Nicholas G.
Published: August 2004

Background: Because alcohol has multiple dose‐dependent consequences, it is important to understand the causes of individual variation in the amount of alcohol used. The aims of this study were to assess the long‐term repeatability and genetic or environmental causes of variation in alcohol intake and to estimate the degree of overlap with causes of susceptibility to alcohol dependence.

Methods: Data were used from three studies conducted between 1980 and 1995 on volunteer adult male and female Australian twin subjects. In each study, alcohol intake was reported both as quantity × frequency and as past‐week data. Repeatability was calculated as correlations between occasions and between measures, and the effects of genes and environment were estimated by multivariate model fitting to the twin pair repeated measures of alcohol use. Relationships between mean alcohol use and the lifetime history of DSM‐III‐R alcohol dependence were tested by bivariate model fitting.

Results: Repeatability of the alcohol intake measures was between 0.54 and 0.85, with the highest repeatability between measures within study and the lowest repeatability between the first and last studies. Reported alcohol consumption was mainly affected by genetic factors affecting all times of study and by nonshared environmental factors (including measurement error) unique to each time of study. Genes that affect alcohol intake do affect alcohol dependence, but genetic effects unique to dependence are also significant; environmental effects are largely unique to either intake and dependence.

Conclusions: Nearly all the repeatable component of variation in alcohol intake is due to genetic effects. Genes affecting intake also affect dependence risk, but there are other genes that affect dependence alone. Studies aiming to identify genes that affect alcohol use disorders need to test loci and candidate genes against both phenotypes.
Modulation of Hypothalamic β‐Endorphin—Regulated Expression of Natural Killer Cell Cytolytic Activity Regulatory Factors by Ethanol in Male Fischer‐344 Rats
Authors: Dokur Madhavi , Boyadjieva Nadka I. , Advis Juan P. , Sarkar Dipak K.
Published: August 2004

Background: We have previously shown that ethanol administration suppresses natural killer (NK) cell cytolytic activity, partly by decreasing the action of hypothalamic β‐endorphin (β‐EP) on the spleens of male Fischer‐344 rats. This study was conducted to examine the effects of ethanol and central administration of β‐EP on perforin, granzyme B, and the cytokine interferon (IFN)‐γ—factors that modulate NK cell cytolytic activity—to understand the mechanism involved in ethanol's suppression of NK cell activity.

Methods: A group of male Fischer‐344 rats were fed an ethanol‐containing diet (8.7% v/v), and a control group was pair‐fed an isocaloric diet. At the end of 2 weeks, both groups were infused with β‐EP 100 ng/hr into the paraventricular nucleus of the hypothalamus for 18 hr, and spleen tissues were immediately removed for analysis of perforin, granzyme B, and IFN‐γ messenger RNA (mRNA) and protein levels. The mRNA levels of perforin, granzyme B, and IFN‐γ were evaluated by quantitative real‐time polymerase chain reaction, and the protein levels of perforin and granzyme B were analyzed by Western blot.

Results: Paraventricular nucleus administration of β‐EP increased the mRNA and protein expression of granzyme B and mRNA expression of IFN‐γ in pair‐fed animals. Ethanol significantly reduced both basal and β‐EP–induced levels of granzyme B and IFN‐γ.

Conclusions: These data suggest that chronic ethanol consumption suppresses β‐EP–induced NK cytolytic activity, granzyme B, and IFN‐γ in male Fischer‐344 rats.
On Sensitivity, Specificity, and the Influence of Various Parameters on Ethyl Glucuronide Levels in Urine—Results From the WHO/ISBRA Study
Authors: Wurst Friedrich Martin , Wiesbeck Gerhard A. , Metzger Jörg W. , Weinmann Wolfgang , Graf Marc ,   the WHO/ISBRA Study on Biological State and Trait Markers of Alcohol Use and Dependence
Published: August 2004

Background: Ethyl glucuronide (EtG), a direct ethanol metabolite, seems to meet the need for a sensitive and specific marker for monitoring recent alcohol consumption in different settings. Our aim was to study sensitivity, specificity, and the influence of various parameters on EtG levels in urine.

Patients and Methods: Urine samples for a total of 453 patients (373 male, 80 female) were statistically analyzed. The mean age was 37.1 years (median 36, SD 12.59), body mass index was 24.7, total ethanol consumed last month was 1817.66 g (each median), and 80 patients reported cannabis use within the last 30 days. Determination of EtG was performed with a liquid chromatography‐tandem mass spectrometry method with deuterium‐labeled EtG as internal standard.

Results: For EtG in urine, a good correlation was found with other state markers and days of sobriety. In a regression analysis, age, gender, marijuana use, kidney disease, and total grams of ethanol consumed last month were the variables that significantly influenced EtG levels in contrast to race, smoking, body mass index, cirrhosis of liver, age began drinking regularly, packs of cigarettes smoked last month, and total body water. Furthermore, in a receiver operating characteristic curve analysis to distinguish between nondrinkers and individuals sober >4 days versus individuals drinking in the recent 4 days, area under the curve was 0.834. At a cutoff of 0.145 mg/liter, sensitivity was 83.5% and specificity 68.3%. A receiver operating characteristic curve was calculated for lifetime alcohol abuse or dependence against those who had never been abusers or dependent. In this case, subjects were either never dependent or lifetime dependent, but those currently dependent were excluded. The resulting area under the curve was 0.694. At a cutoff of 0.145 mg/liter, sensitivity was 73.8% and specificity 60.3%. For those with a self‐reported sobriety of less than 24 hr, the area under the curve was 0.899, sensitivity was 90.8%, and specificity was 76.5% at a cutoff of 0.435 mg/liter when we calculated nondrinkers and light drinkers against heavy drinkers and drinkers needing treatment. Cannabis‐using patients showed significant differences with regard to almost all state markers when compared with nonconsuming subjects.

Conclusions: Age, gender, marijuana use, kidney disease, and total grams of ethanol consumed last month should be taken into consideration when interpreting results of EtG in urine. Sensitivity and specificity seem promising. Cannabis use can be regarded as an indicator for other serious mental problems in alcohol‐using subjects.
ADH1B*1, ADH1C*2, DRD2 (−141C Ins), and 5‐HTTLPR Are Associated With Alcoholism in Mexican American Men Living in Los Angeles
Authors: Konishi Tamiko , Luo Huai‐Rong , Calvillo Maria , Mayo Matthew S. , Lin Keh‐Ming , Wan Yu‐Jui Yvonne
Published: August 2004

Background: The aim of the present study was to use a candidate gene approach to identify the genetic risk factors for alcoholism in Mexican Americans residing in the Los Angeles area. The genes selected include alcohol metabolizing genes and neurotransmitter genes, which have been shown in the literature to be associated with alcoholism in other ethnic groups.

Methods: Thirteen allelic variants from seven genes were evaluated for their role in alcoholism using alcoholic (n= 200) and nonalcoholic (n= 251) Mexican Americans. Those polymorphic sites include alcohol dehydrogenase (ADH1B, ADH1C), aldehyde dehydrogenase (ALDH2), cytochrome P‐450 2E1 (CYP2E1) TaqI, DraI, RsaI, dopamine D2 receptor (DRD2) TaqI A, B, intron 6, exon 7, −141C Ins/Del, serotonin transporter (5‐HTTLPR), and GABAA receptor β3 subunit (GABRβ3).

Results: The results demonstrate that Mexican Americans have extremely low allele frequency for both ALDH2*2 and ADH1B*2 and a relatively high frequency of ADH1C*2 and CYP2E1 c2 alleles. ADH1B*1, ADH1C*2, DRD2 (−141C Ins), and 5‐HTTLPR were associated with alcoholism in Mexican Americans (p < 0.05). DRD2 Ins was associated with alcoholism in those alcoholics who carried the ADH1B*2 or ADH1C*1 protective alleles (p= 0.032 in genotype level and p= 0.015 in allele level). DRD2 TaqI A and B alleles were associated with early age of onset for drinking (p= 0.016 for TaqI A1 and p= 0.049 for TaqI B1 allele).

Conclusions: Together, the data reveal unique genetic patterns in Mexican Americans that may be in part responsible for the heightened risk for alcoholism and alcohol‐associated health problems in this population.
Ethanol‐induced elevation of 3α‐hydroxy‐5α‐pregnan‐20‐one does not modulate motor incoordination in rats
Authors: Khisti Rahul T. , VanDoren Margaret J. , Matthews Douglas B. , Morrow A Leslie
Published: August 2004

Background: Ethanol administration elevates the levels of GABAergic neuroactive steroids in brain and contributes to some of its behavioral actions. In the present study, we investigated whether such elevation of GABAergic neuroactive steroids contributes to the motor incoordinating effects of ethanol.

Methods: Sprague‐Dawley rats were administered ethanol (2 g/kg intraperitoneally) or saline, and the level of 3α‐hydroxy‐5α‐pregnan‐20‐one (3α,5α‐THP) was measured across time in cerebral cortex and in various brain regions at the peak time by radioimmunoassay. To study whether increases in GABAergic neuroactive steroids are responsible for the motor incoordinating actions of ethanol, rats were subjected to chemical (5α‐reductase inhibitor, finasteride) and surgical (adrenalectomy) manipulations before receiving ethanol (2 g/kg intraperitoneally) injections. The rats were then subjected to different paradigms to evaluate motor impairment including the Majchrowicz motor intoxication rating scale, Rotarod test, and aerial righting reflex task at different time points.

Results: The radioimmunoassay of 3α,5α‐THP in different brain regions showed that ethanol increases 3α,5α‐THP levels by 3‐ and 9‐fold in cerebral cortex and hippocampus, respectively. There was no change in 3α,5α‐THP levels in cerebellum and midbrain. The time course of 3α,5α‐THP elevations in the cerebral cortex showed significant increases 20‐min after ethanol injection with a peak at 60 min. In contrast, motor toxicity peaked between 5 and 10 min after ethanol injections and gradually decreased over time. Furthermore, adrenalectomy or pretreatment with finasteride (2 × 50 mg/kg, subcutaneously) did not reduce motor incoordinating effects of ethanol as assessed by the Majchrowicz intoxication rating score, Rotarod test, or aerial righting reflex task.

Conclusions: Ethanol increases GABAergic neuroactive steroids in a time‐ and brain region‐selective manner. The role of neuroactive steroids in alcohol action is specific for certain behaviors. Alcohol‐induced deficits in motor coordination are not mediated by elevated neuroactive steroid biosynthesis.
Patterns of Dispensed Disulfiram and Naltrexone for Alcoholism Treatment in a Veteran Patient Population
Authors: Hermos John A. , Young Melissa M. , Gagnon David R. , Fiore Louis D.
Published: August 2004

Background:Short‐term treatment trials indicate that two Food and Drug Administration–approved agents, disulfiram and naltrexone, may each curtail alcohol consumption, but two large 1‐year Veterans Administration cooperative studies showed no long‐term benefits for these agents over placebo. To assess whether these agents are being prescribed for extended periods, as an indicator of long‐term use in nonexperimental settings, we compared dispensing patterns in a veteran patient population.

Methods:The New England Veterans Integrated Service Network outpatient pharmacy files between January 1, 1998, and June 30, 2001, were analyzed; only patients with prescriptions on or after March 1, 1998, were included. Measurements for each patient included data on new and refilled prescriptions of disulfiram, naltrexone, and control medications. Prescription survival curves with right censoring were constructed. Distinct treatment episodes were defined by having six or more months between the end date of a prior prescription and the start date of a new prescription.

Results:From eight New England Veterans Integrated Service Network centers, 754 patients were dispensed disulfiram, and 971 were dispensed naltrexone, encompassing 873 and 1075 treatment episodes, respectively. Treatment episode durations were virtually identical for both drugs: more than 35% of episodes were 1 month or shorter, more than 50% were 2 months or shorter, and 75% were 5 months or shorter. Concurrently prescribed neuroleptic or statin medications predicted longer disulfiram and naltrexone treatment episodes. However, for patients newly prescribed common neuroleptic, antidepressant, or statin agents, the risks for discontinuing disulfiram or naltrexone were 1.4 to 2.3 times greater than for discontinuing these other agents.

Conclusions:In clinical settings, veteran patients were likely to be dispensed either disulfiram or naltrexone for only several months or less. The contexts and reasons for these predominantly short‐term treatment episodes or the benefits derived were not known and merit further study.
Ethanol‐Inhibited [3H]Thymidine Incorporation via Protein Kinase C‐p44/42 Mitogen‐Activated Protein Kinase/Phospholipase A2 Signal Pathway in Renal Proximal Tubule Cells
Authors: Lee Yun Jung , Lee Jang Hern , Han Ho Jae
Published: August 2004

Background: Ethanol exposure leads to changes of cell proliferation in a variety of cell types. However, how ethanol affects the proliferation of renal proximal tubule cells is not known.

Methods: To examine the effect of ethanol on cell proliferation and its related signaling pathway, [3H]thymidine incorporation, release of [3H]arachidonic acid (AA), and Western blotting of protein kinase C (PKC)/mitogen‐activated protein kinase (MAPK) were performed in primary cultured rabbit renal proximal tubule cells.

Results: Ethanol inhibited [3H]thymidine incorporation in a time‐ and dose‐dependent manner. An inhibitory effect of ethanol on [3H]thymidine incorporation was predominantly observed after 12 hr of treatment with 100 mM ethanol. Ethanol increased AA release and prostaglandin E2 production. In addition, ethanol‐induced inhibition of [3H]thymidine incorporation was blocked by phospholipase A2 inhibitors and was significantly blocked by PKC inhibitors. Indeed, ethanol induced a PKC translocation from the cytosolic to the membrane fraction. In addition, ethanol‐induced inhibition of [3H]thymidine incorporation was blocked by PD 98059 (a p44/42 MAPK inhibitor), but not by SB 203580 (a p38 MAPK inhibitor), and ethanol increased the phosphorylation of p44/42 MAPK. Results of phosphorylated p44/42 MAPK by ethanol were consistent with those of [3H]thymidine incorporation and [3H]AA‐release experiments.

Conclusions: Ethanol inhibited [3H]thymidine incorporation via PKC, p44/42 MAPK, and phospholipase A2 signaling pathways in primary cultured renal proximal tubule cells.
Progress in the Development of Topiramate for Treating Alcohol Dependence: From a Hypothesis to a Proof‐of‐Concept Study
Authors: Johnson Bankole A.
Published: August 2004

Advances in neuroscientific knowledge have evoked interest in developing effective medications for the treatment of alcohol dependence. Pharmacological approaches that involve the use of relatively specific medications at a particular neuronal target to modulate corticomesolimbic dopamine neuronal activity, the critical pathway for expression of the reinforcing effects of abused drugs, have yielded modest efficacy in the treatment of alcohol dependence. A new approach is needed. Because corticomesolimbic dopamine neurons interact with a variety of neurotransmitters that modulate its effects in the nucleus accumbens, it might be possible to more reliably control these dopaminergic effects with a medication that acted contemporaneously on more than one neuromodulator of dopamine function. Additionally, because alcohol use results in neuronal adaptations due to sensitization, the chances of effective therapy might be bolstered by administering a medication that also has utility with mitigating its chronic effects. My proposed conceptual framework suggests that a medication that facilitates inhibitory γ‐aminobutyric acid‐A input and antagonizes excitatory glutaminergic afferents to the nucleus accumbens would have pharmacotherapeutic potential in treating the alcohol dependence syndrome because these effects would act contemporaneously to suppress corticomesolimbic dopamine release. Through similar effects, topiramate might also aid chronic drinkers to wean themselves off alcohol and might ameliorate the symptoms of alcohol withdrawal. This commentary highlights the scientific concepts and clinical evidence for the development of topiramate in the treatment of alcohol dependence.
An Association Between Ethanol‐Evoked Enhancement of c‐jun Gene Expression in the Nucleus Tractus Solitarius and the Attenuation of Baroreflexes
Authors: Wang Xu , Abdel‐Rahman Abdel A.
Published: August 2004

Background: An increased expression of Fos, the protein product of the immediate early gene c‐fos, in the nucleus tractus solitarius (NTS) is associated with dysfunction in baroreceptor reflex control of heart rate. Our previous studies demonstrated that ethanol attenuates baroreflex sensitivity (BRS) in rats and humans. In this study, we tested the hypothesis that enhanced expression of the immediate early gene c‐jun (an index of neuronal activity) in the NTS contributes to the baroreflex dysfunction caused by ethanol.

Methods: Conscious male spontaneously hypertensive (SHR) and Wistar‐Kyoto (WKY) rats were used to measure blood pressure, heart rate, and baroreflex sensitivity (Oxford method). The c‐jun messenger RNA (mRNA) expression in NTS was measured by in situ hybridization.

Results: Ethanol elicited dose‐dependent attenuation in BRS in WKY rats, which was associated with significant increases in c‐jun mRNA in the NTS. In contrast, ethanol had no effect on BRS or c‐jun mRNA in the NTS of the SHRs; the latter exhibited significantly lower BRS and higher c‐jun mRNA in the NTS compared with WKY rats.

Conclusions: An increased basal level of c‐jun mRNA in the NTS may contribute to the reduced BRS in the SHR, and ethanol enhancement of neuronal activity of the NTS, expressed as increased c‐jun mRNA expression, may contribute to its attenuation of BRS, which highlights the NTS as a neuroanatomical target for ethanol action on baroreflexes.
Effect of 5‐HT3 Receptor Over‐Expression on the Discriminative Stimulus Effects of Ethanol
Authors: Shelton Keith L. , Dukat Malgorzata , Allan Andrea M.
Published: August 2004

Background: Drug discrimination studies using selective antagonists and agonists have suggested that 5‐HT3 receptors may modulate ethanol's discriminative stimulus effects. However, conflicting data between laboratories leaves the issue of 5‐HT3 receptor involvement in ethanol's discriminative stimulus effects in question. The present study utilized transgenic mice that over‐express 5‐HT3 receptors in conjunction with traditional pharmacological techniques to examine the contribution of 5‐HT3 receptors to ethanol's discriminative stimulus.

Methods: Ten 5‐HT3 over‐expressing (5‐HT3 OE) and 18 B6SJL wild‐type (WT) mice were trained to discriminate 1.5 g/kg ethanol from saline in daily 15 min, milk reinforced operant sessions. After training, ethanol substitution and response‐rate suppression dose response curves were determined for ethanol, midazolam, dizocilpine, cocaine, mCPP, MD‐354, YC‐30 and MDL‐72222. Antagonism tests combining ethanol with MDL‐72222 and ondansetron were also conducted.

Results: The 5‐HT3 OE and WT mice learned the ethanol discrimination in a comparable number of training sessions. Similar patterns of substitution were generated in both groups of mice for most test drugs. 5‐HT3 OE mice were more sensitive to the rate suppressing effects of dizocilpine and MDL‐72222 than were WT mice. Neither of the 5‐HT3 antagonist tested significantly attenuated ethanol's discriminative stimulus effects in either 5‐HT3 OE or WT mice.

Conclusions: The results of the present study are consistent with a minimal role of 5‐HT3 receptors in transducing ethanol's discriminative stimulus effects. Over‐expression of 5‐HT3 receptors does not alter the relative efficacy of GABAA positive modulators or NMDA antagonists for producing ethanol‐like discriminative stimulus effects. However, 5‐HT3 receptor over‐expression does appear to modulate the response‐rate altering effects of the uncompetitive NMDA antagonist, dizocilpine, and the 5‐HT3 antagonist, MDL‐72222.
Understanding well–being in the evolutionary context of brain development
Authors: Keverne Eric B.
Published: August 2004

Much of the work on well–being and positive emotions has tended to focus on the adult, partly because this is when problems are manifest and well–being often becomes an issue by its absence. However, it is pertinent to ask if early life events might engender certain predispositions that have consequences for adult well–being. The human brain undergoes much of its growth and development postnatally until the age of seven and continues to extend its synaptic connections well into the second decade. Indeed, the prefrontal association cortex, areas of the brain concerned with forward planning and regulatory control of emotional behaviour, continue to develop until the age of 20. In this article, I consider the significance of this extended postnatal developmental period for brain maturation and how brain evolution has encompassed certain biological changes and predispositions that, with our modern lifestyle, represent risk factors for well–being. An awareness of these sensitive phases in brain development is important in understanding how we might facilitate secure relationships and high self–esteem in our children. This will provide the firm foundations on which to develop meaningful lifestyles and relationships that are crucial to well–being.
The viral protein Apoptin associates with the anaphase-promoting complex to induce G2/M arrest and apoptosis in the absence of p53
Authors: Teodoro Jose G. , Heilman Destin W. , Parker Albert E. , Green Michael R.
Published: August 2004

The chicken anemia virus protein Apoptin induces apoptosis in the absence of p53 by a mechanism that remains to be elucidated. Here we show that in transformed cells, Apoptin is associated with APC1, a subunit of the anaphase-promoting complex/cyclosome (APC/C). We demonstrate that Apoptin expression, or depletion of APC1 by RNA interference, inhibits APC/C function in p53 null cells, resulting in G2/M arrest and apoptosis. Our results explain the ability of Apoptin to induce apoptosis in the absence of p53 and suggest that the APC/C is an attractive target for anticancer drug development.
Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors
Authors: Bilder David
Published: August 2004

Mammalian epithelial tumors lose polarity as they progress toward malignancy, but whether polarity loss might causally contribute to cancer has remained unclear. In Drosophila, mutations in the “neoplastic tumor suppressor genes” (nTSGs) scribble, discs-large, and lethal giant larvae disrupt polarity of epithelia and neuroblasts, and simultaneously induce extensive overproliferation of these cells, which exhibit malignant-like characteristics. Herein I review what is known about the role of the fly nTSGs in controlling cell polarity and cell proliferation. Incorporating data from mammalian studies, I consider how polarity and proliferation can be coupled, and how disruption of polarity could promote cancer.
Tethering of eIF4G to adenoviral mRNAs by viral 100k protein drives ribosome shunting
Authors: Xi Qiaoran , Cuesta Rafael , Schneider Robert J.
Published: August 2004

Although most mRNAs initiate translation by 5′ ribosome scanning, some small fraction of mammalian and viral mRNAs utilize either of two alternate mechanisms, known as internal ribosome entry and ribosome shunting. Ribosome shunting is a poorly understood form of initiation in which 40S ribosome subunits are loaded onto mRNA through interactions with the m7GTP cap, but then bypass large segments of the mRNA as directed by cis-acting RNA shunting elements and trans-acting protein factors. Here, we describe the molecular mechanism by which ribosome shunting occurs with high efficiency on adenovirus late mRNAs. We show that the viral 100k protein possesses a selective binding element for the 5′ noncoding region (5′NCR) of viral late mRNAs (known as the tripartite leader), forms a complex with initiation factor eIF4G and poly(A)-binding protein (PABP), and strongly and selectively enhances the level of both factors and 40S ribosome subunits on viral mRNAs in polysomes. Mutational and biochemical studies demonstrate that the ability of 100k protein to bind both the tripartite leader and eIF4G are critical to promote a high level of ribosome shunting. A molecular mechanism for ribosome shunting is described by which enhanced binding of eIF4G and possibly PABP with 100k protein, and simultaneous interaction with the tripartite leader 5′NCR, drives 40S ribosome recruitment and initiation on mRNAs.
Upstream and downstream of mTOR
Authors: Hay Nissim , Sonenberg Nahum
Published: August 2004

The evolutionarily conserved checkpoint protein kinase, TOR (target of rapamycin), has emerged as a major effector of cell growth and proliferation via the regulation of protein synthesis. Work in the last decade clearly demonstrates that TOR controls protein synthesis through a stunning number of downstream targets. Some of the targets are phosphorylated directly by TOR, but many are phosphorylated indirectly. In this review, we summarize some recent developments in this fast-evolving field. We describe both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis. We also summarize the roles of mTOR in the control of cell growth and proliferation, as well as its relevance to cancer and synaptic plasticity.
An essential role of the JIP1 scaffold protein for JNK activation in adipose tissue
Authors: Jaeschke Anja , Czech Michael P. , Davis Roger J.
Published: August 2004

The c-Jun NH2-terminal kinase (JNK) is activated during obesity. One consequence of obesity is that JNK phosphorylates the adapter protein insulin receptor substrate 1 (IRS-1) on Ser 307 and inhibits signaling by the insulin receptor. JNK can therefore cause peripheral insulin resistance during obesity and may contribute to the development of type 2 diabetes. Here we report that the JNK-interacting protein 1 (JIP1) scaffold protein, which binds components of the JNK signaling module, is essential for JNK activation in the adipose tissue of obese mice. These data identify JIP1 as a novel molecular target for therapeutic intervention in the development of obesity.
UNR, a new partner of poly(A)-binding protein, plays a key role in translationally coupled mRNA turnover mediated by the c-fos major coding-region determinant
Authors: Chang Tsung-Cheng , Yamashita Akio , Chen Chyi-Ying A. , Yamashita Yukiko , Zhu Wenmiao , Durdan Simon , Kahvejian Avak , Sonenberg Nahum , Shyu Ann-Bin
Published: August 2004

Messenger RNA decay mediated by the c-fos major protein coding-region determinant of instability (mCRD) is a useful system for studying translationally coupled mRNA turnover. Among the five mCRD-associated proteins identified previously, UNR was found to be an mCRD-binding protein and also a PABP-interacting protein. Interaction between UNR and PABP is necessary for the full destabilization function of the mCRD. By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in vivo and also associated with UNR. Blocking either translation initiation or elongation greatly impeded poly(A) shortening and mRNA decay mediated by the mCRD, demonstrating that the deadenylation step is coupled to ongoing translation of the message. These findings suggest a model in which the mCRD/UNR complex serves as a “landing/assembly” platform for formation of a deadenylation/decay mRNA-protein complex on an mCRD-containing transcript. The complex is dormant prior to translation. Accelerated deadenylation and decay of the transcript follows ribosome transit through the mCRD. This study provides new insights into a mechanism by which interplay between mRNA turnover and translation determines the lifespan of an mCRD-containing mRNA in the cytoplasm.
Arginine methyltransferase affects interactions and recruitment of mRNA processing and export factors
Authors: Yu Michael C. , Bachand François , McBride Anne E. , Komili Suzanne , Casolari Jason M. , Silver Pamela A.
Published: August 2004

Hmt1 is the major type I arginine methyltransferase in the yeast Saccharomyces cerevisiae and facilitates the nucleocytoplasmic transport of mRNA-binding proteins through their methylation. Here we demonstrate that Hmt1 is recruited during the beginning of the transcriptional elongation process. Hmt1 methylates Yra1 and Hrp1, two mRNA-binding proteins important for mRNA processing and export. Moreover, loss of Hmt1 affects interactions between mRNA-binding proteins and Tho2, a component of the TREX (transcription/export) complex that is important for transcriptional elongation and recruitment of mRNA export factors. Furthermore, RNA in situ hybridization analysis demonstrates that loss of Hmt1 results in slowed release of HSP104 mRNA from the sites of transcription. Genome-wide location analysis shows that Hmt1 is bound to specific functional gene classes, many of which are also bound by Tho2 and other mRNA-processing factors. These data suggest a model whereby Hmt1 affects transcriptional elongation and, as a result, influences recruitment of RNA-processing factors.
Risk Factors for Harm in Cognitively Impaired Seniors Who Live Alone: A Prospective Study
Authors: Tierney Mary C. , Charles Jocelyn , Naglie Gary , Jaglal Susan , Kiss Alex , Fisher Rory H.
Published: August 2004

Objectives: To identify risk factors for harm due to self‐neglect or behaviors related to disorientation in cognitively impaired seniors who live alone that can be used in primary care.

Design: Inception cohort followed prospectively for 18 months.

Setting: Participants were referred by their primary care physicians and community service agencies or were patients of several medical units of a large teaching hospital.

Participants: One hundred thirty‐nine community‐residing participants, aged 65 and older who scored less than 131 on the Dementia Rating Scale and lived alone.

Measurements: Baseline Mini‐Mental State Examination (MMSE); a social resources questionnaire; presence of chronic obstructive pulmonary disease (COPD), cerebrovascular disease, diabetes mellitus, Charlson Comorbidity Index, and medication use were examined as predictors of incident harm. Informants and primary care physicians provided information about the nature of any harm at 3‐month intervals over an 18‐month period. An incident of harm was included if it occurred as the result of self‐neglect or behaviors related to disorientation, resulted in physical injury or property loss or damage, and required emergency community interventions.

Results: Based on the consensual agreement of four raters, 21.6% had an incident of harm. The proportional hazards model was highly significant (P<.001) and supported by bootstrapping estimates. Four variables were significantly predictive of time to incident harm: perception of fewer social resources, poorer performance on MMSE, presence of COPD, and presence of cerebrovascular disorders.

Conclusion: Predictors of incident harm can be identified in the primary care setting and provide direction for the early identification of those at highest risk. Validation of findings with a new cohort is necessary.
Folk Theories of the Third Kind
Authors: Braddon‐Mitchell David
Published: August 2004

The idea of a folk theory has played many important roles in much recent philosophy. To do the work they are designed for, they need to be both internal features of agents who possess them, and yet scrutable without the full resources of empirical cognitive science. The worry for the theorist of folk theories, is that only one of these desiderata is met in each plausible conception of a folk theory. This paper outlines a third conception that meets them both.1
Self‐Deception and Moral Responsibility
Authors: Levy Neil
Published: August 2004

The self‐deceived are usually held to be moral responsible for their state. I argue that this attribution of responsibility makes sense only against the background of the traditional conception of self‐deception, a conception that is now widely rejected. In its place, a new conception of self‐deception has been articulated, which requires neither intentional action by self‐deceived agents, nor that they posses contradictory beliefs. This new conception has neither need nor place for attributions of moral responsibility to the self‐deceived in paradigmatic cases. Accordingly, we should take the final step toward abandoning the traditional conception, and drop the automatic attribution of responsibility. Self‐deception is simply a kind of mistake, and has no more necessary connection to culpability than have other intellectual errors.